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[ { "id": "PMID-10085159__text", "type": "abstract", "text": [ "The Cdc6 protein is ubiquitinated in vivo for proteolysis in Saccharomyces cerevisiae. \nThe Saccharomyces cerevisiae Cdc6 protein is necessary for the formation of pre-replicative complexes that are required for firing DNA replication at origins at the beginning of S phase. Cdc6p protein levels oscillate during the cell cycle. In a normal cell cycle the presence of this protein is restricted to G1, partly because the CDC6 gene is transcribed only during G1 and partly because the Cdc6p protein is rapidly degraded at late G1/early S phase. We report here that the Cdc6p protein is degraded in a Cdc4-dependent manner, suggesting that phosphorylated Cdc6 is specifically recognized by the ubiquitin-mediated proteolysis machinery. Indeed, we have found that Cdc6 is ubiquitinated in vivo and degraded by a Cdc4-dependent mechanism. Our data, together with previous observations regarding Cdc6 stability, suggest that under physiological conditions budding yeast cells degrade ubiquitinated Cdc6 every cell cycle at the beginning of S phase.\n" ], "offsets": [ [ 0, 1044 ] ] } ]

[ { "id": "PMID-10085159_T1", "type": "Gene_or_gene_product", "text": [ "Cdc6" ], "offsets": [ [ 4, 8 ] ], "normalized": [] }, { "id": "PMID-10085159_T2", "type": "Gene_or_gene_product", "text": [ "Cdc6" ], "offsets": [ [ 117, 121 ] ], "normalized": [] }, { "id": "PMID-10085159_T3", "type": "Complex", "text": [ "pre-replicative complexes" ], "offsets": [ [ 164, 189 ] ], "normalized": [] }, { "id": "PMID-10085159_T4", "type": "Gene_or_gene_product", "text": [ "Cdc6p" ], "offsets": [ [ 275, 280 ] ], "normalized": [] }, { "id": "PMID-10085159_T5", "type": "Gene_or_gene_product", "text": [ "CDC6" ], "offsets": [ [ 421, 425 ] ], "normalized": [] }, { "id": "PMID-10085159_T6", "type": "Gene_or_gene_product", "text": [ "Cdc6p" ], "offsets": [ [ 484, 489 ] ], "normalized": [] }, { "id": "PMID-10085159_T7", "type": "Gene_or_gene_product", "text": [ "Cdc6p" ], "offsets": [ [ 568, 573 ] ], "normalized": [] }, { "id": "PMID-10085159_T8", "type": "Gene_or_gene_product", "text": [ "Cdc4" ], "offsets": [ [ 599, 603 ] ], "normalized": [] }, { "id": "PMID-10085159_T9", "type": "Gene_or_gene_product", "text": [ "Cdc6" ], "offsets": [ [ 653, 657 ] ], "normalized": [] }, { "id": "PMID-10085159_T10", "type": "Gene_or_gene_product", "text": [ "ubiquitin" ], "offsets": [ [ 692, 701 ] ], "normalized": [] }, { "id": "PMID-10085159_T11", "type": "Gene_or_gene_product", "text": [ "Cdc6" ], "offsets": [ [ 761, 765 ] ], "normalized": [] }, { "id": "PMID-10085159_T12", "type": "Gene_or_gene_product", "text": [ "Cdc4" ], "offsets": [ [ 809, 813 ] ], "normalized": [] }, { "id": "PMID-10085159_T13", "type": "Gene_or_gene_product", "text": [ "Cdc6" ], "offsets": [ [ 891, 895 ] ], "normalized": [] }, { "id": "PMID-10085159_T14", "type": "Gene_or_gene_product", "text": [ "Cdc6" ], "offsets": [ [ 993, 997 ] ], "normalized": [] } ]

[ { "id": "PMID-10085159_E1", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinated" ], "offsets": [ [ 20, 33 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10085159_T1" } ] }, { "id": "PMID-10085159_E2", "type": "Degradation", "trigger": { "text": [ "proteolysis" ], "offsets": [ [ 46, 57 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10085159_T1" } ] }, { "id": "PMID-10085159_E3", "type": "Positive_regulation", "trigger": { "text": [ "necessary" ], "offsets": [ [ 133, 142 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10085159_E4" }, { "role": "Cause", "ref_id": "PMID-10085159_T2" } ] }, { "id": "PMID-10085159_E4", "type": "Binding", "trigger": { "text": [ "formation" ], "offsets": [ [ 151, 160 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-10085159_T3" } ] }, { "id": "PMID-10085159_E5", "type": "Regulation", "trigger": { "text": [ "oscillate" ], "offsets": [ [ 296, 305 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10085159_T4" }, { "role": "Cause", "ref_id": "PMID-10085159_E6" } ] }, { "id": "PMID-10085159_E6", "type": "Pathway", "trigger": { "text": [ "cell cycl" ], "offsets": [ [ 317, 326 ] ] }, "arguments": [] }, { "id": "PMID-10085159_E7", "type": "Transcription", "trigger": { "text": [ "transcribed" ], "offsets": [ [ 434, 445 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10085159_T5" } ] }, { "id": "PMID-10085159_E8", "type": "Degradation", "trigger": { "text": [ "degraded" ], "offsets": [ [ 509, 517 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10085159_T6" } ] }, { "id": "PMID-10085159_E9", "type": "Degradation", "trigger": { "text": [ "degraded" ], "offsets": [ [ 585, 593 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10085159_T7" } ] }, { "id": "PMID-10085159_E10", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 604, 613 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10085159_T8" }, { "role": "Theme", "ref_id": "PMID-10085159_E9" } ] }, { "id": "PMID-10085159_E11", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 638, 652 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10085159_T9" } ] }, { "id": "PMID-10085159_E12", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinated" ], "offsets": [ [ 769, 782 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10085159_T11" } ] }, { "id": "PMID-10085159_E13", "type": "Degradation", "trigger": { "text": [ "degraded" ], "offsets": [ [ 795, 803 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10085159_T11" } ] }, { "id": "PMID-10085159_E14", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 814, 823 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10085159_T12" }, { "role": "Theme", "ref_id": "PMID-10085159_E13" } ] }, { "id": "PMID-10085159_E15", "type": "Degradation", "trigger": { "text": [ "degrade" ], "offsets": [ [ 971, 978 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10085159_T14" } ] }, { "id": "PMID-10085159_E16", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinated" ], "offsets": [ [ 979, 992 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10085159_T14" } ] }, { "id": "PMID-10085159_E17", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 1004, 1014 ] ] }, "arguments": [] }, { "id": "PMID-10085159_E18", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 341, 351 ] ] }, "arguments": [] } ]

[]

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[ { "id": "PMID-10224130__text", "type": "abstract", "text": [ "Regulation of NF-kappaB RelA phosphorylation and transcriptional activity by p21(ras) and protein kinase Czeta in primary endothelial cells. \nThe activity of the transcription factor NF-kappaB is thought to be regulated mainly through cytoplasmic retention by IkappaB molecules. Here we present evidence of a second mechanism of regulation acting on NF-kappaB after release from IkappaB. In endothelial cells this mechanism involves phosphorylation of the RelA subunit of NF-kappaB through a pathway involving activation of protein kinase Czeta (PKCzeta) and p21(ras). We show that transcriptional activity of RelA is dependent on phosphorylation of the N-terminal Rel homology domain but not the C-terminal transactivation domain. Inhibition of phosphorylation by dominant negative mutants of PKCzeta or p21(ras) results in loss of RelA transcriptional activity without interfering with DNA binding. Raf/MEK, small GTPases, phosphatidylinositol 3-kinase, and stress-activated protein kinase pathways are not involved in this mechanism of regulation.\n" ], "offsets": [ [ 0, 1051 ] ] } ]

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"Regulation", "trigger": { "text": [ "Regulation" ], "offsets": [ [ 0, 10 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224130_E9" }, { "role": "Cause", "ref_id": "PMID-10224130_T4" } ] }, { "id": "PMID-10224130_E6", "type": "Regulation", "trigger": { "text": [ "Regulation" ], "offsets": [ [ 0, 10 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224130_E9" }, { "role": "Cause", "ref_id": "PMID-10224130_T5" } ] }, { "id": "PMID-10224130_E7", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 29, 44 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224130_T1" } ] }, { "id": "PMID-10224130_E8", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 29, 44 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224130_T2" } ] }, { "id": "PMID-10224130_E9", "type": "Transcription", "trigger": { "text": [ "transcriptional" ], "offsets": [ [ 49, 64 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224130_T2" } ] }, { "id": "PMID-10224130_E10", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 210, 219 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224130_T6" }, { "role": "Cause", "ref_id": "PMID-10224130_E11" } ] }, { "id": "PMID-10224130_E11", "type": "Localization", "trigger": { "text": [ "retention" ], "offsets": [ [ 247, 256 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-10224130_T7" }, { "role": "Theme", "ref_id": "PMID-10224130_T6" } ] }, { "id": "PMID-10224130_E12", "type": "Positive_regulation", "trigger": { "text": [ "retention" ], "offsets": [ [ 247, 256 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224130_E11" }, { "role": "Cause", "ref_id": "PMID-10224130_T8" } ] }, { "id": "PMID-10224130_E13", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 329, 339 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224130_T9" } ] }, { "id": "PMID-10224130_E14", "type": 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"role": "Theme", "ref_id": "PMID-10224130_E17" }, { "role": "Cause", "ref_id": "PMID-10224130_E20" } ] }, { "id": "PMID-10224130_E19", "type": "Regulation", "trigger": { "text": [ "involving" ], "offsets": [ [ 500, 509 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224130_E17" }, { "role": "Cause", "ref_id": "PMID-10224130_E21" } ] }, { "id": "PMID-10224130_E20", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 510, 520 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224130_T14" } ] }, { "id": "PMID-10224130_E21", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 510, 520 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224130_T16" } ] }, { "id": "PMID-10224130_E22", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 618, 627 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10224130_E23" }, { "role": "Theme", "ref_id": "PMID-10224130_T17" } ] }, { "id": "PMID-10224130_E23", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 631, 646 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224130_T17" } ] }, { "id": "PMID-10224130_E24", "type": "Negative_regulation", "trigger": { "text": [ "Inhibition" ], "offsets": [ [ 732, 742 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224130_E26" }, { "role": "Cause", "ref_id": "PMID-10224130_T19" } ] }, { "id": "PMID-10224130_E25", "type": "Negative_regulation", "trigger": { "text": [ "Inhibition" ], "offsets": [ [ 732, 742 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224130_E26" }, { "role": "Cause", "ref_id": "PMID-10224130_T21" } ] }, { "id": "PMID-10224130_E26", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 746, 761 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224130_T18" } ] }, { "id": "PMID-10224130_E27", "type": "Positive_regulation", "trigger": { "text": [ "results" ], "offsets": [ [ 814, 821 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224130_E29" }, { "role": "Cause", "ref_id": "PMID-10224130_E24" } ] }, { "id": "PMID-10224130_E28", "type": "Positive_regulation", "trigger": { "text": [ "results" ], "offsets": [ [ 814, 821 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224130_E29" }, { "role": "Cause", "ref_id": "PMID-10224130_E25" } ] }, { "id": "PMID-10224130_E29", "type": "Negative_regulation", "trigger": { "text": [ "loss" ], "offsets": [ [ 825, 829 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224130_E30" } ] }, { "id": "PMID-10224130_E30", "type": "Transcription", "trigger": { "text": [ "transcriptional" ], "offsets": [ [ 838, 853 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224130_T22" } ] }, { "id": "PMID-10224130_E31", "type": "Negative_regulation", "trigger": { "text": [ "interfering" ], "offsets": [ [ 871, 882 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10224130_E29" }, { "role": "Theme", "ref_id": "PMID-10224130_E32" } ] }, { "id": "PMID-10224130_E32", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 892, 899 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10224130_T22" } ] }, { "id": "PMID-10224130_E33", "type": "Pathway", "trigger": { "text": [ "pathways" ], "offsets": [ [ 992, 1000 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-10224130_T23" }, { "role": "Participant", "ref_id": "PMID-10224130_T24" }, { "role": "Participant", "ref_id": "PMID-10224130_T25" }, { "role": "Participant", "ref_id": "PMID-10224130_T26" } ] } ]

[ { "id": "PMID-10224130_1", "entity_ids": [ "PMID-10224130_T3", "PMID-10224130_T4" ] }, { "id": "PMID-10224130_2", "entity_ids": [ "PMID-10224130_T13", "PMID-10224130_T14" ] }, { "id": "PMID-10224130_3", "entity_ids": [ "PMID-10224130_T15", "PMID-10224130_T16" ] }, { "id": "PMID-10224130_4", "entity_ids": [ "PMID-10224130_T20", "PMID-10224130_T21" ] } ]

[]

[ { "id": "PMID-10329026__text", "type": "abstract", "text": [ "Cloning and characterization of retinol dehydrogenase transcripts expressed in human epidermal keratinocytes. \nThe normal growth and differentiation of the epidermis require an adequate supply of vitamin A. The active form of vitamin A for normal epidermal homeostasis is retinoic acid (RA). Retinoic acid controls the expression of retinoid-responsive genes via interactions of the retinoic acid/nuclear receptor complexes at specific DNA sequences in their control regions. The message conveyed by RA is likely modulated by the concentration of the ligand available for binding to the receptors. Following the uptake of plasma retinol, epidermal keratinocytes synthesize retinoic acid via two sequential reactions with retinaldehyde as an intermediate. Several retinol dehydrogenase (RDH) enzymes, members of the short-chain dehydrogenase/reductase (SDR) gene superfamily, catalyze the first and rate-limiting step that generates retinaldehyde from retinol bound to cellular retinol-binding protein (holo-CRBP). However, little is known about these enzymes and their genes in the epidermal cells. Our work describes the first member of the RDH family found in epidermis. We show that this gene is expressed predominantly in the differentiating spinous layers and that it is under positive, feed-forward regulation by retinoic acid. It encodes a protein that, using NAD+ as a preferred cofactor, utilizes free and CRBP-bound all-trans-retinol and steroids as substrates.\n" ], "offsets": [ [ 0, 1472 ] ] } ]

[ { "id": "PMID-10329026_T1", "type": "Gene_or_gene_product", "text": [ "retinol dehydrogenase" ], "offsets": [ [ 32, 53 ] ], "normalized": [] }, { "id": "PMID-10329026_T2", "type": "Simple_chemical", "text": [ "vitamin A" ], "offsets": [ [ 196, 205 ] ], "normalized": [] }, { "id": "PMID-10329026_T3", "type": "Simple_chemical", "text": [ "vitamin A" ], "offsets": [ [ 226, 235 ] ], "normalized": [] }, { "id": "PMID-10329026_T4", "type": "Simple_chemical", "text": [ "retinoic acid" ], "offsets": [ [ 272, 285 ] ], "normalized": [] }, { "id": "PMID-10329026_T5", "type": "Simple_chemical", "text": [ "RA" ], "offsets": [ [ 287, 289 ] ], "normalized": [] }, { "id": "PMID-10329026_T6", "type": "Simple_chemical", "text": [ "Retinoic acid" ], "offsets": [ [ 292, 305 ] ], "normalized": [] }, { "id": "PMID-10329026_T7", "type": "Simple_chemical", "text": [ "retinoid" ], "offsets": [ [ 333, 341 ] ], "normalized": [] }, { "id": "PMID-10329026_T8", "type": "Complex", "text": [ "retinoic acid/nuclear receptor" ], "offsets": [ [ 383, 413 ] ], "normalized": [] }, { "id": "PMID-10329026_T9", "type": "Simple_chemical", "text": [ "RA" ], "offsets": [ [ 500, 502 ] ], "normalized": [] }, { "id": "PMID-10329026_T10", "type": "Simple_chemical", "text": [ "retinol" ], "offsets": [ [ 629, 636 ] ], "normalized": [] }, { "id": "PMID-10329026_T11", "type": "Simple_chemical", "text": [ "retinoic acid" ], "offsets": [ [ 673, 686 ] ], "normalized": [] }, { "id": "PMID-10329026_T12", "type": "Simple_chemical", "text": [ "retinaldehyde" ], "offsets": [ [ 721, 734 ] ], "normalized": [] }, { "id": "PMID-10329026_T13", "type": "Gene_or_gene_product", "text": [ "retinol dehydrogenase" ], "offsets": [ [ 763, 784 ] ], "normalized": [] }, { "id": "PMID-10329026_T14", "type": "Gene_or_gene_product", "text": [ "RDH" ], "offsets": [ [ 786, 789 ] ], "normalized": [] }, { "id": "PMID-10329026_T15", "type": "Gene_or_gene_product", "text": [ "short-chain dehydrogenase/reductase" ], "offsets": [ [ 815, 850 ] ], "normalized": [] }, { "id": "PMID-10329026_T16", "type": "Gene_or_gene_product", "text": [ "SDR" ], "offsets": [ [ 852, 855 ] ], "normalized": [] }, { "id": "PMID-10329026_T17", "type": "Simple_chemical", "text": [ "retinaldehyde" ], "offsets": [ [ 932, 945 ] ], "normalized": [] }, { "id": "PMID-10329026_T18", "type": "Simple_chemical", "text": [ "retinol" ], "offsets": [ [ 951, 958 ] ], "normalized": [] }, { "id": "PMID-10329026_T19", "type": "Gene_or_gene_product", "text": [ "cellular retinol-binding protein" ], "offsets": [ [ 968, 1000 ] ], "normalized": [] }, { "id": "PMID-10329026_T20", "type": "Gene_or_gene_product", "text": [ "CRBP" ], "offsets": [ [ 1007, 1011 ] ], "normalized": [] }, { "id": "PMID-10329026_T21", "type": "Gene_or_gene_product", "text": [ "RDH" ], "offsets": [ [ 1142, 1145 ] ], "normalized": [] }, { "id": "PMID-10329026_T22", "type": "Simple_chemical", "text": [ "retinoic acid" ], "offsets": [ [ 1319, 1332 ] ], "normalized": [] }, { "id": "PMID-10329026_T23", "type": "Simple_chemical", "text": [ "NAD+" ], "offsets": [ [ 1367, 1371 ] ], "normalized": [] }, { "id": "PMID-10329026_T24", "type": "Gene_or_gene_product", "text": [ "CRBP" ], "offsets": [ [ 1415, 1419 ] ], "normalized": [] }, { "id": "PMID-10329026_T25", "type": "Simple_chemical", "text": [ "all-trans-retinol" ], "offsets": [ [ 1426, 1443 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-10346818__text", "type": "abstract", "text": [ "Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain. \nInterleukin-1 (IL-1) and tumor necrosis factor (TNF-alpha) stimulate transcription factors AP-1 and NF-kappaB through activation of the MAP kinases JNK and p38 and the IkappaB kinase (IKK), respectively. The TNF-alpha and IL-1 signals are transduced through TRAF2 and TRAF6, respectively. Overexpressed TRAF2 or TRAF6 activate JNK, p38, or IKK in the absence of extracellular stimulation. By replacing the carboxy-terminal TRAF domain of TRAF2 and TRAF6 with repeats of the immunophilin FKBP12, we demonstrate that their effector domains are composed of their amino-terminal Zn and RING fingers. Oligomerization of the TRAF2 effector domain results in specific binding to MEKK1, a protein kinase capable of JNK, p38, and IKK activation, and induction of TNF-alpha and IL-1 responsive genes. TNF-alpha also enhances the binding of native TRAF2 to MEKK1 and stimulates the kinase activity of the latter. Thus, TNF-alpha and IL-1 signaling is based on oligomerization of TRAF2 and TRAF6 leading to activation of effector kinases.\n" ], "offsets": [ [ 0, 1209 ] ] } ]

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"offsets": [ [ 230, 239 ] ], "normalized": [] }, { "id": "PMID-10346818_T9", "type": "Gene_or_gene_product", "text": [ "AP-1" ], "offsets": [ [ 273, 277 ] ], "normalized": [] }, { "id": "PMID-10346818_T10", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 282, 291 ] ], "normalized": [] }, { "id": "PMID-10346818_T11", "type": "Gene_or_gene_product", "text": [ "MAP kinases" ], "offsets": [ [ 318, 329 ] ], "normalized": [] }, { "id": "PMID-10346818_T12", "type": "Gene_or_gene_product", "text": [ "JNK" ], "offsets": [ [ 330, 333 ] ], "normalized": [] }, { "id": "PMID-10346818_T13", "type": "Gene_or_gene_product", "text": [ "p38" ], "offsets": [ [ 338, 341 ] ], "normalized": [] }, { "id": "PMID-10346818_T14", "type": "Complex", "text": [ "IkappaB kinase" ], "offsets": [ [ 350, 364 ] ], "normalized": [] }, { "id": "PMID-10346818_T15", "type": "Complex", "text": [ "IKK" ], "offsets": [ [ 366, 369 ] ], "normalized": [] }, { "id": "PMID-10346818_T16", "type": "Gene_or_gene_product", "text": [ "TNF-alpha" ], "offsets": [ [ 390, 399 ] ], "normalized": [] }, { "id": "PMID-10346818_T17", "type": "Gene_or_gene_product", "text": [ "IL-1" ], "offsets": [ [ 404, 408 ] ], "normalized": [] }, { "id": "PMID-10346818_T18", "type": "Gene_or_gene_product", "text": [ "TRAF2" ], "offsets": [ [ 440, 445 ] ], "normalized": [] }, { "id": "PMID-10346818_T19", "type": "Gene_or_gene_product", "text": [ "TRAF6" ], "offsets": [ [ 450, 455 ] ], "normalized": [] }, { "id": "PMID-10346818_T20", "type": "Gene_or_gene_product", "text": [ "TRAF2" ], "offsets": [ [ 485, 490 ] ], "normalized": [] }, { "id": "PMID-10346818_T21", "type": "Gene_or_gene_product", "text": [ "TRAF6" ], "offsets": [ [ 494, 499 ] ], "normalized": [] }, { "id": "PMID-10346818_T22", "type": "Gene_or_gene_product", "text": [ "JNK" ], "offsets": [ [ 509, 512 ] ], "normalized": [] }, { "id": "PMID-10346818_T23", "type": "Gene_or_gene_product", "text": [ "p38" ], "offsets": [ [ 514, 517 ] ], "normalized": [] }, { "id": "PMID-10346818_T24", "type": "Complex", "text": [ "IKK" ], "offsets": [ [ 522, 525 ] ], "normalized": [] }, { "id": "PMID-10346818_T25", "type": "Cellular_component", "text": [ "extracellular" ], "offsets": [ [ 544, 557 ] ], "normalized": [] }, { "id": "PMID-10346818_T26", "type": "Gene_or_gene_product", "text": [ "TRAF" ], "offsets": [ [ 605, 609 ] ], "normalized": [] }, { "id": "PMID-10346818_T27", "type": "Gene_or_gene_product", "text": [ "TRAF2" ], "offsets": [ [ 620, 625 ] ], "normalized": [] }, { "id": "PMID-10346818_T28", "type": "Gene_or_gene_product", "text": [ "TRAF6" ], "offsets": [ [ 630, 635 ] ], "normalized": [] }, { "id": "PMID-10346818_T29", "type": "Gene_or_gene_product", "text": [ "FKBP12" ], "offsets": [ [ 669, 675 ] ], "normalized": [] }, { "id": "PMID-10346818_T30", "type": "Simple_chemical", "text": [ "Zn" ], "offsets": [ [ 757, 759 ] ], "normalized": [] }, { "id": "PMID-10346818_T31", "type": "Gene_or_gene_product", "text": [ "TRAF2" ], "offsets": [ [ 801, 806 ] ], "normalized": [] }, { "id": "PMID-10346818_T32", "type": "Gene_or_gene_product", "text": [ "MEKK1" ], "offsets": [ [ 854, 859 ] ], "normalized": [] }, { "id": "PMID-10346818_T33", "type": "Gene_or_gene_product", "text": [ "JNK" ], "offsets": [ [ 889, 892 ] ], "normalized": [] }, { "id": "PMID-10346818_T34", "type": "Gene_or_gene_product", "text": [ "p38" ], "offsets": [ [ 894, 897 ] ], "normalized": [] }, { "id": "PMID-10346818_T35", "type": "Complex", "text": [ "IKK" ], "offsets": [ [ 903, 906 ] ], "normalized": [] }, { "id": "PMID-10346818_T36", "type": "Gene_or_gene_product", "text": [ "TNF-alpha" ], "offsets": [ [ 936, 945 ] ], "normalized": [] }, { "id": "PMID-10346818_T37", "type": "Gene_or_gene_product", "text": [ "IL-1" ], "offsets": [ [ 950, 954 ] ], "normalized": [] }, { "id": "PMID-10346818_T38", "type": "Gene_or_gene_product", "text": [ "TNF-alpha" ], "offsets": [ [ 973, 982 ] ], "normalized": [] }, { "id": "PMID-10346818_T39", "type": "Gene_or_gene_product", "text": [ "TRAF2" ], "offsets": [ [ 1019, 1024 ] ], "normalized": [] }, { "id": "PMID-10346818_T40", "type": "Gene_or_gene_product", "text": [ "MEKK1" ], "offsets": [ [ 1028, 1033 ] ], "normalized": [] }, { "id": "PMID-10346818_T41", "type": "Gene_or_gene_product", "text": [ "TNF-alpha" ], "offsets": [ [ 1090, 1099 ] ], "normalized": [] }, { "id": "PMID-10346818_T42", "type": "Gene_or_gene_product", "text": [ "IL-1" ], "offsets": [ [ 1104, 1108 ] ], "normalized": [] }, { "id": "PMID-10346818_T43", "type": "Gene_or_gene_product", "text": [ "TRAF2" ], "offsets": [ [ 1150, 1155 ] ], "normalized": [] }, { "id": "PMID-10346818_T44", "type": "Gene_or_gene_product", "text": [ "TRAF6" ], "offsets": [ [ 1160, 1165 ] ], "normalized": [] } ]

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"PMID-10346818_E23" } ] }, { "id": "PMID-10346818_E14", "type": "Positive_regulation", "trigger": { "text": [ "stimulate" ], "offsets": [ [ 241, 250 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10346818_T10" }, { "role": "Cause", "ref_id": "PMID-10346818_E23" } ] }, { "id": "PMID-10346818_E15", "type": "Positive_regulation", "trigger": { "text": [ "stimulate" ], "offsets": [ [ 241, 250 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10346818_T9" }, { "role": "Cause", "ref_id": "PMID-10346818_E24" } ] }, { "id": "PMID-10346818_E16", "type": "Positive_regulation", "trigger": { "text": [ "stimulate" ], "offsets": [ [ 241, 250 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10346818_T10" }, { "role": "Cause", "ref_id": "PMID-10346818_E24" } ] }, { "id": "PMID-10346818_E17", "type": "Positive_regulation", "trigger": { "text": [ "stimulate" ], "offsets": [ [ 241, 250 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10346818_T9" }, { "role": "Cause", 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[ { "id": "PMID-10346818_1", "entity_ids": [ "PMID-10346818_T5", "PMID-10346818_T6" ] }, { "id": "PMID-10346818_2", "entity_ids": [ "PMID-10346818_T7", "PMID-10346818_T8" ] }, { "id": "PMID-10346818_3", "entity_ids": [ "PMID-10346818_T14", "PMID-10346818_T15" ] } ]

[]

[ { "id": "PMID-10364168__text", "type": "abstract", "text": [ "Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2. \nThe life-threatening complications of sepsis in humans are elicited by infection with Gram-negative as well as Gram-positive bacteria. Recently, lipopolysaccharide (LPS), a major biologically active agent of Gram-negative bacteria, was shown to mediate cellular activation by a member of the human Toll-like receptor family, Toll-like receptor (TLR) 2. Here we investigate the mechanism of cellular activation by soluble peptidoglycan (sPGN) and lipoteichoic acid (LTA), main stimulatory components of Gram-positive bacteria. Like LPS, sPGN and LTA bind to the glycosylphosphatidylinositol-anchored membrane protein CD14 and induce activation of the transcription factor NF-kappaB in host cells like macrophages. We show that whole Gram-positive bacteria, sPGN and LTA induce the activation of NF-kappaB in HEK293 cells expressing TLR2 but not in cells expressing TLR1 or TLR4. The sPGN- and LTA-induced NF-kappaB activation was not inhibited by polymyxin B, an antibiotic that binds and neutralizes LPS. Coexpression together with membrane CD14 enhances sPGN signal transmission through TLR2. In contrast to LPS signaling, activation of TLR2 by sPGN and LTA does not require serum. These findings identify TLR2 as a signal transducer for sPGN and LTA in addition to LPS.\n" ], "offsets": [ [ 0, 1371 ] ] } ]

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"Simple_chemical", "text": [ "peptidoglycan" ], "offsets": [ [ 520, 533 ] ], "normalized": [] }, { "id": "PMID-10364168_T9", "type": "Simple_chemical", "text": [ "sPGN" ], "offsets": [ [ 535, 539 ] ], "normalized": [] }, { "id": "PMID-10364168_T10", "type": "Simple_chemical", "text": [ "lipoteichoic acid" ], "offsets": [ [ 545, 562 ] ], "normalized": [] }, { "id": "PMID-10364168_T11", "type": "Simple_chemical", "text": [ "LTA" ], "offsets": [ [ 564, 567 ] ], "normalized": [] }, { "id": "PMID-10364168_T12", "type": "Simple_chemical", "text": [ "LPS" ], "offsets": [ [ 630, 633 ] ], "normalized": [] }, { "id": "PMID-10364168_T13", "type": "Simple_chemical", "text": [ "sPGN" ], "offsets": [ [ 635, 639 ] ], "normalized": [] }, { "id": "PMID-10364168_T14", "type": "Simple_chemical", "text": [ "LTA" ], "offsets": [ [ 644, 647 ] ], "normalized": [] }, { "id": "PMID-10364168_T15", "type": "Simple_chemical", "text": [ "glycosylphosphatidylinositol" ], "offsets": [ [ 660, 688 ] ], "normalized": [] }, { "id": "PMID-10364168_T16", "type": "Cellular_component", "text": [ "membrane" ], "offsets": [ [ 698, 706 ] ], "normalized": [] }, { "id": "PMID-10364168_T17", "type": "Gene_or_gene_product", "text": [ "CD14" ], "offsets": [ [ 715, 719 ] ], "normalized": [] }, { "id": "PMID-10364168_T18", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 770, 779 ] ], "normalized": [] }, { "id": "PMID-10364168_T19", "type": "Simple_chemical", "text": [ "sPGN" ], "offsets": [ [ 855, 859 ] ], "normalized": [] }, { "id": "PMID-10364168_T20", "type": "Simple_chemical", "text": [ "LTA" ], "offsets": [ [ 864, 867 ] ], "normalized": [] }, { "id": "PMID-10364168_T21", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 893, 902 ] ], "normalized": [] }, { "id": "PMID-10364168_T22", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 930, 934 ] ], "normalized": [] }, { "id": "PMID-10364168_T23", "type": "Gene_or_gene_product", "text": [ "TLR1" ], "offsets": [ [ 963, 967 ] ], "normalized": [] }, { "id": "PMID-10364168_T24", "type": "Gene_or_gene_product", "text": [ "TLR4" ], "offsets": [ [ 971, 975 ] ], "normalized": [] }, { "id": "PMID-10364168_T25", "type": "Simple_chemical", "text": [ "sPGN" ], "offsets": [ [ 981, 985 ] ], "normalized": [] }, { "id": "PMID-10364168_T26", "type": "Simple_chemical", "text": [ "LTA" ], "offsets": [ [ 991, 994 ] ], "normalized": [] }, { "id": "PMID-10364168_T27", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1003, 1012 ] ], "normalized": [] }, { "id": "PMID-10364168_T28", "type": "Simple_chemical", "text": [ "polymyxin B" ], "offsets": [ [ 1045, 1056 ] ], "normalized": [] }, { "id": "PMID-10364168_T29", "type": "Simple_chemical", "text": [ "LPS" ], "offsets": [ [ 1099, 1102 ] ], "normalized": [] }, { "id": "PMID-10364168_T30", "type": "Cellular_component", "text": [ "membrane" ], "offsets": [ [ 1131, 1139 ] ], "normalized": [] }, { "id": "PMID-10364168_T31", "type": "Gene_or_gene_product", "text": [ "CD14" ], "offsets": [ [ 1140, 1144 ] ], "normalized": [] }, { "id": "PMID-10364168_T32", "type": "Simple_chemical", "text": [ "sPGN" ], "offsets": [ [ 1154, 1158 ] ], "normalized": [] }, { "id": "PMID-10364168_T33", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 1187, 1191 ] ], "normalized": [] }, { "id": "PMID-10364168_T34", "type": "Simple_chemical", "text": [ "LPS" ], "offsets": [ [ 1208, 1211 ] ], "normalized": [] }, { "id": "PMID-10364168_T35", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 1237, 1241 ] ], "normalized": [] }, { "id": "PMID-10364168_T36", "type": "Simple_chemical", "text": [ "sPGN" ], "offsets": [ [ 1245, 1249 ] ], "normalized": [] }, { "id": "PMID-10364168_T37", "type": "Simple_chemical", "text": [ "LTA" ], "offsets": [ [ 1254, 1257 ] ], "normalized": [] }, { "id": "PMID-10364168_T38", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 1306, 1310 ] ], "normalized": [] }, { "id": "PMID-10364168_T39", "type": "Simple_chemical", "text": [ "sPGN" ], "offsets": [ [ 1338, 1342 ] ], "normalized": [] }, { "id": "PMID-10364168_T40", "type": "Simple_chemical", "text": [ "LTA" ], "offsets": [ [ 1347, 1350 ] ], "normalized": [] }, { "id": "PMID-10364168_T41", "type": "Simple_chemical", "text": [ "LPS" ], "offsets": [ [ 1366, 1369 ] ], "normalized": [] } ]

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"ref_id": "PMID-10364168_T22" } ] }, { "id": "PMID-10364168_E10", "type": "Gene_expression", "trigger": { "text": [ "expressing" ], "offsets": [ [ 952, 962 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364168_T23" } ] }, { "id": "PMID-10364168_E11", "type": "Gene_expression", "trigger": { "text": [ "expressing" ], "offsets": [ [ 952, 962 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364168_T24" } ] }, { "id": "PMID-10364168_E12", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 995, 1002 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364168_E14" }, { "role": "Cause", "ref_id": "PMID-10364168_T25" } ] }, { "id": "PMID-10364168_E13", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 995, 1002 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364168_E14" }, { "role": "Cause", "ref_id": "PMID-10364168_T26" } ] }, { "id": "PMID-10364168_E14", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1013, 1023 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364168_T27" } ] }, { "id": "PMID-10364168_E15", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 1032, 1041 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10364168_T28" }, { "role": "Theme", "ref_id": "PMID-10364168_E14" } ] }, { "id": "PMID-10364168_E16", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 1077, 1082 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364168_T28" }, { "role": "Theme", "ref_id": "PMID-10364168_T29" } ] }, { "id": "PMID-10364168_E17", "type": "Negative_regulation", "trigger": { "text": [ "neutralizes" ], "offsets": [ [ 1087, 1098 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10364168_T28" }, { "role": "Theme", "ref_id": "PMID-10364168_T29" } ] }, { "id": "PMID-10364168_E18", "type": "Gene_expression", "trigger": { "text": [ "Coexpression" ], "offsets": [ [ 1104, 1116 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364168_T31" } ] }, { "id": "PMID-10364168_E19", "type": "Positive_regulation", "trigger": { "text": [ "enhances" ], "offsets": [ [ 1145, 1153 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10364168_T33" }, { "role": "Theme", "ref_id": "PMID-10364168_E18" } ] }, { "id": "PMID-10364168_E20", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1223, 1233 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364168_T35" }, { "role": "Cause", "ref_id": "PMID-10364168_T36" } ] }, { "id": "PMID-10364168_E21", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1223, 1233 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10364168_T35" }, { "role": "Cause", "ref_id": "PMID-10364168_T37" } ] }, { "id": "PMID-10364168_E22", "type": "Positive_regulation", "trigger": { "text": [ "signal transducer" ], "offsets": [ [ 1316, 1333 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10364168_T38" }, { "role": "Theme", "ref_id": "PMID-10364168_T39" } ] }, { "id": "PMID-10364168_E23", "type": "Positive_regulation", "trigger": { "text": [ "signal transducer" ], "offsets": [ [ 1316, 1333 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10364168_T38" }, { "role": "Theme", "ref_id": "PMID-10364168_T40" } ] }, { "id": "PMID-10364168_E24", "type": "Positive_regulation", "trigger": { "text": [ "signal transducer" ], "offsets": [ [ 1316, 1333 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10364168_T38" }, { "role": "Theme", "ref_id": "PMID-10364168_T41" } ] } ]

[ { "id": "PMID-10364168_1", "entity_ids": [ "PMID-10364168_T4", "PMID-10364168_T5" ] }, { "id": "PMID-10364168_2", "entity_ids": [ "PMID-10364168_T8", "PMID-10364168_T9" ] }, { "id": "PMID-10364168_3", "entity_ids": [ "PMID-10364168_T10", "PMID-10364168_T11" ] } ]

[]

[ { "id": "PMID-10369669__text", "type": "abstract", "text": [ "Glycoprotein reglucosylation and nucleotide sugar utilization in the secretory pathway: identification of a nucleoside diphosphatase in the endoplasmic reticulum. \nUDP is generated in the lumen of the endoplasmic reticulum (ER) as a product of the UDP-glucose-dependent glycoprotein reglucosylation in the calnexin/calreticulin cycle. We describe here the identification, purification and characterization of an ER enzyme that hydrolyzes UDP to UMP. This nucleoside diphosphatase is a ubiquitously expressed, soluble 45 kDa glycoprotein devoid of transmembrane domains and KDEL-related ER localization sequences. It requires divalent cations for activity and hydrolyzes UDP, GDP and IDP but not any other nucleoside di-, mono- or triphosphates, nor thiamine pyrophosphate. By eliminating UDP, which is an inhibitory product of the UDP-Glc:glycoprotein glucosyltransferase, it is likely to promote reglucosylation reactions involved in glycoprotein folding and quality control in the ER.\n" ], "offsets": [ [ 0, 987 ] ] } ]

[ { "id": "PMID-10369669_T1", "type": "Gene_or_gene_product", "text": [ "nucleoside diphosphatase" ], "offsets": [ [ 108, 132 ] ], "normalized": [] }, { "id": "PMID-10369669_T2", "type": "Cellular_component", "text": [ "endoplasmic reticulum" ], "offsets": [ [ 140, 161 ] ], "normalized": [] }, { "id": "PMID-10369669_T3", "type": "Simple_chemical", "text": [ "UDP" ], "offsets": [ [ 164, 167 ] ], "normalized": [] }, { "id": "PMID-10369669_T4", "type": "Cellular_component", "text": [ "lumen" ], "offsets": [ [ 188, 193 ] ], "normalized": [] }, { "id": "PMID-10369669_T5", "type": "Cellular_component", "text": [ "endoplasmic reticulum" ], "offsets": [ [ 201, 222 ] ], "normalized": [] }, { "id": "PMID-10369669_T6", "type": "Cellular_component", "text": [ "ER" ], "offsets": [ [ 224, 226 ] ], "normalized": [] }, { "id": "PMID-10369669_T7", "type": "Simple_chemical", "text": [ "UDP-glucose" ], "offsets": [ [ 248, 259 ] ], "normalized": [] }, { "id": "PMID-10369669_T8", "type": "Gene_or_gene_product", "text": [ "calnexin" ], "offsets": [ [ 306, 314 ] ], "normalized": [] }, { "id": "PMID-10369669_T9", "type": "Gene_or_gene_product", "text": [ "calreticulin" ], "offsets": [ [ 315, 327 ] ], "normalized": [] }, { "id": "PMID-10369669_T10", "type": "Cellular_component", "text": [ "ER" ], "offsets": [ [ 412, 414 ] ], "normalized": [] }, { "id": "PMID-10369669_T11", "type": "Simple_chemical", "text": [ "UDP" ], "offsets": [ [ 438, 441 ] ], "normalized": [] }, { "id": "PMID-10369669_T12", "type": "Simple_chemical", "text": [ "UMP" ], "offsets": [ [ 445, 448 ] ], "normalized": [] }, { "id": "PMID-10369669_T13", "type": "Gene_or_gene_product", "text": [ "nucleoside diphosphatase" ], "offsets": [ [ 455, 479 ] ], "normalized": [] }, { "id": "PMID-10369669_T14", "type": "Gene_or_gene_product", "text": [ "KDEL" ], "offsets": [ [ 573, 577 ] ], "normalized": [] }, { "id": "PMID-10369669_T15", "type": "Cellular_component", "text": [ "ER" ], "offsets": [ [ 586, 588 ] ], "normalized": [] }, { "id": "PMID-10369669_T16", "type": "Simple_chemical", "text": [ "divalent cations" ], "offsets": [ [ 625, 641 ] ], "normalized": [] }, { "id": "PMID-10369669_T17", "type": "Simple_chemical", "text": [ "UDP" ], "offsets": [ [ 670, 673 ] ], "normalized": [] }, { "id": "PMID-10369669_T18", "type": "Simple_chemical", "text": [ "GDP" ], "offsets": [ [ 675, 678 ] ], "normalized": [] }, { "id": "PMID-10369669_T19", "type": "Simple_chemical", "text": [ "IDP" ], "offsets": [ [ 683, 686 ] ], "normalized": [] }, { "id": "PMID-10369669_T20", "type": "Simple_chemical", "text": [ "nucleoside di-" ], "offsets": [ [ 705, 719 ] ], "normalized": [] }, { "id": "PMID-10369669_T21", "type": "Simple_chemical", "text": [ "mono-" ], "offsets": [ [ 721, 726 ] ], "normalized": [] }, { "id": "PMID-10369669_T22", "type": "Simple_chemical", "text": [ "triphosphates" ], "offsets": [ [ 730, 743 ] ], "normalized": [] }, { "id": "PMID-10369669_T23", "type": "Simple_chemical", "text": [ "thiamine pyrophosphate" ], "offsets": [ [ 749, 771 ] ], "normalized": [] }, { "id": "PMID-10369669_T24", "type": "Simple_chemical", "text": [ "UDP" ], "offsets": [ [ 788, 791 ] ], "normalized": [] }, { "id": "PMID-10369669_T25", "type": "Simple_chemical", "text": [ "UDP-Glc" ], "offsets": [ [ 831, 838 ] ], "normalized": [] }, { "id": "PMID-10369669_T26", "type": "Gene_or_gene_product", "text": [ "glycoprotein glucosyltransferase" ], "offsets": [ [ 839, 871 ] ], "normalized": [] }, { "id": "PMID-10369669_T27", "type": "Cellular_component", "text": [ "ER" ], "offsets": [ [ 983, 985 ] ], "normalized": [] } ]

[ { "id": "PMID-10369669_E1", "type": "Conversion", "trigger": { "text": [ "generated" ], "offsets": [ [ 171, 180 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-10369669_T3" } ] }, { "id": "PMID-10369669_E2", "type": "Pathway", "trigger": { "text": [ "cycle" ], "offsets": [ [ 328, 333 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-10369669_T8" }, { "role": "Participant", "ref_id": "PMID-10369669_T9" } ] }, { "id": "PMID-10369669_E3", "type": "Conversion", "trigger": { "text": [ "hydrolyzes" ], "offsets": [ [ 427, 437 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10369669_T11" }, { "role": "Product", "ref_id": "PMID-10369669_T12" } ] }, { "id": "PMID-10369669_E4", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitously" ], "offsets": [ [ 485, 497 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10369669_T13" } ] }, { "id": "PMID-10369669_E5", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 498, 507 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10369669_T13" } ] }, { "id": "PMID-10369669_E6", "type": "Positive_regulation", "trigger": { "text": [ "requires" ], "offsets": [ [ 616, 624 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10369669_T13" }, { "role": "Cause", "ref_id": "PMID-10369669_T16" } ] }, { "id": "PMID-10369669_E7", "type": "Conversion", "trigger": { "text": [ "hydrolyzes" ], "offsets": [ [ 659, 669 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10369669_T17" } ] }, { "id": "PMID-10369669_E8", "type": "Conversion", "trigger": { "text": [ "hydrolyzes" ], "offsets": [ [ 659, 669 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10369669_T20" } ] }, { "id": "PMID-10369669_E9", "type": "Positive_regulation", "trigger": { "text": [ "hydrolyzes" ], "offsets": [ [ 659, 669 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10369669_T13" }, { "role": "Theme", "ref_id": "PMID-10369669_E8" } ] }, { "id": "PMID-10369669_E10", "type": "Conversion", "trigger": { "text": [ "hydrolyzes" ], "offsets": [ [ 659, 669 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10369669_T22" } ] }, { "id": "PMID-10369669_E11", "type": "Conversion", "trigger": { "text": [ "hydrolyzes" ], "offsets": [ [ 659, 669 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10369669_T23" } ] }, { "id": "PMID-10369669_E12", "type": "Conversion", "trigger": { "text": [ "hydrolyzes" ], "offsets": [ [ 659, 669 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10369669_T21" } ] }, { "id": "PMID-10369669_E13", "type": "Conversion", "trigger": { "text": [ "hydrolyzes" ], "offsets": [ [ 659, 669 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10369669_T18" } ] }, { "id": "PMID-10369669_E14", "type": "Conversion", "trigger": { "text": [ "hydrolyzes" ], "offsets": [ [ 659, 669 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10369669_T19" } ] }, { "id": "PMID-10369669_E15", "type": "Positive_regulation", "trigger": { "text": [ "hydrolyzes" ], "offsets": [ [ 659, 669 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10369669_T13" }, { "role": "Theme", "ref_id": "PMID-10369669_E7" } ] }, { "id": "PMID-10369669_E16", "type": "Positive_regulation", "trigger": { "text": [ "hydrolyzes" ], "offsets": [ [ 659, 669 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10369669_T13" }, { "role": "Theme", "ref_id": "PMID-10369669_E10" } ] }, { "id": "PMID-10369669_E17", "type": "Positive_regulation", "trigger": { "text": [ "hydrolyzes" ], "offsets": [ [ 659, 669 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10369669_T13" }, { "role": "Theme", "ref_id": "PMID-10369669_E11" } ] }, { "id": "PMID-10369669_E18", "type": "Positive_regulation", "trigger": { "text": [ "hydrolyzes" ], "offsets": [ [ 659, 669 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10369669_T13" }, { "role": "Theme", "ref_id": "PMID-10369669_E12" } ] }, { "id": "PMID-10369669_E19", "type": "Positive_regulation", "trigger": { "text": [ "hydrolyzes" ], "offsets": [ [ 659, 669 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10369669_T13" }, { "role": "Theme", "ref_id": "PMID-10369669_E13" } ] }, { "id": "PMID-10369669_E20", "type": "Positive_regulation", "trigger": { "text": [ "hydrolyzes" ], "offsets": [ [ 659, 669 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10369669_T13" }, { "role": "Theme", "ref_id": "PMID-10369669_E14" } ] }, { "id": "PMID-10369669_E21", "type": "Negative_regulation", "trigger": { "text": [ "eliminating" ], "offsets": [ [ 776, 787 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10369669_T24" }, { "role": "Cause", "ref_id": "PMID-10369669_T13" } ] }, { "id": "PMID-10369669_E22", "type": "Negative_regulation", "trigger": { "text": [ "inhibitory" ], "offsets": [ [ 805, 815 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10369669_T24" }, { "role": "Theme", "ref_id": "PMID-10369669_T26" } ] } ]

[ { "id": "PMID-10369669_1", "entity_ids": [ "PMID-10369669_T5", "PMID-10369669_T6" ] } ]

[]

[ { "id": "PMID-10373560__text", "type": "abstract", "text": [ "Overproduction of human Myt1 kinase induces a G2 cell cycle delay by interfering with the intracellular trafficking of Cdc2-cyclin B1 complexes. \nThe Myt1 protein kinase functions to negatively regulate Cdc2-cyclin B complexes by phosphorylating Cdc2 on threonine 14 and tyrosine 15. Throughout interphase, human Myt1 localizes to the endoplasmic reticulum and Golgi complex, whereas Cdc2-cyclin B1 complexes shuttle between the nucleus and the cytoplasm. Here we report that overproduction of either kinase-active or kinase-inactive forms of Myt1 blocked the nuclear-cytoplasmic shuttling of cyclin B1 and caused cells to delay in the G2 phase of the cell cycle. The COOH-terminal 63 amino acids of Myt1 were identified as a Cdc2-cyclin B1 interaction domain. Myt1 mutants lacking this domain no longer bound cyclin B1 and did not efficiently phosphorylate Cdc2-cyclin B1 complexes in vitro. In addition, cells overproducing mutant forms of Myt1 lacking the interaction domain exhibited normal trafficking of cyclin B1 and unperturbed cell cycle progression. These results suggest that the docking of Cdc2-cyclin B1 complexes to the COOH terminus of Myt1 facilitates the phosphorylation of Cdc2 by Myt1 and that overproduction of Myt1 perturbs cell cycle progression by sequestering Cdc2-cyclin B1 complexes in the cytoplasm.\n" ], "offsets": [ [ 0, 1327 ] ] } ]

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[ { "id": "PMID-10383454__text", "type": "abstract", "text": [ "IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family. \nThe interleukin-1 receptor-associated kinase (IRAK) was first described as a signal transducer for interleukin-1 (IL-1) and has later been implicated in signal transduction of other members of the Toll/IL-1 receptor family. We now report the identification and characterization of a novel IRAK-like molecule. In contrast to the ubiquitously expressed IRAK and IRAK-2, this new IRAK-like molecule is found mainly in cells of monomyeloic origin and is, therefore, designated IRAK-M. Although IRAK-M and IRAK-2 exhibit only a negligible autophosphorylation activity, they can reconstitute the IL-1 response in a 293 mutant cell line lacking IRAK. In addition, we show for the first time that members of the IRAK family are indispensable elements of lipopolysaccharide signal transduction. The discovery of IRAK-M adds another level of complexity to our understanding of signaling by members of the Toll/IL-1 receptor family.\n" ], "offsets": [ [ 0, 1017 ] ] } ]

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[]

[ { "id": "PMID-10385526__text", "type": "abstract", "text": [ "The zinc finger protein A20 inhibits TNF-induced NF-kappaB-dependent gene expression by interfering with an RIP- or TRAF2-mediated transactivation signal and directly binds to a novel NF-kappaB-inhibiting protein ABIN. \nThe zinc finger protein A20 is a tumor necrosis factor (TNF)- and interleukin 1 (IL-1)-inducible protein that negatively regulates nuclear factor-kappa B (NF-kappaB)-dependent gene expression. However, the molecular mechanism by which A20 exerts this effect is still unclear. We show that A20 does not inhibit TNF- induced nuclear translocation and DNA binding of NF-kappaB, although it completely prevents the TNF- induced activation of an NF-kappaB-dependent reporter gene, as well as TNF-induced IL-6 and granulocyte macrophage-colony stimulating factor gene expression. Moreover, NF-kappaB activation induced by overexpression of the TNF receptor-associated proteins TNF receptor-associated death domain protein (TRADD), receptor interacting protein (RIP), and TNF recep- tor-associated factor 2 (TRAF2) was also inhibited by expression of A20, whereas NF-kappaB activation induced by overexpression of NF-kappaB-inducing kinase (NIK) or the human T cell leukemia virus type 1 (HTLV-1) Tax was unaffected. These results demonstrate that A20 inhibits NF-kappaB-dependent gene expression by interfering with a novel TNF-induced and RIP- or TRAF2-mediated pathway that is different from the NIK-IkappaB kinase pathway and that is specifically involved in the transactivation of NF-kappaB. Via yeast two-hybrid screening, we found that A20 binds to a novel protein, ABIN, which mimics the NF-kappaB inhibiting effects of A20 upon overexpression, suggesting that the effect of A20 is mediated by its interaction with this NF-kappaB inhibiting protein, ABIN.\n" ], "offsets": [ [ 0, 1777 ] ] } ]

[ { "id": "PMID-10385526_T1", "type": "Simple_chemical", "text": [ "zinc" ], "offsets": [ [ 4, 8 ] ], "normalized": [] }, { "id": "PMID-10385526_T2", "type": "Gene_or_gene_product", "text": [ "A20" ], "offsets": [ [ 24, 27 ] ], "normalized": [] }, { "id": "PMID-10385526_T3", "type": "Gene_or_gene_product", "text": [ "TNF" ], "offsets": [ [ 37, 40 ] ], "normalized": [] }, { "id": "PMID-10385526_T4", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 49, 58 ] ], "normalized": [] }, { "id": "PMID-10385526_T5", "type": "Gene_or_gene_product", "text": [ "RIP" ], "offsets": [ [ 108, 111 ] ], "normalized": [] }, { "id": "PMID-10385526_T6", "type": "Gene_or_gene_product", "text": [ "TRAF2" ], "offsets": [ [ 116, 121 ] ], "normalized": [] }, { "id": "PMID-10385526_T7", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 184, 193 ] ], "normalized": [] }, { "id": "PMID-10385526_T8", "type": "Gene_or_gene_product", "text": [ "ABIN" ], "offsets": [ [ 213, 217 ] ], "normalized": [] }, { "id": "PMID-10385526_T9", "type": "Simple_chemical", "text": [ "zinc" ], "offsets": [ [ 224, 228 ] ], "normalized": [] }, { "id": "PMID-10385526_T10", "type": "Gene_or_gene_product", "text": [ "A20" ], "offsets": [ [ 244, 247 ] ], "normalized": [] }, { "id": "PMID-10385526_T11", "type": "Gene_or_gene_product", "text": [ "tumor necrosis factor" ], "offsets": [ [ 253, 274 ] ], "normalized": [] }, { "id": "PMID-10385526_T12", "type": "Gene_or_gene_product", "text": [ "TNF" ], "offsets": [ [ 276, 279 ] ], "normalized": [] }, { "id": "PMID-10385526_T13", "type": "Gene_or_gene_product", "text": [ "interleukin 1" ], "offsets": [ [ 286, 299 ] ], "normalized": [] }, { "id": "PMID-10385526_T14", "type": "Gene_or_gene_product", "text": [ "IL-1" ], "offsets": [ [ 301, 305 ] ], "normalized": [] }, { "id": "PMID-10385526_T15", "type": "Complex", "text": [ "nuclear factor-kappa B" ], "offsets": [ [ 351, 373 ] ], "normalized": [] }, { "id": "PMID-10385526_T16", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 375, 384 ] ], "normalized": [] }, { "id": "PMID-10385526_T17", "type": "Gene_or_gene_product", "text": [ "A20" ], "offsets": [ [ 455, 458 ] ], "normalized": [] }, { "id": "PMID-10385526_T18", "type": "Gene_or_gene_product", "text": [ "A20" ], "offsets": [ [ 509, 512 ] ], "normalized": [] }, { "id": "PMID-10385526_T19", "type": "Gene_or_gene_product", "text": [ "TNF" ], "offsets": [ [ 530, 533 ] ], "normalized": [] }, { "id": "PMID-10385526_T20", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 543, 550 ] ], "normalized": [] }, { "id": "PMID-10385526_T21", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 584, 593 ] ], "normalized": [] }, { "id": "PMID-10385526_T22", "type": "Gene_or_gene_product", "text": [ "TNF" ], "offsets": [ [ 631, 634 ] ], "normalized": [] }, { "id": "PMID-10385526_T23", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 661, 670 ] ], "normalized": [] }, { "id": "PMID-10385526_T24", "type": "Gene_or_gene_product", "text": [ "TNF" ], "offsets": [ [ 707, 710 ] ], "normalized": [] }, { "id": "PMID-10385526_T25", "type": "Gene_or_gene_product", "text": [ "IL-6" ], "offsets": [ [ 719, 723 ] ], "normalized": [] }, { "id": "PMID-10385526_T26", "type": "Gene_or_gene_product", "text": [ "granulocyte macrophage-colony stimulating factor" ], "offsets": [ [ 728, 776 ] ], "normalized": [] }, { "id": "PMID-10385526_T27", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 804, 813 ] ], "normalized": [] }, { "id": "PMID-10385526_T28", "type": "Gene_or_gene_product", "text": [ "TNF receptor" ], "offsets": [ [ 858, 870 ] ], "normalized": [] }, { "id": "PMID-10385526_T29", "type": "Gene_or_gene_product", "text": [ "TNF receptor-associated death domain protein" ], "offsets": [ [ 891, 935 ] ], "normalized": [] }, { "id": "PMID-10385526_T30", "type": "Gene_or_gene_product", "text": [ "TRADD" ], "offsets": [ [ 937, 942 ] ], "normalized": [] }, { "id": "PMID-10385526_T31", "type": "Gene_or_gene_product", "text": [ "receptor interacting protein" ], "offsets": [ [ 945, 973 ] ], "normalized": [] }, { "id": "PMID-10385526_T32", "type": "Gene_or_gene_product", "text": [ "RIP" ], "offsets": [ [ 975, 978 ] ], "normalized": [] }, { "id": "PMID-10385526_T33", "type": "Gene_or_gene_product", "text": [ "TNF recep- tor-associated factor 2" ], "offsets": [ [ 985, 1019 ] ], "normalized": [] }, { "id": "PMID-10385526_T34", "type": "Gene_or_gene_product", "text": [ "TRAF2" ], "offsets": [ [ 1021, 1026 ] ], "normalized": [] }, { "id": "PMID-10385526_T35", "type": "Gene_or_gene_product", "text": [ "A20" ], "offsets": [ [ 1064, 1067 ] ], "normalized": [] }, { "id": "PMID-10385526_T36", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1077, 1086 ] ], "normalized": [] }, { "id": "PMID-10385526_T37", "type": "Gene_or_gene_product", "text": [ "NF-kappaB-inducing kinase" ], "offsets": [ [ 1127, 1152 ] ], "normalized": [] }, { "id": "PMID-10385526_T38", "type": "Gene_or_gene_product", "text": [ "NIK" ], "offsets": [ [ 1154, 1157 ] ], "normalized": [] }, { "id": "PMID-10385526_T39", "type": "Gene_or_gene_product", "text": [ "Tax" ], "offsets": [ [ 1210, 1213 ] ], "normalized": [] }, { "id": "PMID-10385526_T40", "type": "Gene_or_gene_product", "text": [ "A20" ], "offsets": [ [ 1261, 1264 ] ], "normalized": [] }, { "id": "PMID-10385526_T41", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1274, 1283 ] ], "normalized": [] }, { "id": "PMID-10385526_T42", "type": "Gene_or_gene_product", "text": [ "TNF" ], "offsets": [ [ 1338, 1341 ] ], "normalized": [] }, { "id": "PMID-10385526_T43", "type": "Gene_or_gene_product", "text": [ "RIP" ], "offsets": [ [ 1354, 1357 ] ], "normalized": [] }, { "id": "PMID-10385526_T44", "type": "Gene_or_gene_product", "text": [ "TRAF2" ], "offsets": [ [ 1362, 1367 ] ], "normalized": [] }, { "id": "PMID-10385526_T45", "type": "Gene_or_gene_product", "text": [ "NIK" ], "offsets": [ [ 1412, 1415 ] ], "normalized": [] }, { "id": "PMID-10385526_T46", "type": "Complex", "text": [ "IkappaB kinase" ], "offsets": [ [ 1416, 1430 ] ], "normalized": [] }, { "id": "PMID-10385526_T47", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1499, 1508 ] ], "normalized": [] }, { "id": "PMID-10385526_T48", "type": "Gene_or_gene_product", "text": [ "A20" ], "offsets": [ [ 1556, 1559 ] ], "normalized": [] }, { "id": "PMID-10385526_T49", "type": "Gene_or_gene_product", "text": [ "ABIN" ], "offsets": [ [ 1586, 1590 ] ], "normalized": [] }, { "id": "PMID-10385526_T50", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1609, 1618 ] ], "normalized": [] }, { "id": "PMID-10385526_T51", "type": "Gene_or_gene_product", "text": [ "A20" ], "offsets": [ [ 1641, 1644 ] ], "normalized": [] }, { "id": "PMID-10385526_T52", "type": "Gene_or_gene_product", "text": [ "A20" ], "offsets": [ [ 1696, 1699 ] ], "normalized": [] }, { "id": "PMID-10385526_T53", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1741, 1750 ] ], "normalized": [] }, { "id": "PMID-10385526_T54", "type": "Gene_or_gene_product", "text": [ "ABIN" ], "offsets": [ [ 1771, 1775 ] ], "normalized": [] } ]

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"ref_id": "PMID-10385526_T21" } ] }, { "id": "PMID-10385526_E9", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 573, 580 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10385526_T21" } ] }, { "id": "PMID-10385526_E10", "type": "Negative_regulation", "trigger": { "text": [ "prevents" ], "offsets": [ [ 618, 626 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10385526_T18" }, { "role": "Theme", "ref_id": "PMID-10385526_E15" } ] }, { "id": "PMID-10385526_E11", "type": "Negative_regulation", "trigger": { "text": [ "prevents" ], "offsets": [ [ 618, 626 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10385526_T18" }, { "role": "Theme", "ref_id": "PMID-10385526_E14" } ] }, { "id": "PMID-10385526_E12", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 711, 718 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10385526_T24" }, { "role": "Theme", "ref_id": "PMID-10385526_E14" } ] }, { "id": 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"ref_id": "PMID-10385526_E16" }, { "role": "Cause", "ref_id": "PMID-10385526_E20" } ] }, { "id": "PMID-10385526_E18", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 825, 832 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10385526_E16" }, { "role": "Cause", "ref_id": "PMID-10385526_E21" } ] }, { "id": "PMID-10385526_E19", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 825, 832 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10385526_E16" }, { "role": "Cause", "ref_id": "PMID-10385526_E22" } ] }, { "id": "PMID-10385526_E20", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 836, 850 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10385526_T30" } ] }, { "id": "PMID-10385526_E21", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 836, 850 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10385526_T32" } ] }, { "id": "PMID-10385526_E22", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 836, 850 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10385526_T34" } ] }, { "id": "PMID-10385526_E23", "type": "Regulation", "trigger": { "text": [ "associated" ], "offsets": [ [ 871, 881 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10385526_T28" }, { "role": "Theme", "ref_id": "PMID-10385526_T30" } ] }, { "id": "PMID-10385526_E24", "type": "Regulation", "trigger": { "text": [ "associated" ], "offsets": [ [ 871, 881 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10385526_T28" }, { "role": "Theme", "ref_id": "PMID-10385526_T32" } ] }, { "id": "PMID-10385526_E25", "type": "Regulation", "trigger": { "text": [ "associated" ], "offsets": [ [ 871, 881 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10385526_T28" }, { "role": "Theme", "ref_id": "PMID-10385526_T34" } ] }, { "id": "PMID-10385526_E26", "type": "Negative_regulation", "trigger": { 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"ref_id": "PMID-10385526_T38" } ] }, { "id": "PMID-10385526_E31", "type": "Regulation", "trigger": { "text": [ "unaffected" ], "offsets": [ [ 1218, 1228 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10385526_E28" } ] }, { "id": "PMID-10385526_E32", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 1431, 1438 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-10385526_T45" }, { "role": "Participant", "ref_id": "PMID-10385526_T46" } ] }, { "id": "PMID-10385526_E33", "type": "Positive_regulation", "trigger": { "text": [ "involved" ], "offsets": [ [ 1464, 1472 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10385526_T47" } ] }, { "id": "PMID-10385526_E34", "type": "Positive_regulation", "trigger": { "text": [ "transactivation" ], "offsets": [ [ 1480, 1495 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10385526_T47" } ] }, { "id": "PMID-10385526_E35", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 1560, 1565 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10385526_T48" }, { "role": "Theme", "ref_id": "PMID-10385526_T49" } ] }, { "id": "PMID-10385526_E36", "type": "Negative_regulation", "trigger": { "text": [ "inhibiting" ], "offsets": [ [ 1619, 1629 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10385526_T50" } ] }, { "id": "PMID-10385526_E37", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 1630, 1637 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10385526_E36" }, { "role": "Cause", "ref_id": "PMID-10385526_T51" } ] }, { "id": "PMID-10385526_E38", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 1650, 1664 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10385526_T51" } ] }, { "id": "PMID-10385526_E39", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1703, 1711 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10385526_T52" }, { "role": "Cause", "ref_id": "PMID-10385526_E40" } ] }, { "id": "PMID-10385526_E40", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1719, 1730 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10385526_T52" }, { "role": "Theme", "ref_id": "PMID-10385526_T54" } ] }, { "id": "PMID-10385526_E41", "type": "Negative_regulation", "trigger": { "text": [ "inhibiting" ], "offsets": [ [ 1751, 1761 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10385526_T53" }, { "role": "Cause", "ref_id": "PMID-10385526_T54" } ] } ]

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[]

[ { "id": "PMID-10389141__text", "type": "abstract", "text": [ "Role of MAO A and B in neurotransmitter metabolism and behavior. \nMAO (monoamine oxidase) A and B are key isoenzymes that degrade biogenic and dietary amines. MAO A preferentially oxidizes serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE), whereas MAO B preferentially oxidizes phenylethylamine (PEA). Both forms can oxidize dopamine (DA). However, the substrate specificity overlap and the in vivo function of these two isoenzymes is not clear. Recently, we have shown that MAO A and B knock-out (KO) mice exhibit distinct differences in neurotransmitter metabolism and behavior. MAO A KO mice have elevated brain levels of 5-HT, NE and DA and manifest aggressive behavior similar to men with a deletion of MAO A. In contrast, MAO B KO mice do not exhibit aggression and only levels of PEA are increased. Both MAO A and B KO mice show increased reactivity to stress. Taken together, these results suggest that MAO A and B have distinctly different roles in monoamine metabolism. Further, these mice are valuable models for investigating the role of monoamines in psychoses and neurodegenerative and stress-related disorders.\n" ], "offsets": [ [ 0, 1138 ] ] } ]

[ { "id": "PMID-10389141_T1", "type": "Gene_or_gene_product", "text": [ "MAO A" ], "offsets": [ [ 8, 13 ] ], "normalized": [] }, { "id": "PMID-10389141_T2", "type": "Gene_or_gene_product", "text": [ "B" ], "offsets": [ [ 18, 19 ] ], "normalized": [] }, { "id": "PMID-10389141_T3", "type": "Gene_or_gene_product", "text": [ "MAO (monoamine oxidase) A" ], "offsets": [ [ 66, 91 ] ], "normalized": [] }, { "id": "PMID-10389141_T4", "type": "Gene_or_gene_product", "text": [ "B" ], "offsets": [ [ 96, 97 ] ], "normalized": [] }, { "id": "PMID-10389141_T5", "type": "Simple_chemical", "text": [ "amines" ], "offsets": [ [ 151, 157 ] ], "normalized": [] }, { "id": "PMID-10389141_T6", "type": "Gene_or_gene_product", "text": [ "MAO A" ], "offsets": [ [ 159, 164 ] ], "normalized": [] }, { "id": "PMID-10389141_T7", "type": "Simple_chemical", "text": [ "serotonin" ], "offsets": [ [ 189, 198 ] ], "normalized": [] }, { "id": "PMID-10389141_T8", "type": "Simple_chemical", "text": [ "5-hydroxytryptamine" ], "offsets": [ [ 200, 219 ] ], "normalized": [] }, { "id": "PMID-10389141_T9", "type": "Simple_chemical", "text": [ "5-HT" ], "offsets": [ [ 221, 225 ] ], "normalized": [] }, { "id": "PMID-10389141_T10", "type": "Simple_chemical", "text": [ "norepinephrine" ], "offsets": [ [ 231, 245 ] ], "normalized": [] }, { "id": "PMID-10389141_T11", "type": "Simple_chemical", "text": [ "NE" ], "offsets": [ [ 247, 249 ] ], "normalized": [] }, { "id": "PMID-10389141_T12", "type": "Gene_or_gene_product", "text": [ "MAO B" ], "offsets": [ [ 260, 265 ] ], "normalized": [] }, { "id": "PMID-10389141_T13", "type": "Simple_chemical", "text": [ "phenylethylamine" ], "offsets": [ [ 290, 306 ] ], "normalized": [] }, { "id": "PMID-10389141_T14", "type": "Simple_chemical", "text": [ "PEA" ], "offsets": [ [ 308, 311 ] ], "normalized": [] }, { "id": "PMID-10389141_T15", "type": "Simple_chemical", "text": [ "dopamine" ], "offsets": [ [ 337, 345 ] ], "normalized": [] }, { "id": "PMID-10389141_T16", "type": "Simple_chemical", "text": [ "DA" ], "offsets": [ [ 347, 349 ] ], "normalized": [] }, { "id": "PMID-10389141_T17", "type": "Gene_or_gene_product", "text": [ "MAO A" ], "offsets": [ [ 487, 492 ] ], "normalized": [] }, { "id": "PMID-10389141_T18", "type": "Gene_or_gene_product", "text": [ "B" ], "offsets": [ [ 497, 498 ] ], "normalized": [] }, { "id": "PMID-10389141_T19", "type": "Gene_or_gene_product", "text": [ "MAO A" ], "offsets": [ [ 593, 598 ] ], "normalized": [] }, { "id": "PMID-10389141_T20", "type": "Simple_chemical", "text": [ "5-HT" ], "offsets": [ [ 637, 641 ] ], "normalized": [] }, { "id": "PMID-10389141_T21", "type": "Simple_chemical", "text": [ "NE" ], "offsets": [ [ 643, 645 ] ], "normalized": [] }, { "id": "PMID-10389141_T22", "type": "Simple_chemical", "text": [ "DA" ], "offsets": [ [ 650, 652 ] ], "normalized": [] }, { "id": "PMID-10389141_T23", "type": "Gene_or_gene_product", "text": [ "MAO A" ], "offsets": [ [ 720, 725 ] ], "normalized": [] }, { "id": "PMID-10389141_T24", "type": "Gene_or_gene_product", "text": [ "MAO B" ], "offsets": [ [ 740, 745 ] ], "normalized": [] }, { "id": "PMID-10389141_T25", "type": "Simple_chemical", "text": [ "PEA" ], "offsets": [ [ 799, 802 ] ], "normalized": [] }, { "id": "PMID-10389141_T26", "type": "Gene_or_gene_product", "text": [ "MAO A" ], "offsets": [ [ 823, 828 ] ], "normalized": [] }, { "id": "PMID-10389141_T27", "type": "Gene_or_gene_product", "text": [ "B" ], "offsets": [ [ 833, 834 ] ], "normalized": [] }, { "id": "PMID-10389141_T28", "type": "Gene_or_gene_product", "text": [ "MAO A" ], "offsets": [ [ 923, 928 ] ], "normalized": [] }, { "id": "PMID-10389141_T29", "type": "Gene_or_gene_product", "text": [ "B" ], "offsets": [ [ 933, 934 ] ], "normalized": [] }, { "id": "PMID-10389141_T30", "type": "Simple_chemical", "text": [ "monoamine" ], "offsets": [ [ 970, 979 ] ], "normalized": [] } ]

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[ { "id": "PMID-10389141_1", "entity_ids": [ "PMID-10389141_T7", "PMID-10389141_T8", "PMID-10389141_T9" ] }, { "id": "PMID-10389141_2", "entity_ids": [ "PMID-10389141_T10", "PMID-10389141_T11" ] }, { "id": "PMID-10389141_3", "entity_ids": [ "PMID-10389141_T13", "PMID-10389141_T14" ] }, { "id": "PMID-10389141_4", "entity_ids": [ "PMID-10389141_T15", "PMID-10389141_T16" ] } ]

[]

[ { "id": "PMID-10391247__text", "type": "abstract", "text": [ "The TAK1-NLK-MAPK-related pathway antagonizes signalling between beta-catenin and transcription factor TCF. \nThe Wnt signalling pathway regulates many developmental processes through a complex of beta-catenin and the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of high-mobility-group transcription factors. Wnt stabilizes cytosolic beta-catenin, which then binds to TCF and activates gene transcription. This signalling cascade is conserved in vertebrates, Drosophila and Caenorhabditis elegans. In C. elegans, the proteins MOM-4 and LIT-1 regulate Wnt signalling to polarize responding cells during embryogenesis. MOM-4 and LIT-1 are homologous to TAK1 (a kinase activated by transforming growth factor-beta) mitogen-activated protein-kinase-kinase kinase (MAP3K) and MAP kinase (MAPK)-related NEMO-like kinase (NLK), respectively, in mammalian cells. These results raise the possibility that TAK1 and NLK are also involved in Wnt signalling in mammalian cells. Here we show that TAK1 activation stimulates NLK activity and downregulates transcriptional activation mediated by beta-catenin and TCF. Injection of NLK suppresses the induction of axis duplication by microinjected beta-catenin in Xenopus embryos. NLK phosphorylates TCF/LEF factors and inhibits the interaction of the beta-catenin-TCF complex with DNA. Thus, the TAK1-NLK-MAPK-like pathway negatively regulates the Wnt signalling pathway.\n" ], "offsets": [ [ 0, 1416 ] ] } ]

[ { "id": "PMID-10391247_T1", "type": "Gene_or_gene_product", "text": [ "TAK1" ], "offsets": [ [ 4, 8 ] ], "normalized": [] }, { "id": "PMID-10391247_T2", "type": "Gene_or_gene_product", "text": [ "NLK" ], "offsets": [ [ 9, 12 ] ], "normalized": [] }, { "id": "PMID-10391247_T3", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 13, 17 ] ], "normalized": [] }, { "id": "PMID-10391247_T4", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 65, 77 ] ], "normalized": [] }, { "id": "PMID-10391247_T5", "type": "Gene_or_gene_product", "text": [ "TCF" ], "offsets": [ [ 103, 106 ] ], "normalized": [] }, { "id": "PMID-10391247_T6", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 113, 116 ] ], "normalized": [] }, { "id": "PMID-10391247_T7", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 196, 208 ] ], "normalized": [] }, { "id": "PMID-10391247_T8", "type": "Gene_or_gene_product", "text": [ "T-cell factor" ], "offsets": [ [ 217, 230 ] ], "normalized": [] }, { "id": "PMID-10391247_T9", "type": "Gene_or_gene_product", "text": [ "lymphoid enhancer factor" ], "offsets": [ [ 231, 255 ] ], "normalized": [] }, { "id": "PMID-10391247_T10", "type": "Gene_or_gene_product", "text": [ "TCF" ], "offsets": [ [ 257, 260 ] ], "normalized": [] }, { "id": "PMID-10391247_T11", "type": "Gene_or_gene_product", "text": [ "LEF" ], "offsets": [ [ 261, 264 ] ], "normalized": [] }, { "id": "PMID-10391247_T12", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 319, 322 ] ], "normalized": [] }, { "id": "PMID-10391247_T13", "type": "Cellular_component", "text": [ "cytosolic" ], "offsets": [ [ 334, 343 ] ], "normalized": [] }, { "id": "PMID-10391247_T14", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 344, 356 ] ], "normalized": [] }, { "id": "PMID-10391247_T15", "type": "Gene_or_gene_product", "text": [ "TCF" ], "offsets": [ [ 378, 381 ] ], "normalized": [] }, { "id": "PMID-10391247_T16", "type": "Gene_or_gene_product", "text": [ "MOM-4" ], "offsets": [ [ 536, 541 ] ], "normalized": [] }, { "id": "PMID-10391247_T17", "type": "Gene_or_gene_product", "text": [ "LIT-1" ], "offsets": [ [ 546, 551 ] ], "normalized": [] }, { "id": "PMID-10391247_T18", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 561, 564 ] ], "normalized": [] }, { "id": "PMID-10391247_T19", "type": "Gene_or_gene_product", "text": [ "MOM-4" ], "offsets": [ [ 627, 632 ] ], "normalized": [] }, { "id": "PMID-10391247_T20", "type": "Gene_or_gene_product", "text": [ "LIT-1" ], "offsets": [ [ 637, 642 ] ], "normalized": [] }, { "id": "PMID-10391247_T21", "type": "Gene_or_gene_product", "text": [ "TAK1" ], "offsets": [ [ 661, 665 ] ], "normalized": [] }, { "id": "PMID-10391247_T22", "type": "Gene_or_gene_product", "text": [ "transforming growth factor-beta" ], "offsets": [ [ 689, 720 ] ], "normalized": [] }, { "id": "PMID-10391247_T23", "type": "Gene_or_gene_product", "text": [ "mitogen-activated protein-kinase-kinase kinase" ], "offsets": [ [ 722, 768 ] ], "normalized": [] }, { "id": "PMID-10391247_T24", "type": "Gene_or_gene_product", "text": [ "MAP3K" ], "offsets": [ [ 770, 775 ] ], "normalized": [] }, { "id": "PMID-10391247_T25", "type": "Gene_or_gene_product", "text": [ "MAP kinase" ], "offsets": [ [ 781, 791 ] ], "normalized": [] }, { "id": "PMID-10391247_T26", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 793, 797 ] ], "normalized": [] }, { "id": "PMID-10391247_T27", "type": "Gene_or_gene_product", "text": [ "NEMO-like kinase" ], "offsets": [ [ 807, 823 ] ], "normalized": [] }, { "id": "PMID-10391247_T28", "type": "Gene_or_gene_product", "text": [ "NLK" ], "offsets": [ [ 825, 828 ] ], "normalized": [] }, { "id": "PMID-10391247_T29", "type": "Gene_or_gene_product", "text": [ "TAK1" ], "offsets": [ [ 906, 910 ] ], "normalized": [] }, { "id": "PMID-10391247_T30", "type": "Gene_or_gene_product", "text": [ "NLK" ], "offsets": [ [ 915, 918 ] ], "normalized": [] }, { "id": "PMID-10391247_T31", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 940, 943 ] ], "normalized": [] }, { "id": "PMID-10391247_T32", "type": "Gene_or_gene_product", "text": [ "TAK1" ], "offsets": [ [ 993, 997 ] ], "normalized": [] }, { "id": "PMID-10391247_T33", "type": "Gene_or_gene_product", "text": [ "NLK" ], "offsets": [ [ 1020, 1023 ] ], "normalized": [] }, { "id": "PMID-10391247_T34", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 1090, 1102 ] ], "normalized": [] }, { "id": "PMID-10391247_T35", "type": "Gene_or_gene_product", "text": [ "TCF" ], "offsets": [ [ 1107, 1110 ] ], "normalized": [] }, { "id": "PMID-10391247_T36", "type": "Gene_or_gene_product", "text": [ "NLK" ], "offsets": [ [ 1125, 1128 ] ], "normalized": [] }, { "id": "PMID-10391247_T37", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 1191, 1203 ] ], "normalized": [] }, { "id": "PMID-10391247_T38", "type": "Gene_or_gene_product", "text": [ "NLK" ], "offsets": [ [ 1224, 1227 ] ], "normalized": [] }, { "id": "PMID-10391247_T39", "type": "Gene_or_gene_product", "text": [ "TCF" ], "offsets": [ [ 1243, 1246 ] ], "normalized": [] }, { "id": "PMID-10391247_T40", "type": "Gene_or_gene_product", "text": [ "LEF factors" ], "offsets": [ [ 1247, 1258 ] ], "normalized": [] }, { "id": "PMID-10391247_T41", "type": "Complex", "text": [ "beta-catenin-TCF" ], "offsets": [ [ 1295, 1311 ] ], "normalized": [] }, { "id": "PMID-10391247_T42", "type": "Gene_or_gene_product", "text": [ "TAK1" ], "offsets": [ [ 1340, 1344 ] ], "normalized": [] }, { "id": "PMID-10391247_T43", "type": "Gene_or_gene_product", "text": [ "NLK" ], "offsets": [ [ 1345, 1348 ] ], "normalized": [] }, { "id": "PMID-10391247_T44", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 1349, 1353 ] ], "normalized": [] }, { "id": "PMID-10391247_T45", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 1392, 1395 ] ], "normalized": [] } ]

[ { "id": "PMID-10391247_E1", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 26, 33 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-10391247_T1" }, { "role": "Participant", "ref_id": "PMID-10391247_T2" }, { "role": "Participant", "ref_id": "PMID-10391247_T3" } ] }, { "id": "PMID-10391247_E2", "type": "Negative_regulation", "trigger": { "text": [ "antagonizes" ], "offsets": [ [ 34, 45 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10391247_E1" }, { "role": "Theme", "ref_id": "PMID-10391247_E3" } ] }, { "id": "PMID-10391247_E3", "type": "Pathway", "trigger": { "text": [ "signalling" ], "offsets": [ [ 46, 56 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-10391247_T4" }, { "role": "Participant", "ref_id": "PMID-10391247_T5" } ] }, { "id": "PMID-10391247_E4", "type": "Pathway", "trigger": { "text": [ "signalling pathway" ], "offsets": [ [ 117, 135 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-10391247_T6" } ] }, { "id": "PMID-10391247_E5", "type": "Regulation", "trigger": { "text": [ "stabilizes" ], "offsets": [ [ 323, 333 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10391247_T12" }, { "role": "Theme", "ref_id": "PMID-10391247_T14" } ] }, { "id": "PMID-10391247_E6", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 369, 374 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10391247_T14" }, { "role": "Theme", "ref_id": "PMID-10391247_T15" } ] }, { "id": "PMID-10391247_E7", "type": "Regulation", "trigger": { "text": [ "regulate" ], "offsets": [ [ 552, 560 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10391247_E9" }, { "role": "Cause", "ref_id": "PMID-10391247_T17" } ] }, { "id": "PMID-10391247_E8", "type": "Regulation", "trigger": { "text": [ "regulate" ], "offsets": [ [ 552, 560 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10391247_E9" }, { "role": "Cause", "ref_id": "PMID-10391247_T16" } ] }, { "id": "PMID-10391247_E9", "type": "Pathway", "trigger": { "text": [ "signalling" ], "offsets": [ [ 565, 575 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-10391247_T18" } ] }, { "id": "PMID-10391247_E10", "type": "Activation", "trigger": { "text": [ "activated" ], "offsets": [ [ 676, 685 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10391247_T22" }, { "role": "Theme", "ref_id": "PMID-10391247_T21" } ] }, { "id": "PMID-10391247_E11", "type": "Regulation", "trigger": { "text": [ "involved" ], "offsets": [ [ 928, 936 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10391247_E13" }, { "role": "Cause", "ref_id": "PMID-10391247_T29" } ] }, { "id": "PMID-10391247_E12", "type": "Regulation", "trigger": { "text": [ "involved" ], "offsets": [ [ 928, 936 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10391247_E13" }, { "role": "Cause", "ref_id": "PMID-10391247_T30" } ] }, { "id": "PMID-10391247_E13", "type": "Pathway", "trigger": { "text": [ "signalling" ], "offsets": [ [ 944, 954 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-10391247_T31" } ] }, { "id": "PMID-10391247_E14", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 998, 1008 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10391247_T32" } ] }, { "id": "PMID-10391247_E15", "type": "Positive_regulation", "trigger": { "text": [ "stimulates" ], "offsets": [ [ 1009, 1019 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10391247_E14" }, { "role": "Theme", "ref_id": "PMID-10391247_T33" } ] }, { "id": "PMID-10391247_E16", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylates" ], "offsets": [ [ 1228, 1242 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10391247_T38" }, { "role": "Theme", "ref_id": "PMID-10391247_T39" } ] }, { "id": "PMID-10391247_E17", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylates" ], "offsets": [ [ 1228, 1242 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10391247_T38" }, { "role": "Theme", "ref_id": "PMID-10391247_T40" } ] }, { "id": "PMID-10391247_E18", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 1263, 1271 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10391247_E19" }, { "role": "Cause", "ref_id": "PMID-10391247_T38" } ] }, { "id": "PMID-10391247_E19", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1276, 1287 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10391247_T41" } ] }, { "id": "PMID-10391247_E20", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 1359, 1366 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-10391247_T42" }, { "role": "Participant", "ref_id": "PMID-10391247_T43" }, { "role": "Participant", "ref_id": "PMID-10391247_T44" } ] }, { "id": "PMID-10391247_E21", "type": "Negative_regulation", "trigger": { "text": [ "negatively regulates" ], "offsets": [ [ 1367, 1387 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10391247_E20" }, { "role": "Theme", "ref_id": "PMID-10391247_E22" } ] }, { "id": "PMID-10391247_E22", "type": "Pathway", "trigger": { "text": [ "signalling pathway" ], "offsets": [ [ 1396, 1414 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-10391247_T45" } ] } ]

[ { "id": "PMID-10391247_1", "entity_ids": [ "PMID-10391247_T8", "PMID-10391247_T10" ] }, { "id": "PMID-10391247_2", "entity_ids": [ "PMID-10391247_T9", "PMID-10391247_T11" ] } ]

[]

[ { "id": "PMID-10421629__text", "type": "abstract", "text": [ "Wnt-induced dephosphorylation of axin releases beta-catenin from the axin complex. \nThe stabilization of beta-catenin is a key regulatory step during cell fate changes and transformations to tumor cells. Several interacting proteins, including Axin, APC, and the protein kinase GSK-3beta are implicated in regulating beta-catenin phosphorylation and its subsequent degradation. Wnt signaling stabilizes beta-catenin, but it was not clear whether and how Wnt signaling regulates the beta-catenin complex. Here we show that Axin is dephosphorylated in response to Wnt signaling. The dephosphorylated Axin binds beta-catenin less efficiently than the phosphorylated form. Thus, Wnt signaling lowers Axin's affinity for beta-catenin, thereby disengaging beta-catenin from the degradation machinery. \n" ], "offsets": [ [ 0, 796 ] ] } ]

[ { "id": "PMID-10421629_T1", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 0, 3 ] ], "normalized": [] }, { "id": "PMID-10421629_T2", "type": "Gene_or_gene_product", "text": [ "axin" ], "offsets": [ [ 33, 37 ] ], "normalized": [] }, { "id": "PMID-10421629_T3", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 47, 59 ] ], "normalized": [] }, { "id": "PMID-10421629_T4", "type": "Complex", "text": [ "axin complex" ], "offsets": [ [ 69, 81 ] ], "normalized": [] }, { "id": "PMID-10421629_T5", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 105, 117 ] ], "normalized": [] }, { "id": "PMID-10421629_T6", "type": "Gene_or_gene_product", "text": [ "Axin" ], "offsets": [ [ 244, 248 ] ], "normalized": [] }, { "id": "PMID-10421629_T7", "type": "Gene_or_gene_product", "text": [ "APC" ], "offsets": [ [ 250, 253 ] ], "normalized": [] }, { "id": "PMID-10421629_T8", "type": "Gene_or_gene_product", "text": [ "GSK-3beta" ], "offsets": [ [ 278, 287 ] ], "normalized": [] }, { "id": "PMID-10421629_T9", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 317, 329 ] ], "normalized": [] }, { "id": "PMID-10421629_T10", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 378, 381 ] ], "normalized": [] }, { "id": "PMID-10421629_T11", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 403, 415 ] ], "normalized": [] }, { "id": "PMID-10421629_T12", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 454, 457 ] ], "normalized": [] }, { "id": "PMID-10421629_T13", "type": "Complex", "text": [ "beta-catenin complex" ], "offsets": [ [ 482, 502 ] ], "normalized": [] }, { "id": "PMID-10421629_T14", "type": "Gene_or_gene_product", "text": [ "Axin" ], "offsets": [ [ 522, 526 ] ], "normalized": [] }, { "id": "PMID-10421629_T15", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 562, 565 ] ], "normalized": [] }, { "id": "PMID-10421629_T16", "type": "Gene_or_gene_product", "text": [ "Axin" ], "offsets": [ [ 598, 602 ] ], "normalized": [] }, { "id": "PMID-10421629_T17", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 609, 621 ] ], "normalized": [] }, { "id": "PMID-10421629_T18", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 675, 678 ] ], "normalized": [] }, { "id": "PMID-10421629_T19", "type": "Gene_or_gene_product", "text": [ "Axin" ], "offsets": [ [ 696, 700 ] ], "normalized": [] }, { "id": "PMID-10421629_T20", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 716, 728 ] ], "normalized": [] }, { "id": "PMID-10421629_T21", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 750, 762 ] ], "normalized": [] } ]

[ { "id": "PMID-10421629_E1", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 4, 11 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10421629_T1" }, { "role": "Theme", "ref_id": "PMID-10421629_E2" } ] }, { "id": "PMID-10421629_E2", "type": "Dephosphorylation", "trigger": { "text": [ "dephosphorylation" ], "offsets": [ [ 12, 29 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10421629_T2" } ] }, { "id": "PMID-10421629_E3", "type": "Dissociation", "trigger": { "text": [ "releases" ], "offsets": [ [ 38, 46 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10421629_T4" }, { "role": "Product", "ref_id": "PMID-10421629_T3" } ] }, { "id": "PMID-10421629_E4", "type": "Positive_regulation", "trigger": { "text": [ "releases" ], "offsets": [ [ 38, 46 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10421629_E2" }, { "role": "Theme", "ref_id": "PMID-10421629_E3" } ] }, { "id": "PMID-10421629_E5", "type": "Regulation", "trigger": { "text": [ "stabilization" ], "offsets": [ [ 88, 101 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10421629_T5" } ] }, { "id": "PMID-10421629_E6", "type": "Binding", "trigger": { "text": [ "interacting" ], "offsets": [ [ 212, 223 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10421629_T6" } ] }, { "id": "PMID-10421629_E7", "type": "Binding", "trigger": { "text": [ "interacting" ], "offsets": [ [ 212, 223 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10421629_T7" } ] }, { "id": "PMID-10421629_E8", "type": "Binding", "trigger": { "text": [ "interacting" ], "offsets": [ [ 212, 223 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10421629_T8" } ] }, { "id": "PMID-10421629_E9", "type": "Regulation", "trigger": { "text": [ "regulating" ], "offsets": [ [ 306, 316 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10421629_E15" }, { "role": "Cause", "ref_id": "PMID-10421629_T8" } ] }, { "id": "PMID-10421629_E10", "type": "Regulation", "trigger": { "text": [ "regulating" ], "offsets": [ [ 306, 316 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10421629_E15" }, { "role": "Cause", "ref_id": "PMID-10421629_T7" } ] }, { "id": "PMID-10421629_E11", "type": "Regulation", "trigger": { "text": [ "regulating" ], "offsets": [ [ 306, 316 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10421629_E15" }, { "role": "Cause", "ref_id": "PMID-10421629_T6" } ] }, { "id": "PMID-10421629_E12", "type": "Regulation", "trigger": { "text": [ "regulating" ], "offsets": [ [ 306, 316 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10421629_E16" }, { "role": "Cause", "ref_id": "PMID-10421629_T7" } ] }, { "id": "PMID-10421629_E13", "type": "Regulation", "trigger": { "text": [ "regulating" ], "offsets": [ [ 306, 316 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10421629_E16" }, { "role": "Cause", "ref_id": "PMID-10421629_T8" } ] }, { "id": "PMID-10421629_E14", "type": "Regulation", "trigger": { "text": [ "regulating" ], "offsets": [ [ 306, 316 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10421629_E16" }, { "role": "Cause", "ref_id": "PMID-10421629_T6" } ] }, { "id": "PMID-10421629_E15", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 330, 345 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10421629_T9" } ] }, { "id": "PMID-10421629_E16", "type": "Degradation", "trigger": { "text": [ "degradation" ], "offsets": [ [ 365, 376 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10421629_T9" } ] }, { "id": "PMID-10421629_E17", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 382, 391 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-10421629_T10" } ] }, { "id": "PMID-10421629_E18", "type": "Regulation", "trigger": { "text": [ "stabilizes" ], "offsets": [ [ 392, 402 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10421629_E17" }, { "role": "Theme", "ref_id": "PMID-10421629_T11" } ] }, { "id": "PMID-10421629_E19", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 458, 467 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-10421629_T12" } ] }, { "id": "PMID-10421629_E20", "type": "Regulation", "trigger": { "text": [ "regulates" ], "offsets": [ [ 468, 477 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10421629_T13" }, { "role": "Cause", "ref_id": "PMID-10421629_E19" } ] }, { "id": "PMID-10421629_E21", "type": "Phosphorylation", "trigger": { "text": [ "dephosphorylated" ], "offsets": [ [ 530, 546 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10421629_T14" } ] }, { "id": "PMID-10421629_E22", "type": "Regulation", "trigger": { "text": [ "response" ], "offsets": [ [ 550, 558 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10421629_E21" }, { "role": "Cause", "ref_id": "PMID-10421629_E23" } ] }, { "id": "PMID-10421629_E23", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 566, 575 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-10421629_T15" } ] }, { "id": "PMID-10421629_E24", "type": "Dephosphorylation", "trigger": { "text": [ "dephosphorylated" ], "offsets": [ [ 581, 597 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10421629_T16" } ] }, { "id": "PMID-10421629_E25", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 603, 608 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10421629_T16" }, { "role": "Theme", "ref_id": "PMID-10421629_T17" } ] }, { "id": "PMID-10421629_E26", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 648, 662 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10421629_T16" } ] }, { "id": "PMID-10421629_E27", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 679, 688 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-10421629_T18" } ] }, { "id": "PMID-10421629_E28", "type": "Negative_regulation", "trigger": { "text": [ "lowers" ], "offsets": [ [ 689, 695 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10421629_E29" }, { "role": "Cause", "ref_id": "PMID-10421629_E27" } ] }, { "id": "PMID-10421629_E29", "type": "Binding", "trigger": { "text": [ "affinity" ], "offsets": [ [ 703, 711 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10421629_T20" }, { "role": "Theme", "ref_id": "PMID-10421629_T19" } ] }, { "id": "PMID-10421629_E30", "type": "Negative_regulation", "trigger": { "text": [ "disengaging" ], "offsets": [ [ 738, 749 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10421629_E31" }, { "role": "Cause", "ref_id": "PMID-10421629_E28" } ] }, { "id": "PMID-10421629_E31", "type": "Degradation", "trigger": { "text": [ "degradation" ], "offsets": [ [ 772, 783 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10421629_T21" } ] } ]

[]

[]

[ { "id": "PMID-10455013__text", "type": "abstract", "text": [ "Phosphorylation of Ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1: identification of five sites of phosphorylation in vivo. \n3-phosphoinositide-dependent protein kinase-1 (PDK1) expressed in unstimulated 293 cells was phosphorylated at Ser-25, Ser-241, Ser-393, Ser-396 and Ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of Ser-241 to Ala abolished PDK1 activity, whereas mutation of the other phosphorylation sites individually to Ala did not affect PDK1 activity. Ser-241, unlike the other phosphorylation sites on PDK1, was resistant to dephosphorylation by protein phosphatase 2A(1). Ser-241 lies in the activation loop of the PDK1 kinase domain between subdomains VII and VIII in the equivalent position to the site that PDK1 phosphorylates on its protein kinase substrates. PDK1 expressed in bacteria was active and phosphorylated at Ser-241, suggesting that PDK1 can phosphorylate itself at this site, leading to its own activation.\n" ], "offsets": [ [ 0, 1061 ] ] } ]

[ { "id": "PMID-10455013_T1", "type": "Simple_chemical", "text": [ "Ser-241" ], "offsets": [ [ 19, 26 ] ], "normalized": [] }, { "id": "PMID-10455013_T2", "type": "Gene_or_gene_product", "text": [ "3-phosphoinositide-dependent protein kinase-1" ], "offsets": [ [ 60, 105 ] ], "normalized": [] }, { "id": "PMID-10455013_T3", "type": "Gene_or_gene_product", "text": [ "3-phosphoinositide-dependent protein kinase-1" ], "offsets": [ [ 165, 210 ] ], "normalized": [] }, { "id": "PMID-10455013_T4", "type": "Gene_or_gene_product", "text": [ "PDK1" ], "offsets": [ [ 212, 216 ] ], "normalized": [] }, { "id": "PMID-10455013_T5", "type": "Simple_chemical", "text": [ "Ser-25" ], "offsets": [ [ 276, 282 ] ], "normalized": [] }, { "id": "PMID-10455013_T6", "type": "Simple_chemical", "text": [ "Ser-241" ], "offsets": [ [ 284, 291 ] ], "normalized": [] }, { "id": "PMID-10455013_T7", "type": "Simple_chemical", "text": [ "Ser-393" ], "offsets": [ [ 293, 300 ] ], "normalized": [] }, { "id": "PMID-10455013_T8", "type": "Simple_chemical", "text": [ "Ser-396" ], "offsets": [ [ 302, 309 ] ], "normalized": [] }, { "id": "PMID-10455013_T9", "type": "Simple_chemical", "text": [ "Ser-410" ], "offsets": [ [ 314, 321 ] ], "normalized": [] }, { "id": "PMID-10455013_T10", "type": "Gene_or_gene_product", "text": [ "insulin-like growth factor-1" ], "offsets": [ [ 403, 431 ] ], "normalized": [] }, { "id": "PMID-10455013_T11", "type": "Simple_chemical", "text": [ "Ser-241" ], "offsets": [ [ 445, 452 ] ], "normalized": [] }, { "id": "PMID-10455013_T12", "type": "Simple_chemical", "text": [ "Ala" ], "offsets": [ [ 456, 459 ] ], "normalized": [] }, { "id": "PMID-10455013_T13", "type": "Gene_or_gene_product", "text": [ "PDK1" ], "offsets": [ [ 470, 474 ] ], "normalized": [] }, { "id": "PMID-10455013_T14", "type": "Simple_chemical", "text": [ "Ala" ], "offsets": [ [ 553, 556 ] ], "normalized": [] }, { "id": "PMID-10455013_T15", "type": "Gene_or_gene_product", "text": [ "PDK1" ], "offsets": [ [ 572, 576 ] ], "normalized": [] }, { "id": "PMID-10455013_T16", "type": "Simple_chemical", "text": [ "Ser-241" ], "offsets": [ [ 587, 594 ] ], "normalized": [] }, { "id": "PMID-10455013_T17", "type": "Gene_or_gene_product", "text": [ "PDK1" ], "offsets": [ [ 638, 642 ] ], "normalized": [] }, { "id": "PMID-10455013_T18", "type": "Gene_or_gene_product", "text": [ "protein phosphatase 2A(1)" ], "offsets": [ [ 682, 707 ] ], "normalized": [] }, { "id": "PMID-10455013_T19", "type": "Simple_chemical", "text": [ "Ser-241" ], "offsets": [ [ 709, 716 ] ], "normalized": [] }, { "id": "PMID-10455013_T20", "type": "Gene_or_gene_product", "text": [ "PDK1" ], "offsets": [ [ 752, 756 ] ], "normalized": [] }, { "id": "PMID-10455013_T21", "type": "Gene_or_gene_product", "text": [ "PDK1" ], "offsets": [ [ 847, 851 ] ], "normalized": [] }, { "id": "PMID-10455013_T22", "type": "Gene_or_gene_product", "text": [ "PDK1" ], "offsets": [ [ 901, 905 ] ], "normalized": [] }, { "id": "PMID-10455013_T23", "type": "Simple_chemical", "text": [ "Ser-241" ], "offsets": [ [ 961, 968 ] ], "normalized": [] }, { "id": "PMID-10455013_T24", "type": "Gene_or_gene_product", "text": [ "PDK1" ], "offsets": [ [ 986, 990 ] ], "normalized": [] } ]

[ { "id": "PMID-10455013_E1", "type": "Phosphorylation", "trigger": { "text": [ "Phosphorylation" ], "offsets": [ [ 0, 15 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-10455013_T1" }, { "role": "Theme", "ref_id": "PMID-10455013_T2" } ] }, { "id": "PMID-10455013_E2", "type": "Positive_regulation", "trigger": { "text": [ "essential" ], "offsets": [ [ 30, 39 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10455013_T2" }, { "role": "Cause", "ref_id": "PMID-10455013_E1" } ] }, { "id": "PMID-10455013_E3", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 218, 227 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10455013_T3" } ] }, { "id": "PMID-10455013_E4", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 258, 272 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10455013_T3" }, { "role": "Site", "ref_id": "PMID-10455013_T5" } ] }, { "id": "PMID-10455013_E5", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 258, 272 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10455013_T3" }, { "role": "Site", "ref_id": "PMID-10455013_T6" } ] }, { "id": "PMID-10455013_E6", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 258, 272 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10455013_T3" }, { "role": "Site", "ref_id": "PMID-10455013_T7" } ] }, { "id": "PMID-10455013_E7", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 258, 272 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10455013_T3" }, { "role": "Site", "ref_id": "PMID-10455013_T8" } ] }, { "id": "PMID-10455013_E8", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 258, 272 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10455013_T3" }, { "role": "Site", "ref_id": "PMID-10455013_T9" } ] }, { "id": "PMID-10455013_E9", "type": "Phosphorylation", 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"Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 906, 915 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10455013_T22" } ] }, { "id": "PMID-10455013_E22", "type": "Activation", "trigger": { "text": [ "active" ], "offsets": [ [ 932, 938 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10455013_T22" } ] }, { "id": "PMID-10455013_E23", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 943, 957 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-10455013_T23" }, { "role": "Theme", "ref_id": "PMID-10455013_T22" } ] }, { "id": "PMID-10455013_E24", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylate" ], "offsets": [ [ 995, 1008 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10455013_T24" }, { "role": "Site", "ref_id": "PMID-10455013_T23" }, { "role": "Cause", "ref_id": "PMID-10455013_T24" } ] }, { "id": "PMID-10455013_E25", "type": "Positive_regulation", "trigger": { "text": [ "leading" ], "offsets": [ [ 1030, 1037 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10455013_E26" }, { "role": "Cause", "ref_id": "PMID-10455013_E24" } ] }, { "id": "PMID-10455013_E26", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1049, 1059 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10455013_T24" } ] } ]

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[]

[ { "id": "PMID-10487762__text", "type": "abstract", "text": [ "NuA4, an essential transcription adaptor/histone H4 acetyltransferase complex containing Esa1p and the ATM-related cofactor Tra1p. \nPost-translational acetylation of histone H4 N-terminal tail in chromatin has been associated with several nuclear processes including transcription. We report the purification and characterization of a native multisubunit complex (NuA4) from yeast that acetylates nucleosomal histone H4. NuA4 has an apparent molecular mass of 1.3 MDa. All four conserved lysines of histone H4 can be acetylated by NuA4. We have identified the catalytic subunit of the complex as the product of ESA1, an essential gene required for cell cycle progression in yeast. Antibodies against Esa1p specifically immunoprecipitate NuA4 activity whereas the complex purified from a temperature-sensitive esa1 mutant loses its acetyltransferase activity at the restrictive temperature. Additionally, we have identified another subunit of the complex as the product of TRA1, an ATM-related essential gene homologous to human TRRAP, an essential cofactor for c-Myc- and E2F-mediated oncogenic transformation. Finally, the ability of NuA4 to stimulate GAL4-VP16-driven transcription from chromatin templates in vitro is also lost in the temperature-sensitive esa1 mutant. The function of the essential Esa1 protein as the HAT subunit of NuA4 and the presence of Tra1p, a putative transcription activator-interacting subunit, supports an essential link between nuclear H4 acetylation, transcriptional regulation and cell cycle control.\n" ], "offsets": [ [ 0, 1536 ] ] } ]

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[]

[]

[ { "id": "PMID-10508167__text", "type": "abstract", "text": [ "Two co-existing mechanisms for nuclear import of MAP kinase: passive diffusion of a monomer and active transport of a dimer. \nIn response to extracellular stimuli, mitogen-activated protein kinase (MAPK, also known as ERK) translocates from the cytoplasm to the nucleus. MAP kinase kinase (MAPKK, also know as MEK), which possesses a nuclear export signal (NES), acts as a cytoplasmic anchor of MAPK. Here we show evidence that tyrosine (Tyr190 in Xenopus MPK1/ERK2) phosphorylation of MAPK by MAPKK is necessary and sufficient for the dissociation of the MAPKK-MAPK complex, and that the dissociation of the complex is required for the nuclear translocation of MAPK. We then show that nuclear entry of MAPK through a nuclear pore occurs via two distinct mechanisms. Nuclear import of wild-type MAPK (mol. wt 42 kDa) was induced by activation of the MAPK pathway even in the presence of wheat germ agglutinin or dominant-negative Ran, whereas nuclear import of beta-galactosidase (beta-gal)-fused MAPK (mol. wt 160 kDa), which occurred in response to stimuli, was completely blocked by these inhibitors. Moreover, while a dimerization-deficient mutant of MAPK was able to translocate to the nucleus upon stimulation, this mutant MAPK, when fused to beta-gal, became unable to enter the nucleus. These results suggest that monomeric and dimeric forms of MAPK enter the nucleus by passive diffusion and active transport mechanisms, respectively.\n" ], "offsets": [ [ 0, 1444 ] ] } ]

[ { "id": "PMID-10508167_T1", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 31, 38 ] ], "normalized": [] }, { "id": "PMID-10508167_T2", "type": "Gene_or_gene_product", "text": [ "MAP kinase" ], "offsets": [ [ 49, 59 ] ], "normalized": [] }, { "id": "PMID-10508167_T3", "type": "Gene_or_gene_product", "text": [ "mitogen-activated protein kinase" ], "offsets": [ [ 164, 196 ] ], "normalized": [] }, { "id": "PMID-10508167_T4", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 198, 202 ] ], "normalized": [] }, { "id": "PMID-10508167_T5", "type": "Gene_or_gene_product", "text": [ "ERK" ], "offsets": [ [ 218, 221 ] ], "normalized": [] }, { "id": "PMID-10508167_T6", "type": "Cellular_component", "text": [ "cytoplasm" ], "offsets": [ [ 245, 254 ] ], "normalized": [] }, { "id": "PMID-10508167_T7", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 262, 269 ] ], "normalized": [] }, { "id": "PMID-10508167_T8", "type": "Gene_or_gene_product", "text": [ "MAP kinase kinase" ], "offsets": [ [ 271, 288 ] ], "normalized": [] }, { "id": "PMID-10508167_T9", "type": "Gene_or_gene_product", "text": [ "MAPKK" ], "offsets": [ [ 290, 295 ] ], "normalized": [] }, { "id": "PMID-10508167_T10", "type": "Gene_or_gene_product", "text": [ "MEK" ], "offsets": [ [ 310, 313 ] ], "normalized": [] }, { "id": "PMID-10508167_T11", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 334, 341 ] ], "normalized": [] }, { "id": "PMID-10508167_T12", "type": "Cellular_component", "text": [ "cytoplasmic" ], "offsets": [ [ 373, 384 ] ], "normalized": [] }, { "id": "PMID-10508167_T13", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 395, 399 ] ], "normalized": [] }, { "id": "PMID-10508167_T14", "type": "Simple_chemical", "text": [ "tyrosine" ], "offsets": [ [ 428, 436 ] ], "normalized": [] }, { "id": "PMID-10508167_T15", "type": "Simple_chemical", "text": [ "Tyr190" ], "offsets": [ [ 438, 444 ] ], "normalized": [] }, { "id": "PMID-10508167_T16", "type": "Gene_or_gene_product", "text": [ "MPK1" ], "offsets": [ [ 456, 460 ] ], "normalized": [] }, { "id": "PMID-10508167_T17", "type": "Gene_or_gene_product", "text": [ "ERK2" ], "offsets": [ [ 461, 465 ] ], "normalized": [] }, { "id": "PMID-10508167_T18", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 486, 490 ] ], "normalized": [] }, { "id": "PMID-10508167_T19", "type": "Gene_or_gene_product", "text": [ "MAPKK" ], "offsets": [ [ 494, 499 ] ], "normalized": [] }, { "id": "PMID-10508167_T20", "type": "Complex", "text": [ "MAPKK-MAPK" ], "offsets": [ [ 556, 566 ] ], "normalized": [] }, { "id": "PMID-10508167_T21", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 637, 644 ] ], "normalized": [] }, { "id": "PMID-10508167_T22", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 662, 666 ] ], "normalized": [] }, { "id": "PMID-10508167_T23", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 686, 693 ] ], "normalized": [] }, { "id": "PMID-10508167_T24", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 703, 707 ] ], "normalized": [] }, { "id": "PMID-10508167_T25", "type": "Cellular_component", "text": [ "nuclear pore" ], "offsets": [ [ 718, 730 ] ], "normalized": [] }, { "id": "PMID-10508167_T26", "type": "Cellular_component", "text": [ "Nuclear" ], "offsets": [ [ 767, 774 ] ], "normalized": [] }, { "id": "PMID-10508167_T27", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 795, 799 ] ], "normalized": [] }, { "id": "PMID-10508167_T28", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 850, 854 ] ], "normalized": [] }, { "id": "PMID-10508167_T29", "type": "Gene_or_gene_product", "text": [ "agglutinin" ], "offsets": [ [ 898, 908 ] ], "normalized": [] }, { "id": "PMID-10508167_T30", "type": "Gene_or_gene_product", "text": [ "Ran" ], "offsets": [ [ 930, 933 ] ], "normalized": [] }, { "id": "PMID-10508167_T31", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 943, 950 ] ], "normalized": [] }, { "id": "PMID-10508167_T32", "type": "Gene_or_gene_product", "text": [ "beta-galactosidase" ], "offsets": [ [ 961, 979 ] ], "normalized": [] }, { "id": "PMID-10508167_T33", "type": "Gene_or_gene_product", "text": [ "beta-gal" ], "offsets": [ [ 981, 989 ] ], "normalized": [] }, { "id": "PMID-10508167_T34", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 997, 1001 ] ], "normalized": [] }, { "id": "PMID-10508167_T35", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 1155, 1159 ] ], "normalized": [] }, { "id": "PMID-10508167_T36", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 1191, 1198 ] ], "normalized": [] }, { "id": "PMID-10508167_T37", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 1229, 1233 ] ], "normalized": [] }, { "id": "PMID-10508167_T38", "type": "Gene_or_gene_product", "text": [ "beta-gal" ], "offsets": [ [ 1249, 1257 ] ], "normalized": [] }, { "id": "PMID-10508167_T39", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 1286, 1293 ] ], "normalized": [] }, { "id": "PMID-10508167_T40", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 1353, 1357 ] ], "normalized": [] }, { "id": "PMID-10508167_T41", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 1368, 1375 ] ], "normalized": [] } ]

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[ { "id": "PMID-10508167_1", "entity_ids": [ "PMID-10508167_T3", "PMID-10508167_T4", "PMID-10508167_T5" ] }, { "id": "PMID-10508167_2", "entity_ids": [ "PMID-10508167_T8", "PMID-10508167_T9", "PMID-10508167_T10" ] }, { "id": "PMID-10508167_3", "entity_ids": [ "PMID-10508167_T16", "PMID-10508167_T17" ] }, { "id": "PMID-10508167_4", "entity_ids": [ "PMID-10508167_T32", "PMID-10508167_T33" ] } ]

[]

[ { "id": "PMID-10508788__text", "type": "abstract", "text": [ "The structure of phosphorylated p38gamma is monomeric and reveals a conserved activation-loop conformation. \nBACKGROUND: Mitogen-activated protein (MAP) kinases mediate the cellular response to stimuli such as pro-inflammatory cytokines and environmental stress. P38gamma is a new member of the MAP kinase family, and is expressed at its highest levels in skeletal muscle. P38gamma is 63% identical in sequence to P38alpha. The structure of P38alpha MAP kinase has been determined in the apo, unphosphorylated, inactive form. The structures of apo unphosphorylated ERK2, a related MAP kinase, and apo phosphorylated ERK2 have also been determined. RESULTS: We have determined the structure of doubly phosphorylated P38gamma in complex with an ATP analog by X-ray crystallography. This is the first report of a structure of an activated kinase in the P38 subfamily, and the first bound to a nucleotide. P38gamma residue phosphoryl-Thr183 forms hydrogen bonds with five basic amino acids, and these interactions induce an interdomain rotation. The conformation of the activation loop of P38gamma is almost identical to that observed in the structure of activated ERK2. However, unlike ERK2, the crystal structure and solution studies indicate that activated P38gamma exists as a monomer. CONCLUSIONS: Interactions mediated by phosphoryl-Thr183 induce structural changes that direct the domains and active-site residues of P38gamma into a conformation consistent with catalytic activity. The conformation of the phosphorylation loop is likely to be similar in all activated MAP kinases, but not all activated MAP kinases form dimers.\n" ], "offsets": [ [ 0, 1631 ] ] } ]

[ { "id": "PMID-10508788_T1", "type": "Gene_or_gene_product", "text": [ "p38gamma" ], "offsets": [ [ 32, 40 ] ], "normalized": [] }, { "id": "PMID-10508788_T2", "type": "Gene_or_gene_product", "text": [ "Mitogen-activated protein (MAP) kinases" ], "offsets": [ [ 121, 160 ] ], "normalized": [] }, { "id": "PMID-10508788_T3", "type": "Gene_or_gene_product", "text": [ "P38gamma" ], "offsets": [ [ 263, 271 ] ], "normalized": [] }, { "id": "PMID-10508788_T4", "type": "Gene_or_gene_product", "text": [ "MAP kinase" ], "offsets": [ [ 295, 305 ] ], "normalized": [] }, { "id": "PMID-10508788_T5", "type": "Gene_or_gene_product", "text": [ "P38gamma" ], "offsets": [ [ 373, 381 ] ], "normalized": [] }, { "id": "PMID-10508788_T6", "type": "Gene_or_gene_product", "text": [ "P38alpha" ], "offsets": [ [ 414, 422 ] ], "normalized": [] }, { "id": "PMID-10508788_T7", "type": "Gene_or_gene_product", "text": [ "P38alpha MAP kinase" ], "offsets": [ [ 441, 460 ] ], "normalized": [] }, { "id": "PMID-10508788_T8", "type": "Gene_or_gene_product", "text": [ "ERK2" ], "offsets": [ [ 565, 569 ] ], "normalized": [] }, { "id": "PMID-10508788_T9", "type": "Gene_or_gene_product", "text": [ "MAP kinase" ], "offsets": [ [ 581, 591 ] ], "normalized": [] }, { "id": "PMID-10508788_T10", "type": "Gene_or_gene_product", "text": [ "ERK2" ], "offsets": [ [ 616, 620 ] ], "normalized": [] }, { "id": "PMID-10508788_T11", "type": "Gene_or_gene_product", "text": [ "P38gamma" ], "offsets": [ [ 715, 723 ] ], "normalized": [] }, { "id": "PMID-10508788_T12", "type": "Simple_chemical", "text": [ "ATP" ], "offsets": [ [ 743, 746 ] ], "normalized": [] }, { "id": "PMID-10508788_T13", "type": "Gene_or_gene_product", "text": [ "P38" ], "offsets": [ [ 850, 853 ] ], "normalized": [] }, { "id": "PMID-10508788_T14", "type": "Gene_or_gene_product", "text": [ "P38gamma" ], "offsets": [ [ 902, 910 ] ], "normalized": [] }, { "id": "PMID-10508788_T15", "type": "Simple_chemical", "text": [ "Thr183" ], "offsets": [ [ 930, 936 ] ], "normalized": [] }, { "id": "PMID-10508788_T16", "type": "Simple_chemical", "text": [ "hydrogen" ], "offsets": [ [ 943, 951 ] ], "normalized": [] }, { "id": "PMID-10508788_T17", "type": "Gene_or_gene_product", "text": [ "P38gamma" ], "offsets": [ [ 1085, 1093 ] ], "normalized": [] }, { "id": "PMID-10508788_T18", "type": "Gene_or_gene_product", "text": [ "ERK2" ], "offsets": [ [ 1161, 1165 ] ], "normalized": [] }, { "id": "PMID-10508788_T19", "type": "Gene_or_gene_product", "text": [ "ERK2" ], "offsets": [ [ 1183, 1187 ] ], "normalized": [] }, { "id": "PMID-10508788_T20", "type": "Gene_or_gene_product", "text": [ "P38gamma" ], "offsets": [ [ 1256, 1264 ] ], "normalized": [] }, { "id": "PMID-10508788_T21", "type": "Simple_chemical", "text": [ "Thr183" ], "offsets": [ [ 1335, 1341 ] ], "normalized": [] }, { "id": "PMID-10508788_T22", "type": "Gene_or_gene_product", "text": [ "P38gamma" ], "offsets": [ [ 1420, 1428 ] ], "normalized": [] }, { "id": "PMID-10508788_T23", "type": "Gene_or_gene_product", "text": [ "MAP kinases" ], "offsets": [ [ 1571, 1582 ] ], "normalized": [] }, { "id": "PMID-10508788_T24", "type": "Gene_or_gene_product", "text": [ "MAP kinases" ], "offsets": [ [ 1606, 1617 ] ], "normalized": [] } ]

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[]

[]

[ { "id": "PMID-10517323__text", "type": "abstract", "text": [ "Regulated nuclear localisation of the yeast transcription factor Ace2p controls expression of chitinase (CTS1) in Saccharomyces cerevisiae. \nThe yeast transcription factor Ace2p regulates expression of the chitinase gene CTS1 in a cell cycle-dependent manner. Nuclear localisation of Ace2p is restricted to late M and early G phases of the mitotic cell cycle. We show here that this nuclear localisation is directly associated with regulation of CTS1 expression. Using a version of Ace2p tagged with a c-myc epitope, we show that the protein is excluded from the nucleus of cells during most phases of the mitotic cell cycle. A mutant derivative in which one threonine and two serine residues, which are candidate phosphorylation sites, were replaced by alanine (to mimic constitutive dephosphorylation) is localised in the nucleus throughout the cell cycle. The mechanism of localisation of Ace2p therefore involves regulation of its phosphorylation state, and closely resembles that used by the homologous transcription factor Swi5p. The wild-type Ace2 protein associates with Cdc28p in vivo, suggesting this may be the kinase that mediates the phosphorylation event. The stability of the protein is greatly reduced in a mutant that is constitutively localised to the nucleus, but is restored in a deletion derivative which remains in the cytoplasm. Ace2p is therefore controlled throughout the cell cycle at three levels: transcription, nuclear localisation, and proteolysis.\n" ], "offsets": [ [ 0, 1479 ] ] } ]

[ { "id": "PMID-10517323_T1", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 10, 17 ] ], "normalized": [] }, { "id": "PMID-10517323_T2", "type": "Gene_or_gene_product", "text": [ "Ace2p" ], "offsets": [ [ 65, 70 ] ], "normalized": [] }, { "id": "PMID-10517323_T3", "type": "Gene_or_gene_product", "text": [ "chitinase" ], "offsets": [ [ 94, 103 ] ], "normalized": [] }, { "id": "PMID-10517323_T4", "type": "Gene_or_gene_product", "text": [ "CTS1" ], "offsets": [ [ 105, 109 ] ], "normalized": [] }, { "id": "PMID-10517323_T5", "type": "Gene_or_gene_product", "text": [ "Ace2p" ], "offsets": [ [ 172, 177 ] ], "normalized": [] }, { "id": "PMID-10517323_T6", "type": "Gene_or_gene_product", "text": [ "chitinase" ], "offsets": [ [ 206, 215 ] ], "normalized": [] }, { "id": "PMID-10517323_T7", "type": "Gene_or_gene_product", "text": [ "CTS1" ], "offsets": [ [ 221, 225 ] ], "normalized": [] }, { "id": "PMID-10517323_T8", "type": "Cellular_component", "text": [ "Nuclear" ], "offsets": [ [ 260, 267 ] ], "normalized": [] }, { "id": "PMID-10517323_T9", "type": "Gene_or_gene_product", "text": [ "Ace2p" ], "offsets": [ [ 284, 289 ] ], "normalized": [] }, { "id": "PMID-10517323_T10", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 383, 390 ] ], "normalized": [] }, { "id": "PMID-10517323_T11", "type": "Gene_or_gene_product", "text": [ "CTS1" ], "offsets": [ [ 446, 450 ] ], "normalized": [] }, { "id": "PMID-10517323_T12", "type": "Gene_or_gene_product", "text": [ "Ace2p" ], "offsets": [ [ 482, 487 ] ], "normalized": [] }, { "id": "PMID-10517323_T13", "type": "Gene_or_gene_product", "text": [ "c-myc" ], "offsets": [ [ 502, 507 ] ], "normalized": [] }, { "id": "PMID-10517323_T14", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 563, 570 ] ], "normalized": [] }, { "id": "PMID-10517323_T15", "type": "Simple_chemical", "text": [ "threonine" ], "offsets": [ [ 659, 668 ] ], "normalized": [] }, { "id": "PMID-10517323_T16", "type": "Simple_chemical", "text": [ "serine" ], "offsets": [ [ 677, 683 ] ], "normalized": [] }, { "id": "PMID-10517323_T17", "type": "Simple_chemical", "text": [ "alanine" ], "offsets": [ [ 754, 761 ] ], "normalized": [] }, { "id": "PMID-10517323_T18", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 824, 831 ] ], "normalized": [] }, { "id": "PMID-10517323_T19", "type": "Gene_or_gene_product", "text": [ "Ace2p" ], "offsets": [ [ 892, 897 ] ], "normalized": [] }, { "id": "PMID-10517323_T20", "type": "Gene_or_gene_product", "text": [ "Swi5p" ], "offsets": [ [ 1029, 1034 ] ], "normalized": [] }, { "id": "PMID-10517323_T21", "type": "Gene_or_gene_product", "text": [ "Ace2" ], "offsets": [ [ 1050, 1054 ] ], "normalized": [] }, { "id": "PMID-10517323_T22", "type": "Gene_or_gene_product", "text": [ "Cdc28p" ], "offsets": [ [ 1079, 1085 ] ], "normalized": [] }, { "id": "PMID-10517323_T23", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 1270, 1277 ] ], "normalized": [] }, { "id": "PMID-10517323_T24", "type": "Cellular_component", "text": [ "cytoplasm" ], "offsets": [ [ 1341, 1350 ] ], "normalized": [] }, { "id": "PMID-10517323_T25", "type": "Gene_or_gene_product", "text": [ "Ace2p" ], "offsets": [ [ 1352, 1357 ] ], "normalized": [] }, { "id": "PMID-10517323_T26", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 1440, 1447 ] ], "normalized": [] } ]

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"role": "Cause", "ref_id": "PMID-10517323_T5" }, { "role": "Theme", "ref_id": "PMID-10517323_E7" } ] }, { "id": "PMID-10517323_E6", "type": "Regulation", "trigger": { "text": [ "regulates" ], "offsets": [ [ 178, 187 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10517323_T5" }, { "role": "Theme", "ref_id": "PMID-10517323_E8" } ] }, { "id": "PMID-10517323_E7", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 188, 198 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10517323_T6" } ] }, { "id": "PMID-10517323_E8", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 188, 198 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10517323_T7" } ] }, { "id": "PMID-10517323_E9", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 231, 241 ] ] }, "arguments": [] }, { "id": "PMID-10517323_E10", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 242, 251 ] ] }, 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{ "id": "PMID-10517323_E15", "type": "Regulation", "trigger": { "text": [ "associated" ], "offsets": [ [ 416, 426 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10517323_E14" }, { "role": "Theme", "ref_id": "PMID-10517323_E16" } ] }, { "id": "PMID-10517323_E16", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 432, 442 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10517323_E17" } ] }, { "id": "PMID-10517323_E17", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 451, 461 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10517323_T11" } ] }, { "id": "PMID-10517323_E18", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 614, 624 ] ] }, "arguments": [] }, { "id": "PMID-10517323_E19", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 847, 857 ] ] }, "arguments": [] }, { "id": "PMID-10517323_E20", "type": "Localization", "trigger": { "text": [ "localisation" ], "offsets": [ [ 876, 888 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10517323_T19" } ] }, { "id": "PMID-10517323_E21", "type": "Regulation", "trigger": { "text": [ "involves" ], "offsets": [ [ 908, 916 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10517323_E20" }, { "role": "Theme", "ref_id": "PMID-10517323_E22" } ] }, { "id": "PMID-10517323_E22", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 917, 927 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10517323_E23" } ] }, { "id": "PMID-10517323_E23", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 935, 950 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10517323_T19" } ] }, { "id": "PMID-10517323_E24", "type": "Regulation", "trigger": { "text": [ "associates" ], "offsets": [ [ 1063, 1073 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10517323_T21" }, { "role": "Theme", "ref_id": "PMID-10517323_T22" } ] }, { "id": "PMID-10517323_E25", "type": "Regulation", "trigger": { "text": [ "controlled" ], "offsets": [ [ 1371, 1381 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10517323_T25" } ] }, { "id": "PMID-10517323_E26", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 1397, 1407 ] ] }, "arguments": [] }, { "id": "PMID-10517323_E27", "type": "Localization", "trigger": { "text": [ "localisation" ], "offsets": [ [ 1448, 1460 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-10517323_T26" }, { "role": "Theme", "ref_id": "PMID-10517323_T25" } ] }, { "id": "PMID-10517323_E28", "type": "Degradation", "trigger": { "text": [ "proteolysis" ], "offsets": [ [ 1466, 1477 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10517323_T25" } ] } ]

[]

[]

[ { "id": "PMID-10523842__text", "type": "abstract", "text": [ "Role of two upstream open reading frames in the translational control of oncogene mdm2. \nOverexpression of oncoprotein MDM2 has been found in a significant number of human soft tissue tumors. In a subset of these tumors, overexpression is a result of enhanced translation of mdm2 mRNA. There are two transcripts from the mdm2 gene that differ only in their 5' leaders: a long form (L-mdm2) and a short form (S-mdm2) that arise from the use of different promoters. L-mdm2 mRNA contains two upstream open reading frames (uORFs) and this mRNA was loaded with ribosomes inefficiently in comparison with S-mdm2. The 5' leader of L-mdm2 was sufficient to transfer translational repression to a reporter gene and the two uORFs acted synergistically to achieve full suppression. In contrast, the 5' leader of S-mdm2 allowed efficient translation of an attached reporter gene in the tumor cells. These results are consistent with a model in which overexpression of MDM2 in certain tumors results from a change in mRNA structure due to a switch in promoter usage.\n" ], "offsets": [ [ 0, 1054 ] ] } ]

[ { "id": "PMID-10523842_T1", "type": "Gene_or_gene_product", "text": [ "mdm2" ], "offsets": [ [ 82, 86 ] ], "normalized": [] }, { "id": "PMID-10523842_T2", "type": "Gene_or_gene_product", "text": [ "MDM2" ], "offsets": [ [ 119, 123 ] ], "normalized": [] }, { "id": "PMID-10523842_T3", "type": "Gene_or_gene_product", "text": [ "mdm2" ], "offsets": [ [ 275, 279 ] ], "normalized": [] }, { "id": "PMID-10523842_T4", "type": "Gene_or_gene_product", "text": [ "mdm2" ], "offsets": [ [ 321, 325 ] ], "normalized": [] }, { "id": "PMID-10523842_T5", "type": "Gene_or_gene_product", "text": [ "L-mdm2" ], "offsets": [ [ 382, 388 ] ], "normalized": [] }, { "id": "PMID-10523842_T6", "type": "Gene_or_gene_product", "text": [ "S-mdm2" ], "offsets": [ [ 408, 414 ] ], "normalized": [] }, { "id": "PMID-10523842_T7", "type": "Gene_or_gene_product", "text": [ "L-mdm2" ], "offsets": [ [ 464, 470 ] ], "normalized": [] }, { "id": "PMID-10523842_T8", "type": "Gene_or_gene_product", "text": [ "S-mdm2" ], "offsets": [ [ 599, 605 ] ], "normalized": [] }, { "id": "PMID-10523842_T9", "type": "Gene_or_gene_product", "text": [ "L-mdm2" ], "offsets": [ [ 624, 630 ] ], "normalized": [] }, { "id": "PMID-10523842_T10", "type": "Gene_or_gene_product", "text": [ "S-mdm2" ], "offsets": [ [ 801, 807 ] ], "normalized": [] }, { "id": "PMID-10523842_T11", "type": "Gene_or_gene_product", "text": [ "MDM2" ], "offsets": [ [ 956, 960 ] ], "normalized": [] } ]

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[]

[]

[ { "id": "PMID-10542212__text", "type": "abstract", "text": [ "Interleukin-10 signaling blocks inhibitor of kappaB kinase activity and nuclear factor kappaB DNA binding. \nThe transcription factor nuclear factor kappaB (NF-kappaB) coordinates the activation of numerous genes in response to pathogens and proinflammatory cytokines and is, therefore, pivotal in the development of acute and chronic inflammatory diseases. In its inactive state, NF-kappaB is constitutively present in the cytoplasm as a p50-p65 heterodimer bound to its inhibitory protein IkappaB. Proinflammatory cytokines, such as tumor necrosis factor (TNF), activate NF-kappaB by stimulating the activity of the IkappaB kinases (IKKs) which phosphorylate IkappaBalpha on serine residues 32 and 36, targeting it for rapid degradation by the 26 S proteasome. This enables the release and nuclear translocation of the NF-kappaB complex and activation of gene transcription. Interleukin-10 (IL-10) is a pleiotropic cytokine that controls inflammatory processes by suppressing the production of proinflammatory cytokines which are known to be transcriptionally controlled by NF-kappaB. Conflicting data exists on the effects of IL-10 on TNF- and LPS-induced NF-kappaB activity in human monocytes and the molecular mechanisms involved have not been elucidated. In this study, we show that IL-10 functions to block NF-kappaB activity at two levels: 1) through the suppression of IKK activity and 2) through the inhibition of NF-kappaB DNA binding activity. This is the first evidence of an anti-inflammatory protein inhibiting IKK activity and demonstrates that IKK is a logical target for blocking inflammatory diseases.\n" ], "offsets": [ [ 0, 1620 ] ] } ]

[ { "id": "PMID-10542212_T1", "type": "Gene_or_gene_product", "text": [ "Interleukin-10" ], "offsets": [ [ 0, 14 ] ], "normalized": [] }, { "id": "PMID-10542212_T2", "type": "Complex", "text": [ "inhibitor of kappaB kinase" ], "offsets": [ [ 32, 58 ] ], "normalized": [] }, { "id": "PMID-10542212_T3", "type": "Complex", "text": [ "nuclear factor kappaB" ], "offsets": [ [ 72, 93 ] ], "normalized": [] }, { "id": "PMID-10542212_T4", "type": "Complex", "text": [ "nuclear factor kappaB" ], "offsets": [ [ 133, 154 ] ], "normalized": [] }, { "id": "PMID-10542212_T5", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 156, 165 ] ], "normalized": [] }, { "id": "PMID-10542212_T6", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 380, 389 ] ], "normalized": [] }, { "id": "PMID-10542212_T7", "type": "Cellular_component", "text": [ "cytoplasm" ], "offsets": [ [ 423, 432 ] ], "normalized": [] }, { "id": "PMID-10542212_T8", "type": "Complex", "text": [ "p50-p65" ], "offsets": [ [ 438, 445 ] ], "normalized": [] }, { "id": "PMID-10542212_T9", "type": "Gene_or_gene_product", "text": [ "IkappaB" ], "offsets": [ [ 490, 497 ] ], "normalized": [] }, { "id": "PMID-10542212_T10", "type": "Gene_or_gene_product", "text": [ "tumor necrosis factor" ], "offsets": [ [ 534, 555 ] ], "normalized": [] }, { "id": "PMID-10542212_T11", "type": "Gene_or_gene_product", "text": [ "TNF" ], "offsets": [ [ 557, 560 ] ], "normalized": [] }, { "id": "PMID-10542212_T12", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 572, 581 ] ], "normalized": [] }, { "id": "PMID-10542212_T13", "type": "Complex", "text": [ "IkappaB kinases" ], "offsets": [ [ 617, 632 ] ], "normalized": [] }, { "id": "PMID-10542212_T14", "type": "Complex", "text": [ "IKKs" ], "offsets": [ [ 634, 638 ] ], "normalized": [] }, { "id": "PMID-10542212_T15", "type": "Gene_or_gene_product", "text": [ "IkappaBalpha" ], "offsets": [ [ 660, 672 ] ], "normalized": [] }, { "id": "PMID-10542212_T16", "type": "Simple_chemical", "text": [ "serine residues 32" ], "offsets": [ [ 676, 694 ] ], "normalized": [] }, { "id": "PMID-10542212_T17", "type": "Simple_chemical", "text": [ "36" ], "offsets": [ [ 699, 701 ] ], "normalized": [] }, { "id": "PMID-10542212_T18", "type": "Cellular_component", "text": [ "26 S proteasome" ], "offsets": [ [ 745, 760 ] ], "normalized": [] }, { "id": "PMID-10542212_T19", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 791, 798 ] ], "normalized": [] }, { "id": "PMID-10542212_T20", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 820, 829 ] ], "normalized": [] }, { "id": "PMID-10542212_T21", "type": "Gene_or_gene_product", "text": [ "Interleukin-10" ], "offsets": [ [ 876, 890 ] ], "normalized": [] }, { "id": "PMID-10542212_T22", "type": "Gene_or_gene_product", "text": [ "IL-10" ], "offsets": [ [ 892, 897 ] ], "normalized": [] }, { "id": "PMID-10542212_T23", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1075, 1084 ] ], "normalized": [] }, { "id": "PMID-10542212_T24", "type": "Gene_or_gene_product", "text": [ "IL-10" ], "offsets": [ [ 1128, 1133 ] ], "normalized": [] }, { "id": "PMID-10542212_T25", "type": "Gene_or_gene_product", "text": [ "TNF" ], "offsets": [ [ 1137, 1140 ] ], "normalized": [] }, { "id": "PMID-10542212_T26", "type": "Simple_chemical", "text": [ "LPS" ], "offsets": [ [ 1146, 1149 ] ], "normalized": [] }, { "id": "PMID-10542212_T27", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1158, 1167 ] ], "normalized": [] }, { "id": "PMID-10542212_T28", "type": "Gene_or_gene_product", "text": [ "IL-10" ], "offsets": [ [ 1288, 1293 ] ], "normalized": [] }, { "id": "PMID-10542212_T29", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1313, 1322 ] ], "normalized": [] }, { "id": "PMID-10542212_T30", "type": "Complex", "text": [ "IKK" ], "offsets": [ [ 1377, 1380 ] ], "normalized": [] }, { "id": "PMID-10542212_T31", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1423, 1432 ] ], "normalized": [] }, { "id": "PMID-10542212_T32", "type": "Complex", "text": [ "IKK" ], "offsets": [ [ 1525, 1528 ] ], "normalized": [] }, { "id": "PMID-10542212_T33", "type": "Complex", "text": [ "IKK" ], "offsets": [ [ 1560, 1563 ] ], "normalized": [] } ]

[ { "id": "PMID-10542212_E1", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 15, 24 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-10542212_T1" } ] }, { "id": "PMID-10542212_E2", "type": "Negative_regulation", "trigger": { "text": [ "blocks" ], "offsets": [ [ 25, 31 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10542212_E1" }, { "role": "Theme", "ref_id": "PMID-10542212_T2" } ] }, { "id": "PMID-10542212_E3", "type": "Negative_regulation", "trigger": { "text": [ "blocks" ], "offsets": [ [ 25, 31 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10542212_E1" }, { "role": "Theme", "ref_id": "PMID-10542212_E4" } ] }, { "id": "PMID-10542212_E4", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 98, 105 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10542212_T3" } ] }, { "id": "PMID-10542212_E5", "type": "Inactivation", "trigger": { "text": [ "inactive" ], "offsets": [ [ 364, 372 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10542212_T6" } ] }, { "id": "PMID-10542212_E6", "type": "Localization", "trigger": { "text": [ "present" ], "offsets": [ [ 408, 415 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10542212_T6" }, { "role": "AtLoc", "ref_id": "PMID-10542212_T7" } ] }, { "id": "PMID-10542212_E7", "type": "Binding", "trigger": { "text": [ "bound" ], "offsets": [ [ 458, 463 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10542212_T8" }, { "role": "Theme", "ref_id": "PMID-10542212_T9" } ] }, { "id": "PMID-10542212_E8", "type": "Positive_regulation", "trigger": { "text": [ "activate" ], "offsets": [ [ 563, 571 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10542212_T12" }, { "role": "Cause", "ref_id": "PMID-10542212_T11" } ] }, { "id": "PMID-10542212_E9", "type": "Positive_regulation", "trigger": { "text": [ "stimulating" ], "offsets": [ [ 585, 596 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10542212_T14" }, { "role": "Cause", "ref_id": "PMID-10542212_E8" } ] }, { "id": "PMID-10542212_E10", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylate" ], "offsets": [ [ 646, 659 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10542212_T14" }, { "role": "Theme", "ref_id": "PMID-10542212_T15" }, { "role": "Site", "ref_id": "PMID-10542212_T16" } ] }, { "id": "PMID-10542212_E11", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylate" ], "offsets": [ [ 646, 659 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10542212_T14" }, { "role": "Theme", "ref_id": "PMID-10542212_T15" }, { "role": "Site", "ref_id": "PMID-10542212_T17" } ] }, { "id": "PMID-10542212_E12", "type": "Regulation", "trigger": { "text": [ "targeting" ], "offsets": [ [ 703, 712 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10542212_E14" }, { "role": "Cause", "ref_id": "PMID-10542212_E11" } ] }, { "id": "PMID-10542212_E13", "type": "Regulation", "trigger": { "text": [ "targeting" ], "offsets": [ [ 703, 712 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10542212_E14" }, { "role": "Cause", "ref_id": "PMID-10542212_E10" } ] }, { "id": "PMID-10542212_E14", "type": "Degradation", "trigger": { "text": [ "degradation" ], "offsets": [ [ 726, 737 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10542212_T15" } ] }, { "id": "PMID-10542212_E15", "type": "Dissociation", "trigger": { "text": [ "release" ], "offsets": [ [ 779, 786 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10542212_T20" } ] }, { "id": "PMID-10542212_E16", "type": "Transport", "trigger": { "text": [ "translocation" ], "offsets": [ [ 799, 812 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10542212_T20" }, { "role": "FromLoc", "ref_id": "PMID-10542212_T19" } ] }, { "id": "PMID-10542212_E17", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 1117, 1124 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10542212_T24" }, { "role": "Theme", "ref_id": "PMID-10542212_T25" } ] }, { "id": "PMID-10542212_E18", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1150, 1157 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10542212_T26" }, { "role": "Theme", "ref_id": "PMID-10542212_T27" } ] }, { "id": "PMID-10542212_E19", "type": "Negative_regulation", "trigger": { "text": [ "block" ], "offsets": [ [ 1307, 1312 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10542212_T29" }, { "role": "Cause", "ref_id": "PMID-10542212_T28" } ] }, { "id": "PMID-10542212_E20", "type": "Negative_regulation", "trigger": { "text": [ "block" ], "offsets": [ [ 1307, 1312 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10542212_T29" }, { "role": "Cause", "ref_id": "PMID-10542212_E22" } ] }, { "id": "PMID-10542212_E21", "type": "Negative_regulation", "trigger": { "text": [ "block" ], "offsets": [ [ 1307, 1312 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10542212_T29" }, { "role": "Cause", "ref_id": "PMID-10542212_E23" } ] }, { "id": "PMID-10542212_E22", "type": "Negative_regulation", "trigger": { "text": [ "suppression" ], "offsets": [ [ 1362, 1373 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10542212_T30" } ] }, { "id": "PMID-10542212_E23", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1409, 1419 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10542212_E24" } ] }, { "id": "PMID-10542212_E24", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1437, 1444 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10542212_T31" } ] }, { "id": "PMID-10542212_E25", "type": "Negative_regulation", "trigger": { "text": [ "inhibiting" ], "offsets": [ [ 1514, 1524 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10542212_T32" } ] } ]

[ { "id": "PMID-10542212_1", "entity_ids": [ "PMID-10542212_T4", "PMID-10542212_T5" ] }, { "id": "PMID-10542212_2", "entity_ids": [ "PMID-10542212_T10", "PMID-10542212_T11" ] }, { "id": "PMID-10542212_3", "entity_ids": [ "PMID-10542212_T13", "PMID-10542212_T14" ] }, { "id": "PMID-10542212_4", "entity_ids": [ "PMID-10542212_T21", "PMID-10542212_T22" ] } ]

[]

[ { "id": "PMID-10556521__text", "type": "abstract", "text": [ "Cloning and functional characterization of the human sodium-dependent vitamin C transporters hSVCT1 and hSVCT2. \nTwo sodium-dependent vitamin C transporters, hSVCT1 and hSVCT2, were cloned from a human kidney cDNA library. hSVCT1 had a 1797 bp open reading frame encoding a 598 amino acid polypeptide. The 1953 bp open reading frame of hSVCT2 encoded a 650 amino acid polypeptide. Using a Xenopus laevis oocyte expression system, both transporters were functionally expressed. By Eadie-Hofstee transformation the apparent K(m) of hSVCT1 for ascorbate was 252.0 microM and of hSVCT2 for ascorbate was 21.3 microM. Both transporters were sodium-dependent and did not transport dehydroascorbic acid. Incubation of oocytes expressing either transporter with phorbol 12-myristate 13-acetate (PMA) inhibited ascorbate transport activity. Availability of the human transporter clones may facilitate new strategies for determining vitamin C intake.\n" ], "offsets": [ [ 0, 941 ] ] } ]

[ { "id": "PMID-10556521_T1", "type": "Simple_chemical", "text": [ "sodium" ], "offsets": [ [ 53, 59 ] ], "normalized": [] }, { "id": "PMID-10556521_T2", "type": "Simple_chemical", "text": [ "vitamin C" ], "offsets": [ [ 70, 79 ] ], "normalized": [] }, { "id": "PMID-10556521_T3", "type": "Gene_or_gene_product", "text": [ "hSVCT1" ], "offsets": [ [ 93, 99 ] ], "normalized": [] }, { "id": "PMID-10556521_T4", "type": "Gene_or_gene_product", "text": [ "hSVCT2" ], "offsets": [ [ 104, 110 ] ], "normalized": [] }, { "id": "PMID-10556521_T5", "type": "Simple_chemical", "text": [ "sodium" ], "offsets": [ [ 117, 123 ] ], "normalized": [] }, { "id": "PMID-10556521_T6", "type": "Simple_chemical", "text": [ "vitamin C" ], "offsets": [ [ 134, 143 ] ], "normalized": [] }, { "id": "PMID-10556521_T7", "type": "Gene_or_gene_product", "text": [ "hSVCT1" ], "offsets": [ [ 158, 164 ] ], "normalized": [] }, { "id": "PMID-10556521_T8", "type": "Gene_or_gene_product", "text": [ "hSVCT2" ], "offsets": [ [ 169, 175 ] ], "normalized": [] }, { "id": "PMID-10556521_T9", "type": "Gene_or_gene_product", "text": [ "hSVCT1" ], "offsets": [ [ 223, 229 ] ], "normalized": [] }, { "id": "PMID-10556521_T10", "type": "Gene_or_gene_product", "text": [ "hSVCT2" ], "offsets": [ [ 336, 342 ] ], "normalized": [] }, { "id": "PMID-10556521_T11", "type": "Gene_or_gene_product", "text": [ "hSVCT1" ], "offsets": [ [ 530, 536 ] ], "normalized": [] }, { "id": "PMID-10556521_T12", "type": "Simple_chemical", "text": [ "ascorbate" ], "offsets": [ [ 541, 550 ] ], "normalized": [] }, { "id": "PMID-10556521_T13", "type": "Gene_or_gene_product", "text": [ "hSVCT2" ], "offsets": [ [ 575, 581 ] ], "normalized": [] }, { "id": "PMID-10556521_T14", "type": "Simple_chemical", "text": [ "ascorbate" ], "offsets": [ [ 586, 595 ] ], "normalized": [] }, { "id": "PMID-10556521_T15", "type": "Simple_chemical", "text": [ "sodium" ], "offsets": [ [ 636, 642 ] ], "normalized": [] }, { "id": "PMID-10556521_T16", "type": "Simple_chemical", "text": [ "dehydroascorbic acid" ], "offsets": [ [ 675, 695 ] ], "normalized": [] }, { "id": "PMID-10556521_T17", "type": "Simple_chemical", "text": [ "phorbol 12-myristate 13-acetate" ], "offsets": [ [ 754, 785 ] ], "normalized": [] }, { "id": "PMID-10556521_T18", "type": "Simple_chemical", "text": [ "PMA" ], "offsets": [ [ 787, 790 ] ], "normalized": [] }, { "id": "PMID-10556521_T19", "type": "Simple_chemical", "text": [ "ascorbate" ], "offsets": [ [ 802, 811 ] ], "normalized": [] }, { "id": "PMID-10556521_T20", "type": "Simple_chemical", "text": [ "vitamin C" ], "offsets": [ [ 923, 932 ] ], "normalized": [] } ]

[ { "id": "PMID-10556521_E1", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 60, 69 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10556521_T1" }, { "role": "Theme", "ref_id": "PMID-10556521_E2" } ] }, { "id": "PMID-10556521_E2", "type": "Transport", "trigger": { "text": [ "transporters" ], "offsets": [ [ 80, 92 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10556521_T2" } ] }, { "id": "PMID-10556521_E3", "type": "Positive_regulation", "trigger": { "text": [ "transporters" ], "offsets": [ [ 80, 92 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10556521_E2" }, { "role": "Cause", "ref_id": "PMID-10556521_T3" } ] }, { "id": "PMID-10556521_E4", "type": "Positive_regulation", "trigger": { "text": [ "transporters" ], "offsets": [ [ 80, 92 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10556521_E2" }, { "role": "Cause", "ref_id": "PMID-10556521_T4" } ] }, { "id": "PMID-10556521_E5", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 124, 133 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10556521_T5" }, { "role": "Theme", "ref_id": "PMID-10556521_E6" } ] }, { "id": "PMID-10556521_E6", "type": "Transport", "trigger": { "text": [ "transporters" ], "offsets": [ [ 144, 156 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10556521_T6" } ] }, { "id": "PMID-10556521_E7", "type": "Positive_regulation", "trigger": { "text": [ "transporters" ], "offsets": [ [ 144, 156 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10556521_E6" }, { "role": "Cause", "ref_id": "PMID-10556521_T7" } ] }, { "id": "PMID-10556521_E8", "type": "Positive_regulation", "trigger": { "text": [ "transporters" ], "offsets": [ [ 144, 156 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10556521_E6" }, { "role": "Cause", "ref_id": "PMID-10556521_T8" } ] }, { "id": "PMID-10556521_E9", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 643, 652 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10556521_T15" }, { "role": "Theme", "ref_id": "PMID-10556521_T11" } ] }, { "id": "PMID-10556521_E10", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 643, 652 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10556521_T15" }, { "role": "Theme", "ref_id": "PMID-10556521_T13" } ] }, { "id": "PMID-10556521_E11", "type": "Transport", "trigger": { "text": [ "transport" ], "offsets": [ [ 665, 674 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10556521_T16" } ] }, { "id": "PMID-10556521_E12", "type": "Positive_regulation", "trigger": { "text": [ "transport" ], "offsets": [ [ 665, 674 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10556521_E11" }, { "role": "Cause", "ref_id": "PMID-10556521_T11" } ] }, { "id": "PMID-10556521_E13", "type": "Positive_regulation", "trigger": { "text": [ "transport" ], "offsets": [ [ 665, 674 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10556521_E11" }, { "role": "Cause", "ref_id": "PMID-10556521_T13" } ] }, { "id": "PMID-10556521_E14", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 792, 801 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10556521_E15" }, { "role": "Cause", "ref_id": "PMID-10556521_T18" } ] }, { "id": "PMID-10556521_E15", "type": "Transport", "trigger": { "text": [ "transport" ], "offsets": [ [ 812, 821 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10556521_T19" } ] }, { "id": "PMID-10556521_E16", "type": "Transport", "trigger": { "text": [ "intake" ], "offsets": [ [ 933, 939 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10556521_T20" } ] } ]

[ { "id": "PMID-10556521_1", "entity_ids": [ "PMID-10556521_T17", "PMID-10556521_T18" ] } ]

[]

[ { "id": "PMID-10567559__text", "type": "abstract", "text": [ "PDK1 homologs activate the Pkc1-mitogen-activated protein kinase pathway in yeast. \nPDK1 (phosphoinositide-dependent kinase 1) is a mammalian growth factor-regulated serine/threonine kinase. Using a genetic selection based on a mutant form of the yeast MAP kinase kinase Ste7, we isolated a gene, PKH2, encoding a structurally and functionally conserved yeast homolog of PDK1. Yeast cells lacking both PKH2 and PKH1, encoding another PDK1 homolog, were nonviable, indicating that Pkh1 and Pkh2 share an essential function. A temperature-sensitive mutant, pkh1(D398G) pkh2, was phenotypically similar to mutants defective in the Pkc1-mitogen-activated protein kinase (MAPK) pathway. Genetic epistasis analyses, the phosphorylation of Pkc1 by Pkh2 in vitro, and reduced Pkc1 activity in the pkh1(D398G) pkh2 mutant indicate that Pkh functions upstream of Pkc1. The Pkh2 phosphorylation site in Pkc1 (Thr-983) is part of a conserved PDK1 target motif and essential for Pkc1 function. Thus, the yeast PDK1 homologs activate Pkc1 and the Pkc1-effector MAPK pathway.\n" ], "offsets": [ [ 0, 1061 ] ] } ]

[ { "id": "PMID-10567559_T1", "type": "Gene_or_gene_product", "text": [ "PDK1" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-10567559_T2", "type": "Gene_or_gene_product", "text": [ "Pkc1" ], "offsets": [ [ 27, 31 ] ], "normalized": [] }, { "id": "PMID-10567559_T3", "type": "Gene_or_gene_product", "text": [ "mitogen-activated protein kinase" ], "offsets": [ [ 32, 64 ] ], "normalized": [] }, { "id": "PMID-10567559_T4", "type": "Gene_or_gene_product", "text": [ "PDK1" ], "offsets": [ [ 84, 88 ] ], "normalized": [] }, { "id": "PMID-10567559_T5", "type": "Gene_or_gene_product", "text": [ "phosphoinositide-dependent kinase 1" ], "offsets": [ [ 90, 125 ] ], "normalized": [] }, { "id": "PMID-10567559_T6", "type": "Simple_chemical", "text": [ "serine" ], "offsets": [ [ 166, 172 ] ], "normalized": [] }, { "id": "PMID-10567559_T7", "type": "Simple_chemical", "text": [ "threonine" ], "offsets": [ [ 173, 182 ] ], "normalized": [] }, { "id": "PMID-10567559_T8", "type": "Gene_or_gene_product", "text": [ "MAP kinase kinase" ], "offsets": [ [ 253, 270 ] ], "normalized": [] }, { "id": "PMID-10567559_T9", "type": "Gene_or_gene_product", "text": [ "Ste7" ], "offsets": [ [ 271, 275 ] ], "normalized": [] }, { "id": "PMID-10567559_T10", "type": "Gene_or_gene_product", "text": [ "PKH2" ], "offsets": [ [ 297, 301 ] ], "normalized": [] }, { "id": "PMID-10567559_T11", "type": "Gene_or_gene_product", "text": [ "PDK1" ], "offsets": [ [ 371, 375 ] ], "normalized": [] }, { "id": "PMID-10567559_T12", "type": "Gene_or_gene_product", "text": [ "PKH2" ], "offsets": [ [ 402, 406 ] ], "normalized": [] }, { "id": "PMID-10567559_T13", "type": "Gene_or_gene_product", "text": [ "PKH1" ], "offsets": [ [ 411, 415 ] ], "normalized": [] }, { "id": "PMID-10567559_T14", "type": "Gene_or_gene_product", "text": [ "PDK1" ], "offsets": [ [ 434, 438 ] ], "normalized": [] }, { "id": "PMID-10567559_T15", "type": "Gene_or_gene_product", "text": [ "Pkh1" ], "offsets": [ [ 480, 484 ] ], "normalized": [] }, { "id": "PMID-10567559_T16", "type": "Gene_or_gene_product", "text": [ "Pkh2" ], "offsets": [ [ 489, 493 ] ], "normalized": [] }, { "id": "PMID-10567559_T17", "type": "Gene_or_gene_product", "text": [ "pkh1" ], "offsets": [ [ 555, 559 ] ], "normalized": [] }, { "id": "PMID-10567559_T18", "type": "Gene_or_gene_product", "text": [ "pkh2" ], "offsets": [ [ 567, 571 ] ], "normalized": [] }, { "id": "PMID-10567559_T19", "type": "Gene_or_gene_product", "text": [ "Pkc1" ], "offsets": [ [ 628, 632 ] ], "normalized": [] }, { "id": "PMID-10567559_T20", "type": "Gene_or_gene_product", "text": [ "mitogen-activated protein kinase" ], "offsets": [ [ 633, 665 ] ], "normalized": [] }, { "id": "PMID-10567559_T21", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 667, 671 ] ], "normalized": [] }, { "id": "PMID-10567559_T22", "type": "Gene_or_gene_product", "text": [ "Pkc1" ], "offsets": [ [ 733, 737 ] ], "normalized": [] }, { "id": "PMID-10567559_T23", "type": "Gene_or_gene_product", "text": [ "Pkh2" ], "offsets": [ [ 741, 745 ] ], "normalized": [] }, { "id": "PMID-10567559_T24", "type": "Gene_or_gene_product", "text": [ "Pkc1" ], "offsets": [ [ 768, 772 ] ], "normalized": [] }, { "id": "PMID-10567559_T25", "type": "Gene_or_gene_product", "text": [ "pkh1" ], "offsets": [ [ 789, 793 ] ], "normalized": [] }, { "id": "PMID-10567559_T26", "type": "Gene_or_gene_product", "text": [ "pkh2" ], "offsets": [ [ 801, 805 ] ], "normalized": [] }, { "id": "PMID-10567559_T27", "type": "Gene_or_gene_product", "text": [ "Pkh" ], "offsets": [ [ 827, 830 ] ], "normalized": [] }, { "id": "PMID-10567559_T28", "type": "Gene_or_gene_product", "text": [ "Pkc1" ], "offsets": [ [ 853, 857 ] ], "normalized": [] }, { "id": "PMID-10567559_T29", "type": "Gene_or_gene_product", "text": [ "Pkh2" ], "offsets": [ [ 863, 867 ] ], "normalized": [] }, { "id": "PMID-10567559_T30", "type": "Gene_or_gene_product", "text": [ "Pkc1" ], "offsets": [ [ 892, 896 ] ], "normalized": [] }, { "id": "PMID-10567559_T31", "type": "Simple_chemical", "text": [ "Thr-983" ], "offsets": [ [ 898, 905 ] ], "normalized": [] }, { "id": "PMID-10567559_T32", "type": "Gene_or_gene_product", "text": [ "PDK1" ], "offsets": [ [ 930, 934 ] ], "normalized": [] }, { "id": "PMID-10567559_T33", "type": "Gene_or_gene_product", "text": [ "Pkc1" ], "offsets": [ [ 966, 970 ] ], "normalized": [] }, { "id": "PMID-10567559_T34", "type": "Gene_or_gene_product", "text": [ "PDK1" ], "offsets": [ [ 997, 1001 ] ], "normalized": [] }, { "id": "PMID-10567559_T35", "type": "Gene_or_gene_product", "text": [ "Pkc1" ], "offsets": [ [ 1020, 1024 ] ], "normalized": [] }, { "id": "PMID-10567559_T36", "type": "Gene_or_gene_product", "text": [ "Pkc1" ], "offsets": [ [ 1033, 1037 ] ], "normalized": [] }, { "id": "PMID-10567559_T37", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 1047, 1051 ] ], "normalized": [] } ]

[ { "id": "PMID-10567559_E1", "type": "Positive_regulation", "trigger": { "text": [ "activate" ], "offsets": [ [ 14, 22 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10567559_T1" }, { "role": "Theme", "ref_id": "PMID-10567559_E2" } ] }, { "id": "PMID-10567559_E2", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 65, 72 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-10567559_T2" }, { "role": "Participant", "ref_id": "PMID-10567559_T3" } ] }, { "id": "PMID-10567559_E3", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 156, 165 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10567559_T4" } ] }, { "id": "PMID-10567559_E4", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 673, 680 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-10567559_T19" }, { "role": "Participant", "ref_id": "PMID-10567559_T21" } ] }, { "id": "PMID-10567559_E5", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 714, 729 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10567559_T22" }, { "role": "Cause", "ref_id": "PMID-10567559_T23" } ] }, { "id": "PMID-10567559_E6", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 760, 767 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10567559_T24" } ] }, { "id": "PMID-10567559_E7", "type": "Positive_regulation", "trigger": { "text": [ "essential" ], "offsets": [ [ 952, 961 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10567559_T33" } ] }, { "id": "PMID-10567559_E8", "type": "Positive_regulation", "trigger": { "text": [ "activate" ], "offsets": [ [ 1011, 1019 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10567559_T34" }, { "role": "Theme", "ref_id": "PMID-10567559_T35" } ] }, { "id": "PMID-10567559_E9", "type": "Positive_regulation", "trigger": { "text": [ "activate" ], "offsets": [ [ 1011, 1019 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10567559_T34" }, { "role": "Theme", "ref_id": "PMID-10567559_E11" } ] }, { "id": "PMID-10567559_E10", "type": "Positive_regulation", "trigger": { "text": [ "effector" ], "offsets": [ [ 1038, 1046 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10567559_T36" }, { "role": "Theme", "ref_id": "PMID-10567559_E11" } ] }, { "id": "PMID-10567559_E11", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 1052, 1059 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-10567559_T37" } ] } ]

[ { "id": "PMID-10567559_1", "entity_ids": [ "PMID-10567559_T4", "PMID-10567559_T5" ] }, { "id": "PMID-10567559_2", "entity_ids": [ "PMID-10567559_T20", "PMID-10567559_T21" ] } ]

[]

[ { "id": "PMID-10574991__text", "type": "abstract", "text": [ "Pig-n, a mammalian homologue of yeast Mcd4p, is involved in transferring phosphoethanolamine to the first mannose of the glycosylphosphatidylinositol. \nMany cell surface proteins are anchored to the membrane via a glycosylphosphatidylinositol (GPI) moiety, which is attached to the C terminus of the proteins. The core of the GPI anchor is conserved in all eukaryotes but is modified by various side chains. We cloned a mouse phosphatidylinositol glycan-class N (Pig-n) gene that encodes a 931amino acid protein expressed in the endoplasmic reticulum, which is homologous to yeast Mcd4p. We disrupted the gene in F9 embryonal carcinoma cells. In the Pig-n knockout cells, the first mannose in the GPI precursors was not modified by phosphoethanolamine. Nevertheless, further biosynthetic steps continued with the addition of the third mannose and the terminal phosphoethanolamine. The surface expression of Thy-1 was only partially affected, indicating that modification of the first mannose by phosphoethanolamine is not essential for attachment of GPI anchors in mammalian cells. An inhibitor of GPI biosynthesis, YW3548/BE49385A, inhibited transfer of phosphoethanolamine to the first mannose in mammalian cells but only slightly affected the surface expression of GPI-anchored proteins. Biosynthesis of GPI in the Pig-n knockout cells was not affected by YW3548/BE49385A, and yeast overexpressing MCD4 was highly resistant to YW3548/BE49385A, suggesting that Pig-n and Mcd4p are targets of this drug.\n" ], "offsets": [ [ 0, 1505 ] ] } ]

[ { "id": "PMID-10574991_T1", "type": "Gene_or_gene_product", "text": [ "Pig-n" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMID-10574991_T2", "type": "Gene_or_gene_product", "text": [ "Mcd4p" ], "offsets": [ [ 38, 43 ] ], "normalized": [] }, { "id": "PMID-10574991_T3", "type": "Simple_chemical", "text": [ "phosphoethanolamine" ], "offsets": [ [ 73, 92 ] ], "normalized": [] }, { "id": "PMID-10574991_T4", "type": "Simple_chemical", "text": [ "mannose" ], "offsets": [ [ 106, 113 ] ], "normalized": [] }, { "id": "PMID-10574991_T5", "type": "Simple_chemical", "text": [ "glycosylphosphatidylinositol" ], "offsets": [ [ 121, 149 ] ], "normalized": [] }, { "id": "PMID-10574991_T6", "type": "Cellular_component", "text": [ "cell surface" ], "offsets": [ [ 157, 169 ] ], "normalized": [] }, { "id": "PMID-10574991_T7", "type": "Cellular_component", "text": [ "membrane" ], "offsets": [ [ 199, 207 ] ], "normalized": [] }, { "id": "PMID-10574991_T8", "type": "Simple_chemical", "text": [ "glycosylphosphatidylinositol" ], "offsets": [ [ 214, 242 ] ], "normalized": [] }, { "id": "PMID-10574991_T9", "type": "Simple_chemical", "text": [ "GPI" ], "offsets": [ [ 244, 247 ] ], "normalized": [] }, { "id": "PMID-10574991_T10", "type": "Simple_chemical", "text": [ "GPI anchor" ], "offsets": [ [ 326, 336 ] ], "normalized": [] }, { "id": "PMID-10574991_T11", "type": "Gene_or_gene_product", "text": [ "phosphatidylinositol glycan-class N" ], "offsets": [ [ 426, 461 ] ], "normalized": [] }, { "id": "PMID-10574991_T12", "type": "Gene_or_gene_product", "text": [ "Pig-n" ], "offsets": [ [ 463, 468 ] ], "normalized": [] }, { "id": "PMID-10574991_T13", "type": "Cellular_component", "text": [ "endoplasmic reticulum" ], "offsets": [ [ 529, 550 ] ], "normalized": [] }, { "id": "PMID-10574991_T14", "type": "Gene_or_gene_product", "text": [ "Mcd4p" ], "offsets": [ [ 581, 586 ] ], "normalized": [] }, { "id": "PMID-10574991_T15", "type": "Gene_or_gene_product", "text": [ "Pig-n" ], "offsets": [ [ 650, 655 ] ], "normalized": [] }, { "id": "PMID-10574991_T16", "type": "Simple_chemical", "text": [ "mannose" ], "offsets": [ [ 682, 689 ] ], "normalized": [] }, { "id": "PMID-10574991_T17", "type": "Simple_chemical", "text": [ "GPI" ], "offsets": [ [ 697, 700 ] ], "normalized": [] }, { "id": "PMID-10574991_T18", "type": "Simple_chemical", "text": [ "phosphoethanolamine" ], "offsets": [ [ 732, 751 ] ], "normalized": [] }, { "id": "PMID-10574991_T19", "type": "Simple_chemical", "text": [ "mannose" ], "offsets": [ [ 835, 842 ] ], "normalized": [] }, { "id": "PMID-10574991_T20", "type": "Simple_chemical", "text": [ "phosphoethanolamine" ], "offsets": [ [ 860, 879 ] ], "normalized": [] }, { "id": "PMID-10574991_T21", "type": "Cellular_component", "text": [ "surface" ], "offsets": [ [ 885, 892 ] ], "normalized": [] }, { "id": "PMID-10574991_T22", "type": "Gene_or_gene_product", "text": [ "Thy-1" ], "offsets": [ [ 907, 912 ] ], "normalized": [] }, { "id": "PMID-10574991_T23", "type": "Simple_chemical", "text": [ "mannose" ], "offsets": [ [ 984, 991 ] ], "normalized": [] }, { "id": "PMID-10574991_T24", "type": "Simple_chemical", "text": [ "phosphoethanolamine" ], "offsets": [ [ 995, 1014 ] ], "normalized": [] }, { "id": "PMID-10574991_T25", "type": "Simple_chemical", "text": [ "GPI anchors" ], "offsets": [ [ 1050, 1061 ] ], "normalized": [] }, { "id": "PMID-10574991_T26", "type": "Simple_chemical", "text": [ "GPI" ], "offsets": [ [ 1098, 1101 ] ], "normalized": [] }, { "id": "PMID-10574991_T27", "type": "Simple_chemical", "text": [ "YW3548" ], "offsets": [ [ 1116, 1122 ] ], "normalized": [] }, { "id": "PMID-10574991_T28", "type": "Simple_chemical", "text": [ "BE49385A" ], "offsets": [ [ 1123, 1131 ] ], "normalized": [] }, { "id": "PMID-10574991_T29", "type": "Simple_chemical", "text": [ "phosphoethanolamine" ], "offsets": [ [ 1155, 1174 ] ], "normalized": [] }, { "id": "PMID-10574991_T30", "type": "Simple_chemical", "text": [ "mannose" ], "offsets": [ [ 1188, 1195 ] ], "normalized": [] }, { "id": "PMID-10574991_T31", "type": "Cellular_component", "text": [ "surface" ], "offsets": [ [ 1246, 1253 ] ], "normalized": [] }, { "id": "PMID-10574991_T32", "type": "Simple_chemical", "text": [ "GPI" ], "offsets": [ [ 1268, 1271 ] ], "normalized": [] }, { "id": "PMID-10574991_T33", "type": "Simple_chemical", "text": [ "GPI" ], "offsets": [ [ 1307, 1310 ] ], "normalized": [] }, { "id": "PMID-10574991_T34", "type": "Gene_or_gene_product", "text": [ "Pig-n" ], "offsets": [ [ 1318, 1323 ] ], "normalized": [] }, { "id": "PMID-10574991_T35", "type": "Simple_chemical", "text": [ "YW3548" ], "offsets": [ [ 1359, 1365 ] ], "normalized": [] }, { "id": "PMID-10574991_T36", "type": "Simple_chemical", "text": [ "BE49385A" ], "offsets": [ [ 1366, 1374 ] ], "normalized": [] }, { "id": "PMID-10574991_T37", "type": "Gene_or_gene_product", "text": [ "MCD4" ], "offsets": [ [ 1401, 1405 ] ], "normalized": [] }, { "id": "PMID-10574991_T38", "type": "Simple_chemical", "text": [ "YW3548" ], "offsets": [ [ 1430, 1436 ] ], "normalized": [] }, { "id": "PMID-10574991_T39", "type": "Simple_chemical", "text": [ "BE49385A" ], "offsets": [ [ 1437, 1445 ] ], "normalized": [] }, { "id": "PMID-10574991_T40", "type": "Gene_or_gene_product", "text": [ "Pig-n" ], "offsets": [ [ 1463, 1468 ] ], "normalized": [] }, { "id": "PMID-10574991_T41", "type": "Gene_or_gene_product", "text": [ "Mcd4p" ], "offsets": [ [ 1473, 1478 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-10608887__text", "type": "abstract", "text": [ "Heparan sulfate D-glucosaminyl 3-O-sulfotransferase-3A sulfates N-unsubstituted glucosamine residues. \n3-O-Sulfation of glucosamine by heparan sulfate D-glucosaminyl 3-O-sulfotransferase (3-OST-1) is the key modification in anticoagulant heparan sulfate synthesis. However, the heparan sulfates modified by 3-OST-2 and 3-OST-3A, isoforms of 3-OST-1, do not have anticoagulant activity, although these isoforms transfer sulfate to the 3-OH position of glucosamine residues. In this study, we characterize the substrate specificity of purified 3-OST-3A at the tetrasaccharide level. The 3-OST-3A enzyme was purified from Sf9 cells infected with recombinant baculovirus containing 3-OST-3A cDNA. Two 3-OST-3A-modified tetrasaccharides were purified from the 3-O-(35)S-sulfated heparan sulfate that was digested by heparin lyases. These tetrasaccharides were analyzed using nitrous acid and enzymatic degradation combined with matrix-assisted laser desorption/ionization-mass spectrometry. Two novel tetrasaccharides were discovered with proposed structures of DeltaUA2S-GlcNS-IdoUA2S-[(35)S]GlcNH(2)3S and DeltaUA2S-GlcNS-IdoUA2S-[3-(35)S]GlcNH(2)3S6S . The results demonstrate that 3-OST-3A sulfates N-unsubstituted glucosamine residues, and the 3-OST-3A modification sites are probably located in defined oligosaccharide sequences. Our study suggests that oligosaccharides with N-unsubstituted glucosamine are precursors for sulfation by 3-OST-3A. The intriguing linkage between N-unsubstituted glucosamine and the 3-O-sulfation by 3-OST-3A may provide a clue to the potential biological functions of 3-OST-3A-modified heparan sulfate.\n" ], "offsets": [ [ 0, 1635 ] ] } ]

[ { "id": "PMID-10608887_T1", "type": "Gene_or_gene_product", "text": [ "Heparan sulfate D-glucosaminyl 3-O-sulfotransferase-3A" ], "offsets": [ [ 0, 54 ] ], "normalized": [] }, { "id": "PMID-10608887_T2", "type": "Simple_chemical", "text": [ "glucosamine" ], "offsets": [ [ 80, 91 ] ], "normalized": [] }, { "id": "PMID-10608887_T3", "type": "Simple_chemical", "text": [ "glucosamine" ], "offsets": [ [ 120, 131 ] ], "normalized": [] }, { "id": "PMID-10608887_T4", "type": "Gene_or_gene_product", "text": [ "heparan sulfate D-glucosaminyl 3-O-sulfotransferase" ], "offsets": [ [ 135, 186 ] ], "normalized": [] }, { "id": "PMID-10608887_T5", "type": "Gene_or_gene_product", "text": [ "3-OST-1" ], "offsets": [ [ 188, 195 ] ], "normalized": [] }, { "id": "PMID-10608887_T6", "type": "Simple_chemical", "text": [ "heparan sulfate" ], "offsets": [ [ 238, 253 ] ], "normalized": [] }, { "id": "PMID-10608887_T7", "type": "Simple_chemical", "text": [ "heparan sulfates" ], "offsets": [ [ 278, 294 ] ], "normalized": [] }, { "id": "PMID-10608887_T8", "type": "Gene_or_gene_product", "text": [ "3-OST-2" ], "offsets": [ [ 307, 314 ] ], "normalized": [] }, { "id": "PMID-10608887_T9", "type": "Gene_or_gene_product", "text": [ "3-OST-3A" ], "offsets": [ [ 319, 327 ] ], "normalized": [] }, { "id": "PMID-10608887_T10", "type": "Gene_or_gene_product", "text": [ "3-OST-1" ], "offsets": [ [ 341, 348 ] ], "normalized": [] }, { "id": "PMID-10608887_T11", "type": "Simple_chemical", "text": [ "sulfate" ], "offsets": [ [ 419, 426 ] ], "normalized": [] }, { "id": "PMID-10608887_T12", "type": "Simple_chemical", "text": [ "3-OH" ], "offsets": [ [ 434, 438 ] ], "normalized": [] }, { "id": "PMID-10608887_T13", "type": "Simple_chemical", "text": [ "glucosamine" ], "offsets": [ [ 451, 462 ] ], "normalized": [] }, { "id": "PMID-10608887_T14", "type": "Gene_or_gene_product", "text": [ "3-OST-3A" ], "offsets": [ [ 542, 550 ] ], "normalized": [] }, { "id": "PMID-10608887_T15", "type": "Simple_chemical", "text": [ "tetrasaccharide" ], "offsets": [ [ 558, 573 ] ], "normalized": [] }, { "id": "PMID-10608887_T16", "type": "Gene_or_gene_product", "text": [ "3-OST-3A" ], "offsets": [ [ 585, 593 ] ], "normalized": [] }, { "id": "PMID-10608887_T17", "type": "Gene_or_gene_product", "text": [ "3-OST-3A" ], "offsets": [ [ 678, 686 ] ], "normalized": [] }, { "id": "PMID-10608887_T18", "type": "Gene_or_gene_product", "text": [ "3-OST-3A" ], "offsets": [ [ 697, 705 ] ], "normalized": [] }, { "id": "PMID-10608887_T19", "type": "Simple_chemical", "text": [ "tetrasaccharides" ], "offsets": [ [ 715, 731 ] ], "normalized": [] }, { "id": "PMID-10608887_T20", "type": "Simple_chemical", "text": [ "heparan sulfate" ], "offsets": [ [ 774, 789 ] ], "normalized": [] }, { "id": "PMID-10608887_T21", "type": "Gene_or_gene_product", "text": [ "heparin lyases" ], "offsets": [ [ 811, 825 ] ], "normalized": [] }, { "id": "PMID-10608887_T22", "type": "Simple_chemical", "text": [ "tetrasaccharides" ], "offsets": [ [ 833, 849 ] ], "normalized": [] }, { "id": "PMID-10608887_T23", "type": "Simple_chemical", "text": [ "nitrous acid" ], "offsets": [ [ 870, 882 ] ], "normalized": [] }, { "id": "PMID-10608887_T24", "type": "Simple_chemical", "text": [ "tetrasaccharides" ], "offsets": [ [ 996, 1012 ] ], "normalized": [] }, { "id": "PMID-10608887_T25", "type": "Simple_chemical", "text": [ "DeltaUA2S-GlcNS-IdoUA2S-[(35)S]GlcNH(2)3S" ], "offsets": [ [ 1057, 1098 ] ], "normalized": [] }, { "id": "PMID-10608887_T26", "type": "Simple_chemical", "text": [ "DeltaUA2S-GlcNS-IdoUA2S-[3-(35)S]GlcNH(2)3S6S" ], "offsets": [ [ 1103, 1148 ] ], "normalized": [] }, { "id": "PMID-10608887_T27", "type": "Gene_or_gene_product", "text": [ "3-OST-3A" ], "offsets": [ [ 1180, 1188 ] ], "normalized": [] }, { "id": "PMID-10608887_T28", "type": "Simple_chemical", "text": [ "glucosamine" ], "offsets": [ [ 1214, 1225 ] ], "normalized": [] }, { "id": "PMID-10608887_T29", "type": "Gene_or_gene_product", "text": [ "3-OST-3A" ], "offsets": [ [ 1244, 1252 ] ], "normalized": [] }, { "id": "PMID-10608887_T30", "type": "Simple_chemical", "text": [ "oligosaccharide" ], "offsets": [ [ 1304, 1319 ] ], "normalized": [] }, { "id": "PMID-10608887_T31", "type": "Simple_chemical", "text": [ "oligosaccharides" ], "offsets": [ [ 1355, 1371 ] ], "normalized": [] }, { "id": "PMID-10608887_T32", "type": "Simple_chemical", "text": [ "glucosamine" ], "offsets": [ [ 1393, 1404 ] ], "normalized": [] }, { "id": "PMID-10608887_T33", "type": "Gene_or_gene_product", "text": [ "3-OST-3A" ], "offsets": [ [ 1437, 1445 ] ], "normalized": [] }, { "id": "PMID-10608887_T34", "type": "Simple_chemical", "text": [ "glucosamine" ], "offsets": [ [ 1494, 1505 ] ], "normalized": [] }, { "id": "PMID-10608887_T35", "type": "Gene_or_gene_product", "text": [ "3-OST-3A" ], "offsets": [ [ 1531, 1539 ] ], "normalized": [] }, { "id": "PMID-10608887_T36", "type": "Gene_or_gene_product", "text": [ "3-OST-3A" ], "offsets": [ [ 1600, 1608 ] ], "normalized": [] }, { "id": "PMID-10608887_T37", "type": "Simple_chemical", "text": [ "heparan sulfate" ], "offsets": [ [ 1618, 1633 ] ], "normalized": [] } ]

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"arguments": [ { "role": "Product", "ref_id": "PMID-10608887_T6" } ] }, { "id": "PMID-10608887_E6", "type": "Conversion", "trigger": { "text": [ "modified" ], "offsets": [ [ 295, 303 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10608887_T7" } ] }, { "id": "PMID-10608887_E7", "type": "Positive_regulation", "trigger": { "text": [ "modified" ], "offsets": [ [ 295, 303 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10608887_E6" }, { "role": "Cause", "ref_id": "PMID-10608887_T8" } ] }, { "id": "PMID-10608887_E8", "type": "Positive_regulation", "trigger": { "text": [ "modified" ], "offsets": [ [ 295, 303 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10608887_E6" }, { "role": "Cause", "ref_id": "PMID-10608887_T9" } ] }, { "id": "PMID-10608887_E9", "type": "Conversion", "trigger": { "text": [ "transfer" ], "offsets": [ [ 410, 418 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10608887_T11" }, { "role": "Theme", "ref_id": "PMID-10608887_T13" } ] }, { "id": "PMID-10608887_E10", "type": "Positive_regulation", "trigger": { "text": [ "transfer" ], "offsets": [ [ 410, 418 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10608887_E9" }, { "role": "Cause", "ref_id": "PMID-10608887_T8" } ] }, { "id": "PMID-10608887_E11", "type": "Positive_regulation", "trigger": { "text": [ "transfer" ], "offsets": [ [ 410, 418 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10608887_E9" }, { "role": "Cause", "ref_id": "PMID-10608887_T9" } ] }, { "id": "PMID-10608887_E12", "type": "Conversion", "trigger": { "text": [ "modified" ], "offsets": [ [ 706, 714 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-10608887_T19" } ] }, { "id": "PMID-10608887_E13", "type": "Positive_regulation", "trigger": { "text": [ "modified" ], "offsets": [ [ 706, 714 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10608887_T18" }, { "role": "Theme", "ref_id": "PMID-10608887_E12" } ] }, { "id": "PMID-10608887_E14", "type": "Conversion", "trigger": { "text": [ "sulfates" ], "offsets": [ [ 1189, 1197 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10608887_T28" } ] }, { "id": "PMID-10608887_E15", "type": "Positive_regulation", "trigger": { "text": [ "sulfates" ], "offsets": [ [ 1189, 1197 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10608887_T27" }, { "role": "Theme", "ref_id": "PMID-10608887_E14" } ] }, { "id": "PMID-10608887_E16", "type": "Conversion", "trigger": { "text": [ "modification" ], "offsets": [ [ 1253, 1265 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10608887_T30" } ] }, { "id": "PMID-10608887_E17", "type": "Positive_regulation", "trigger": { "text": [ "modification" ], "offsets": [ [ 1253, 1265 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10608887_T29" }, { "role": "Theme", "ref_id": "PMID-10608887_E16" } ] }, { "id": "PMID-10608887_E18", "type": "Conversion", "trigger": { "text": [ "sulfation" ], "offsets": [ [ 1424, 1433 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10608887_T31" } ] }, { "id": "PMID-10608887_E19", "type": "Positive_regulation", "trigger": { "text": [ "sulfation" ], "offsets": [ [ 1424, 1433 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10608887_T33" }, { "role": "Theme", "ref_id": "PMID-10608887_E18" } ] }, { "id": "PMID-10608887_E20", "type": "Conversion", "trigger": { "text": [ "sulfation" ], "offsets": [ [ 1424, 1433 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10608887_T32" } ] }, { "id": "PMID-10608887_E21", "type": "Positive_regulation", "trigger": { "text": [ "sulfation" ], "offsets": [ [ 1424, 1433 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10608887_T33" }, { "role": "Theme", "ref_id": "PMID-10608887_E20" } ] }, { "id": "PMID-10608887_E22", "type": "Conversion", "trigger": { "text": [ "modified" ], "offsets": [ [ 1609, 1617 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-10608887_T37" } ] }, { "id": "PMID-10608887_E23", "type": "Positive_regulation", "trigger": { "text": [ "modified" ], "offsets": [ [ 1609, 1617 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10608887_T36" }, { "role": "Theme", "ref_id": "PMID-10608887_E22" } ] } ]

[ { "id": "PMID-10608887_1", "entity_ids": [ "PMID-10608887_T4", "PMID-10608887_T5" ] } ]

[]

[ { "id": "PMID-10639137__text", "type": "abstract", "text": [ "The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate. \nHereditary multiple exostoses, a dominantly inherited genetic disorder characterized by multiple cartilaginous tumors, is caused by mutations in members of the EXT gene family, EXT1 or EXT2. The proteins encoded by these genes, EXT1 and EXT2, are endoplasmic reticulum-localized type II transmembrane glycoproteins that possess or are tightly associated with glycosyltransferase activities involved in the polymerization of heparan sulfate. Here, by testing a cell line with a specific defect in EXT1 in in vivo and in vitro assays, we show that EXT2 does not harbor significant glycosyltransferase activity in the absence of EXT1. Instead, it appears that EXT1 and EXT2 form a hetero-oligomeric complex in vivo that leads to the accumulation of both proteins in the Golgi apparatus. Remarkably, the Golgi-localized EXT1/EXT2 complex possesses substantially higher glycosyltransferase activity than EXT1 or EXT2 alone, which suggests that the complex represents the biologically relevant form of the enzyme(s). These findings provide a rationale to explain how inherited mutations in either of the two EXT genes can cause loss of activity, resulting in hereditary multiple exostoses.\n" ], "offsets": [ [ 0, 1340 ] ] } ]

[ { "id": "PMID-10639137_T1", "type": "Gene_or_gene_product", "text": [ "EXT1" ], "offsets": [ [ 31, 35 ] ], "normalized": [] }, { "id": "PMID-10639137_T2", "type": "Gene_or_gene_product", "text": [ "EXT2" ], "offsets": [ [ 40, 44 ] ], "normalized": [] }, { "id": "PMID-10639137_T3", "type": "Cellular_component", "text": [ "Golgi apparatus" ], "offsets": [ [ 91, 106 ] ], "normalized": [] }, { "id": "PMID-10639137_T4", "type": "Simple_chemical", "text": [ "heparan sulfate" ], "offsets": [ [ 138, 153 ] ], "normalized": [] }, { "id": "PMID-10639137_T5", "type": "Gene_or_gene_product", "text": [ "EXT" ], "offsets": [ [ 316, 319 ] ], "normalized": [] }, { "id": "PMID-10639137_T6", "type": "Gene_or_gene_product", "text": [ "EXT1" ], "offsets": [ [ 333, 337 ] ], "normalized": [] }, { "id": "PMID-10639137_T7", "type": "Gene_or_gene_product", "text": [ "EXT2" ], "offsets": [ [ 341, 345 ] ], "normalized": [] }, { "id": "PMID-10639137_T8", "type": "Gene_or_gene_product", "text": [ "EXT1" ], "offsets": [ [ 384, 388 ] ], "normalized": [] }, { "id": "PMID-10639137_T9", "type": "Gene_or_gene_product", "text": [ "EXT2" ], "offsets": [ [ 393, 397 ] ], "normalized": [] }, { "id": "PMID-10639137_T10", "type": "Cellular_component", "text": [ "endoplasmic reticulum" ], "offsets": [ [ 403, 424 ] ], "normalized": [] }, { "id": "PMID-10639137_T11", "type": "Gene_or_gene_product", "text": [ "type II transmembrane glycoproteins" ], "offsets": [ [ 435, 470 ] ], "normalized": [] }, { "id": "PMID-10639137_T12", "type": "Simple_chemical", "text": [ "heparan sulfate" ], "offsets": [ [ 580, 595 ] ], "normalized": [] }, { "id": "PMID-10639137_T13", "type": "Gene_or_gene_product", "text": [ "EXT1" ], "offsets": [ [ 652, 656 ] ], "normalized": [] }, { "id": "PMID-10639137_T14", "type": "Gene_or_gene_product", "text": [ "EXT2" ], "offsets": [ [ 702, 706 ] ], "normalized": [] }, { "id": "PMID-10639137_T15", "type": "Gene_or_gene_product", "text": [ "EXT1" ], "offsets": [ [ 782, 786 ] ], "normalized": [] }, { "id": "PMID-10639137_T16", "type": "Gene_or_gene_product", "text": [ "EXT1" ], "offsets": [ [ 813, 817 ] ], "normalized": [] }, { "id": "PMID-10639137_T17", "type": "Gene_or_gene_product", "text": [ "EXT2" ], "offsets": [ [ 822, 826 ] ], "normalized": [] }, { "id": "PMID-10639137_T18", "type": "Cellular_component", "text": [ "Golgi apparatus" ], "offsets": [ [ 923, 938 ] ], "normalized": [] }, { "id": "PMID-10639137_T19", "type": "Cellular_component", "text": [ "Golgi" ], "offsets": [ [ 956, 961 ] ], "normalized": [] }, { "id": "PMID-10639137_T20", "type": "Gene_or_gene_product", "text": [ "EXT1" ], "offsets": [ [ 972, 976 ] ], "normalized": [] }, { "id": "PMID-10639137_T21", "type": "Gene_or_gene_product", "text": [ "EXT2" ], "offsets": [ [ 977, 981 ] ], "normalized": [] }, { "id": "PMID-10639137_T22", "type": "Gene_or_gene_product", "text": [ "EXT1" ], "offsets": [ [ 1055, 1059 ] ], "normalized": [] }, { "id": "PMID-10639137_T23", "type": "Gene_or_gene_product", "text": [ "EXT2" ], "offsets": [ [ 1063, 1067 ] ], "normalized": [] }, { "id": "PMID-10639137_T24", "type": "Gene_or_gene_product", "text": [ "EXT" ], "offsets": [ [ 1258, 1261 ] ], "normalized": [] } ]

[ { "id": "PMID-10639137_E1", "type": "Binding", "trigger": { "text": [ "form a stable complex" ], "offsets": [ [ 45, 66 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10639137_T1" }, { "role": "Theme", "ref_id": "PMID-10639137_T2" } ] }, { "id": "PMID-10639137_E2", "type": "Localization", "trigger": { "text": [ "accumulates" ], "offsets": [ [ 72, 83 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-10639137_T3" }, { "role": "Theme", "ref_id": "PMID-10639137_T2" } ] }, { "id": "PMID-10639137_E3", "type": "Localization", "trigger": { "text": [ "accumulates" ], "offsets": [ [ 72, 83 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-10639137_T3" }, { "role": "Theme", "ref_id": "PMID-10639137_T1" } ] }, { "id": "PMID-10639137_E4", "type": "Positive_regulation", "trigger": { "text": [ "catalyzes" ], "offsets": [ [ 111, 120 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10639137_E5" }, { "role": "Cause", "ref_id": "PMID-10639137_E1" } ] }, { "id": "PMID-10639137_E5", "type": "Conversion", "trigger": { "text": [ "synthesis" ], "offsets": [ [ 125, 134 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-10639137_T4" } ] }, { "id": "PMID-10639137_E6", "type": "Localization", "trigger": { "text": [ "localized" ], "offsets": [ [ 425, 434 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-10639137_T10" }, { "role": "Theme", "ref_id": "PMID-10639137_T11" } ] }, { "id": "PMID-10639137_E7", "type": "Localization", "trigger": { "text": [ "localized" ], "offsets": [ [ 425, 434 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-10639137_T10" }, { "role": "Theme", "ref_id": "PMID-10639137_T9" } ] }, { "id": "PMID-10639137_E8", "type": "Localization", "trigger": { "text": [ "localized" ], "offsets": [ [ 425, 434 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-10639137_T10" }, { "role": "Theme", "ref_id": "PMID-10639137_T8" } ] }, { "id": "PMID-10639137_E9", "type": "Binding", "trigger": { "text": [ "form a hetero-oligomeric complex" ], "offsets": [ [ 827, 859 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10639137_T17" }, { "role": "Theme", "ref_id": "PMID-10639137_T16" } ] }, { "id": "PMID-10639137_E10", "type": "Positive_regulation", "trigger": { "text": [ "leads" ], "offsets": [ [ 873, 878 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10639137_E9" }, { "role": "Theme", "ref_id": "PMID-10639137_E12" } ] }, { "id": "PMID-10639137_E11", "type": "Positive_regulation", "trigger": { "text": [ "leads" ], "offsets": [ [ 873, 878 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10639137_E9" }, { "role": "Theme", "ref_id": "PMID-10639137_E13" } ] }, { "id": "PMID-10639137_E12", "type": "Localization", "trigger": { "text": [ "accumulation" ], "offsets": [ [ 886, 898 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-10639137_T18" }, { "role": "Theme", "ref_id": "PMID-10639137_T16" } ] }, { "id": "PMID-10639137_E13", "type": "Localization", "trigger": { "text": [ "accumulation" ], "offsets": [ [ 886, 898 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-10639137_T18" }, { "role": "Theme", "ref_id": "PMID-10639137_T17" } ] }, { "id": "PMID-10639137_E14", "type": "Localization", "trigger": { "text": [ "localized" ], "offsets": [ [ 962, 971 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-10639137_T19" }, { "role": "Theme", "ref_id": "PMID-10639137_T20" } ] }, { "id": "PMID-10639137_E15", "type": "Localization", "trigger": { "text": [ "localized" ], "offsets": [ [ 962, 971 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-10639137_T19" }, { "role": "Theme", "ref_id": "PMID-10639137_T21" } ] }, { "id": "PMID-10639137_E16", "type": "Binding", "trigger": { "text": [ "complex" ], "offsets": [ [ 982, 989 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10639137_T20" }, { "role": "Theme", "ref_id": "PMID-10639137_T21" } ] } ]

[]

[]

[ { "id": "PMID-10642555__text", "type": "abstract", "text": [ "Rad6-dependent ubiquitination of histone H2B in yeast. \nAlthough ubiquitinated histones are present in substantial levels in vertebrate cells, the roles they play in specific biological processes and the cellular factors that regulate this modification are not well characterized. Ubiquitinated H2B (uH2B) has been identified in the yeast Saccharomyces cerevisiae, and mutation of the conserved ubiquitination site is shown to confer defects in mitotic cell growth and meiosis. uH2B was not detected in rad6 mutants, which are defective for the ubiquitin-conjugating enzyme Ubc2, thus identifying Rad6 as the major cellular activity that ubiquitinates H2B in yeast.\n" ], "offsets": [ [ 0, 666 ] ] } ]

[ { "id": "PMID-10642555_T1", "type": "Gene_or_gene_product", "text": [ "Rad6" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-10642555_T2", "type": "Gene_or_gene_product", "text": [ "histone H2B" ], "offsets": [ [ 33, 44 ] ], "normalized": [] }, { "id": "PMID-10642555_T3", "type": "Gene_or_gene_product", "text": [ "histones" ], "offsets": [ [ 79, 87 ] ], "normalized": [] }, { "id": "PMID-10642555_T4", "type": "Gene_or_gene_product", "text": [ "H2B" ], "offsets": [ [ 295, 298 ] ], "normalized": [] }, { "id": "PMID-10642555_T5", "type": "Gene_or_gene_product", "text": [ "uH2B" ], "offsets": [ [ 300, 304 ] ], "normalized": [] }, { "id": "PMID-10642555_T6", "type": "Gene_or_gene_product", "text": [ "uH2B" ], "offsets": [ [ 478, 482 ] ], "normalized": [] }, { "id": "PMID-10642555_T7", "type": "Gene_or_gene_product", "text": [ "rad6" ], "offsets": [ [ 503, 507 ] ], "normalized": [] }, { "id": "PMID-10642555_T8", "type": "Gene_or_gene_product", "text": [ "ubiquitin" ], "offsets": [ [ 545, 554 ] ], "normalized": [] }, { "id": "PMID-10642555_T9", "type": "Gene_or_gene_product", "text": [ "Ubc2" ], "offsets": [ [ 574, 578 ] ], "normalized": [] }, { "id": "PMID-10642555_T10", "type": "Gene_or_gene_product", "text": [ "Rad6" ], "offsets": [ [ 597, 601 ] ], "normalized": [] }, { "id": "PMID-10642555_T11", "type": "Gene_or_gene_product", "text": [ "H2B" ], "offsets": [ [ 652, 655 ] ], "normalized": [] } ]

[ { "id": "PMID-10642555_E1", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 5, 14 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10642555_E2" }, { "role": "Cause", "ref_id": "PMID-10642555_T1" } ] }, { "id": "PMID-10642555_E2", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 15, 29 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10642555_T2" } ] }, { "id": "PMID-10642555_E3", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinated" ], "offsets": [ [ 65, 78 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10642555_T3" } ] }, { "id": "PMID-10642555_E4", "type": "Ubiquitination", "trigger": { "text": [ "Ubiquitinated" ], "offsets": [ [ 281, 294 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10642555_T5" } ] }, { "id": "PMID-10642555_E5", "type": "Binding", "trigger": { "text": [ "conjugating" ], "offsets": [ [ 555, 566 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10642555_T8" }, { "role": "Theme", "ref_id": "PMID-10642555_T9" } ] }, { "id": "PMID-10642555_E6", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinates" ], "offsets": [ [ 638, 651 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10642555_T11" }, { "role": "Cause", "ref_id": "PMID-10642555_T10" } ] } ]

[ { "id": "PMID-10642555_1", "entity_ids": [ "PMID-10642555_T4", "PMID-10642555_T5" ] } ]

[]

[ { "id": "PMID-10655592__text", "type": "abstract", "text": [ "Nuclear sequestration of the exchange factor Cdc24 by Far1 regulates cell polarity during yeast mating. \nCytoskeletal rearrangements during the cell cycle and in response to signals are regulated by small Rho-type GTPases, but it is not known how these GTPases are activated in a spatial and temporal manner. Here we show that Cdc24, the guanine-nucleotide exchange factor for the yeast GTPase Cdc42, is sequestered in the cell nucleus by Far1. Export of Cdc24 to a site of cell polarization is mediated by two mechanisms. At bud emergence, activation of the G1 cyclin-dependent kinase Cdc28-Cln triggers degradation of Far1 and, as a result, relocation of Cdc24 to the cytoplasm. Cells overexpressing a non-degradable Far1 were unable to polarize their actin cytoskeleton because they failed to relocate Cdc24 to the incipient bud site. In contrast, in response to mating pheromones, the Far1-Cdc24 complex is exported from the nucleus by Msn5. This mechanism ensures that Cdc24 is targeted to the site of receptor-associated heterotrimeric G-protein activation at the plasma membrane, thereby allowing polarization of the actin cytoskeleton along the morphogenetic gradient of pheromone. Either degradation of Far1 or its nuclear export by Msn5 was sufficient for cell growth, suggesting that the two mechanisms are redundant for cell viability. Taken together, our results indicate that Far1 functions as a nuclear anchor for Cdc24. This sequestration regulates cell polarity in response to pheromones by restricting activation of Cdc42 to the site of pheromone receptor activation.\n" ], "offsets": [ [ 0, 1586 ] ] } ]

[ { "id": "PMID-10655592_T1", "type": "Cellular_component", "text": [ "Nuclear" ], "offsets": [ [ 0, 7 ] ], "normalized": [] }, { "id": "PMID-10655592_T2", "type": "Gene_or_gene_product", "text": [ "Cdc24" ], "offsets": [ [ 45, 50 ] ], "normalized": [] }, { "id": "PMID-10655592_T3", "type": "Gene_or_gene_product", "text": [ "Far1" ], "offsets": [ [ 54, 58 ] ], "normalized": [] }, { "id": "PMID-10655592_T4", "type": "Cellular_component", "text": [ "Cytoskeletal" ], "offsets": [ [ 105, 117 ] ], "normalized": [] }, { "id": "PMID-10655592_T5", "type": "Gene_or_gene_product", "text": [ "Rho" ], "offsets": [ [ 205, 208 ] ], "normalized": [] }, { "id": "PMID-10655592_T6", "type": "Gene_or_gene_product", "text": [ "Cdc24" ], "offsets": [ [ 327, 332 ] ], "normalized": [] }, { "id": "PMID-10655592_T7", "type": "Simple_chemical", "text": [ "guanine" ], "offsets": [ [ 338, 345 ] ], "normalized": [] }, { "id": "PMID-10655592_T8", "type": "Gene_or_gene_product", "text": [ "Cdc42" ], "offsets": [ [ 394, 399 ] ], "normalized": [] }, { "id": "PMID-10655592_T9", "type": "Cellular_component", "text": [ "cell nucleus" ], "offsets": [ [ 423, 435 ] ], "normalized": [] }, { "id": "PMID-10655592_T10", "type": "Gene_or_gene_product", "text": [ "Far1" ], "offsets": [ [ 439, 443 ] ], "normalized": [] }, { "id": "PMID-10655592_T11", "type": "Gene_or_gene_product", "text": [ "Cdc24" ], "offsets": [ [ 455, 460 ] ], "normalized": [] }, { "id": "PMID-10655592_T12", "type": "Gene_or_gene_product", "text": [ "cyclin-dependent kinase" ], "offsets": [ [ 562, 585 ] ], "normalized": [] }, { "id": "PMID-10655592_T13", "type": "Complex", "text": [ "Cdc28-Cln" ], "offsets": [ [ 586, 595 ] ], "normalized": [] }, { "id": "PMID-10655592_T14", "type": "Gene_or_gene_product", "text": [ "Far1" ], "offsets": [ [ 620, 624 ] ], "normalized": [] }, { "id": "PMID-10655592_T15", "type": "Gene_or_gene_product", "text": [ "Cdc24" ], "offsets": [ [ 657, 662 ] ], "normalized": [] }, { "id": "PMID-10655592_T16", "type": "Cellular_component", "text": [ "cytoplasm" ], "offsets": [ [ 670, 679 ] ], "normalized": [] }, { "id": "PMID-10655592_T17", "type": "Gene_or_gene_product", "text": [ "Far1" ], "offsets": [ [ 719, 723 ] ], "normalized": [] }, { "id": "PMID-10655592_T18", "type": "Gene_or_gene_product", "text": [ "actin" ], "offsets": [ [ 754, 759 ] ], "normalized": [] }, { "id": "PMID-10655592_T19", "type": "Cellular_component", "text": [ "cytoskeleton" ], "offsets": [ [ 760, 772 ] ], "normalized": [] }, { "id": "PMID-10655592_T20", "type": "Gene_or_gene_product", "text": [ "Cdc24" ], "offsets": [ [ 805, 810 ] ], "normalized": [] }, { "id": "PMID-10655592_T21", "type": "Cellular_component", "text": [ "bud site" ], "offsets": [ [ 828, 836 ] ], "normalized": [] }, { "id": "PMID-10655592_T22", "type": "Complex", "text": [ "Far1-Cdc24" ], "offsets": [ [ 889, 899 ] ], "normalized": [] }, { "id": "PMID-10655592_T23", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 929, 936 ] ], "normalized": [] }, { "id": "PMID-10655592_T24", "type": "Gene_or_gene_product", "text": [ "Msn5" ], "offsets": [ [ 940, 944 ] ], "normalized": [] }, { "id": "PMID-10655592_T25", "type": "Gene_or_gene_product", "text": [ "Cdc24" ], "offsets": [ [ 974, 979 ] ], "normalized": [] }, { "id": "PMID-10655592_T26", "type": "Cellular_component", "text": [ "plasma membrane" ], "offsets": [ [ 1070, 1085 ] ], "normalized": [] }, { "id": "PMID-10655592_T27", "type": "Gene_or_gene_product", "text": [ "actin" ], "offsets": [ [ 1124, 1129 ] ], "normalized": [] }, { "id": "PMID-10655592_T28", "type": "Cellular_component", "text": [ "cytoskeleton" ], "offsets": [ [ 1130, 1142 ] ], "normalized": [] }, { "id": "PMID-10655592_T29", "type": "Gene_or_gene_product", "text": [ "Far1" ], "offsets": [ [ 1212, 1216 ] ], "normalized": [] }, { "id": "PMID-10655592_T30", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 1224, 1231 ] ], "normalized": [] }, { "id": "PMID-10655592_T31", "type": "Gene_or_gene_product", "text": [ "Msn5" ], "offsets": [ [ 1242, 1246 ] ], "normalized": [] }, { "id": "PMID-10655592_T32", "type": "Gene_or_gene_product", "text": [ "Far1" ], "offsets": [ [ 1390, 1394 ] ], "normalized": [] }, { "id": "PMID-10655592_T33", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 1410, 1417 ] ], "normalized": [] }, { "id": "PMID-10655592_T34", "type": "Gene_or_gene_product", "text": [ "Cdc24" ], "offsets": [ [ 1429, 1434 ] ], "normalized": [] }, { "id": "PMID-10655592_T35", "type": "Gene_or_gene_product", "text": [ "Cdc42" ], "offsets": [ [ 1534, 1539 ] ], "normalized": [] } ]

[ { "id": "PMID-10655592_E1", "type": "Transport", "trigger": { "text": [ "sequestration" ], "offsets": [ [ 8, 21 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-10655592_T1" }, { "role": "Theme", "ref_id": "PMID-10655592_T2" } ] }, { "id": "PMID-10655592_E2", "type": "Positive_regulation", "trigger": { "text": [ "sequestratio" ], "offsets": [ [ 8, 20 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10655592_T3" }, { "role": "Theme", "ref_id": "PMID-10655592_E1" } ] }, { "id": "PMID-10655592_E3", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 144, 154 ] ] }, "arguments": [] }, { "id": "PMID-10655592_E4", "type": "Transport", "trigger": { "text": [ "sequestered" ], "offsets": [ [ 404, 415 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10655592_T6" }, { "role": "ToLoc", "ref_id": "PMID-10655592_T9" } ] }, { "id": "PMID-10655592_E5", "type": "Positive_regulation", "trigger": { "text": [ "sequestered" ], "offsets": [ [ 404, 415 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10655592_T10" }, { "role": "Theme", "ref_id": "PMID-10655592_E4" } ] }, { "id": "PMID-10655592_E6", "type": "Transport", "trigger": { "text": [ "Export" ], "offsets": [ [ 445, 451 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10655592_T11" } ] }, { "id": "PMID-10655592_E7", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 541, 551 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10655592_T13" } ] }, { "id": "PMID-10655592_E8", "type": "Positive_regulation", "trigger": { "text": [ "triggers" ], "offsets": [ [ 596, 604 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10655592_E7" }, { "role": "Theme", "ref_id": "PMID-10655592_E10" } ] }, { "id": "PMID-10655592_E9", "type": "Positive_regulation", "trigger": { "text": [ "triggers" ], "offsets": [ [ 596, 604 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10655592_E7" }, { "role": "Theme", "ref_id": "PMID-10655592_E11" } ] }, { "id": "PMID-10655592_E10", "type": "Degradation", "trigger": { "text": [ "degradation" ], "offsets": [ [ 605, 616 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10655592_T14" } ] }, { "id": "PMID-10655592_E11", "type": "Localization", "trigger": { "text": [ "relocation" ], "offsets": [ [ 643, 653 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10655592_T15" }, { "role": "ToLoc", "ref_id": "PMID-10655592_T16" } ] }, { "id": "PMID-10655592_E12", "type": "Gene_expression", "trigger": { "text": [ "overexpressing" ], "offsets": [ [ 687, 701 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10655592_T17" } ] }, { "id": "PMID-10655592_E13", "type": "Degradation", "trigger": { "text": [ "non-degradable" ], "offsets": [ [ 704, 718 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10655592_T17" } ] }, { "id": "PMID-10655592_E14", "type": "Localization", "trigger": { "text": [ "relocate" ], "offsets": [ [ 796, 804 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10655592_T20" }, { "role": "ToLoc", "ref_id": "PMID-10655592_T21" } ] }, { "id": "PMID-10655592_E15", "type": "Transport", "trigger": { "text": [ "exported" ], "offsets": [ [ 911, 919 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10655592_T22" }, { "role": "FromLoc", "ref_id": "PMID-10655592_T23" } ] }, { "id": "PMID-10655592_E16", "type": "Positive_regulation", "trigger": { "text": [ "exported" ], "offsets": [ [ 911, 919 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10655592_T24" }, { "role": "Theme", "ref_id": "PMID-10655592_E15" } ] }, { "id": "PMID-10655592_E17", "type": "Degradation", "trigger": { "text": [ "degradation" ], "offsets": [ [ 1197, 1208 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10655592_T29" } ] }, { "id": "PMID-10655592_E18", "type": "Transport", "trigger": { "text": [ "export" ], "offsets": [ [ 1232, 1238 ] ] }, "arguments": [ { "role": "FromLoc", "ref_id": "PMID-10655592_T30" }, { "role": "Theme", "ref_id": "PMID-10655592_T29" } ] }, { "id": "PMID-10655592_E19", "type": "Positive_regulation", "trigger": { "text": [ "export" ], "offsets": [ [ 1232, 1238 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10655592_E18" }, { "role": "Cause", "ref_id": "PMID-10655592_T31" } ] }, { "id": "PMID-10655592_E20", "type": "Negative_regulation", "trigger": { "text": [ "restricting" ], "offsets": [ [ 1508, 1519 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10655592_E21" } ] }, { "id": "PMID-10655592_E21", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1520, 1530 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10655592_T35" } ] } ]

[]

[]

[ { "id": "PMID-10748143__text", "type": "abstract", "text": [ "Molecular cloning of globotriaosylceramide/CD77 synthase, a glycosyltransferase that initiates the synthesis of globo series glycosphingolipids. \nThe expression cloning of a cDNA for globotriaosylceramide (Gb3)/CD77 synthase (alpha1,4-galactosyltransferase) was achieved using an anti-Gb3 antibody and mouse L cells as a recipient cell line for the transfection. The isolated cDNA clone designated pVTR1 predicted a type II membrane protein with 19 amino acids of cytoplasmic domain, 26 amino acids of transmembrane region, and a catalytic domain with 308 amino acids. Introduction of the cDNA clone into L cells resulted in the neosynthesis of Gb3/CD77, and the extracts of the transfectant cells showed alpha1, 4-galactosyltransferase activity only on lactosylceramide and galactosylceramide. In Northern blotting, a 2.3-kilobase mRNA was strongly expressed in heart, kidney, spleen, and placenta and weakly in colon, small intestine, and brain. Transfection of the cDNA into L cells resulted in the constitution of sensitivity to the apoptosis with Shiga-like toxins (verotoxins). Since Gb3/CD77 synthase initiates the synthesis of globo series glycolipids, the isolation of this cDNA will make possible further investigations into the function of its important series of glycolipids.\n" ], "offsets": [ [ 0, 1288 ] ] } ]

[ { "id": "PMID-10748143_T1", "type": "Gene_or_gene_product", "text": [ "globotriaosylceramide/CD77 synthase" ], "offsets": [ [ 21, 56 ] ], "normalized": [] }, { "id": "PMID-10748143_T2", "type": "Simple_chemical", "text": [ "glycosphingolipids" ], "offsets": [ [ 125, 143 ] ], "normalized": [] }, { "id": "PMID-10748143_T3", "type": "Gene_or_gene_product", "text": [ "globotriaosylceramide (Gb3)/CD77 synthase" ], "offsets": [ [ 183, 224 ] ], "normalized": [] }, { "id": "PMID-10748143_T4", "type": "Gene_or_gene_product", "text": [ "alpha1,4-galactosyltransferase" ], "offsets": [ [ 226, 256 ] ], "normalized": [] }, { "id": "PMID-10748143_T5", "type": "Simple_chemical", "text": [ "Gb3" ], "offsets": [ [ 285, 288 ] ], "normalized": [] }, { "id": "PMID-10748143_T6", "type": "Gene_or_gene_product", "text": [ "pVTR1" ], "offsets": [ [ 398, 403 ] ], "normalized": [] }, { "id": "PMID-10748143_T7", "type": "Cellular_component", "text": [ "membrane" ], "offsets": [ [ 424, 432 ] ], "normalized": [] }, { "id": "PMID-10748143_T8", "type": "Cellular_component", "text": [ "cytoplasmic" ], "offsets": [ [ 464, 475 ] ], "normalized": [] }, { "id": "PMID-10748143_T9", "type": "Cellular_component", "text": [ "transmembrane" ], "offsets": [ [ 502, 515 ] ], "normalized": [] }, { "id": "PMID-10748143_T10", "type": "Simple_chemical", "text": [ "Gb3" ], "offsets": [ [ 645, 648 ] ], "normalized": [] }, { "id": "PMID-10748143_T11", "type": "Simple_chemical", "text": [ "CD77" ], "offsets": [ [ 649, 653 ] ], "normalized": [] }, { "id": "PMID-10748143_T12", "type": "Gene_or_gene_product", "text": [ "alpha1, 4-galactosyltransferase" ], "offsets": [ [ 705, 736 ] ], "normalized": [] }, { "id": "PMID-10748143_T13", "type": "Simple_chemical", "text": [ "lactosylceramide" ], "offsets": [ [ 754, 770 ] ], "normalized": [] }, { "id": "PMID-10748143_T14", "type": "Simple_chemical", "text": [ "galactosylceramide" ], "offsets": [ [ 775, 793 ] ], "normalized": [] }, { "id": "PMID-10748143_T15", "type": "Gene_or_gene_product", "text": [ "Shiga-like toxins" ], "offsets": [ [ 1052, 1069 ] ], "normalized": [] }, { "id": "PMID-10748143_T16", "type": "Gene_or_gene_product", "text": [ "verotoxins" ], "offsets": [ [ 1071, 1081 ] ], "normalized": [] }, { "id": "PMID-10748143_T17", "type": "Gene_or_gene_product", "text": [ "Gb3/CD77 synthase" ], "offsets": [ [ 1090, 1107 ] ], "normalized": [] }, { "id": "PMID-10748143_T18", "type": "Simple_chemical", "text": [ "glycolipids" ], "offsets": [ [ 1148, 1159 ] ], "normalized": [] }, { "id": "PMID-10748143_T19", "type": "Simple_chemical", "text": [ "glycolipids" ], "offsets": [ [ 1275, 1286 ] ], "normalized": [] } ]

[ { "id": "PMID-10748143_E1", "type": "Positive_regulation", "trigger": { "text": [ "initiates" ], "offsets": [ [ 85, 94 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10748143_T1" }, { "role": "Theme", "ref_id": "PMID-10748143_E2" } ] }, { "id": "PMID-10748143_E2", "type": "Conversion", "trigger": { "text": [ "synthesis" ], "offsets": [ [ 99, 108 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-10748143_T2" } ] }, { "id": "PMID-10748143_E3", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 613, 621 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10748143_E4" } ] }, { "id": "PMID-10748143_E4", "type": "Conversion", "trigger": { "text": [ "neosynthesis" ], "offsets": [ [ 629, 641 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-10748143_T10" } ] }, { "id": "PMID-10748143_E5", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 986, 994 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10748143_E6" } ] }, { "id": "PMID-10748143_E6", "type": "Regulation", "trigger": { "text": [ "sensitivity" ], "offsets": [ [ 1018, 1029 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10748143_E7" }, { "role": "Cause", "ref_id": "PMID-10748143_T16" } ] }, { "id": "PMID-10748143_E7", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 1037, 1046 ] ] }, "arguments": [] }, { "id": "PMID-10748143_E8", "type": "Positive_regulation", "trigger": { "text": [ "initiates" ], "offsets": [ [ 1108, 1117 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10748143_T17" }, { "role": "Theme", "ref_id": "PMID-10748143_E9" } ] }, { "id": "PMID-10748143_E9", "type": "Conversion", "trigger": { "text": [ "synthesis" ], "offsets": [ [ 1122, 1131 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-10748143_T18" } ] } ]

[ { "id": "PMID-10748143_1", "entity_ids": [ "PMID-10748143_T3", "PMID-10748143_T4" ] }, { "id": "PMID-10748143_2", "entity_ids": [ "PMID-10748143_T10", "PMID-10748143_T11" ] }, { "id": "PMID-10748143_3", "entity_ids": [ "PMID-10748143_T15", "PMID-10748143_T16" ] } ]

[]

[ { "id": "PMID-10753885__text", "type": "abstract", "text": [ "E2F family members are differentially regulated by reversible acetylation. \nThe six members of the E2F family of transcription factors play a key role in the control of cell cycle progression by regulating the expression of genes involved in DNA replication and cell proliferation. E2F-1, -2, and -3 belong to a structural and functional subfamily distinct from those of the other E2F family members. Here we report that E2F-1, -2, and -3, but not E2F-4, -5, and -6, associate with and are acetylated by p300 and cAMP-response element-binding protein acetyltransferases. Acetylation occurs at three conserved lysine residues located at the N-terminal boundary of their DNA binding domains. Acetylation of E2F-1 in vitro and in vivo markedly increases its binding affinity for a consensus E2F DNA-binding site, which is paralleled by enhanced transactivation of an E2F-responsive promoter. Acetylation of E2F-1 can be reversed by histone deacetylase-1, indicating that reversible acetylation is a mechanism for regulation also of non-histone proteins.\n" ], "offsets": [ [ 0, 1051 ] ] } ]

[ { "id": "PMID-10753885_T1", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 0, 3 ] ], "normalized": [] }, { "id": "PMID-10753885_T2", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 99, 102 ] ], "normalized": [] }, { "id": "PMID-10753885_T3", "type": "Gene_or_gene_product", "text": [ "E2F-1" ], "offsets": [ [ 282, 287 ] ], "normalized": [] }, { "id": "PMID-10753885_T4", "type": "Gene_or_gene_product", "text": [ "-2" ], "offsets": [ [ 289, 291 ] ], "normalized": [] }, { "id": "PMID-10753885_T5", "type": "Gene_or_gene_product", "text": [ "-3" ], "offsets": [ [ 297, 299 ] ], "normalized": [] }, { "id": "PMID-10753885_T6", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 381, 384 ] ], "normalized": [] }, { "id": "PMID-10753885_T7", "type": "Gene_or_gene_product", "text": [ "E2F-1" ], "offsets": [ [ 421, 426 ] ], "normalized": [] }, { "id": "PMID-10753885_T8", "type": "Gene_or_gene_product", "text": [ "-2" ], "offsets": [ [ 428, 430 ] ], "normalized": [] }, { "id": "PMID-10753885_T9", "type": "Gene_or_gene_product", "text": [ "-3" ], "offsets": [ [ 436, 438 ] ], "normalized": [] }, { "id": "PMID-10753885_T10", "type": "Gene_or_gene_product", "text": [ "E2F-4" ], "offsets": [ [ 448, 453 ] ], "normalized": [] }, { "id": "PMID-10753885_T11", "type": "Gene_or_gene_product", "text": [ "-5" ], "offsets": [ [ 455, 457 ] ], "normalized": [] }, { "id": "PMID-10753885_T12", "type": "Gene_or_gene_product", "text": [ "-6" ], "offsets": [ [ 463, 465 ] ], "normalized": [] }, { "id": "PMID-10753885_T13", "type": "Gene_or_gene_product", "text": [ "p300" ], "offsets": [ [ 504, 508 ] ], "normalized": [] }, { "id": "PMID-10753885_T14", "type": "Gene_or_gene_product", "text": [ "cAMP-response element-binding protein" ], "offsets": [ [ 513, 550 ] ], "normalized": [] }, { "id": "PMID-10753885_T15", "type": "Simple_chemical", "text": [ "lysine" ], "offsets": [ [ 609, 615 ] ], "normalized": [] }, { "id": "PMID-10753885_T16", "type": "Gene_or_gene_product", "text": [ "E2F-1" ], "offsets": [ [ 705, 710 ] ], "normalized": [] }, { "id": "PMID-10753885_T17", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 788, 791 ] ], "normalized": [] }, { "id": "PMID-10753885_T18", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 864, 867 ] ], "normalized": [] }, { "id": "PMID-10753885_T19", "type": "Gene_or_gene_product", "text": [ "E2F-1" ], "offsets": [ [ 904, 909 ] ], "normalized": [] }, { "id": "PMID-10753885_T20", "type": "Gene_or_gene_product", "text": [ "histone deacetylase-1" ], "offsets": [ [ 929, 950 ] ], "normalized": [] }, { "id": "PMID-10753885_T21", "type": "Gene_or_gene_product", "text": [ "histone" ], "offsets": [ [ 1033, 1040 ] ], "normalized": [] } ]

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} ] }, { "id": "PMID-10753885_E6", "type": "Regulation", "trigger": { "text": [ "associate" ], "offsets": [ [ 467, 476 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10753885_T10" }, { "role": "Theme", "ref_id": "PMID-10753885_T13" } ] }, { "id": "PMID-10753885_E7", "type": "Regulation", "trigger": { "text": [ "associate" ], "offsets": [ [ 467, 476 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10753885_T11" }, { "role": "Theme", "ref_id": "PMID-10753885_T13" } ] }, { "id": "PMID-10753885_E8", "type": "Regulation", "trigger": { "text": [ "associate" ], "offsets": [ [ 467, 476 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10753885_T12" }, { "role": "Theme", "ref_id": "PMID-10753885_T13" } ] }, { "id": "PMID-10753885_E9", "type": "Regulation", "trigger": { "text": [ "associate" ], "offsets": [ [ 467, 476 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10753885_T10" }, { "role": "Theme", "ref_id": "PMID-10753885_T14" } ] }, { "id": "PMID-10753885_E10", "type": "Regulation", "trigger": { "text": [ "associate" ], "offsets": [ [ 467, 476 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10753885_T11" }, { "role": "Theme", "ref_id": "PMID-10753885_T14" } ] }, { "id": "PMID-10753885_E11", "type": "Regulation", "trigger": { "text": [ "associate" ], "offsets": [ [ 467, 476 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10753885_T12" }, { "role": "Theme", "ref_id": "PMID-10753885_T14" } ] }, { "id": "PMID-10753885_E12", "type": "Regulation", "trigger": { "text": [ "associate" ], "offsets": [ [ 467, 476 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10753885_T8" }, { "role": "Theme", "ref_id": "PMID-10753885_T13" } ] }, { "id": "PMID-10753885_E13", "type": "Regulation", "trigger": { "text": [ "associate" ], "offsets": [ [ 467, 476 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10753885_T9" }, { "role": "Theme", "ref_id": "PMID-10753885_T13" } ] }, { "id": "PMID-10753885_E14", "type": "Regulation", "trigger": { "text": [ "associate" ], "offsets": [ [ 467, 476 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10753885_T7" }, { "role": "Theme", "ref_id": "PMID-10753885_T14" } ] }, { "id": "PMID-10753885_E15", "type": "Regulation", "trigger": { "text": [ "associate" ], "offsets": [ [ 467, 476 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10753885_T8" }, { "role": "Theme", "ref_id": "PMID-10753885_T14" } ] }, { "id": "PMID-10753885_E16", "type": "Regulation", "trigger": { "text": [ "associate" ], "offsets": [ [ 467, 476 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10753885_T9" }, { "role": "Theme", "ref_id": "PMID-10753885_T14" } ] }, { "id": "PMID-10753885_E17", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 490, 500 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10753885_T13" }, { "role": "Theme", "ref_id": "PMID-10753885_T9" } ] }, { "id": "PMID-10753885_E18", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 490, 500 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10753885_T13" }, { "role": "Theme", "ref_id": "PMID-10753885_T10" } ] }, { "id": "PMID-10753885_E19", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 490, 500 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10753885_T14" }, { "role": "Theme", "ref_id": "PMID-10753885_T10" } ] }, { "id": "PMID-10753885_E20", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 490, 500 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10753885_T13" }, { "role": "Theme", "ref_id": "PMID-10753885_T11" } ] }, { "id": "PMID-10753885_E21", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 490, 500 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10753885_T14" }, { "role": "Theme", "ref_id": "PMID-10753885_T11" } ] }, { "id": "PMID-10753885_E22", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 490, 500 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10753885_T13" }, { "role": "Theme", "ref_id": "PMID-10753885_T12" } ] }, { "id": "PMID-10753885_E23", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 490, 500 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10753885_T14" }, { "role": "Theme", "ref_id": "PMID-10753885_T12" } ] }, { "id": "PMID-10753885_E24", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 490, 500 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10753885_T14" }, { "role": "Theme", "ref_id": "PMID-10753885_T9" } ] }, { "id": "PMID-10753885_E25", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 490, 500 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10753885_T13" }, { "role": "Theme", "ref_id": "PMID-10753885_T8" } ] }, { "id": "PMID-10753885_E26", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 490, 500 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10753885_T14" }, { "role": "Theme", "ref_id": "PMID-10753885_T8" } ] }, { "id": "PMID-10753885_E27", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 490, 500 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10753885_T13" }, { "role": "Theme", "ref_id": "PMID-10753885_T7" } ] }, { "id": "PMID-10753885_E28", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 490, 500 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10753885_T14" }, { "role": "Theme", "ref_id": "PMID-10753885_T7" } ] }, { "id": "PMID-10753885_E29", "type": "Acetylation", "trigger": { "text": [ "Acetylation" ], "offsets": [ [ 571, 582 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-10753885_T15" }, { "role": "Theme", "ref_id": "PMID-10753885_T7" } ] }, { "id": "PMID-10753885_E30", "type": "Acetylation", "trigger": { "text": [ "Acetylation" ], "offsets": [ [ 571, 582 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-10753885_T15" }, { "role": "Theme", "ref_id": "PMID-10753885_T8" } ] }, { "id": "PMID-10753885_E31", "type": "Acetylation", "trigger": { "text": [ "Acetylation" ], "offsets": [ [ 571, 582 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-10753885_T15" }, { "role": "Theme", "ref_id": "PMID-10753885_T9" } ] }, { "id": "PMID-10753885_E32", "type": "Acetylation", "trigger": { "text": [ "Acetylation" ], "offsets": [ [ 690, 701 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10753885_T16" } ] }, { "id": "PMID-10753885_E33", "type": "Positive_regulation", "trigger": { "text": [ "increases" ], "offsets": [ [ 741, 750 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10753885_E32" }, { "role": "Theme", "ref_id": "PMID-10753885_E34" } ] }, { "id": "PMID-10753885_E34", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 755, 762 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10753885_T16" }, { "role": "Theme", "ref_id": "PMID-10753885_T17" } ] }, { "id": "PMID-10753885_E35", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 833, 841 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10753885_E32" }, { "role": "Theme", "ref_id": "PMID-10753885_E36" } ] }, { "id": "PMID-10753885_E36", "type": "Activation", "trigger": { "text": [ "transactivation" ], "offsets": [ [ 842, 857 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10753885_T18" } ] }, { "id": "PMID-10753885_E37", "type": "Acetylation", "trigger": { "text": [ "t" ], "offsets": [ [ 896, 897 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10753885_T19" } ] }, { "id": "PMID-10753885_E38", "type": "Negative_regulation", "trigger": { "text": [ "reversed" ], "offsets": [ [ 917, 925 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10753885_E37" }, { "role": "Cause", "ref_id": "PMID-10753885_T20" } ] }, { "id": "PMID-10753885_E39", "type": "Negative_regulation", "trigger": { "text": [ "reversible" ], "offsets": [ [ 968, 978 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10753885_E40" } ] }, { "id": "PMID-10753885_E40", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 979, 990 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10753885_T19" } ] } ]

[]

[]

[ { "id": "PMID-10777476__text", "type": "abstract", "text": [ "Mechanism of reaction of myeloperoxidase with nitrite. \nMyeloperoxidase (MPO) is a major neutrophil protein and may be involved in the nitration of tyrosine residues observed in a wide range of inflammatory diseases that involve neutrophils and macrophage activation. In order to clarify if nitrite could be a physiological substrate of myeloperoxidase, we investigated the reactions of the ferric enzyme and its redox intermediates, compound I and compound II, with nitrite under pre-steady state conditions by using sequential mixing stopped-flow analysis in the pH range 4-8. At 15 degrees C the rate of formation of the low spin MPO-nitrite complex is (2.5 +/- 0.2) x 10(4) m(-1) s(-1) at pH 7 and (2.2 +/- 0.7) x 10(6) m(-1) s(-1) at pH 5. The dissociation constant of nitrite bound to the native enzyme is 2.3 +/- 0.1 mm at pH 7 and 31.3 +/- 0.5 micrometer at pH 5. Nitrite is oxidized by two one-electron steps in the MPO peroxidase cycle. The second-order rate constant of reduction of compound I to compound II at 15 degrees C is (2.0 +/- 0.2) x 10(6) m(-1) s(-1) at pH 7 and (1.1 +/- 0.2) x 10(7) m(-1) s(-1) at pH 5. The rate constant of reduction of compound II to the ferric native enzyme at 15 degrees C is (5.5 +/- 0.1) x 10(2) m(-1) s(-1) at pH 7 and (8.9 +/- 1.6) x 10(4) m(-1) s(-1) at pH 5. pH dependence studies suggest that both complex formation between the ferric enzyme and nitrite and nitrite oxidation by compounds I and II are controlled by a residue with a pK(a) of (4.3 +/- 0.3). Protonation of this group (which is most likely the distal histidine) is necessary for optimum nitrite binding and oxidation.\n" ], "offsets": [ [ 0, 1635 ] ] } ]

[ { "id": "PMID-10777476_T1", "type": "Gene_or_gene_product", "text": [ "myeloperoxidase" ], "offsets": [ [ 25, 40 ] ], "normalized": [] }, { "id": "PMID-10777476_T2", "type": "Simple_chemical", "text": [ "nitrite" ], "offsets": [ [ 46, 53 ] ], "normalized": [] }, { "id": "PMID-10777476_T3", "type": "Gene_or_gene_product", "text": [ "Myeloperoxidase" ], "offsets": [ [ 56, 71 ] ], "normalized": [] }, { "id": "PMID-10777476_T4", "type": "Gene_or_gene_product", "text": [ "MPO" ], "offsets": [ [ 73, 76 ] ], "normalized": [] }, { "id": "PMID-10777476_T5", "type": "Simple_chemical", "text": [ "nitrite" ], "offsets": [ [ 291, 298 ] ], "normalized": [] }, { "id": "PMID-10777476_T6", "type": "Gene_or_gene_product", "text": [ "myeloperoxidase" ], "offsets": [ [ 337, 352 ] ], "normalized": [] }, { "id": "PMID-10777476_T7", "type": "Gene_or_gene_product", "text": [ "compound I" ], "offsets": [ [ 434, 444 ] ], "normalized": [] }, { "id": "PMID-10777476_T8", "type": "Gene_or_gene_product", "text": [ "compound II" ], "offsets": [ [ 449, 460 ] ], "normalized": [] }, { "id": "PMID-10777476_T9", "type": "Simple_chemical", "text": [ "nitrite" ], "offsets": [ [ 467, 474 ] ], "normalized": [] }, { "id": "PMID-10777476_T10", "type": "Gene_or_gene_product", "text": [ "MPO" ], "offsets": [ [ 633, 636 ] ], "normalized": [] }, { "id": "PMID-10777476_T11", "type": "Simple_chemical", "text": [ "nitrite" ], "offsets": [ [ 637, 644 ] ], "normalized": [] }, { "id": "PMID-10777476_T12", "type": "Simple_chemical", "text": [ "nitrite" ], "offsets": [ [ 774, 781 ] ], "normalized": [] }, { "id": "PMID-10777476_T13", "type": "Simple_chemical", "text": [ "Nitrite" ], "offsets": [ [ 872, 879 ] ], "normalized": [] }, { "id": "PMID-10777476_T14", "type": "Gene_or_gene_product", "text": [ "MPO" ], "offsets": [ [ 925, 928 ] ], "normalized": [] }, { "id": "PMID-10777476_T15", "type": "Gene_or_gene_product", "text": [ "compound I" ], "offsets": [ [ 994, 1004 ] ], "normalized": [] }, { "id": "PMID-10777476_T16", "type": "Gene_or_gene_product", "text": [ "compound II" ], "offsets": [ [ 1008, 1019 ] ], "normalized": [] }, { "id": "PMID-10777476_T17", "type": "Gene_or_gene_product", "text": [ "compound II" ], "offsets": [ [ 1162, 1173 ] ], "normalized": [] }, { "id": "PMID-10777476_T18", "type": "Simple_chemical", "text": [ "nitrite" ], "offsets": [ [ 1398, 1405 ] ], "normalized": [] }, { "id": "PMID-10777476_T19", "type": "Simple_chemical", "text": [ "nitrite" ], "offsets": [ [ 1410, 1417 ] ], "normalized": [] }, { "id": "PMID-10777476_T20", "type": "Gene_or_gene_product", "text": [ "compounds I" ], "offsets": [ [ 1431, 1442 ] ], "normalized": [] }, { "id": "PMID-10777476_T21", "type": "Gene_or_gene_product", "text": [ "II" ], "offsets": [ [ 1447, 1449 ] ], "normalized": [] }, { "id": "PMID-10777476_T22", "type": "Simple_chemical", "text": [ "histidine" ], "offsets": [ [ 1568, 1577 ] ], "normalized": [] }, { "id": "PMID-10777476_T23", "type": "Simple_chemical", "text": [ "nitrite" ], "offsets": [ [ 1604, 1611 ] ], "normalized": [] } ]

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[ { "id": "PMID-10777476_1", "entity_ids": [ "PMID-10777476_T3", "PMID-10777476_T4" ] } ]

[]

[ { "id": "PMID-10811867__text", "type": "abstract", "text": [ "Bruton's tyrosine kinase is required for activation of IkappaB kinase and nuclear factor kappaB in response to B cell receptor engagement. \nMutations in the gene encoding Bruton's tyrosine kinase (btk) cause the B cell deficiency diseases X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. In vivo and in vitro studies indicate that the BTK protein is essential for B cell survival, cell cycle progression, and proliferation in response to B cell antigen receptor (BCR) stimulation. BCR stimulation leads to the activation of transcription factor nuclear factor (NF)-kappaB, which in turn regulates genes controlling B cell growth. We now demonstrate that a null mutation in btk known to cause the xid phenotype prevents BCR-induced activation of NF-kappaB. This defect can be rescued by reconstitution with wild-type BTK. This mutation also interferes with BCR-directed activation of IkappaB kinase (IKK), which normally targets the NF-kappaB inhibitor IkappaBalpha for degradation. Taken together, these findings indicate that BTK couples IKK and NF-kappaB to the BCR. Interference with this coupling mechanism may contribute to the B cell deficiencies observed in XLA and xid.\n" ], "offsets": [ [ 0, 1218 ] ] } ]

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[]

[ { "id": "PMID-10837071__text", "type": "abstract", "text": [ "Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. \nNF-kappaB (nuclear factor-kappaB) is a collective name for inducible dimeric transcription factors composed of members of the Rel family of DNA-binding proteins that recognize a common sequence motif. NF-kappaB is found in essentially all cell types and is involved in activation of an exceptionally large number of genes in response to infections, inflammation, and other stressful situations requiring rapid reprogramming of gene expression. NF-kappaB is normally sequestered in the cytoplasm of nonstimulated cells and consequently must be translocated into the nucleus to function. The subcellular location of NF-kappaB is controlled by a family of inhibitory proteins, IkappaBs, which bind NF-kappaB and mask its nuclear localization signal, thereby preventing nuclear uptake. Exposure of cells to a variety of extracellular stimuli leads to the rapid phosphorylation, ubiquitination, and ultimately proteolytic degradation of IkappaB, which frees NF-kappaB to translocate to the nucleus where it regulates gene transcription. NF-kappaB activation represents a paradigm for controlling the function of a regulatory protein via ubiquitination-dependent proteolysis, as an integral part of a phosphorylationbased signaling cascade. Recently, considerable progress has been made in understanding the details of the signaling pathways that regulate NF-kappaB activity, particularly those responding to the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1. The multisubunit IkappaB kinase (IKK) responsible for inducible IkappaB phosphorylation is the point of convergence for most NF-kappaB-activating stimuli. IKK contains two catalytic subunits, IKKalpha and IKKbeta, both of which are able to correctly phosphorylate IkappaB. Gene knockout studies have shed light on the very different physiological functions of IKKalpha and IKKbeta. After phosphorylation, the IKK phosphoacceptor sites on IkappaB serve as an essential part of a specific recognition site for E3RS(IkappaB/beta-TrCP), an SCF-type E3 ubiquitin ligase, thereby explaining how IKK controls IkappaB ubiquitination and degradation. A variety of other signaling events, including phosphorylation of NF-kappaB, hyperphosphorylation of IKK, induction of IkappaB synthesis, and the processing of NF-kappaB precursors, provide additional mechanisms that modulate the level and duration of NF-kappaB activity. \n" ], "offsets": [ [ 0, 2471 ] ] } ]

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[]

[ { "id": "PMID-10873608__text", "type": "abstract", "text": [ "p63 and p73 transactivate differentiation gene promoters in human keratinocytes. \np53 and its two homologues, p73 and p63, share considerable structural similarities, an ability to interact between themselves and to transactivate the same promoters, including for example p21. Furthermore, p73 can induce cell death via its interaction with c-Abl. In contrast, p63 has been demonstrated to be essential for limb and skin formation. We evaluated the expression of p63 and p73 in differentiating human keratinocytes in vitro. Skin biopsy and primary cultures of normal human epidermal keratinocytes (NHEK) express both p73 and p63. NHEK induced to differentiate in vitro by high calcium exposure show induction of p73 delta and downregulation of all isoforms of p63. This latter gene is predominantly expressed in its transcriptionally inactive form, DeltaNp63. We further evaluated the effect of either p73s or p63 transfected in either NHEK or transformed human keratinocytes (HaCat cells). p73 gamma, delta, and p63 were able to transactivate the promoters of loricrin and involucrin in both NHEK and HaCat cells. These results suggest the involvement of both p73 and p63 genes in keratinocyte terminal differentiation.\n" ], "offsets": [ [ 0, 1221 ] ] } ]

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"arguments": [ { "role": "Theme", "ref_id": "PMID-10873608_T13" } ] }, { "id": "PMID-10873608_E10", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 699, 708 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10873608_T15" } ] }, { "id": "PMID-10873608_E11", "type": "Negative_regulation", "trigger": { "text": [ "downregulation" ], "offsets": [ [ 726, 740 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10873608_T16" } ] }, { "id": "PMID-10873608_E12", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 799, 808 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10873608_T16" } ] }, { "id": "PMID-10873608_E13", "type": "Inactivation", "trigger": { "text": [ "inactive" ], "offsets": [ [ 834, 842 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10873608_T17" } ] }, { "id": "PMID-10873608_E14", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 885, 891 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10873608_T18" } ] }, { "id": "PMID-10873608_E15", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 885, 891 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10873608_T19" } ] }, { "id": "PMID-10873608_E16", "type": "Positive_regulation", "trigger": { "text": [ "transactivate" ], "offsets": [ [ 1030, 1043 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10873608_T20" }, { "role": "Theme", "ref_id": "PMID-10873608_T23" } ] }, { "id": "PMID-10873608_E17", "type": "Positive_regulation", "trigger": { "text": [ "transactivate" ], "offsets": [ [ 1030, 1043 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10873608_T21" }, { "role": "Theme", "ref_id": "PMID-10873608_T23" } ] }, { "id": "PMID-10873608_E18", "type": "Positive_regulation", "trigger": { "text": [ "transactivate" ], "offsets": [ [ 1030, 1043 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10873608_T22" }, { "role": "Theme", "ref_id": "PMID-10873608_T23" } ] }, { "id": "PMID-10873608_E19", "type": "Positive_regulation", "trigger": { "text": [ "transactivate" ], "offsets": [ [ 1030, 1043 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10873608_T20" }, { "role": "Theme", "ref_id": "PMID-10873608_T24" } ] }, { "id": "PMID-10873608_E20", "type": "Positive_regulation", "trigger": { "text": [ "transactivate" ], "offsets": [ [ 1030, 1043 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10873608_T21" }, { "role": "Theme", "ref_id": "PMID-10873608_T24" } ] }, { "id": "PMID-10873608_E21", "type": "Positive_regulation", "trigger": { "text": [ "transactivate" ], "offsets": [ [ 1030, 1043 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10873608_T22" }, { "role": "Theme", "ref_id": "PMID-10873608_T24" } ] }, { "id": "PMID-10873608_E22", "type": "Regulation", "trigger": { "text": [ "involvement" ], "offsets": [ [ 1141, 1152 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10873608_T25" } ] }, { "id": "PMID-10873608_E23", "type": "Regulation", "trigger": { "text": [ "involvement" ], "offsets": [ [ 1141, 1152 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10873608_T26" } ] } ]

[]

[]

[ { "id": "PMID-10899305__text", "type": "abstract", "text": [ "Translocation of Akt/PKB to the nucleus of osteoblast-like MC3T3-E1 cells exposed to proliferative growth factors. \nAn active phosphatidylinositol 3-kinase (PI3K) has been shown in nuclei of different cell types. The products of this enzyme, i.e. inositides phosphorylated in the D3 position of the inositol ring, may act as second messengers themselves. Nuclear PI3K translocation has been demonstrated to be related to an analogous translocation of a PtdIns(3,4,5)P(3) activated PKC, the zeta isozyme. We have examined the issue of whether or not in the osteoblast-like clonal cell line MC3T3-E1 there may be observed an insulin-like growth factor-I- (IGF-I) and platelet-derived growth factor- (PDGF) dependent nuclear translocation of an active Akt/PKB. Western blot analysis showed a maximal nuclear translocation after 20 min of IGF-I stimulation or after 30 min of PDGF treatment. Both growth factors increased rapidly and transiently the enzyme activity of immunoprecipitable nuclear Akt/PKB on a similar time scale and after 60 min the values were slightly higher than the basal levels. Enzyme translocation was blocked by the specific PI3K inhibitor, LY294002, as well as cell entry into S-phase. Confocal microscopy showed an evident increase in immunostaining intensity in the nuclear interior after growth factor treatment but no changes in the subcellular distribution of Akt/PKB when a LY294002 pre-treatment was administered to the cells. These findings strongly suggest that the intranuclear translocation of Akt/PKB is an important step in signalling pathways that mediate cell proliferation.\n" ], "offsets": [ [ 0, 1611 ] ] } ]

[ { "id": "PMID-10899305_T1", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 17, 20 ] ], "normalized": [] }, { "id": "PMID-10899305_T2", "type": "Gene_or_gene_product", "text": [ "PKB" ], "offsets": [ [ 21, 24 ] ], "normalized": [] }, { "id": "PMID-10899305_T3", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 32, 39 ] ], "normalized": [] }, { "id": "PMID-10899305_T4", "type": "Gene_or_gene_product", "text": [ "phosphatidylinositol 3-kinase" ], "offsets": [ [ 126, 155 ] ], "normalized": [] }, { "id": "PMID-10899305_T5", "type": "Gene_or_gene_product", "text": [ "PI3K" ], "offsets": [ [ 157, 161 ] ], "normalized": [] }, { "id": "PMID-10899305_T6", "type": "Cellular_component", "text": [ "nuclei" ], "offsets": [ [ 181, 187 ] ], "normalized": [] }, { "id": "PMID-10899305_T7", "type": "Simple_chemical", "text": [ "inositides" ], "offsets": [ [ 247, 257 ] ], "normalized": [] }, { "id": "PMID-10899305_T8", "type": "Simple_chemical", "text": [ "inositol" ], "offsets": [ [ 299, 307 ] ], "normalized": [] }, { "id": "PMID-10899305_T9", "type": "Cellular_component", "text": [ "Nuclear" ], "offsets": [ [ 355, 362 ] ], "normalized": [] }, { "id": "PMID-10899305_T10", "type": "Gene_or_gene_product", "text": [ "PI3K" ], "offsets": [ [ 363, 367 ] ], "normalized": [] }, { "id": "PMID-10899305_T11", "type": "Simple_chemical", "text": [ "PtdIns(3,4,5)P(3)" ], "offsets": [ [ 453, 470 ] ], "normalized": [] }, { "id": "PMID-10899305_T12", "type": "Gene_or_gene_product", "text": [ "PKC" ], "offsets": [ [ 481, 484 ] ], "normalized": [] }, { "id": "PMID-10899305_T13", "type": "Gene_or_gene_product", "text": [ "insulin-like growth factor-I" ], "offsets": [ [ 623, 651 ] ], "normalized": [] }, { "id": "PMID-10899305_T14", "type": "Gene_or_gene_product", "text": [ "IGF-I" ], "offsets": [ [ 654, 659 ] ], "normalized": [] }, { "id": "PMID-10899305_T15", "type": "Gene_or_gene_product", "text": [ "platelet-derived growth factor-" ], "offsets": [ [ 665, 696 ] ], "normalized": [] }, { "id": "PMID-10899305_T16", "type": "Gene_or_gene_product", "text": [ "PDGF" ], "offsets": [ [ 698, 702 ] ], "normalized": [] }, { "id": "PMID-10899305_T17", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 714, 721 ] ], "normalized": [] }, { "id": "PMID-10899305_T18", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 749, 752 ] ], "normalized": [] }, { "id": "PMID-10899305_T19", "type": "Gene_or_gene_product", "text": [ "PKB" ], "offsets": [ [ 753, 756 ] ], "normalized": [] }, { "id": "PMID-10899305_T20", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 797, 804 ] ], "normalized": [] }, { "id": "PMID-10899305_T21", "type": "Gene_or_gene_product", "text": [ "IGF-I" ], "offsets": [ [ 835, 840 ] ], "normalized": [] }, { "id": "PMID-10899305_T22", "type": "Gene_or_gene_product", "text": [ "PDGF" ], "offsets": [ [ 872, 876 ] ], "normalized": [] }, { "id": "PMID-10899305_T23", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 984, 991 ] ], "normalized": [] }, { "id": "PMID-10899305_T24", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 992, 995 ] ], "normalized": [] }, { "id": "PMID-10899305_T25", "type": "Gene_or_gene_product", "text": [ "PKB" ], "offsets": [ [ 996, 999 ] ], "normalized": [] }, { "id": "PMID-10899305_T26", "type": "Gene_or_gene_product", "text": [ "PI3K" ], "offsets": [ [ 1145, 1149 ] ], "normalized": [] }, { "id": "PMID-10899305_T27", "type": "Simple_chemical", "text": [ "LY294002" ], "offsets": [ [ 1161, 1169 ] ], "normalized": [] }, { "id": "PMID-10899305_T28", "type": "Cellular_component", "text": [ "nuclear interior" ], "offsets": [ [ 1289, 1305 ] ], "normalized": [] }, { "id": "PMID-10899305_T29", "type": "Cellular_component", "text": [ "subcellular" ], "offsets": [ [ 1358, 1369 ] ], "normalized": [] }, { "id": "PMID-10899305_T30", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 1386, 1389 ] ], "normalized": [] }, { "id": "PMID-10899305_T31", "type": "Gene_or_gene_product", "text": [ "PKB" ], "offsets": [ [ 1390, 1393 ] ], "normalized": [] }, { "id": "PMID-10899305_T32", "type": "Simple_chemical", "text": [ "LY294002" ], "offsets": [ [ 1401, 1409 ] ], "normalized": [] }, { "id": "PMID-10899305_T33", "type": "Cellular_component", "text": [ "intranuclear" ], "offsets": [ [ 1496, 1508 ] ], "normalized": [] }, { "id": "PMID-10899305_T34", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 1526, 1529 ] ], "normalized": [] }, { "id": "PMID-10899305_T35", "type": "Gene_or_gene_product", "text": [ "PKB" ], "offsets": [ [ 1530, 1533 ] ], "normalized": [] } ]

[ { "id": "PMID-10899305_E1", "type": "Transport", "trigger": { "text": [ "Translocation" ], "offsets": [ [ 0, 13 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10899305_T1" }, { "role": "ToLoc", "ref_id": "PMID-10899305_T3" } ] }, { "id": "PMID-10899305_E2", "type": "Activation", "trigger": { "text": [ "active" ], "offsets": [ [ 119, 125 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10899305_T4" } ] }, { "id": "PMID-10899305_E3", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 258, 272 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10899305_T7" } ] }, { "id": "PMID-10899305_E4", "type": "Transport", "trigger": { "text": [ "translocation" ], "offsets": [ [ 368, 381 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10899305_T10" }, { "role": "ToLoc", "ref_id": "PMID-10899305_T9" } ] }, { "id": "PMID-10899305_E5", "type": "Transport", "trigger": { "text": [ "translocation" ], "offsets": [ [ 434, 447 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10899305_T12" } ] }, { "id": "PMID-10899305_E6", "type": "Activation", "trigger": { "text": [ "activated" ], "offsets": [ [ 471, 480 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10899305_T11" }, { "role": "Theme", "ref_id": "PMID-10899305_T12" } ] }, { "id": "PMID-10899305_E7", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 704, 713 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10899305_E9" }, { "role": "Cause", "ref_id": "PMID-10899305_T13" } ] }, { "id": "PMID-10899305_E8", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 704, 713 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10899305_E9" }, { "role": "Cause", "ref_id": "PMID-10899305_T15" } ] }, { "id": "PMID-10899305_E9", "type": "Transport", "trigger": { "text": [ "translocation" ], "offsets": [ [ 722, 735 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-10899305_T17" }, { "role": "Theme", "ref_id": "PMID-10899305_T18" } ] }, { "id": "PMID-10899305_E10", "type": "Activation", "trigger": { "text": [ "active" ], "offsets": [ [ 742, 748 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10899305_T18" } ] }, { "id": "PMID-10899305_E11", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 908, 917 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10899305_T24" } ] }, { "id": "PMID-10899305_E12", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 1150, 1159 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10899305_T26" }, { "role": "Cause", "ref_id": "PMID-10899305_T27" } ] }, { "id": "PMID-10899305_E13", "type": "Transport", "trigger": { "text": [ "translocation" ], "offsets": [ [ 1509, 1522 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-10899305_T33" }, { "role": "Theme", "ref_id": "PMID-10899305_T34" } ] } ]

[ { "id": "PMID-10899305_1", "entity_ids": [ "PMID-10899305_T1", "PMID-10899305_T2" ] }, { "id": "PMID-10899305_2", "entity_ids": [ "PMID-10899305_T4", "PMID-10899305_T5" ] }, { "id": "PMID-10899305_3", "entity_ids": [ "PMID-10899305_T13", "PMID-10899305_T14" ] }, { "id": "PMID-10899305_4", "entity_ids": [ "PMID-10899305_T15", "PMID-10899305_T16" ] }, { "id": "PMID-10899305_5", "entity_ids": [ "PMID-10899305_T18", "PMID-10899305_T19" ] }, { "id": "PMID-10899305_6", "entity_ids": [ "PMID-10899305_T24", "PMID-10899305_T25" ] }, { "id": "PMID-10899305_7", "entity_ids": [ "PMID-10899305_T30", "PMID-10899305_T31" ] }, { "id": "PMID-10899305_8", "entity_ids": [ "PMID-10899305_T34", "PMID-10899305_T35" ] } ]

[]

[ { "id": "PMID-10915796__text", "type": "abstract", "text": [ "Characterization of a cDNA encoding a novel human Golgi alpha 1, 2-mannosidase (IC) involved in N-glycan biosynthesis. \nA human cDNA encoding a 70.9-kDa type II membrane protein with sequence similarity to class I alpha1,2-mannosidases was isolated. The enzymatic properties of the novel alpha1,2-mannosidase IC were studied by expressing its catalytic domain in Pichia pastoris as a secreted glycoprotein. alpha1,2-Mannosidase IC sequentially hydrolyzes the alpha1,2-linked mannose residues of [(3)H]mannose-labeled Man(9)GlcNAc to form [(3)H]Man(6)GlcNAc and a small amount of [(3)H]Man(5)GlcNAc. The enzyme requires calcium for activity and is inhibited by both 1-deoxymannojirimycin and kifunensine. The order of mannose removal was determined by separating oligosaccharide isomers formed from pyridylaminated Man(9)GlcNAc(2) by high performance liquid chromatography. The terminal alpha1,2-linked mannose residue from the middle branch is the last mannose removed by the enzyme. This residue is the mannose cleaved from Man(9)GlcNAc(2) by the endoplasmic reticulum alpha1, 2-mannosidase I to form Man(8)GlcNAc(2) isomer B. The order of mannose hydrolysis from either pyridylaminated Man(9)GlcNAc(2) or Man(8)GlcNAc(2) isomer B differs from that previously reported for mammalian Golgi alpha1,2-mannosidases IA and IB. The full-length alpha1,2-mannosidase IC was localized to the Golgi of MDBK and MDCK cells by indirect immunofluorescence. Northern blot analysis showed tissue-specific expression of a major transcript of 3.8 kilobase pairs. The expression pattern is different from that of human Golgi alpha1,2-mannosidases IA and IB. Therefore, the human genome contains at least three differentially regulated Golgi alpha1, 2-mannosidase genes encoding enzymes with similar, but not identical specificities.\n" ], "offsets": [ [ 0, 1816 ] ] } ]

[ { "id": "PMID-10915796_T1", "type": "Cellular_component", "text": [ "Golgi" ], "offsets": [ [ 50, 55 ] ], "normalized": [] }, { "id": "PMID-10915796_T2", "type": "Gene_or_gene_product", "text": [ "alpha 1, 2-mannosidase" ], "offsets": [ [ 56, 78 ] ], "normalized": [] }, { "id": "PMID-10915796_T3", "type": "Gene_or_gene_product", "text": [ "IC" ], "offsets": [ [ 80, 82 ] ], "normalized": [] }, { "id": "PMID-10915796_T4", "type": "Simple_chemical", "text": [ "N-glycan" ], "offsets": [ [ 96, 104 ] ], "normalized": [] }, { "id": "PMID-10915796_T5", "type": "Cellular_component", "text": [ "membrane" ], "offsets": [ [ 161, 169 ] ], "normalized": [] }, { "id": "PMID-10915796_T6", "type": "Gene_or_gene_product", "text": [ "class I alpha1,2-mannosidases" ], "offsets": [ [ 206, 235 ] ], "normalized": [] }, { "id": "PMID-10915796_T7", "type": "Gene_or_gene_product", "text": [ "alpha1,2-mannosidase IC" ], "offsets": [ [ 288, 311 ] ], "normalized": [] }, { "id": "PMID-10915796_T8", "type": "Gene_or_gene_product", "text": [ "alpha1,2-Mannosidase IC" ], "offsets": [ [ 407, 430 ] ], "normalized": [] }, { "id": "PMID-10915796_T9", "type": "Simple_chemical", "text": [ "mannose" ], "offsets": [ [ 475, 482 ] ], "normalized": [] }, { "id": "PMID-10915796_T10", "type": "Simple_chemical", "text": [ "[(3)H]mannose" ], "offsets": [ [ 495, 508 ] ], "normalized": [] }, { "id": "PMID-10915796_T11", "type": "Simple_chemical", "text": [ "Man(9)GlcNAc" ], "offsets": [ [ 517, 529 ] ], "normalized": [] }, { "id": "PMID-10915796_T12", "type": "Simple_chemical", "text": [ "[(3)H]Man(6)GlcNAc" ], "offsets": [ [ 538, 556 ] ], "normalized": [] }, { "id": "PMID-10915796_T13", "type": "Simple_chemical", "text": [ "[(3)H]Man(5)GlcNAc" ], "offsets": [ [ 579, 597 ] ], "normalized": [] }, { "id": "PMID-10915796_T14", "type": "Simple_chemical", "text": [ "calcium" ], "offsets": [ [ 619, 626 ] ], "normalized": [] }, { "id": "PMID-10915796_T15", "type": "Simple_chemical", "text": [ "1-deoxymannojirimycin" ], "offsets": [ [ 665, 686 ] ], "normalized": [] }, { "id": "PMID-10915796_T16", "type": "Simple_chemical", "text": [ "kifunensine" ], "offsets": [ [ 691, 702 ] ], "normalized": [] }, { "id": "PMID-10915796_T17", "type": "Simple_chemical", "text": [ "mannose" ], "offsets": [ [ 717, 724 ] ], "normalized": [] }, { "id": "PMID-10915796_T18", "type": "Simple_chemical", "text": [ "Man(9)GlcNAc(2)" ], "offsets": [ [ 814, 829 ] ], "normalized": [] }, { "id": "PMID-10915796_T19", "type": "Simple_chemical", "text": [ "mannose" ], "offsets": [ [ 902, 909 ] ], "normalized": [] }, { "id": "PMID-10915796_T20", "type": "Simple_chemical", "text": [ "mannose" ], "offsets": [ [ 953, 960 ] ], "normalized": [] }, { "id": "PMID-10915796_T21", "type": "Simple_chemical", "text": [ "mannose" ], "offsets": [ [ 1004, 1011 ] ], "normalized": [] }, { "id": "PMID-10915796_T22", "type": "Simple_chemical", "text": [ "Man(9)GlcNAc(2)" ], "offsets": [ [ 1025, 1040 ] ], "normalized": [] }, { "id": "PMID-10915796_T23", "type": "Cellular_component", "text": [ "endoplasmic reticulum" ], "offsets": [ [ 1048, 1069 ] ], "normalized": [] }, { "id": "PMID-10915796_T24", "type": "Gene_or_gene_product", "text": [ "alpha1, 2-mannosidase I" ], "offsets": [ [ 1070, 1093 ] ], "normalized": [] }, { "id": "PMID-10915796_T25", "type": "Simple_chemical", "text": [ "Man(8)GlcNAc(2) isomer B" ], "offsets": [ [ 1102, 1126 ] ], "normalized": [] }, { "id": "PMID-10915796_T26", "type": "Simple_chemical", "text": [ "mannose" ], "offsets": [ [ 1141, 1148 ] ], "normalized": [] }, { "id": "PMID-10915796_T27", "type": "Simple_chemical", "text": [ "Man(9)GlcNAc(2)" ], "offsets": [ [ 1188, 1203 ] ], "normalized": [] }, { "id": "PMID-10915796_T28", "type": "Simple_chemical", "text": [ "Man(8)GlcNAc(2) isomer B" ], "offsets": [ [ 1207, 1231 ] ], "normalized": [] }, { "id": "PMID-10915796_T29", "type": "Cellular_component", "text": [ "Golgi" ], "offsets": [ [ 1284, 1289 ] ], "normalized": [] }, { "id": "PMID-10915796_T30", "type": "Gene_or_gene_product", "text": [ "alpha1,2-mannosidases IA" ], "offsets": [ [ 1290, 1314 ] ], "normalized": [] }, { "id": "PMID-10915796_T31", "type": "Gene_or_gene_product", "text": [ "IB" ], "offsets": [ [ 1319, 1321 ] ], "normalized": [] }, { "id": "PMID-10915796_T32", "type": "Gene_or_gene_product", "text": [ "alpha1,2-mannosidase IC" ], "offsets": [ [ 1339, 1362 ] ], "normalized": [] }, { "id": "PMID-10915796_T33", "type": "Cellular_component", "text": [ "Golgi" ], "offsets": [ [ 1384, 1389 ] ], "normalized": [] }, { "id": "PMID-10915796_T34", "type": "Cellular_component", "text": [ "Golgi" ], "offsets": [ [ 1602, 1607 ] ], "normalized": [] }, { "id": "PMID-10915796_T35", "type": "Gene_or_gene_product", "text": [ "alpha1,2-mannosidases IA" ], "offsets": [ [ 1608, 1632 ] ], "normalized": [] }, { "id": "PMID-10915796_T36", "type": "Gene_or_gene_product", "text": [ "IB" ], "offsets": [ [ 1637, 1639 ] ], "normalized": [] }, { "id": "PMID-10915796_T37", 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[]

[]

[ { "id": "PMID-10918611__text", "type": "abstract", "text": [ "SCF(beta-TRCP) and phosphorylation dependent ubiquitinationof I kappa B alpha catalyzed by Ubc3 and Ubc4. \nNF kappa B is an important transcriptional regulator of multiple pro-inflammatory genes. In non-stimulated cells NF kappa B is anchored in the cytoplasm via the inhibitory protein I kappa B alpha. Following exposure to diverse pro-inflammatory signals (e.g. TNF alpha, IL1, LPS) various signal transduction cascades are initiated converging on the I kappa B kinase (IKK). IKK phosphorylates I kappa B alpha on serines 32 and 36 signaling the inhibitory protein for ubiquitin-mediated degradation. The SCF beta-TRCP complex is the ubiquitin ligase responsible for mediating phosphorylation dependent ubiquitination of I kappa B alpha. Here we reconstitute phosphorylation dependent ubiquitination of I kappa B alpha using recombinant components. Our results suggest that the cullin specificity of the SCF complex may reflect its ability to associate with Rbx1. We demonstrate specific ubiquitination of I kappa B alpha by Ubc3 and Ubc4 in a phosphorylation and SCF beta-TRCP dependent manner and that both are capable of associating with the SCF beta-TRCP complex isolated from human cells. Finally, we show that Ubc4 is in excess to Ubc3 in THP.1 cells and 19 times more efficient in catalyzing the reaction, suggesting that Ubc4 is the preferentially used Ubc in this reaction in vivo. Our results also suggest that ubiquitin is transferred directly from the Ubc to phospho-I kappa B alpha in a SCF beta-TRCP dependent reaction. Oncogene (2000) 19, 3529 - 3536\n" ], "offsets": [ [ 0, 1569 ] ] } ]

[ { "id": "PMID-10918611_T1", "type": "Complex", "text": [ "SCF(beta-TRCP)" ], "offsets": [ [ 0, 14 ] ], "normalized": [] }, { "id": "PMID-10918611_T2", "type": "Gene_or_gene_product", "text": [ "I kappa B alpha" ], "offsets": [ [ 62, 77 ] ], "normalized": [] }, { "id": "PMID-10918611_T3", "type": "Gene_or_gene_product", "text": [ "Ubc3" ], "offsets": [ [ 91, 95 ] ], "normalized": [] }, { "id": "PMID-10918611_T4", "type": "Gene_or_gene_product", "text": [ "Ubc4" ], "offsets": [ [ 100, 104 ] ], "normalized": [] }, { "id": "PMID-10918611_T5", "type": "Complex", "text": [ "NF kappa B" ], "offsets": [ [ 107, 117 ] ], "normalized": [] }, { "id": "PMID-10918611_T6", "type": "Complex", "text": [ "NF kappa B" ], "offsets": [ [ 220, 230 ] ], "normalized": [] }, { "id": "PMID-10918611_T7", "type": "Cellular_component", "text": [ "cytoplasm" ], "offsets": [ [ 250, 259 ] ], "normalized": [] }, { "id": "PMID-10918611_T8", "type": "Gene_or_gene_product", "text": [ "I kappa B alpha" ], "offsets": [ [ 287, 302 ] ], "normalized": [] }, { "id": "PMID-10918611_T9", "type": "Gene_or_gene_product", "text": [ "TNF alpha" ], "offsets": [ [ 365, 374 ] ], "normalized": [] }, { "id": "PMID-10918611_T10", "type": "Gene_or_gene_product", "text": [ "IL1" ], "offsets": [ [ 376, 379 ] ], "normalized": [] }, { "id": "PMID-10918611_T11", "type": "Simple_chemical", "text": [ "LPS" ], "offsets": [ [ 381, 384 ] ], "normalized": [] }, { "id": "PMID-10918611_T12", "type": "Complex", "text": [ "I kappa B kinase" ], "offsets": [ [ 455, 471 ] ], "normalized": [] }, { "id": "PMID-10918611_T13", "type": "Complex", "text": [ "IKK" ], "offsets": [ [ 473, 476 ] ], "normalized": [] }, { "id": "PMID-10918611_T14", "type": "Complex", "text": [ "IKK" ], "offsets": [ [ 479, 482 ] ], "normalized": [] }, { "id": "PMID-10918611_T15", "type": "Gene_or_gene_product", "text": [ "I kappa B alpha" ], "offsets": [ [ 498, 513 ] ], "normalized": [] }, { "id": "PMID-10918611_T16", "type": "Simple_chemical", "text": [ "serines 32" ], "offsets": [ [ 517, 527 ] ], "normalized": [] }, { "id": "PMID-10918611_T17", "type": "Simple_chemical", "text": [ "36" ], "offsets": [ [ 532, 534 ] ], "normalized": [] }, { "id": "PMID-10918611_T18", "type": "Gene_or_gene_product", "text": [ "ubiquitin" ], "offsets": [ [ 572, 581 ] ], "normalized": [] }, { "id": "PMID-10918611_T19", "type": "Complex", "text": [ "SCF beta-TRCP" ], "offsets": [ [ 608, 621 ] ], "normalized": [] }, { "id": "PMID-10918611_T20", "type": "Gene_or_gene_product", "text": [ "ubiquitin" ], "offsets": [ [ 637, 646 ] ], "normalized": [] }, { "id": "PMID-10918611_T21", "type": "Gene_or_gene_product", "text": [ "I kappa B alpha" ], "offsets": [ [ 724, 739 ] ], "normalized": [] }, { "id": "PMID-10918611_T22", "type": "Gene_or_gene_product", "text": [ "I kappa B alpha" ], "offsets": [ [ 806, 821 ] ], "normalized": [] }, { "id": "PMID-10918611_T23", "type": "Gene_or_gene_product", "text": [ "cullin" ], "offsets": [ [ 881, 887 ] ], "normalized": [] }, { "id": "PMID-10918611_T24", "type": "Complex", "text": [ "SCF complex" ], "offsets": [ [ 907, 918 ] ], "normalized": [] }, { "id": "PMID-10918611_T25", "type": "Gene_or_gene_product", "text": [ "Rbx1" ], "offsets": [ [ 961, 965 ] ], "normalized": [] }, { "id": "PMID-10918611_T26", "type": "Gene_or_gene_product", "text": [ "I kappa B alpha" ], "offsets": [ [ 1009, 1024 ] ], "normalized": [] }, { "id": "PMID-10918611_T27", "type": "Gene_or_gene_product", "text": [ "Ubc3" ], "offsets": [ [ 1028, 1032 ] ], "normalized": [] }, { "id": "PMID-10918611_T28", "type": "Gene_or_gene_product", "text": [ "Ubc4" ], "offsets": [ [ 1037, 1041 ] ], "normalized": [] }, { "id": "PMID-10918611_T29", "type": "Complex", "text": [ "SCF beta-TRCP" ], "offsets": [ [ 1067, 1080 ] ], "normalized": [] }, { "id": "PMID-10918611_T30", "type": "Complex", "text": [ "SCF beta-TRCP" ], "offsets": [ [ 1148, 1161 ] ], "normalized": [] }, { "id": "PMID-10918611_T31", "type": "Gene_or_gene_product", "text": [ "Ubc4" ], "offsets": [ [ 1219, 1223 ] ], "normalized": [] }, { "id": "PMID-10918611_T32", "type": "Gene_or_gene_product", "text": [ "Ubc3" ], "offsets": [ [ 1240, 1244 ] ], "normalized": [] }, { "id": "PMID-10918611_T33", "type": "Gene_or_gene_product", "text": [ "Ubc4" ], "offsets": [ [ 1332, 1336 ] ], "normalized": [] }, { "id": "PMID-10918611_T34", "type": "Gene_or_gene_product", "text": [ "Ubc" ], "offsets": [ [ 1364, 1367 ] ], "normalized": [] }, { "id": "PMID-10918611_T35", "type": "Gene_or_gene_product", "text": [ "ubiquitin" ], "offsets": [ [ 1424, 1433 ] ], "normalized": [] }, { "id": "PMID-10918611_T36", "type": "Gene_or_gene_product", "text": [ "Ubc" ], "offsets": [ [ 1467, 1470 ] ], "normalized": [] }, { "id": "PMID-10918611_T37", "type": "Gene_or_gene_product", "text": [ "I kappa B alpha" ], "offsets": [ [ 1482, 1497 ] ], "normalized": [] }, { "id": "PMID-10918611_T38", "type": "Complex", "text": [ "SCF beta-TRCP" ], "offsets": [ [ 1503, 1516 ] ], "normalized": [] } ]

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[ 78, 87 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10918611_T3" }, { "role": "Theme", "ref_id": "PMID-10918611_E4" } ] }, { "id": "PMID-10918611_E6", "type": "Positive_regulation", "trigger": { "text": [ "catalyzed" ], "offsets": [ [ 78, 87 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10918611_T4" }, { "role": "Theme", "ref_id": "PMID-10918611_E4" } ] }, { "id": "PMID-10918611_E7", "type": "Localization", "trigger": { "text": [ "anchored" ], "offsets": [ [ 234, 242 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-10918611_T7" }, { "role": "Theme", "ref_id": "PMID-10918611_T6" } ] }, { "id": "PMID-10918611_E8", "type": "Pathway", "trigger": { "text": [ "cascades" ], "offsets": [ [ 414, 422 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-10918611_T9" }, { "role": "Participant", "ref_id": "PMID-10918611_T10" }, { "role": "Participant", "ref_id": "PMID-10918611_T11" }, { "role": "Participant", "ref_id": "PMID-10918611_T12" } ] }, { "id": "PMID-10918611_E9", "type": "Positive_regulation", "trigger": { "text": [ "initiated" ], "offsets": [ [ 427, 436 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10918611_E8" } ] }, { "id": "PMID-10918611_E10", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylates" ], "offsets": [ [ 483, 497 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10918611_T14" }, { "role": "Theme", "ref_id": "PMID-10918611_T15" }, { "role": "Site", "ref_id": "PMID-10918611_T16" } ] }, { "id": "PMID-10918611_E11", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylates" ], "offsets": [ [ 483, 497 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10918611_T14" }, { "role": "Theme", "ref_id": "PMID-10918611_T15" }, { "role": "Site", "ref_id": "PMID-10918611_T17" } ] }, { "id": "PMID-10918611_E12", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 582, 590 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10918611_T18" }, { "role": "Theme", "ref_id": "PMID-10918611_E13" } ] }, { "id": "PMID-10918611_E13", "type": "Degradation", "trigger": { "text": [ "degradation" ], "offsets": [ [ 591, 602 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10918611_T15" } ] }, { "id": "PMID-10918611_E14", "type": "Positive_regulation", "trigger": { "text": [ "mediating" ], "offsets": [ [ 670, 679 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10918611_E15" }, { "role": "Cause", "ref_id": "PMID-10918611_T19" } ] }, { "id": "PMID-10918611_E15", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 680, 695 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10918611_T21" } ] }, { "id": "PMID-10918611_E16", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 696, 705 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10918611_E17" }, { "role": "Cause", "ref_id": "PMID-10918611_E15" } ] }, { "id": "PMID-10918611_E17", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 706, 720 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10918611_T21" } ] }, { "id": "PMID-10918611_E18", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 762, 777 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10918611_T22" } ] }, { "id": "PMID-10918611_E19", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 778, 787 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10918611_E20" }, { "role": "Cause", "ref_id": "PMID-10918611_E18" } ] }, { "id": "PMID-10918611_E20", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 788, 802 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10918611_T22" } ] }, { "id": "PMID-10918611_E21", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 991, 1005 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10918611_T26" }, { "role": "Cause", "ref_id": "PMID-10918611_T27" } ] }, { "id": "PMID-10918611_E22", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 991, 1005 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10918611_T26" }, { "role": "Cause", "ref_id": "PMID-10918611_T28" } ] }, { "id": "PMID-10918611_E23", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1047, 1062 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10918611_T26" } ] }, { "id": "PMID-10918611_E24", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1081, 1090 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10918611_E22" }, { "role": "Cause", "ref_id": "PMID-10918611_E23" } ] }, { "id": "PMID-10918611_E25", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1081, 1090 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10918611_E21" }, { "role": "Cause", "ref_id": "PMID-10918611_E23" } ] }, { "id": "PMID-10918611_E26", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1081, 1090 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10918611_E22" }, { "role": "Cause", "ref_id": "PMID-10918611_T29" } ] }, { "id": "PMID-10918611_E27", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1081, 1090 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10918611_E21" }, { "role": "Cause", "ref_id": "PMID-10918611_T29" } ] }, { "id": "PMID-10918611_E28", "type": "Transport", "trigger": { "text": [ "isolated" ], "offsets": [ [ 1170, 1178 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10918611_T30" } ] }, { "id": "PMID-10918611_E29", "type": "Transport", "trigger": { "text": [ "transferred" ], "offsets": [ [ 1437, 1448 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10918611_T35" } ] }, { "id": "PMID-10918611_E30", "type": "Phosphorylation", "trigger": { "text": [ "phospho" ], "offsets": [ [ 1474, 1481 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10918611_T37" } ] }, { "id": "PMID-10918611_E31", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1517, 1526 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10918611_T38" }, { "role": "Theme", "ref_id": "PMID-10918611_E29" } ] } ]

[ { "id": "PMID-10918611_1", "entity_ids": [ "PMID-10918611_T12", "PMID-10918611_T13" ] } ]

[]

[ { "id": "PMID-10975521__text", "type": "abstract", "text": [ "Regulation of transcription by ubiquitination without proteolysis: Cdc34/SCF(Met30)-mediated inactivation of the transcription factor Met4. \nPolyubiquitination of proteins by Cdc34/SCF complexes targets them for degradation by the 26S proteasome. The essential F-box protein Met30 is the substrate recognition subunit of the ubiquitin ligase SCF(Met30). The critical target of SCF(Met30) is the transcription factor Met4, as deletion of MET4 suppresses the lethality of met30 mutants. Surprisingly, Met4 is a relatively stable protein and its abundance is not influenced by Met30. However, transcriptional repression of Met4 target genes correlates with Cdc34/SCF(Met30)-dependent ubiquitination of Met4. Functionally, ubiquitinated Met4 associates with target promoters but fails to form functional transcription complexes. Our data reveal a novel proteolysis-independent function for Cdc34/SCF and indicate that ubiquitination of transcription factors can be utilized to directly regulate their activities.\n" ], "offsets": [ [ 0, 1009 ] ] } ]

[ { "id": "PMID-10975521_T1", "type": "Complex", "text": [ "Cdc34/SCF(Met30)" ], "offsets": [ [ 67, 83 ] ], "normalized": [] }, { "id": "PMID-10975521_T2", "type": "Gene_or_gene_product", "text": [ "Met4" ], "offsets": [ [ 134, 138 ] ], "normalized": [] }, { "id": "PMID-10975521_T3", "type": "Complex", "text": [ "Cdc34/SCF" ], "offsets": [ [ 175, 184 ] ], "normalized": [] }, { "id": "PMID-10975521_T4", "type": "Cellular_component", "text": [ "26S proteasome" ], "offsets": [ [ 231, 245 ] ], "normalized": [] }, { "id": "PMID-10975521_T5", "type": "Gene_or_gene_product", "text": [ "Met30" ], "offsets": [ [ 275, 280 ] ], "normalized": [] }, { "id": "PMID-10975521_T6", "type": "Gene_or_gene_product", "text": [ "ubiquitin" ], "offsets": [ [ 325, 334 ] ], "normalized": [] }, { "id": "PMID-10975521_T7", "type": "Complex", "text": [ "SCF(Met30)" ], "offsets": [ [ 342, 352 ] ], "normalized": [] }, { "id": "PMID-10975521_T8", "type": "Complex", "text": [ "SCF(Met30)" ], "offsets": [ [ 377, 387 ] ], "normalized": [] }, { "id": "PMID-10975521_T9", "type": "Gene_or_gene_product", "text": [ "Met4" ], "offsets": [ [ 416, 420 ] ], "normalized": [] }, { "id": "PMID-10975521_T10", "type": "Gene_or_gene_product", "text": [ "MET4" ], "offsets": [ [ 437, 441 ] ], "normalized": [] }, { "id": "PMID-10975521_T11", "type": "Gene_or_gene_product", "text": [ "met30" ], "offsets": [ [ 470, 475 ] ], "normalized": [] }, { "id": "PMID-10975521_T12", "type": "Gene_or_gene_product", "text": [ "Met4" ], "offsets": [ [ 499, 503 ] ], "normalized": [] }, { "id": "PMID-10975521_T13", "type": "Gene_or_gene_product", "text": [ "Met30" ], "offsets": [ [ 574, 579 ] ], "normalized": [] }, { "id": "PMID-10975521_T14", "type": "Gene_or_gene_product", "text": [ "Met4" ], "offsets": [ [ 620, 624 ] ], "normalized": [] }, { "id": "PMID-10975521_T15", "type": "Complex", "text": [ "Cdc34/SCF(Met30)" ], "offsets": [ [ 654, 670 ] ], "normalized": [] }, { "id": "PMID-10975521_T16", "type": "Gene_or_gene_product", "text": [ "Met4" ], "offsets": [ [ 699, 703 ] ], "normalized": [] }, { "id": "PMID-10975521_T17", "type": "Gene_or_gene_product", "text": [ "Met4" ], "offsets": [ [ 733, 737 ] ], "normalized": [] }, { "id": "PMID-10975521_T18", "type": "Complex", "text": [ "Cdc34/SCF" ], "offsets": [ [ 886, 895 ] ], "normalized": [] } ]

[ { "id": "PMID-10975521_E1", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 84, 92 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10975521_T1" }, { "role": "Theme", "ref_id": "PMID-10975521_E2" } ] }, { "id": "PMID-10975521_E2", "type": "Inactivation", "trigger": { "text": [ "inactivation" ], "offsets": [ [ 93, 105 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10975521_T2" } ] }, { "id": "PMID-10975521_E3", "type": "Regulation", "trigger": { "text": [ "target" ], "offsets": [ [ 367, 373 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10975521_T8" }, { "role": "Theme", "ref_id": "PMID-10975521_T9" } ] }, { "id": "PMID-10975521_E4", "type": "Inactivation", "trigger": { "text": [ "deletion" ], "offsets": [ [ 425, 433 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10975521_T10" } ] }, { "id": "PMID-10975521_E5", "type": "Regulation", "trigger": { "text": [ "influenced" ], "offsets": [ [ 560, 570 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10975521_T13" }, { "role": "Theme", "ref_id": "PMID-10975521_T12" } ] }, { "id": "PMID-10975521_E6", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 671, 680 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-10975521_T15" }, { "role": "Theme", "ref_id": "PMID-10975521_E7" } ] }, { "id": "PMID-10975521_E7", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 681, 695 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-10975521_T16" } ] } ]

[]

[]

[ { "id": "PMID-11101520__text", "type": "abstract", "text": [ "Nud1p links astral microtubule organization and the control of exit from mitosis. \nThe budding yeast spindle pole body (SPB) not only organizes the astral and nuclear microtubules but is also associated with a number of cell-cycle regulators that control mitotic exit. Here, we describe that the core SPB component Nud1p is a key protein that functions in both processes. The astral microtubule organizing function of Nud1p is mediated by its interaction with the gamma-tubulin complex binding protein Spc72p. This function of Nud1p is distinct from its role in cell-cycle control: Nud1p binds the spindle checkpoint control proteins Bfa1p and Bub2p to the SPB, and is part of the mitotic exit network (MEN) in which it functions upstream of CDC15 but downstream of LTE1. In conditional lethal nud1-2 cells, the MEN component Tem1p, a GTPase, is mislocalized, whereas the kinase Cdc15p is still associated with the SPB. Thus, in nud1-2 cells the failure of Tem1p to interact with Cdc15p at the SPB probably prevents mitotic exit.\n" ], "offsets": [ [ 0, 1030 ] ] } ]

[ { "id": "PMID-11101520_T1", "type": "Gene_or_gene_product", "text": [ "Nud1p" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMID-11101520_T2", "type": "Cellular_component", "text": [ "astral microtubule" ], "offsets": [ [ 12, 30 ] ], "normalized": [] }, { "id": "PMID-11101520_T3", "type": "Cellular_component", "text": [ "spindle pole body" ], "offsets": [ [ 101, 118 ] ], "normalized": [] }, { "id": "PMID-11101520_T4", "type": "Cellular_component", "text": [ "SPB" ], "offsets": [ [ 120, 123 ] ], "normalized": [] }, { "id": "PMID-11101520_T5", "type": "Cellular_component", "text": [ "astral" ], "offsets": [ [ 148, 154 ] ], "normalized": [] }, { "id": "PMID-11101520_T6", "type": "Cellular_component", "text": [ "nuclear microtubules" ], "offsets": [ [ 159, 179 ] ], "normalized": [] }, { "id": "PMID-11101520_T7", "type": "Cellular_component", "text": [ "SPB" ], "offsets": [ [ 301, 304 ] ], "normalized": [] }, { "id": "PMID-11101520_T8", "type": "Gene_or_gene_product", "text": [ "Nud1p" ], "offsets": [ [ 315, 320 ] ], "normalized": [] }, { "id": "PMID-11101520_T9", "type": "Cellular_component", "text": [ "astral microtubule" ], "offsets": [ [ 376, 394 ] ], "normalized": [] }, { "id": "PMID-11101520_T10", "type": "Gene_or_gene_product", "text": [ "Nud1p" ], "offsets": [ [ 418, 423 ] ], "normalized": [] }, { "id": "PMID-11101520_T11", "type": "Complex", "text": [ "gamma-tubulin" ], "offsets": [ [ 464, 477 ] ], "normalized": [] }, { "id": "PMID-11101520_T12", "type": "Gene_or_gene_product", "text": [ "Spc72p" ], "offsets": [ [ 502, 508 ] ], "normalized": [] }, { "id": "PMID-11101520_T13", "type": "Gene_or_gene_product", "text": [ "Nud1p" ], "offsets": [ [ 527, 532 ] ], "normalized": [] }, { "id": "PMID-11101520_T14", "type": "Gene_or_gene_product", "text": [ "Nud1p" ], "offsets": [ [ 582, 587 ] ], "normalized": [] }, { "id": "PMID-11101520_T15", "type": "Cellular_component", "text": [ "spindle" ], "offsets": [ [ 598, 605 ] ], "normalized": [] }, { "id": "PMID-11101520_T16", "type": "Gene_or_gene_product", "text": [ "Bfa1p" ], "offsets": [ [ 634, 639 ] ], "normalized": [] }, { "id": "PMID-11101520_T17", "type": "Gene_or_gene_product", "text": [ "Bub2p" ], "offsets": [ [ 644, 649 ] ], "normalized": [] }, { "id": "PMID-11101520_T18", "type": "Cellular_component", "text": [ "SPB" ], "offsets": [ [ 657, 660 ] ], "normalized": [] }, { "id": "PMID-11101520_T19", "type": "Gene_or_gene_product", "text": [ "CDC15" ], "offsets": [ [ 742, 747 ] ], "normalized": [] }, { "id": "PMID-11101520_T20", "type": "Gene_or_gene_product", "text": [ "LTE1" ], "offsets": [ [ 766, 770 ] ], "normalized": [] }, { "id": "PMID-11101520_T21", "type": "Gene_or_gene_product", "text": [ "nud1-2" ], "offsets": [ [ 794, 800 ] ], "normalized": [] }, { "id": "PMID-11101520_T22", "type": "Gene_or_gene_product", "text": [ "Tem1p" ], "offsets": [ [ 826, 831 ] ], "normalized": [] }, { "id": "PMID-11101520_T23", "type": "Gene_or_gene_product", "text": [ "Cdc15p" ], "offsets": [ [ 879, 885 ] ], "normalized": [] }, { "id": "PMID-11101520_T24", "type": "Cellular_component", "text": [ "SPB" ], "offsets": [ [ 915, 918 ] ], "normalized": [] }, { "id": "PMID-11101520_T25", "type": "Gene_or_gene_product", "text": [ "nud1-2" ], "offsets": [ [ 929, 935 ] ], "normalized": [] }, { "id": "PMID-11101520_T26", "type": "Gene_or_gene_product", "text": [ "Tem1p" ], "offsets": [ [ 957, 962 ] ], "normalized": [] }, { "id": "PMID-11101520_T27", "type": "Gene_or_gene_product", "text": [ "Cdc15p" ], "offsets": [ [ 980, 986 ] ], "normalized": [] }, { "id": "PMID-11101520_T28", "type": "Cellular_component", "text": [ "SPB" ], "offsets": [ [ 994, 997 ] ], "normalized": [] } ]

[ { "id": "PMID-11101520_E1", "type": "Pathway", "trigger": { "text": [ "cell-cycle" ], "offsets": [ [ 220, 230 ] ] }, "arguments": [] }, { "id": "PMID-11101520_E2", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 427, 435 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11101520_T10" }, { "role": "Cause", "ref_id": "PMID-11101520_E3" } ] }, { "id": "PMID-11101520_E3", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 443, 454 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11101520_T10" }, { "role": "Theme", "ref_id": "PMID-11101520_T12" } ] }, { "id": "PMID-11101520_E4", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 486, 493 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11101520_T12" }, { "role": "Theme", "ref_id": "PMID-11101520_T11" } ] }, { "id": "PMID-11101520_E5", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 554, 558 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11101520_E7" } ] }, { "id": "PMID-11101520_E6", "type": "Pathway", "trigger": { "text": [ "cell-cycle" ], "offsets": [ [ 562, 572 ] ] }, "arguments": [] }, { "id": "PMID-11101520_E7", "type": "Regulation", "trigger": { "text": [ "control" ], "offsets": [ [ 573, 580 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11101520_E6" } ] }, { "id": "PMID-11101520_E8", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 588, 593 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11101520_T16" }, { "role": "Theme", "ref_id": "PMID-11101520_T14" } ] }, { "id": "PMID-11101520_E9", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 588, 593 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11101520_T17" }, { "role": "Theme", "ref_id": "PMID-11101520_T14" } ] }, { "id": "PMID-11101520_E10", "type": "Localization", "trigger": { "text": [ "mislocalized" ], "offsets": [ [ 846, 858 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11101520_T22" } ] }, { "id": "PMID-11101520_E11", "type": "Binding", "trigger": { "text": [ "associated" ], "offsets": [ [ 895, 905 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11101520_T23" } ] }, { "id": "PMID-11101520_E12", "type": "Binding", "trigger": { "text": [ "interact" ], "offsets": [ [ 966, 974 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11101520_T27" }, { "role": "Theme", "ref_id": "PMID-11101520_T26" } ] } ]

[ { "id": "PMID-11101520_1", "entity_ids": [ "PMID-11101520_T3", "PMID-11101520_T4" ] } ]

[]

[ { "id": "PMID-11101877__text", "type": "abstract", "text": [ "Toll-like receptor 2-mediated NF-kappa B activation requires a Rac1-dependent pathway. \nMammalian Toll-like receptors (TLRs) are expressed on innate immune cells and respond to the membrane components of Gram-positive or Gram-negative bacteria. When activated, they convey signals to transcription factors that orchestrate the inflammatory response. However, the intracellular signaling events following TLR activation are largely unknown. Here we show that TLR2 stimulation by Staphylococcus aureus induces a fast and transient activation of the Rho GTPases Rac1 and Cdc42 in the human monocytic cell line THP-1 and in 293 cells expressing TLR2. Dominant-negative Rac1N17, but not dominant-negative Cdc42N17, block nuclear factor-kappa B (NF-kappa B) transactivation. S. aureus stimulation causes the recruitment of active Rac1 and phosphatidylinositol-3 kinase (PI3K) to the TLR2 cytosolic domain. Tyrosine phosphorylation of TLR2 is required for assembly of a multiprotein complex that is necessary for subsequent NF-kappa B transcriptional activity. A signaling cascade composed of Rac1, PI3K and Akt targets nuclear p65 transactivation independently of I kappa B alpha degradation. Thus Rac1 controls a second, I kappa B-independent, pathway to NF-kappa B activation and is essential in innate immune cell signaling via TLR2.\n" ], "offsets": [ [ 0, 1331 ] ] } ]

[ { "id": "PMID-11101877_T1", "type": "Gene_or_gene_product", "text": [ "Toll-like receptor 2" ], "offsets": [ [ 0, 20 ] ], "normalized": [] }, { "id": "PMID-11101877_T2", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 30, 40 ] ], "normalized": [] }, { "id": "PMID-11101877_T3", "type": "Gene_or_gene_product", "text": [ "Rac1" ], "offsets": [ [ 63, 67 ] ], "normalized": [] }, { "id": "PMID-11101877_T4", "type": "Gene_or_gene_product", "text": [ "Toll-like receptors" ], "offsets": [ [ 98, 117 ] ], "normalized": [] }, { "id": "PMID-11101877_T5", "type": "Gene_or_gene_product", "text": [ "TLRs" ], "offsets": [ [ 119, 123 ] ], "normalized": [] }, { "id": "PMID-11101877_T6", "type": "Cellular_component", "text": [ "membrane components" ], "offsets": [ [ 181, 200 ] ], "normalized": [] }, { "id": "PMID-11101877_T7", "type": "Cellular_component", "text": [ "intracellular" ], "offsets": [ [ 363, 376 ] ], "normalized": [] }, { "id": "PMID-11101877_T8", "type": "Gene_or_gene_product", "text": [ "TLR" ], "offsets": [ [ 404, 407 ] ], "normalized": [] }, { "id": "PMID-11101877_T9", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 458, 462 ] ], "normalized": [] }, { "id": "PMID-11101877_T10", "type": "Gene_or_gene_product", "text": [ "Rho" ], "offsets": [ [ 547, 550 ] ], "normalized": [] }, { "id": "PMID-11101877_T11", "type": "Gene_or_gene_product", "text": [ "Rac1" ], "offsets": [ [ 559, 563 ] ], "normalized": [] }, { "id": "PMID-11101877_T12", "type": "Gene_or_gene_product", "text": [ "Cdc42" ], "offsets": [ [ 568, 573 ] ], "normalized": [] }, { "id": "PMID-11101877_T13", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 641, 645 ] ], "normalized": [] }, { "id": "PMID-11101877_T14", "type": "Gene_or_gene_product", "text": [ "Rac1N17" ], "offsets": [ [ 665, 672 ] ], "normalized": [] }, { "id": "PMID-11101877_T15", "type": "Gene_or_gene_product", "text": [ "Cdc42N17" ], "offsets": [ [ 700, 708 ] ], "normalized": [] }, { "id": "PMID-11101877_T16", "type": "Complex", "text": [ "nuclear factor-kappa B" ], "offsets": [ [ 716, 738 ] ], "normalized": [] }, { "id": "PMID-11101877_T17", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 740, 750 ] ], "normalized": [] }, { "id": "PMID-11101877_T18", "type": "Gene_or_gene_product", "text": [ "Rac1" ], "offsets": [ [ 824, 828 ] ], "normalized": [] }, { "id": "PMID-11101877_T19", "type": "Gene_or_gene_product", "text": [ "phosphatidylinositol-3 kinase" ], "offsets": [ [ 833, 862 ] ], "normalized": [] }, { "id": "PMID-11101877_T20", "type": "Gene_or_gene_product", "text": [ "PI3K" ], "offsets": [ [ 864, 868 ] ], "normalized": [] }, { "id": "PMID-11101877_T21", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 877, 881 ] ], "normalized": [] }, { "id": "PMID-11101877_T22", "type": "Cellular_component", "text": [ "cytosolic" ], "offsets": [ [ 882, 891 ] ], "normalized": [] }, { "id": "PMID-11101877_T23", "type": "Simple_chemical", "text": [ "Tyrosine" ], "offsets": [ [ 900, 908 ] ], "normalized": [] }, { "id": "PMID-11101877_T24", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 928, 932 ] ], "normalized": [] }, { "id": "PMID-11101877_T25", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 1017, 1027 ] ], "normalized": [] }, { "id": "PMID-11101877_T26", "type": "Gene_or_gene_product", "text": [ "Rac1" ], "offsets": [ [ 1086, 1090 ] ], "normalized": [] }, { "id": "PMID-11101877_T27", "type": "Gene_or_gene_product", "text": [ "PI3K" ], "offsets": [ [ 1092, 1096 ] ], "normalized": [] }, { "id": "PMID-11101877_T28", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 1101, 1104 ] ], "normalized": [] }, { "id": "PMID-11101877_T29", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 1113, 1120 ] ], "normalized": [] }, { "id": "PMID-11101877_T30", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 1121, 1124 ] ], "normalized": [] }, { "id": "PMID-11101877_T31", "type": "Gene_or_gene_product", "text": [ "I kappa B alpha" ], "offsets": [ [ 1158, 1173 ] ], "normalized": [] }, { "id": "PMID-11101877_T32", "type": "Gene_or_gene_product", "text": [ "Rac1" ], "offsets": [ [ 1192, 1196 ] ], "normalized": [] }, { "id": "PMID-11101877_T33", "type": "Gene_or_gene_product", "text": [ "I kappa B" ], "offsets": [ [ 1216, 1225 ] ], "normalized": [] }, { "id": "PMID-11101877_T34", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 1250, 1260 ] ], "normalized": [] }, { "id": "PMID-11101877_T35", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 1325, 1329 ] ], "normalized": [] } ]

[ { "id": "PMID-11101877_E1", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 21, 29 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11101877_T1" }, { "role": "Theme", "ref_id": "PMID-11101877_E2" } ] }, { "id": "PMID-11101877_E2", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 41, 51 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11101877_T2" } ] }, { "id": "PMID-11101877_E3", "type": "Positive_regulation", "trigger": { "text": [ "requires" ], "offsets": [ [ 52, 60 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11101877_E5" }, { "role": "Cause", "ref_id": "PMID-11101877_E2" } ] }, { "id": "PMID-11101877_E4", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 68, 77 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11101877_T3" }, { "role": "Theme", "ref_id": "PMID-11101877_E5" } ] }, { "id": "PMID-11101877_E5", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 78, 85 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-11101877_T3" } ] }, { "id": "PMID-11101877_E6", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 129, 138 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11101877_T4" } ] }, { "id": "PMID-11101877_E7", "type": "Activation", "trigger": { "text": [ "activated" ], "offsets": [ [ 250, 259 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11101877_T4" } ] }, { "id": "PMID-11101877_E8", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 408, 418 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11101877_T8" } ] }, { "id": "PMID-11101877_E9", "type": "Positive_regulation", "trigger": { "text": [ "stimulation" ], "offsets": [ [ 463, 474 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11101877_T9" } ] }, { "id": "PMID-11101877_E10", "type": "Positive_regulation", "trigger": { "text": [ "induces" ], "offsets": [ 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"PMID-11101877_T11" } ] }, { "id": "PMID-11101877_E15", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 529, 539 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11101877_T12" } ] }, { "id": "PMID-11101877_E16", "type": "Gene_expression", "trigger": { "text": [ "expressing" ], "offsets": [ [ 630, 640 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11101877_T13" } ] }, { "id": "PMID-11101877_E17", "type": "Negative_regulation", "trigger": { "text": [ "block" ], "offsets": [ [ 710, 715 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11101877_T14" }, { "role": "Theme", "ref_id": "PMID-11101877_E19" } ] }, { "id": "PMID-11101877_E18", "type": "Negative_regulation", "trigger": { "text": [ "block" ], "offsets": [ [ 710, 715 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11101877_T15" }, { "role": "Theme", "ref_id": "PMID-11101877_E19" } ] }, { "id": "PMID-11101877_E19", "type": "Positive_regulation", "trigger": { "text": [ "transactivation" ], "offsets": [ [ 752, 767 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11101877_T16" } ] }, { "id": "PMID-11101877_E20", "type": "Transport", "trigger": { "text": [ "recruitment" ], "offsets": [ [ 802, 813 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-11101877_T22" }, { "role": "Theme", "ref_id": "PMID-11101877_T18" } ] }, { "id": "PMID-11101877_E21", "type": "Transport", "trigger": { "text": [ "recruitment" ], "offsets": [ [ 802, 813 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-11101877_T22" }, { "role": "Theme", "ref_id": "PMID-11101877_T19" } ] }, { "id": "PMID-11101877_E22", "type": "Activation", "trigger": { "text": [ "active" ], "offsets": [ [ 817, 823 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11101877_T18" } ] }, { "id": "PMID-11101877_E23", "type": "Activation", "trigger": { "text": [ "active" ], "offsets": [ [ 817, 823 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11101877_T19" } ] }, { "id": "PMID-11101877_E24", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 909, 924 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-11101877_T23" }, { "role": "Theme", "ref_id": "PMID-11101877_T24" } ] }, { "id": "PMID-11101877_E25", "type": "Positive_regulation", "trigger": { "text": [ "necessary" ], "offsets": [ [ 992, 1001 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11101877_T25" } ] }, { "id": "PMID-11101877_E26", "type": "Pathway", "trigger": { "text": [ "cascade" ], "offsets": [ [ 1066, 1073 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-11101877_T26" }, { "role": "Participant", "ref_id": "PMID-11101877_T27" }, { "role": "Participant", "ref_id": "PMID-11101877_T28" } ] }, { "id": "PMID-11101877_E27", "type": "Regulation", "trigger": { "text": [ "targets" ], "offsets": [ [ 1105, 1112 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11101877_E28" }, { "role": "Cause", "ref_id": "PMID-11101877_E26" } ] }, { 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[ { "id": "PMID-11101877_1", "entity_ids": [ "PMID-11101877_T4", "PMID-11101877_T5" ] }, { "id": "PMID-11101877_2", "entity_ids": [ "PMID-11101877_T16", "PMID-11101877_T17" ] }, { "id": "PMID-11101877_3", "entity_ids": [ "PMID-11101877_T19", "PMID-11101877_T20" ] } ]

[]

[ { "id": "PMID-11139340__text", "type": "abstract", "text": [ "p53-independent upregulation of KILLER/DR5 TRAIL receptor expression by glucocorticoids and interferon-gamma. \nKILLER/DR5 is a death-domain-containing proapoptotic receptor that binds to the cytotoxic ligand TRAIL. It was originally reported that induction of KILLER/DR5 mRNA following DNA damage was p53-dependent, but some drugs that induce apoptosis can upregulate KILLER/DR5 mRNA expression in cell lines with mutated p53. We further extend those findings by classifying the capability of various apoptosis-inducing drugs to increase the expression of KILLER/DR5 mRNA in a p53-independent manner. beta-Lapachone, a topoisomerase inhibitor, increased KILLER/DR5 mRNA in colon cancer cell lines with wild-type p53 but not with mutant p53. In contrast, betulinic acid, a novel chemotherapeutic compound, induced apoptosis and KILLER/DR5 mRNA in melanoma and glioblastoma cells through a p53-independent mechanism. The synthetic glucocorticoid dexamethasone elevated KILLER/DR5 mRNA in glioblastoma, ovarian cancer, and colon cancer cell lines with mutant p53 undergoing apoptosis, and this induction was inhibited by the transcriptional inhibitor actinomycin D. Although another glucocorticoid, prednisolone, also induced apoptosis, it did not increase KILLER/DR5 mRNA. Finally, the cytokine interferon-gamma (IFN-gamma) induced apoptosis and KILLER/DR5 in cell lines with mutant p53, and the induction of KILLER/DR5 mRNA by IFN-gamma was delayed in cells lacking wild-type STAT1, a transcription factor implicated in IFN-gamma signaling. Similarly, the induction of KILLER/DR5 mRNA by the cytokine TNF-alpha was also delayed in cell lines with mutated STAT1. These findings suggest that KILLER/DR5 may play a role in p53-independent apoptosis induced by specific drugs and warrants further investigation as a novel target for chemotherapy of tumors lacking wild-type p53.\n" ], "offsets": [ [ 0, 1874 ] ] } ]

[ { "id": "PMID-11139340_T1", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 0, 3 ] ], "normalized": [] }, { "id": "PMID-11139340_T2", "type": "Gene_or_gene_product", "text": [ "KILLER" ], "offsets": [ [ 32, 38 ] ], "normalized": [] }, { "id": "PMID-11139340_T3", "type": "Gene_or_gene_product", "text": [ "DR5" ], "offsets": [ [ 39, 42 ] ], "normalized": [] }, { "id": "PMID-11139340_T4", "type": "Gene_or_gene_product", "text": [ "TRAIL" ], "offsets": [ [ 43, 48 ] ], "normalized": [] }, { "id": "PMID-11139340_T5", "type": "Simple_chemical", "text": [ "glucocorticoids" ], "offsets": [ [ 72, 87 ] ], "normalized": [] }, { "id": "PMID-11139340_T6", "type": "Gene_or_gene_product", "text": [ "interferon-gamma" ], "offsets": [ [ 92, 108 ] ], "normalized": [] }, { "id": "PMID-11139340_T7", "type": "Gene_or_gene_product", "text": [ "KILLER" ], "offsets": [ [ 111, 117 ] ], "normalized": [] }, { "id": "PMID-11139340_T8", "type": "Gene_or_gene_product", "text": [ "DR5" ], "offsets": [ [ 118, 121 ] ], "normalized": [] }, { "id": "PMID-11139340_T9", "type": "Gene_or_gene_product", "text": [ "proapoptotic" ], "offsets": [ [ 151, 163 ] ], "normalized": [] }, { "id": "PMID-11139340_T10", "type": "Gene_or_gene_product", "text": [ "TRAIL" ], "offsets": [ [ 208, 213 ] ], "normalized": [] }, { "id": "PMID-11139340_T11", "type": "Gene_or_gene_product", "text": [ "KILLER" ], "offsets": [ [ 260, 266 ] ], "normalized": [] }, { "id": "PMID-11139340_T12", "type": "Gene_or_gene_product", "text": [ "DR5" ], "offsets": [ [ 267, 270 ] ], "normalized": [] }, { "id": "PMID-11139340_T13", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 301, 304 ] ], "normalized": [] }, { "id": "PMID-11139340_T14", "type": "Gene_or_gene_product", "text": [ "KILLER" ], "offsets": [ [ 368, 374 ] ], "normalized": [] }, { "id": "PMID-11139340_T15", "type": "Gene_or_gene_product", "text": [ "DR5" ], "offsets": [ [ 375, 378 ] ], "normalized": [] }, { "id": "PMID-11139340_T16", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 422, 425 ] ], "normalized": [] }, { "id": "PMID-11139340_T17", "type": "Gene_or_gene_product", "text": [ "KILLER" ], "offsets": [ [ 556, 562 ] ], "normalized": [] }, { "id": "PMID-11139340_T18", "type": "Gene_or_gene_product", "text": [ "DR5" ], "offsets": [ [ 563, 566 ] ], "normalized": [] }, { "id": "PMID-11139340_T19", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 577, 580 ] ], "normalized": [] }, { "id": "PMID-11139340_T20", "type": "Gene_or_gene_product", "text": [ "beta-Lapachone" ], "offsets": [ [ 601, 615 ] ], "normalized": [] }, { "id": "PMID-11139340_T21", "type": "Gene_or_gene_product", "text": [ "KILLER" ], "offsets": [ [ 654, 660 ] ], "normalized": [] }, { "id": "PMID-11139340_T22", "type": "Gene_or_gene_product", "text": [ "DR5" ], "offsets": [ [ 661, 664 ] ], "normalized": [] }, { "id": "PMID-11139340_T23", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 712, 715 ] ], "normalized": [] }, { "id": "PMID-11139340_T24", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 736, 739 ] ], "normalized": [] }, { "id": "PMID-11139340_T25", "type": "Simple_chemical", "text": [ "betulinic acid" ], "offsets": [ [ 754, 768 ] ], "normalized": [] }, { "id": "PMID-11139340_T26", "type": "Gene_or_gene_product", "text": [ "KILLER" ], "offsets": [ [ 827, 833 ] ], "normalized": [] }, { "id": "PMID-11139340_T27", "type": "Gene_or_gene_product", "text": [ "DR5" ], "offsets": [ [ 834, 837 ] ], "normalized": [] }, { "id": "PMID-11139340_T28", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 888, 891 ] ], "normalized": [] }, { "id": "PMID-11139340_T29", "type": "Simple_chemical", "text": [ "glucocorticoid" ], "offsets": [ [ 929, 943 ] ], "normalized": [] }, { "id": "PMID-11139340_T30", "type": "Simple_chemical", "text": [ "dexamethasone" ], "offsets": [ [ 944, 957 ] ], "normalized": [] }, { "id": "PMID-11139340_T31", "type": "Gene_or_gene_product", "text": [ "KILLER" ], "offsets": [ [ 967, 973 ] ], "normalized": [] }, { "id": "PMID-11139340_T32", "type": "Gene_or_gene_product", "text": [ "DR5" ], "offsets": [ [ 974, 977 ] ], "normalized": [] }, { "id": "PMID-11139340_T33", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1056, 1059 ] ], "normalized": [] }, { "id": "PMID-11139340_T34", "type": "Gene_or_gene_product", "text": [ "actinomycin D" ], "offsets": [ [ 1148, 1161 ] ], "normalized": [] }, { "id": "PMID-11139340_T35", "type": "Simple_chemical", "text": [ "glucocorticoid" ], "offsets": [ [ 1180, 1194 ] ], "normalized": [] }, { "id": "PMID-11139340_T36", "type": "Simple_chemical", "text": [ "prednisolone" ], "offsets": [ [ 1196, 1208 ] ], "normalized": [] }, { "id": "PMID-11139340_T37", "type": "Gene_or_gene_product", "text": [ "KILLER" ], "offsets": [ [ 1254, 1260 ] ], "normalized": [] }, { "id": "PMID-11139340_T38", "type": "Gene_or_gene_product", "text": [ "DR5" ], "offsets": [ [ 1261, 1264 ] ], "normalized": [] }, { "id": "PMID-11139340_T39", "type": "Gene_or_gene_product", "text": [ "interferon-gamma" ], "offsets": [ [ 1293, 1309 ] ], "normalized": [] }, { "id": "PMID-11139340_T40", "type": "Gene_or_gene_product", "text": [ "IFN-gamma" ], "offsets": [ [ 1311, 1320 ] ], "normalized": [] }, { "id": "PMID-11139340_T41", "type": "Gene_or_gene_product", "text": [ "KILLER" ], "offsets": [ [ 1344, 1350 ] ], "normalized": [] }, { "id": "PMID-11139340_T42", "type": "Gene_or_gene_product", "text": [ "DR5" ], "offsets": [ [ 1351, 1354 ] ], "normalized": [] }, { "id": "PMID-11139340_T43", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1381, 1384 ] ], "normalized": [] }, { "id": "PMID-11139340_T44", "type": "Gene_or_gene_product", "text": [ "KILLER" ], "offsets": [ [ 1407, 1413 ] ], "normalized": [] }, { "id": "PMID-11139340_T45", "type": "Gene_or_gene_product", "text": [ "DR5" ], "offsets": [ [ 1414, 1417 ] ], "normalized": [] }, { "id": "PMID-11139340_T46", "type": "Gene_or_gene_product", "text": [ "IFN-gamma" ], "offsets": [ [ 1426, 1435 ] ], "normalized": [] }, { "id": "PMID-11139340_T47", "type": "Gene_or_gene_product", "text": [ "STAT1" ], "offsets": [ [ 1475, 1480 ] ], "normalized": [] }, { "id": "PMID-11139340_T48", "type": "Gene_or_gene_product", "text": [ "IFN-gamma" ], "offsets": [ [ 1519, 1528 ] ], "normalized": [] }, { "id": "PMID-11139340_T49", "type": "Gene_or_gene_product", "text": [ "KILLER" ], "offsets": [ [ 1568, 1574 ] ], "normalized": [] }, { "id": "PMID-11139340_T50", "type": "Gene_or_gene_product", "text": [ "DR5" ], "offsets": [ [ 1575, 1578 ] ], "normalized": [] }, { "id": "PMID-11139340_T51", "type": "Gene_or_gene_product", "text": [ "TNF-alpha" ], "offsets": [ [ 1600, 1609 ] ], "normalized": [] }, { "id": "PMID-11139340_T52", "type": "Gene_or_gene_product", "text": [ "STAT1" ], "offsets": [ [ 1654, 1659 ] ], "normalized": [] }, { "id": "PMID-11139340_T53", "type": "Gene_or_gene_product", "text": [ "KILLER" ], "offsets": [ [ 1689, 1695 ] ], "normalized": [] }, { "id": "PMID-11139340_T54", "type": "Gene_or_gene_product", "text": [ "DR5" ], "offsets": [ [ 1696, 1699 ] ], "normalized": [] }, { "id": "PMID-11139340_T55", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1719, 1722 ] ], "normalized": [] }, { "id": "PMID-11139340_T56", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1869, 1872 ] ], "normalized": [] } ]

[ { "id": "PMID-11139340_E1", "type": "Regulation", "trigger": { "text": [ "independent" ], "offsets": [ [ 4, 15 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11139340_T1" }, { "role": "Theme", "ref_id": "PMID-11139340_E3" } ] }, { "id": "PMID-11139340_E2", "type": "Regulation", "trigger": { "text": [ "independent" ], "offsets": [ [ 4, 15 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11139340_T1" }, { "role": "Theme", "ref_id": "PMID-11139340_E4" } ] }, { "id": "PMID-11139340_E3", "type": "Positive_regulation", "trigger": { "text": [ "upregulation" ], "offsets": [ [ 16, 28 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11139340_E5" }, { "role": "Cause", "ref_id": "PMID-11139340_T5" } ] }, { "id": "PMID-11139340_E4", "type": "Positive_regulation", "trigger": { "text": [ "upregulation" ], "offsets": [ [ 16, 28 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11139340_E5" }, { "role": "Cause", "ref_id": "PMID-11139340_T6" } ] }, { "id": "PMID-11139340_E5", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 58, 68 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11139340_T2" } ] }, { "id": "PMID-11139340_E6", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 178, 183 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11139340_T7" }, { "role": "Theme", "ref_id": "PMID-11139340_T10" } ] }, { "id": "PMID-11139340_E7", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 247, 256 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11139340_T11" } ] }, { "id": "PMID-11139340_E8", "type": "Regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 305, 314 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11139340_T13" }, { "role": "Theme", "ref_id": "PMID-11139340_E7" } ] }, { "id": "PMID-11139340_E9", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 336, 342 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11139340_E10" } ] }, { "id": "PMID-11139340_E10", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 343, 352 ] ] }, "arguments": [] }, { "id": "PMID-11139340_E11", "type": "Positive_regulation", "trigger": { "text": [ "upregulate" ], "offsets": [ [ 357, 367 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11139340_E12" } ] }, { "id": "PMID-11139340_E12", "type": "Transcription", "trigger": { "text": [ "mRNA expression" ], "offsets": [ [ 379, 394 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11139340_T14" } ] }, { "id": "PMID-11139340_E13", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 501, 510 ] ] }, "arguments": [] }, { "id": "PMID-11139340_E14", "type": "Positive_regulation", "trigger": { "text": [ "inducing" ], "offsets": [ [ 511, 519 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11139340_E13" } ] }, { "id": "PMID-11139340_E15", "type": "Positive_regulation", "trigger": { 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[]

[ { "id": "PMID-11171059__text", "type": "abstract", "text": [ "Phosphorylation of elongation factor-2 kinase on serine 499 by cAMP-dependent protein kinase induces Ca2+/calmodulin-independent activity. \nElongation factor-2 kinase (eEF-2K) negatively regulates mRNA translation via the phosphorylation and inactivation of elongation factor-2 (eEF-2). We have shown previously that purified eEF-2K can be phosphorylated in vitro by cAMP-dependent protein kinase (PKA) and that this induces significant Ca(2+)/calmodulin (CaM)-independent eEF-2K activity [Redpath and Proud (1993) Biochem. J. 293, 31-34]. Furthermore, elevation of cAMP levels in adipocytes also increases the level of Ca(2+)/CaM-independent eEF-2K activity to a similar extent, providing a mechanistic link between elevated cAMP and the inhibition of protein synthesis [Diggle, Redpath, Heesom and Denton (1998) Biochem. J. 336, 525-529]. Here we describe the expression of glutathione S-transferase (GST)-eEF-2K fusion protein and the identification of two serine residues that are phosphorylated by PKA in vitro. Endoproteinase Arg-C digestion of GST-eEF-2K produced two phosphopeptides that were separated by HPLC and sequenced. (32)P Radioactivity release from these peptides indicated that the sites of phosphorylation were Ser-365 and Ser-499, both of which lie C-terminal to the catalytic domain. Mutation of these sites to non-phosphorylatable residues indicated that both sites need to be phosphorylated to induce Ca(2+)/CaM-independent eEF-2K activity in vitro. However, expression of Myc-tagged eEF-2K in HEK 293 cells, followed by treatment with chlorophenylthio-cAMP (CPT-cAMP), showed that Ser-499 phosphorylation alone induced Ca(2+)/CaM-independent eEF-2K activity in cells. Co-expression of wild-type eEF-2K with luciferase resulted in a 2-3-fold reduction in luciferase expression. Expression of eEF-2K S499D resulted in a 10-fold reduction in luciferase expression despite the fact that this mutant was expressed at very low levels. This indicates that eEF-2K S499D is constitutively active when expressed in cells, thus leading to the suppression of its own expression. Our data demonstrate an important role for the phosphorylation of Ser-499 in the activation of eEF-2K by PKA and the inhibition of protein synthesis. \n" ], "offsets": [ [ 0, 2243 ] ] } ]

[ { "id": "PMID-11171059_T1", "type": "Gene_or_gene_product", "text": [ "elongation factor-2 kinase" ], "offsets": [ [ 19, 45 ] ], "normalized": [] }, { "id": "PMID-11171059_T2", "type": "Simple_chemical", "text": [ "serine 499" ], "offsets": [ [ 49, 59 ] ], "normalized": [] }, { "id": "PMID-11171059_T3", "type": "Complex", "text": [ "cAMP-dependent protein kinase" ], "offsets": [ [ 63, 92 ] ], "normalized": [] }, { "id": "PMID-11171059_T4", "type": "Simple_chemical", "text": [ "Ca2+" ], "offsets": [ [ 101, 105 ] ], "normalized": [] }, { "id": "PMID-11171059_T5", "type": "Gene_or_gene_product", "text": [ "calmodulin" ], "offsets": [ [ 106, 116 ] ], "normalized": [] }, { "id": "PMID-11171059_T6", "type": "Gene_or_gene_product", "text": [ "Elongation factor-2 kinase" ], "offsets": [ [ 140, 166 ] ], "normalized": [] }, { "id": "PMID-11171059_T7", "type": "Gene_or_gene_product", "text": [ "eEF-2K" ], "offsets": [ [ 168, 174 ] ], "normalized": [] }, { "id": "PMID-11171059_T8", "type": "Gene_or_gene_product", "text": [ "elongation factor-2" ], "offsets": [ [ 258, 277 ] ], "normalized": [] }, { "id": "PMID-11171059_T9", "type": "Gene_or_gene_product", "text": [ "eEF-2" ], "offsets": [ [ 279, 284 ] ], "normalized": [] }, { "id": "PMID-11171059_T10", "type": "Gene_or_gene_product", "text": [ "eEF-2K" ], "offsets": [ [ 326, 332 ] ], "normalized": [] }, { "id": "PMID-11171059_T11", "type": "Complex", "text": [ "cAMP-dependent protein kinase" ], "offsets": [ [ 367, 396 ] ], "normalized": [] }, { "id": "PMID-11171059_T12", "type": "Complex", "text": [ "PKA" ], "offsets": [ [ 398, 401 ] ], "normalized": [] }, { "id": "PMID-11171059_T13", "type": "Simple_chemical", "text": [ "Ca(2+)" ], "offsets": [ [ 437, 443 ] ], "normalized": [] }, { "id": "PMID-11171059_T14", "type": "Gene_or_gene_product", "text": [ "calmodulin" ], "offsets": [ [ 444, 454 ] ], "normalized": [] }, { "id": "PMID-11171059_T15", "type": "Gene_or_gene_product", "text": [ "CaM" ], "offsets": [ [ 456, 459 ] ], "normalized": [] }, { "id": "PMID-11171059_T16", "type": "Gene_or_gene_product", "text": [ "eEF-2K" ], "offsets": [ [ 473, 479 ] ], "normalized": [] }, { "id": "PMID-11171059_T17", "type": "Simple_chemical", "text": [ "cAMP" ], "offsets": [ [ 566, 570 ] ], "normalized": [] }, { "id": "PMID-11171059_T18", "type": "Simple_chemical", "text": [ "Ca(2+)" ], "offsets": [ [ 620, 626 ] ], "normalized": [] }, { "id": "PMID-11171059_T19", "type": "Gene_or_gene_product", "text": [ "CaM" ], "offsets": [ [ 627, 630 ] ], "normalized": [] }, { "id": "PMID-11171059_T20", "type": "Gene_or_gene_product", "text": [ "eEF-2K" ], "offsets": [ [ 643, 649 ] ], "normalized": [] }, { "id": "PMID-11171059_T21", "type": "Simple_chemical", "text": [ "cAMP" ], "offsets": [ [ 726, 730 ] ], "normalized": [] }, { "id": "PMID-11171059_T22", "type": "Gene_or_gene_product", "text": [ "glutathione S-transferase (GST)-eEF-2K" ], "offsets": [ [ 876, 914 ] ], "normalized": [] }, { "id": "PMID-11171059_T23", "type": "Simple_chemical", "text": [ "serine" ], "offsets": [ [ 960, 966 ] ], "normalized": [] }, { "id": "PMID-11171059_T24", "type": "Complex", "text": [ "PKA" ], "offsets": [ [ 1003, 1006 ] ], "normalized": [] }, { "id": "PMID-11171059_T25", "type": "Gene_or_gene_product", "text": [ "Arg-C" ], "offsets": [ [ 1032, 1037 ] ], "normalized": [] }, { "id": "PMID-11171059_T26", "type": "Gene_or_gene_product", "text": [ "GST-eEF-2K" ], "offsets": [ [ 1051, 1061 ] ], "normalized": [] }, { "id": "PMID-11171059_T27", "type": "Simple_chemical", "text": [ "Ser-365" ], "offsets": [ [ 1231, 1238 ] ], "normalized": [] }, { "id": "PMID-11171059_T28", "type": "Simple_chemical", "text": [ "Ser-499" ], "offsets": [ [ 1243, 1250 ] ], "normalized": [] }, { "id": "PMID-11171059_T29", "type": "Simple_chemical", "text": [ "Ca(2+)" ], "offsets": [ [ 1425, 1431 ] ], "normalized": [] }, { "id": "PMID-11171059_T30", "type": "Gene_or_gene_product", "text": [ "CaM" ], "offsets": [ [ 1432, 1435 ] ], "normalized": [] }, { "id": "PMID-11171059_T31", "type": "Gene_or_gene_product", "text": [ "eEF-2K" ], "offsets": [ [ 1448, 1454 ] ], "normalized": [] }, { "id": "PMID-11171059_T32", "type": "Gene_or_gene_product", "text": [ "Myc" ], "offsets": [ [ 1497, 1500 ] ], "normalized": [] }, { "id": "PMID-11171059_T33", "type": "Gene_or_gene_product", "text": [ "eEF-2K" ], "offsets": [ [ 1508, 1514 ] ], "normalized": [] }, { "id": "PMID-11171059_T34", "type": "Simple_chemical", "text": [ "chlorophenylthio-cAMP" ], "offsets": [ [ 1560, 1581 ] ], "normalized": [] }, { "id": "PMID-11171059_T35", "type": "Simple_chemical", "text": [ "CPT-cAMP" ], "offsets": [ [ 1583, 1591 ] ], "normalized": [] }, { "id": "PMID-11171059_T36", "type": "Simple_chemical", "text": [ "Ser-499" ], "offsets": [ [ 1606, 1613 ] ], "normalized": [] }, { "id": "PMID-11171059_T37", "type": "Simple_chemical", "text": [ "Ca(2+)" ], "offsets": [ [ 1644, 1650 ] ], "normalized": [] }, { "id": "PMID-11171059_T38", "type": "Gene_or_gene_product", "text": [ "CaM" ], "offsets": [ [ 1651, 1654 ] ], "normalized": [] }, { "id": "PMID-11171059_T39", "type": "Gene_or_gene_product", "text": [ "eEF-2K" ], "offsets": [ [ 1667, 1673 ] ], "normalized": [] }, { "id": "PMID-11171059_T40", "type": "Gene_or_gene_product", "text": [ "eEF-2K" ], "offsets": [ [ 1720, 1726 ] ], "normalized": [] }, { "id": "PMID-11171059_T41", "type": "Gene_or_gene_product", "text": [ "luciferase" ], "offsets": [ [ 1732, 1742 ] ], "normalized": [] }, { "id": "PMID-11171059_T42", "type": "Gene_or_gene_product", "text": [ "luciferase" ], "offsets": [ [ 1779, 1789 ] ], "normalized": [] }, { "id": "PMID-11171059_T43", "type": "Gene_or_gene_product", "text": [ "eEF-2K S499D" ], "offsets": [ [ 1816, 1828 ] ], "normalized": [] }, { "id": "PMID-11171059_T44", "type": "Gene_or_gene_product", "text": [ "luciferase" ], "offsets": [ [ 1864, 1874 ] ], "normalized": [] }, { "id": "PMID-11171059_T45", "type": "Gene_or_gene_product", "text": [ "eEF-2K S499D" ], "offsets": [ [ 1974, 1986 ] ], "normalized": [] }, { "id": "PMID-11171059_T46", "type": "Simple_chemical", "text": [ "Ser-499" ], "offsets": [ [ 2158, 2165 ] ], "normalized": [] }, { "id": "PMID-11171059_T47", "type": "Gene_or_gene_product", "text": [ "eEF-2K" ], "offsets": [ [ 2187, 2193 ] ], "normalized": [] }, { "id": "PMID-11171059_T48", "type": "Complex", "text": [ "PKA" ], "offsets": [ [ 2197, 2200 ] ], "normalized": [] } ]

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[ { "id": "PMID-11171059_1", "entity_ids": [ "PMID-11171059_T6", "PMID-11171059_T7" ] }, { "id": "PMID-11171059_2", "entity_ids": [ "PMID-11171059_T8", "PMID-11171059_T9" ] }, { "id": "PMID-11171059_3", "entity_ids": [ "PMID-11171059_T11", "PMID-11171059_T12" ] }, { "id": "PMID-11171059_4", "entity_ids": [ "PMID-11171059_T15", "PMID-11171059_T14" ] }, { "id": "PMID-11171059_5", "entity_ids": [ "PMID-11171059_T34", "PMID-11171059_T35" ] } ]

[]

[ { "id": "PMID-11278681__text", "type": "abstract", "text": [ "Yeast Mps1p phosphorylates the spindle pole component Spc110p in the N-terminal domain. \nThe yeast spindle pole body (SPB) component Spc110p (Nuf1p) undergoes specific serine/threonine phosphorylation as the mitotic spindle apparatus forms, and this phosphorylation persists until cells enter anaphase. We demonstrate that the dual-specificity kinase Mps1p is essential for the mitosis-specific phosphorylation of Spc110p in vivo and that Mps1p phosphorylates Spc110p in vitro. Phosphopeptides generated by proteolytic cleavage were identified and sequenced by mass spectrometry. Ser(60), Thr(64), and Thr(68) are the major sites in Spc110p phosphorylated by Mps1p in vitro, and alanine substitution at these sites abolishes the mitosis-specific isoform in vivo. This is the first time that phosphorylation sites of an SPB component have been determined, and these are the first sites of Mps1p phosphorylation identified. Alanine substitution for any one of these phosphorylated residues, in conjunction with an alanine substitution at residue Ser(36), is lethal in combination with alleles of SPC97, which encodes a component of the Tub4p complex. Consistent with a specific dysfunction for the alanine substitution mutations, simultaneous mutation of all four serine/threonine residues to aspartate does not confer any defect. Sites of Mps1p phosphorylation and Ser(36) are located within the N-terminal globular domain of Spc110p, which resides at the inner plaque of the SPB and binds the Tub4p complex.\n" ], "offsets": [ [ 0, 1508 ] ] } ]

[ { "id": "PMID-11278681_T1", "type": "Gene_or_gene_product", "text": [ "Mps1p" ], "offsets": [ [ 6, 11 ] ], "normalized": [] }, { "id": "PMID-11278681_T2", "type": "Cellular_component", "text": [ "spindle pole" ], "offsets": [ [ 31, 43 ] ], "normalized": [] }, { "id": "PMID-11278681_T3", "type": "Gene_or_gene_product", "text": [ "Spc110p" ], "offsets": [ [ 54, 61 ] ], "normalized": [] }, { "id": "PMID-11278681_T4", "type": "Cellular_component", "text": [ "spindle pole body" ], "offsets": [ [ 99, 116 ] ], "normalized": [] }, { "id": "PMID-11278681_T5", "type": "Cellular_component", "text": [ "SPB" ], "offsets": [ [ 118, 121 ] ], "normalized": [] }, { "id": "PMID-11278681_T6", "type": "Gene_or_gene_product", "text": [ "Spc110p" ], "offsets": [ [ 133, 140 ] ], "normalized": [] }, { "id": "PMID-11278681_T7", "type": "Gene_or_gene_product", "text": [ "Nuf1p" ], "offsets": [ [ 142, 147 ] ], "normalized": [] }, { "id": "PMID-11278681_T8", "type": "Simple_chemical", "text": [ "serine" ], "offsets": [ [ 168, 174 ] ], "normalized": [] }, { "id": "PMID-11278681_T9", "type": "Simple_chemical", "text": [ "threonine" ], "offsets": [ [ 175, 184 ] ], "normalized": [] }, { "id": "PMID-11278681_T10", "type": "Cellular_component", "text": [ "spindle apparatus" ], "offsets": [ [ 216, 233 ] ], "normalized": [] }, { "id": "PMID-11278681_T11", "type": "Gene_or_gene_product", "text": [ "Mps1p" ], "offsets": [ [ 351, 356 ] ], "normalized": [] }, { "id": "PMID-11278681_T12", "type": "Gene_or_gene_product", "text": [ "Spc110p" ], "offsets": [ [ 414, 421 ] ], "normalized": [] }, { "id": "PMID-11278681_T13", "type": "Gene_or_gene_product", "text": [ "Mps1p" ], "offsets": [ [ 439, 444 ] ], "normalized": [] }, { "id": "PMID-11278681_T14", "type": "Gene_or_gene_product", "text": [ "Spc110p" ], "offsets": [ [ 460, 467 ] ], "normalized": [] }, { "id": "PMID-11278681_T15", "type": "Simple_chemical", "text": [ "Ser(60)" ], "offsets": [ [ 580, 587 ] ], "normalized": [] }, { "id": "PMID-11278681_T16", "type": "Simple_chemical", "text": [ "Thr(64)" ], "offsets": [ [ 589, 596 ] ], "normalized": [] }, { "id": "PMID-11278681_T17", "type": "Simple_chemical", "text": [ "Thr(68)" ], "offsets": [ [ 602, 609 ] ], "normalized": [] }, { "id": "PMID-11278681_T18", "type": "Gene_or_gene_product", "text": [ "Spc110p" ], "offsets": [ [ 633, 640 ] ], "normalized": [] }, { "id": "PMID-11278681_T19", "type": "Gene_or_gene_product", "text": [ "Mps1p" ], "offsets": [ [ 659, 664 ] ], "normalized": [] }, { "id": "PMID-11278681_T20", "type": "Simple_chemical", "text": [ "alanine" ], "offsets": [ [ 679, 686 ] ], "normalized": [] }, { "id": "PMID-11278681_T21", "type": "Cellular_component", "text": [ "SPB" ], "offsets": [ [ 819, 822 ] ], "normalized": [] }, { "id": "PMID-11278681_T22", "type": "Gene_or_gene_product", "text": [ "Mps1p" ], "offsets": [ [ 888, 893 ] ], "normalized": [] }, { "id": "PMID-11278681_T23", "type": "Simple_chemical", "text": [ "Alanine" ], "offsets": [ [ 922, 929 ] ], "normalized": [] }, { "id": "PMID-11278681_T24", "type": "Simple_chemical", "text": [ "alanine" ], "offsets": [ [ 1012, 1019 ] ], "normalized": [] }, { "id": "PMID-11278681_T25", "type": "Simple_chemical", "text": [ "Ser(36)" ], "offsets": [ [ 1044, 1051 ] ], "normalized": [] }, { "id": "PMID-11278681_T26", "type": "Gene_or_gene_product", "text": [ "SPC97" ], "offsets": [ [ 1094, 1099 ] ], "normalized": [] }, { "id": "PMID-11278681_T27", "type": "Complex", "text": [ "Tub4p" ], "offsets": [ [ 1134, 1139 ] ], "normalized": [] }, { "id": "PMID-11278681_T28", "type": "Simple_chemical", "text": [ "alanine" ], "offsets": [ [ 1196, 1203 ] ], "normalized": [] }, { "id": "PMID-11278681_T29", "type": "Simple_chemical", "text": [ "serine" ], "offsets": [ [ 1262, 1268 ] ], "normalized": [] }, { "id": "PMID-11278681_T30", "type": "Simple_chemical", "text": [ "threonine" ], "offsets": [ [ 1269, 1278 ] ], "normalized": [] }, { "id": "PMID-11278681_T31", "type": "Simple_chemical", "text": [ "aspartate" ], "offsets": [ [ 1291, 1300 ] ], "normalized": [] }, { "id": "PMID-11278681_T32", "type": "Gene_or_gene_product", "text": [ "Mps1p" ], "offsets": [ [ 1338, 1343 ] ], "normalized": [] }, { "id": "PMID-11278681_T33", "type": "Simple_chemical", "text": [ "Ser(36)" ], "offsets": [ [ 1364, 1371 ] ], "normalized": [] }, { "id": "PMID-11278681_T34", "type": "Gene_or_gene_product", "text": [ "Spc110p" ], "offsets": [ [ 1425, 1432 ] ], "normalized": [] }, { "id": "PMID-11278681_T35", "type": "Cellular_component", "text": [ "inner plaque" ], "offsets": [ [ 1455, 1467 ] ], "normalized": [] }, { "id": "PMID-11278681_T36", "type": "Cellular_component", "text": [ "SPB" ], "offsets": [ [ 1475, 1478 ] ], "normalized": [] }, { "id": "PMID-11278681_T37", "type": "Complex", "text": [ "Tub4p" ], "offsets": [ [ 1493, 1498 ] ], "normalized": [] } ]

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[ { "id": "PMID-11278681_1", "entity_ids": [ "PMID-11278681_T4", "PMID-11278681_T5" ] }, { "id": "PMID-11278681_2", "entity_ids": [ "PMID-11278681_T6", "PMID-11278681_T7" ] } ]

[]

[ { "id": "PMID-11313932__text", "type": "abstract", "text": [ "Localization of human Cdc25C is regulated both by nuclear export and 14-3-3 protein binding. \nEntry into mitosis requires activation of the Cdc2 protein kinase by the Cdc25C protein phosphatase. The interactions between Cdc2 and Cdc25C are negatively regulated throughout interphase and in response to G2 checkpoint activation. This is accomplished in part by maintaining the Cdc25 phosphatase in a phosphorylated form that binds 14-3-3 proteins. Here we report that 14-3-3 binding regulates the intracellular trafficking of Cdc25C. Although primarily cytoplasmic, Cdc25C accumulated in the nuclei of leptomycin B (LMB)-treated cells, indicating that Cdc25C is actively exported out of the nucleus. A mutant of Cdc25C that is unable to bind 14-3-3 was partially nuclear in the absence of LMB and its nuclear accumulation was greatly enhanced by LMB-treatment. A nuclear export signal (NES) was identified within the amino terminus of Cdc25C. Although mutation of the NES did not effect 14-3-3 binding, it did cause nuclear accumulation of Cdc25C. These results demonstrate that 14-3-3 binding is dispensable for the nuclear export of Cdc25C. However, complete nuclear accumulation of Cdc25C required loss of both NES function and 14-3-3 binding and this was accomplished both pharmacologically and by mutation. These findings suggest that the nuclear export of Cdc25C is mediated by an intrinsic NES and that 14-3-3 binding negatively regulates nuclear import.\n" ], "offsets": [ [ 0, 1461 ] ] } ]

[ { "id": "PMID-11313932_T1", "type": "Gene_or_gene_product", "text": [ "Cdc25C" ], "offsets": [ [ 22, 28 ] ], "normalized": [] }, { "id": "PMID-11313932_T2", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 50, 57 ] ], "normalized": [] }, { "id": "PMID-11313932_T3", "type": "Gene_or_gene_product", "text": [ "14-3-3" ], "offsets": [ [ 69, 75 ] ], "normalized": [] }, { "id": "PMID-11313932_T4", "type": "Gene_or_gene_product", "text": [ "Cdc2" ], "offsets": [ [ 140, 144 ] ], "normalized": [] }, { "id": "PMID-11313932_T5", "type": "Gene_or_gene_product", "text": [ "Cdc25C" ], "offsets": [ [ 167, 173 ] ], "normalized": [] }, { "id": "PMID-11313932_T6", "type": "Gene_or_gene_product", "text": [ "Cdc2" ], "offsets": [ [ 220, 224 ] ], "normalized": [] }, { "id": "PMID-11313932_T7", "type": "Gene_or_gene_product", "text": [ "Cdc25C" ], "offsets": [ [ 229, 235 ] ], "normalized": [] }, { "id": "PMID-11313932_T8", "type": "Gene_or_gene_product", "text": [ "Cdc25" ], "offsets": [ [ 376, 381 ] ], "normalized": [] }, { "id": "PMID-11313932_T9", "type": "Gene_or_gene_product", "text": [ "14-3-3" ], "offsets": [ [ 430, 436 ] ], "normalized": [] }, { "id": "PMID-11313932_T10", "type": "Gene_or_gene_product", "text": [ "14-3-3" ], "offsets": [ [ 467, 473 ] ], "normalized": [] }, { "id": "PMID-11313932_T11", "type": "Cellular_component", "text": [ "intracellular" ], "offsets": [ [ 496, 509 ] ], "normalized": [] }, { "id": "PMID-11313932_T12", "type": "Gene_or_gene_product", "text": [ "Cdc25C" ], "offsets": [ [ 525, 531 ] ], "normalized": [] }, { "id": "PMID-11313932_T13", "type": "Cellular_component", "text": [ "cytoplasmic" ], "offsets": [ [ 552, 563 ] ], "normalized": [] }, { "id": "PMID-11313932_T14", "type": "Gene_or_gene_product", "text": [ "Cdc25C" ], "offsets": [ [ 565, 571 ] ], "normalized": [] }, { "id": "PMID-11313932_T15", "type": "Cellular_component", "text": [ "nuclei" ], "offsets": [ [ 591, 597 ] ], "normalized": [] }, { "id": "PMID-11313932_T16", "type": "Simple_chemical", "text": [ "leptomycin B" ], "offsets": [ [ 601, 613 ] ], "normalized": [] }, { "id": "PMID-11313932_T17", "type": "Simple_chemical", "text": [ "LMB" ], "offsets": [ [ 615, 618 ] ], "normalized": [] }, { "id": "PMID-11313932_T18", "type": "Gene_or_gene_product", "text": [ "Cdc25C" ], "offsets": [ [ 651, 657 ] ], "normalized": [] }, { "id": "PMID-11313932_T19", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 690, 697 ] ], "normalized": [] }, { "id": "PMID-11313932_T20", "type": "Gene_or_gene_product", "text": [ "Cdc25C" ], "offsets": [ [ 711, 717 ] ], "normalized": [] }, { "id": "PMID-11313932_T21", "type": "Gene_or_gene_product", "text": [ "14-3-3" ], "offsets": [ [ 741, 747 ] ], "normalized": [] }, { "id": "PMID-11313932_T22", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 762, 769 ] ], "normalized": [] }, { "id": "PMID-11313932_T23", "type": "Simple_chemical", "text": [ "LMB" ], "offsets": [ [ 788, 791 ] ], "normalized": [] }, { "id": "PMID-11313932_T24", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 800, 807 ] ], "normalized": [] }, { "id": "PMID-11313932_T25", "type": "Simple_chemical", "text": [ "LMB" ], "offsets": [ [ 845, 848 ] ], "normalized": [] }, { "id": "PMID-11313932_T26", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 862, 869 ] ], "normalized": [] }, { "id": "PMID-11313932_T27", "type": "Gene_or_gene_product", "text": [ "Cdc25C" ], "offsets": [ [ 934, 940 ] ], "normalized": [] }, { "id": "PMID-11313932_T28", "type": "Gene_or_gene_product", "text": [ "14-3-3" ], "offsets": [ [ 986, 992 ] ], "normalized": [] }, { "id": "PMID-11313932_T29", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 1015, 1022 ] ], "normalized": [] }, { "id": "PMID-11313932_T30", "type": "Gene_or_gene_product", "text": [ "Cdc25C" ], "offsets": [ [ 1039, 1045 ] ], "normalized": [] }, { "id": "PMID-11313932_T31", "type": "Gene_or_gene_product", "text": [ "14-3-3" ], "offsets": [ [ 1078, 1084 ] ], "normalized": [] }, { "id": "PMID-11313932_T32", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 1116, 1123 ] ], "normalized": [] }, { "id": "PMID-11313932_T33", "type": "Gene_or_gene_product", "text": [ "Cdc25C" ], "offsets": [ [ 1134, 1140 ] ], "normalized": [] }, { "id": "PMID-11313932_T34", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 1160, 1167 ] ], "normalized": [] }, { "id": "PMID-11313932_T35", "type": "Gene_or_gene_product", "text": [ "Cdc25C" ], "offsets": [ [ 1184, 1190 ] ], "normalized": [] }, { "id": "PMID-11313932_T36", "type": "Gene_or_gene_product", "text": [ "14-3-3" ], "offsets": [ [ 1230, 1236 ] ], "normalized": [] }, { "id": "PMID-11313932_T37", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 1343, 1350 ] ], "normalized": [] }, { "id": "PMID-11313932_T38", "type": "Gene_or_gene_product", "text": [ "Cdc25C" ], "offsets": [ [ 1361, 1367 ] ], "normalized": [] }, { "id": "PMID-11313932_T39", "type": "Gene_or_gene_product", "text": [ "14-3-3" ], "offsets": [ [ 1409, 1415 ] ], "normalized": [] }, { "id": "PMID-11313932_T40", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 1445, 1452 ] ], "normalized": [] } ]

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[ 84, 91 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11313932_T3" } ] }, { "id": "PMID-11313932_E6", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 122, 132 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11313932_T4" }, { "role": "Cause", "ref_id": "PMID-11313932_T5" } ] }, { "id": "PMID-11313932_E7", "type": "Binding", "trigger": { "text": [ "interactions" ], "offsets": [ [ 199, 211 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11313932_T6" }, { "role": "Theme", "ref_id": "PMID-11313932_T7" } ] }, { "id": "PMID-11313932_E8", "type": "Negative_regulation", "trigger": { "text": [ "negatively regulated" ], "offsets": [ [ 240, 260 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11313932_E7" } ] }, { "id": "PMID-11313932_E9", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 424, 429 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11313932_T9" }, { "role": "Theme", "ref_id": 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"Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1371, 1379 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11313932_E27" } ] }, { "id": "PMID-11313932_E29", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1416, 1423 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11313932_T39" } ] }, { "id": "PMID-11313932_E30", "type": "Negative_regulation", "trigger": { "text": [ "negatively regulates" ], "offsets": [ [ 1424, 1444 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11313932_E31" }, { "role": "Cause", "ref_id": "PMID-11313932_E29" } ] }, { "id": "PMID-11313932_E31", "type": "Transport", "trigger": { "text": [ "import" ], "offsets": [ [ 1453, 1459 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-11313932_T40" }, { "role": "Theme", "ref_id": "PMID-11313932_T38" } ] } ]

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[ { "id": "PMID-11313986__text", "type": "abstract", "text": [ "Regulation of the Cdc25A gene by the human papillomavirus Type 16 E7 oncogene. \nCdc25A is a tyrosine phosphatase that is involved in the regulation of the G1/S phase transition by activating cyclin E/Cdk2 and cyclin A/Cdk2 complexes through removal of inhibitory phosphorylations. The E6 and E7 oncoproteins of the high-risk human papillomaviruses (HPV) interact with and functionally abrogate the p53 and pRB proteins, respectively. In the present study we have investigated the regulation of the Cdc25A promoter during G1 and S-phases of the cell cycle and by the HPV-16 E7 oncoprotein. Serum induction leads to a derepression of the Cdc25A promoter and can be mediated through two E2F binding sites, E2F-A and E2F-C. While E2F-A is by both E2F1 and E2F4, E2F-C is regulated only by E2F1. The Cdc25A promoter is transactivated by the E7 oncogene of HPV-16. Furthermore, Cdc25A levels are highly increased in E7-expressing cell lines. Inducible expression of E7 leads to an immediate increase in Cdc25A protein levels. These data suggest that Cdc25A may be a critical target of HPV-16 E7 in the disruption of the G1/S phase transition.\n" ], "offsets": [ [ 0, 1137 ] ] } ]

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[]

[]

[ { "id": "PMID-11355576__text", "type": "abstract", "text": [ "[Molecular mechanisms controlling the cell cycle: fundamental aspects and implications for oncology]. \nINTRODUCTION: Comprehension of cell cycle regulation mechanisms has progressed very quickly these past few years and regulators of the cell cycle have gained widespread importance in cancer. This review first summarizes major advances in the understanding of the control of cell cycle mechanisms. Examples of how this control is altered in tumoral cells are then described. CURRENT KNOWLEDGE AND KEY POINTS: The typical mammalian cell cycle consists of four distinct phases occurring in a well-defined order, each of which should be completed successfully before the next begins. Progression of eukaryotic cells through major cell cycle transitions is mediated by sequential assembly and activation of a family of serine-threonine protein kinases, the cyclin dependent kinases (CDK). The timing of their activation is determined by their post-translational modifications (phosphorylations/dephosphorylations), and by the association of a protein called cyclin, which is the regulatory subunit of the kinase complex. The cyclin family is divided into two main classes. The 'G1 cyclins' include cyclins C, D1-3, and E, and their accumulation is rate-limiting for progression from the G1 to S phase. The 'mitotic or G2 cyclins', which include cyclin A and cyclin B, are involved in the control of G2/M transition and mitosis. The cyclins bind to and activate the CDK, which leads to phosphorylation (and then inhibition) of the tumor suppressor protein, pRb. pRb controls commitment to progress from the G1 to S phase, at least in part by repressing the activity of the E2F transcription factors known to promote cell proliferation. Both the D-type cyclins and their partner kinases CDK4/6 have proto-oncogenic properties, and their activity is carefully regulated at multiple levels including negative control by two families of CDK inhibitors. While members of the INK4 family (p16INK4A, p15INK4B, p18INK4C, p19INK4D) interact specifically with CDK4 and CDK6, the CIP/KIP inhibitors p21CIP1/WAF1, p27KIP1 and p57KIP2 inhibit a broader spectrum of CDK. The interplay between p16INK4A, cyclin D/CDK, and pRb/E2F together constitute a functional unit collectively known as the 'pRb pathway'. Each of the major components of this mechanism may become deregulated in cancer, and accumulating evidence points to the 'pRb pathway' as a candidate obligatory target in multistep oncogenesis of possibly all human tumor types. FUTURE PROSPECTS AND PROJECTS: Major advances in the understanding of cell cycle regulation mechanisms provided a better knowledge of the molecular interactions involved in human cancer. This progress has led to the promotion of new therapeutic agents presently in clinical trials or under development. Moreover, the components of the cell cycle are probably involved in other non-cancerous diseases and their role must be defined.\n" ], "offsets": [ [ 0, 2951 ] ] } ]

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"text": [ "cyclins C" ], "offsets": [ [ 1196, 1205 ] ], "normalized": [] }, { "id": "PMID-11355576_T9", "type": "Gene_or_gene_product", "text": [ "D1" ], "offsets": [ [ 1207, 1209 ] ], "normalized": [] }, { "id": "PMID-11355576_T10", "type": "Gene_or_gene_product", "text": [ "3" ], "offsets": [ [ 1210, 1211 ] ], "normalized": [] }, { "id": "PMID-11355576_T11", "type": "Gene_or_gene_product", "text": [ "E" ], "offsets": [ [ 1217, 1218 ] ], "normalized": [] }, { "id": "PMID-11355576_T12", "type": "Gene_or_gene_product", "text": [ "mitotic" ], "offsets": [ [ 1305, 1312 ] ], "normalized": [] }, { "id": "PMID-11355576_T13", "type": "Gene_or_gene_product", "text": [ "G2 cyclins" ], "offsets": [ [ 1316, 1326 ] ], "normalized": [] }, { "id": "PMID-11355576_T14", "type": "Gene_or_gene_product", "text": [ "cyclin A" ], "offsets": [ [ 1343, 1351 ] ], "normalized": [] }, { "id": "PMID-11355576_T15", "type": "Gene_or_gene_product", "text": [ "cyclin B" ], "offsets": [ [ 1356, 1364 ] ], "normalized": [] }, { "id": "PMID-11355576_T16", "type": "Gene_or_gene_product", "text": [ "cyclins" ], "offsets": [ [ 1430, 1437 ] ], "normalized": [] }, { "id": "PMID-11355576_T17", "type": "Gene_or_gene_product", "text": [ "CDK" ], "offsets": [ [ 1463, 1466 ] ], "normalized": [] }, { "id": "PMID-11355576_T18", "type": "Gene_or_gene_product", "text": [ "pRb" ], "offsets": [ [ 1554, 1557 ] ], "normalized": [] }, { "id": "PMID-11355576_T19", "type": "Gene_or_gene_product", "text": [ "pRb" ], "offsets": [ [ 1559, 1562 ] ], "normalized": [] }, { "id": "PMID-11355576_T20", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1670, 1673 ] ], "normalized": [] }, { "id": "PMID-11355576_T21", "type": "Gene_or_gene_product", "text": [ "D-type cyclins" ], "offsets": [ [ 1742, 1756 ] ], "normalized": [] }, { "id": "PMID-11355576_T22", "type": "Gene_or_gene_product", "text": [ "CDK4" ], "offsets": [ [ 1783, 1787 ] ], "normalized": [] }, { "id": "PMID-11355576_T23", "type": "Gene_or_gene_product", "text": [ "6" ], "offsets": [ [ 1788, 1789 ] ], "normalized": [] }, { "id": "PMID-11355576_T24", "type": "Gene_or_gene_product", "text": [ "CDK" ], "offsets": [ [ 1930, 1933 ] ], "normalized": [] }, { "id": "PMID-11355576_T25", "type": "Gene_or_gene_product", "text": [ "INK4" ], "offsets": [ [ 1967, 1971 ] ], "normalized": [] }, { "id": "PMID-11355576_T26", "type": "Gene_or_gene_product", "text": [ "p16INK4A" ], "offsets": [ [ 1980, 1988 ] ], "normalized": [] }, { "id": "PMID-11355576_T27", "type": "Gene_or_gene_product", "text": [ "p15INK4B" ], "offsets": [ [ 1990, 1998 ] ], "normalized": [] }, { "id": "PMID-11355576_T28", "type": "Gene_or_gene_product", "text": [ "p18INK4C" ], "offsets": [ [ 2000, 2008 ] ], "normalized": [] }, { "id": "PMID-11355576_T29", "type": "Gene_or_gene_product", "text": [ "p19INK4D" ], "offsets": [ [ 2010, 2018 ] ], "normalized": [] }, { "id": "PMID-11355576_T30", "type": "Gene_or_gene_product", "text": [ "CDK4" ], "offsets": [ [ 2047, 2051 ] ], "normalized": [] }, { "id": "PMID-11355576_T31", "type": "Gene_or_gene_product", "text": [ "CDK6" ], "offsets": [ [ 2056, 2060 ] ], "normalized": [] }, { "id": "PMID-11355576_T32", "type": "Gene_or_gene_product", "text": [ "CIP/KIP" ], "offsets": [ [ 2066, 2073 ] ], "normalized": [] }, { "id": "PMID-11355576_T33", "type": "Gene_or_gene_product", "text": [ "p21CIP1" ], "offsets": [ [ 2085, 2092 ] ], "normalized": [] }, { "id": "PMID-11355576_T34", "type": "Gene_or_gene_product", "text": [ "WAF1" ], "offsets": [ [ 2093, 2097 ] ], "normalized": [] }, { "id": "PMID-11355576_T35", "type": "Gene_or_gene_product", "text": [ "p27KIP1" ], "offsets": [ [ 2099, 2106 ] ], "normalized": [] }, { "id": "PMID-11355576_T36", "type": "Gene_or_gene_product", "text": [ "p57KIP2" ], "offsets": [ [ 2111, 2118 ] ], "normalized": [] }, { "id": "PMID-11355576_T37", "type": "Gene_or_gene_product", "text": [ "CDK" ], "offsets": [ [ 2149, 2152 ] ], "normalized": [] }, { "id": "PMID-11355576_T38", "type": "Gene_or_gene_product", "text": [ "p16INK4A" ], "offsets": [ [ 2176, 2184 ] ], "normalized": [] }, { "id": "PMID-11355576_T39", "type": "Gene_or_gene_product", "text": [ "cyclin D" ], "offsets": [ [ 2186, 2194 ] ], "normalized": [] }, { "id": "PMID-11355576_T40", "type": "Gene_or_gene_product", "text": [ "CDK" ], "offsets": [ [ 2195, 2198 ] ], "normalized": [] }, { "id": "PMID-11355576_T41", "type": "Gene_or_gene_product", "text": [ "pRb" ], "offsets": [ [ 2204, 2207 ] ], "normalized": [] }, { "id": "PMID-11355576_T42", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 2208, 2211 ] ], "normalized": [] }, { "id": "PMID-11355576_T43", "type": "Gene_or_gene_product", "text": [ "pRb" ], "offsets": [ [ 2277, 2280 ] ], "normalized": [] }, { "id": "PMID-11355576_T44", "type": "Gene_or_gene_product", "text": [ "pRb" ], "offsets": [ [ 2413, 2416 ] ], "normalized": [] } ]

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[ { "id": "PMID-11355576_1", "entity_ids": [ "PMID-11355576_T3", "PMID-11355576_T4" ] }, { "id": "PMID-11355576_2", "entity_ids": [ "PMID-11355576_T12", "PMID-11355576_T13" ] }, { "id": "PMID-11355576_3", "entity_ids": [ "PMID-11355576_T33", "PMID-11355576_T34" ] } ]

[]

[ { "id": "PMID-11420729__text", "type": "abstract", "text": [ "The Rb/chromatin connection and epigenetic control: opinion. \nThe balance between cell differentiation and proliferation is regulated at the transcriptional level. In the cell cycle, the transition from G1 to S phase (G1/S transition) is of paramount importance in this regard. Indeed, it is only before this point that cells can be oriented toward the differentiation pathway: beyond, cells progress into the cycle in an autonomous manner. The G1/S transition is orchestrated by the transcription factor E2F. E2F controls the expression of a group of checkpoint genes whose products are required either for the G1-to-S transition itself or for DNA replication (e.g. DNA polymerase alpha). E2F activity is repressed in growth-arrested cells and in early G1, and is activated at mid-to-late G1. E2F is controlled by the retinoblastoma tumor suppressor protein Rb. Rb represses E2F mainly by recruiting chromatin remodeling factors (histone deacetylases and SWI/SNF complexes), the DNA methyltransferase DNMT1, and a histone methyltransferase. This review will focus on the molecular mechanisms of E2F repression by Rb during the cell cycle and during cell-cycle exit by differentiating cells. A model in which Rb irreversibly represses E2F-regulated genes in differentiated cells by an epigenetic mechanism linked to heterochromatin, and involving histone H3 and promoter DNA methylation, is discussed.\n" ], "offsets": [ [ 0, 1402 ] ] } ]

[ { "id": "PMID-11420729_T1", "type": "Gene_or_gene_product", "text": [ "Rb" ], "offsets": [ [ 4, 6 ] ], "normalized": [] }, { "id": "PMID-11420729_T2", "type": "Cellular_component", "text": [ "chromatin" ], "offsets": [ [ 7, 16 ] ], "normalized": [] }, { "id": "PMID-11420729_T3", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 505, 508 ] ], "normalized": [] }, { "id": "PMID-11420729_T4", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 510, 513 ] ], "normalized": [] }, { "id": "PMID-11420729_T5", "type": "Complex", "text": [ "DNA polymerase alpha" ], "offsets": [ [ 667, 687 ] ], "normalized": [] }, { "id": "PMID-11420729_T6", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 690, 693 ] ], "normalized": [] }, { "id": "PMID-11420729_T7", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 794, 797 ] ], "normalized": [] }, { "id": "PMID-11420729_T8", "type": "Gene_or_gene_product", "text": [ "Rb" ], "offsets": [ [ 859, 861 ] ], "normalized": [] }, { "id": "PMID-11420729_T9", "type": "Gene_or_gene_product", "text": [ "Rb" ], "offsets": [ [ 863, 865 ] ], "normalized": [] }, { "id": "PMID-11420729_T10", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 876, 879 ] ], "normalized": [] }, { "id": "PMID-11420729_T11", "type": "Cellular_component", "text": [ "chromatin" ], "offsets": [ [ 901, 910 ] ], "normalized": [] }, { "id": "PMID-11420729_T12", "type": "Gene_or_gene_product", "text": [ "histone deacetylases" ], "offsets": [ [ 931, 951 ] ], "normalized": [] }, { "id": "PMID-11420729_T13", "type": "Complex", "text": [ "SWI/SNF" ], "offsets": [ [ 956, 963 ] ], "normalized": [] }, { "id": "PMID-11420729_T14", "type": "Gene_or_gene_product", "text": [ "DNA methyltransferase" ], "offsets": [ [ 980, 1001 ] ], "normalized": [] }, { "id": "PMID-11420729_T15", "type": "Gene_or_gene_product", "text": [ "DNMT1" ], "offsets": [ [ 1002, 1007 ] ], "normalized": [] }, { "id": "PMID-11420729_T16", "type": "Gene_or_gene_product", "text": [ "histone methyltransferase" ], "offsets": [ [ 1015, 1040 ] ], "normalized": [] }, { "id": "PMID-11420729_T17", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1096, 1099 ] ], "normalized": [] }, { "id": "PMID-11420729_T18", "type": "Gene_or_gene_product", "text": [ "Rb" ], "offsets": [ [ 1114, 1116 ] ], "normalized": [] }, { "id": "PMID-11420729_T19", "type": "Gene_or_gene_product", "text": [ "Rb" ], "offsets": [ [ 1209, 1211 ] ], "normalized": [] }, { "id": "PMID-11420729_T20", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1235, 1238 ] ], "normalized": [] }, { "id": "PMID-11420729_T21", "type": "Cellular_component", "text": [ "heterochromatin" ], "offsets": [ [ 1316, 1331 ] ], "normalized": [] }, { "id": "PMID-11420729_T22", "type": "Gene_or_gene_product", "text": [ "histone H3" ], "offsets": [ [ 1347, 1357 ] ], "normalized": [] } ]

[ { "id": "PMID-11420729_E1", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 171, 181 ] ] }, "arguments": [] }, { "id": "PMID-11420729_E2", "type": "Negative_regulation", "trigger": { "text": [ "repressed" ], "offsets": [ [ 706, 715 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11420729_T6" } ] }, { "id": "PMID-11420729_E3", "type": "Activation", "trigger": { "text": [ "activated" ], "offsets": [ [ 765, 774 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11420729_T6" } ] }, { "id": "PMID-11420729_E4", "type": "Regulation", "trigger": { "text": [ "controlled" ], "offsets": [ [ 801, 811 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11420729_T7" }, { "role": "Cause", "ref_id": "PMID-11420729_T8" } ] }, { "id": "PMID-11420729_E5", "type": "Negative_regulation", "trigger": { "text": [ "represses" ], "offsets": [ [ 866, 875 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11420729_T10" }, { "role": "Cause", "ref_id": "PMID-11420729_E10" } ] }, { "id": "PMID-11420729_E6", "type": "Negative_regulation", "trigger": { "text": [ "represses" ], "offsets": [ [ 866, 875 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11420729_T10" }, { "role": "Cause", "ref_id": "PMID-11420729_E14" } ] }, { "id": "PMID-11420729_E7", "type": "Negative_regulation", "trigger": { "text": [ "represses" ], "offsets": [ [ 866, 875 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11420729_T10" }, { "role": "Cause", "ref_id": "PMID-11420729_E15" } ] }, { "id": "PMID-11420729_E8", "type": "Negative_regulation", "trigger": { "text": [ "represses" ], "offsets": [ [ 866, 875 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11420729_T10" }, { "role": "Cause", "ref_id": "PMID-11420729_E16" } ] }, { "id": "PMID-11420729_E9", "type": "Transport", "trigger": { "text": [ "recruiting" ], "offsets": [ [ 890, 900 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11420729_T12" } ] }, { "id": "PMID-11420729_E10", "type": "Positive_regulation", "trigger": { "text": [ "recruiting" ], "offsets": [ [ 890, 900 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11420729_T9" }, { "role": "Theme", "ref_id": "PMID-11420729_E9" } ] }, { "id": "PMID-11420729_E11", "type": "Transport", "trigger": { "text": [ "recruiting" ], "offsets": [ [ 890, 900 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11420729_T13" } ] }, { "id": "PMID-11420729_E12", "type": "Transport", "trigger": { "text": [ "recruiting" ], "offsets": [ [ 890, 900 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11420729_T14" } ] }, { "id": "PMID-11420729_E13", "type": "Transport", "trigger": { "text": [ "recruiting" ], "offsets": [ [ 890, 900 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11420729_T16" } ] }, { "id": "PMID-11420729_E14", "type": "Positive_regulation", "trigger": { "text": [ "recruiting" ], "offsets": [ [ 890, 900 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11420729_T9" }, { "role": "Theme", "ref_id": "PMID-11420729_E11" } ] }, { "id": "PMID-11420729_E15", "type": "Positive_regulation", "trigger": { "text": [ "recruiting" ], "offsets": [ [ 890, 900 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11420729_T9" }, { "role": "Theme", "ref_id": "PMID-11420729_E12" } ] }, { "id": "PMID-11420729_E16", "type": "Positive_regulation", "trigger": { "text": [ "recruiting" ], "offsets": [ [ 890, 900 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11420729_T9" }, { "role": "Theme", "ref_id": "PMID-11420729_E13" } ] }, { "id": "PMID-11420729_E17", "type": "Negative_regulation", "trigger": { "text": [ "repression" ], "offsets": [ [ 1100, 1110 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11420729_T18" }, { "role": "Theme", "ref_id": "PMID-11420729_T17" } ] }, { "id": "PMID-11420729_E18", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 1128, 1138 ] ] }, "arguments": [] }, { "id": "PMID-11420729_E19", "type": "Regulation", "trigger": { "text": [ "linked" ], "offsets": [ [ 1306, 1312 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11420729_T21" } ] } ]

[]

[]

[ { "id": "PMID-11438700__text", "type": "abstract", "text": [ "Activation of NF-kappa B by nontypeable Hemophilus influenzae is mediated by toll-like receptor 2-TAK1-dependent NIK-IKK alpha /beta-I kappa B alpha and MKK3/6-p38 MAP kinase signaling pathways in epithelial cells. \nNontypeable Hemophilus influenzae (NTHi) is an important human pathogen in both children and adults. In children, it causes otitis media, the most common childhood infection and the leading cause of conductive hearing loss in the United States. In adults, it causes lower respiratory tract infections in the setting of chronic obstructive pulmonary disease, the fourth leading cause of death in the United States. The molecular mechanisms underlying the pathogenesis of NTHi-induced infections remain undefined, but they may involve activation of NF-kappa B, a transcriptional activator of multiple host defense genes involved in immune and inflammatory responses. Here, we show that NTHi strongly activates NF-kappa B in human epithelial cells via two distinct signaling pathways, NF-kappa B translocation-dependent and -independent pathways. The NF-kappa B translocation-dependent pathway involves activation of NF-kappa B inducing kinase (NIK)--IKK alpha/beta complex leading to I kappa B alpha phosphorylation and degradation, whereas the NF-kappa B translocation-independent pathway involves activation of MKK3/6--p38 mitogen-activated protein (MAP) kinase pathway. Bifurcation of NTHi-induced NIK-IKK alpha/beta-I kappa B alpha and MKK3/6--p38 MAP kinase pathways may occur at transforming growth factor-beta activated kinase 1 (TAK1). Furthermore, we show that toll-like receptor 2 (TLR2) is required for NTHi-induced NF-kappa B activation. In addition, several key inflammatory mediators including IL-1 beta, IL-8, and tumor necrosis factor-alpha are up-regulated by NTHi. Finally, P6, a 16-kDa lipoprotein highly conserved in the outer membrane of all NTHi and H. influenzae type b strains, appears to also activate NF-kappa B via similar signaling pathways. Taken together, our results demonstrate that NTHi activates NF-kappa B via TLR2-TAK1-dependent NIK--IKK alpha/beta-I kappa B alpha and MKK3/6--p38 MAP kinase signaling pathways. These studies may bring new insights into molecular pathogenesis of NTHi-induced infections and open up new therapeutic targets for these diseases.\n" ], "offsets": [ [ 0, 2310 ] ] } ]

[ { "id": "PMID-11438700_T1", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 14, 24 ] ], "normalized": [] }, { "id": "PMID-11438700_T2", "type": "Gene_or_gene_product", "text": [ "toll-like receptor 2" ], "offsets": [ [ 77, 97 ] ], "normalized": [] }, { "id": "PMID-11438700_T3", "type": "Gene_or_gene_product", "text": [ "TAK1" ], "offsets": [ [ 98, 102 ] ], "normalized": [] }, { "id": "PMID-11438700_T4", "type": "Complex", "text": [ "NIK-IKK alpha /beta" ], "offsets": [ [ 113, 132 ] ], "normalized": [] }, { "id": "PMID-11438700_T5", "type": "Gene_or_gene_product", "text": [ "I kappa B alpha" ], "offsets": [ [ 133, 148 ] ], "normalized": [] }, { "id": "PMID-11438700_T6", "type": "Gene_or_gene_product", "text": [ "MKK3/6" ], "offsets": [ [ 153, 159 ] ], "normalized": [] }, { "id": "PMID-11438700_T7", "type": "Gene_or_gene_product", "text": [ "p38 MAP kinase" ], "offsets": [ [ 160, 174 ] ], "normalized": [] }, { "id": "PMID-11438700_T8", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 763, 773 ] ], "normalized": [] }, { "id": "PMID-11438700_T9", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 924, 934 ] ], "normalized": [] }, { "id": "PMID-11438700_T10", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 998, 1008 ] ], "normalized": [] }, { "id": "PMID-11438700_T11", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 1064, 1074 ] ], "normalized": [] }, { "id": "PMID-11438700_T12", "type": "Complex", "text": [ "NF-kappa B inducing kinase (NIK)--IKK alpha/beta" ], "offsets": [ [ 1130, 1178 ] ], "normalized": [] }, { "id": "PMID-11438700_T13", "type": "Gene_or_gene_product", "text": [ "I kappa B alpha" ], "offsets": [ [ 1198, 1213 ] ], "normalized": [] }, { "id": "PMID-11438700_T14", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 1259, 1269 ] ], "normalized": [] }, { "id": "PMID-11438700_T15", "type": "Gene_or_gene_product", "text": [ "MKK3/6" ], "offsets": [ [ 1327, 1333 ] ], "normalized": [] }, { "id": "PMID-11438700_T16", "type": "Gene_or_gene_product", "text": [ "p38 mitogen-activated protein (MAP) kinase" ], "offsets": [ [ 1335, 1377 ] ], "normalized": [] }, { "id": "PMID-11438700_T17", "type": "Complex", "text": [ "NIK-IKK alpha/beta" ], "offsets": [ [ 1415, 1433 ] ], "normalized": [] }, { "id": "PMID-11438700_T18", "type": "Gene_or_gene_product", "text": [ "I kappa B alpha" ], "offsets": [ [ 1434, 1449 ] ], "normalized": [] }, { "id": "PMID-11438700_T19", "type": "Gene_or_gene_product", "text": [ "MKK3/6" ], "offsets": [ [ 1454, 1460 ] ], "normalized": [] }, { "id": "PMID-11438700_T20", "type": "Gene_or_gene_product", "text": [ "p38 MAP kinase" ], "offsets": [ [ 1462, 1476 ] ], "normalized": [] }, { "id": "PMID-11438700_T21", "type": "Gene_or_gene_product", "text": [ "transforming growth factor-beta activated kinase 1" ], "offsets": [ [ 1499, 1549 ] ], "normalized": [] }, { "id": "PMID-11438700_T22", "type": "Gene_or_gene_product", "text": [ "TAK1" ], "offsets": [ [ 1551, 1555 ] ], "normalized": [] }, { "id": "PMID-11438700_T23", "type": "Gene_or_gene_product", "text": [ "toll-like receptor 2" ], "offsets": [ [ 1584, 1604 ] ], "normalized": [] }, { "id": "PMID-11438700_T24", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 1606, 1610 ] ], "normalized": [] }, { "id": "PMID-11438700_T25", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 1641, 1651 ] ], "normalized": [] }, { "id": "PMID-11438700_T26", "type": "Gene_or_gene_product", "text": [ "IL-1 beta" ], "offsets": [ [ 1722, 1731 ] ], "normalized": [] }, { "id": "PMID-11438700_T27", "type": "Gene_or_gene_product", "text": [ "IL-8" ], "offsets": [ [ 1733, 1737 ] ], "normalized": [] }, { "id": "PMID-11438700_T28", "type": "Gene_or_gene_product", "text": [ "tumor necrosis factor-alpha" ], "offsets": [ [ 1743, 1770 ] ], "normalized": [] }, { "id": "PMID-11438700_T29", "type": "Cellular_component", "text": [ "outer membrane" ], "offsets": [ [ 1855, 1869 ] ], "normalized": [] }, { "id": "PMID-11438700_T30", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 1941, 1951 ] ], "normalized": [] }, { "id": "PMID-11438700_T31", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 2044, 2054 ] ], "normalized": [] }, { "id": "PMID-11438700_T32", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 2059, 2063 ] ], "normalized": [] }, { "id": "PMID-11438700_T33", "type": "Gene_or_gene_product", "text": [ "TAK1" ], "offsets": [ [ 2064, 2068 ] ], "normalized": [] }, { "id": "PMID-11438700_T34", "type": "Complex", "text": [ "NIK--IKK alpha/beta" ], "offsets": [ [ 2079, 2098 ] ], "normalized": [] }, { "id": "PMID-11438700_T35", "type": "Gene_or_gene_product", "text": [ "I kappa B alpha" ], "offsets": [ [ 2099, 2114 ] ], "normalized": [] }, { "id": "PMID-11438700_T36", "type": "Gene_or_gene_product", "text": [ "MKK3/6" ], "offsets": [ [ 2119, 2125 ] ], "normalized": [] }, { "id": "PMID-11438700_T37", "type": "Gene_or_gene_product", "text": [ "p38 MAP kinase" ], "offsets": [ [ 2127, 2141 ] ], "normalized": [] } ]

[ { "id": "PMID-11438700_E1", "type": "Activation", "trigger": { "text": [ "Activation" ], "offsets": [ [ 0, 10 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11438700_T1" } ] }, { "id": "PMID-11438700_E2", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 65, 73 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11438700_E1" }, { "role": "Cause", "ref_id": "PMID-11438700_E5" } ] }, { "id": "PMID-11438700_E3", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 103, 112 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11438700_E5" }, { "role": "Cause", "ref_id": "PMID-11438700_T2" } ] }, { "id": "PMID-11438700_E4", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 103, 112 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11438700_E5" }, { "role": "Cause", "ref_id": "PMID-11438700_T3" } ] }, { "id": "PMID-11438700_E5", "type": "Pathway", "trigger": { "text": [ "signaling pathways" ], "offsets": [ [ 175, 193 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-11438700_T4" }, { "role": "Participant", "ref_id": "PMID-11438700_T5" }, { "role": "Participant", "ref_id": "PMID-11438700_T6" }, { "role": "Participant", "ref_id": "PMID-11438700_T7" } ] }, { "id": "PMID-11438700_E6", "type": "Positive_regulation", "trigger": { "text": [ "involve" ], "offsets": [ [ 741, 748 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11438700_E7" } ] }, { "id": "PMID-11438700_E7", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 749, 759 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11438700_T8" } ] }, { "id": "PMID-11438700_E8", "type": "Activation", "trigger": { "text": [ "activates" ], "offsets": [ [ 914, 923 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11438700_T9" }, { "role": "Cause", "ref_id": "PMID-11438700_E14" } ] }, { "id": "PMID-11438700_E9", "type": "Activation", "trigger": { "text": [ "activates" ], "offsets": [ [ 914, 923 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11438700_T9" }, { "role": "Cause", "ref_id": "PMID-11438700_E13" } ] }, { "id": "PMID-11438700_E10", "type": "Transport", "trigger": { "text": [ "translocatio" ], "offsets": [ [ 1009, 1021 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11438700_T10" } ] }, { "id": "PMID-11438700_E11", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1023, 1032 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11438700_E10" }, { "role": "Theme", "ref_id": "PMID-11438700_E14" } ] }, { "id": "PMID-11438700_E12", "type": "Regulation", "trigger": { "text": [ "independent" ], "offsets": [ [ 1038, 1049 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11438700_E10" }, { "role": "Theme", "ref_id": "PMID-11438700_E13" } ] }, { "id": "PMID-11438700_E13", "type": "Pathway", "trigger": { "text": [ "pathways" ], "offsets": [ [ 1050, 1058 ] ] }, 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[ { "id": "PMID-11438700_1", "entity_ids": [ "PMID-11438700_T21", "PMID-11438700_T22" ] }, { "id": "PMID-11438700_2", "entity_ids": [ "PMID-11438700_T23", "PMID-11438700_T24" ] } ]

[]

[ { "id": "PMID-11441107__text", "type": "abstract", "text": [ "Cooperation of Toll-like receptor 2 and 6 for cellular activation by soluble tuberculosis factor and Borrelia burgdorferi outer surface protein A lipoprotein: role of Toll-interacting protein and IL-1 receptor signaling molecules in Toll-like receptor 2 signaling. \nToll-like receptor 2 (TLR2) and TLR4 play important roles in innate immune responses to various microbial agents. We have previously shown that human dermal endothelial cells (HMEC) express TLR4, but very little TLR2, and respond to LPS, but not to Mycobacterium tuberculosis 19-kDa lipoprotein, unless transfected with TLR2. Here we report that HMEC are unresponsive to several additional biologically relevant TLR2 ligands, including, phenol-soluble modulin (PSM), a complex of three small secreted polypeptides from the skin commensal Staphylococcus epidermidis, soluble tuberculosis factor (STF), and Borrelia burgdorferi outer surface protein A lipoprotein (OspA-L). Expression of TLR2 renders HMEC responsive to all these ligands. We further characterized the signaling pathway in response to STF, OspA-L, and PSM in TLR2-transfected HMEC. The TLR2 signaling pathway for NF-kappaB trans-activation shares the IL-1R signaling molecules. Dominant negative constructs of TLR2 or TLR6 inhibit the responses of STF and OspA-L as well as PSM in TLR2-transfected HMEC, supporting the concept of functional cooperation between TLR2 and TLR6 for all these TLR2 ligands. Moreover, we show that Toll-interacting protein (Tollip) coimmunoprecipitates with TLR2 and TLR4 using HEK 293 cells, and overexpression of Tollip inhibits NF-kappaB activation in response to TLR2 and TLR4 signaling. Collectively, these findings suggest that there is functional interaction between TLR2 and TLR6 in the cellular response to STF and OspA-L in addition to S. epidermidis (PSM) Ags, and that engagement of TLR2 triggers a signaling cascade, which shares the IL-1R signaling molecules, similar to the TLR4-LPS signaling cascade. Our data also suggest that Tollip may be an important constituent of both the TLR2 and TLR4 signaling pathways.\n" ], "offsets": [ [ 0, 2087 ] ] } ]

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}, { "id": "PMID-11441107_T8", "type": "Gene_or_gene_product", "text": [ "Toll-like receptor 2" ], "offsets": [ [ 266, 286 ] ], "normalized": [] }, { "id": "PMID-11441107_T9", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 288, 292 ] ], "normalized": [] }, { "id": "PMID-11441107_T10", "type": "Gene_or_gene_product", "text": [ "TLR4" ], "offsets": [ [ 298, 302 ] ], "normalized": [] }, { "id": "PMID-11441107_T11", "type": "Gene_or_gene_product", "text": [ "TLR4" ], "offsets": [ [ 456, 460 ] ], "normalized": [] }, { "id": "PMID-11441107_T12", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 478, 482 ] ], "normalized": [] }, { "id": "PMID-11441107_T13", "type": "Simple_chemical", "text": [ "LPS" ], "offsets": [ [ 499, 502 ] ], "normalized": [] }, { "id": "PMID-11441107_T14", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 586, 590 ] ], "normalized": [] }, { "id": "PMID-11441107_T15", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 678, 682 ] ], "normalized": [] }, { "id": "PMID-11441107_T16", "type": "Complex", "text": [ "phenol-soluble modulin" ], "offsets": [ [ 703, 725 ] ], "normalized": [] }, { "id": "PMID-11441107_T17", "type": "Complex", "text": [ "PSM" ], "offsets": [ [ 727, 730 ] ], "normalized": [] }, { "id": "PMID-11441107_T18", "type": "Gene_or_gene_product", "text": [ "soluble tuberculosis factor" ], "offsets": [ [ 832, 859 ] ], "normalized": [] }, { "id": "PMID-11441107_T19", "type": "Gene_or_gene_product", "text": [ "STF" ], "offsets": [ [ 861, 864 ] ], "normalized": [] }, { "id": "PMID-11441107_T20", "type": "Gene_or_gene_product", "text": [ "outer surface protein A lipoprotein" ], "offsets": [ [ 892, 927 ] ], "normalized": [] }, { "id": "PMID-11441107_T21", "type": "Gene_or_gene_product", "text": [ "OspA-L" ], "offsets": [ [ 929, 935 ] ], "normalized": [] }, { "id": "PMID-11441107_T22", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 952, 956 ] ], 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"TLR2" ], "offsets": [ [ 1240, 1244 ] ], "normalized": [] }, { "id": "PMID-11441107_T31", "type": "Gene_or_gene_product", "text": [ "TLR6" ], "offsets": [ [ 1248, 1252 ] ], "normalized": [] }, { "id": "PMID-11441107_T32", "type": "Gene_or_gene_product", "text": [ "STF" ], "offsets": [ [ 1278, 1281 ] ], "normalized": [] }, { "id": "PMID-11441107_T33", "type": "Gene_or_gene_product", "text": [ "OspA-L" ], "offsets": [ [ 1286, 1292 ] ], "normalized": [] }, { "id": "PMID-11441107_T34", "type": "Complex", "text": [ "PSM" ], "offsets": [ [ 1304, 1307 ] ], "normalized": [] }, { "id": "PMID-11441107_T35", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 1311, 1315 ] ], "normalized": [] }, { "id": "PMID-11441107_T36", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 1391, 1395 ] ], "normalized": [] }, { "id": "PMID-11441107_T37", "type": "Gene_or_gene_product", "text": [ "TLR6" ], "offsets": [ [ 1400, 1404 ] ], "normalized": [] }, { "id": "PMID-11441107_T38", 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"ref_id": "PMID-11441107_E21" } ] }, { "id": "PMID-11441107_E23", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1599, 1609 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11441107_T44" } ] }, { "id": "PMID-11441107_E24", "type": "Positive_regulation", "trigger": { "text": [ "response" ], "offsets": [ [ 1613, 1621 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11441107_E23" }, { "role": "Cause", "ref_id": "PMID-11441107_E26" } ] }, { "id": "PMID-11441107_E25", "type": "Positive_regulation", "trigger": { "text": [ "response" ], "offsets": [ [ 1613, 1621 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11441107_E23" }, { "role": "Cause", "ref_id": "PMID-11441107_E27" } ] }, { "id": "PMID-11441107_E26", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1639, 1648 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-11441107_T45" } ] }, { "id": "PMID-11441107_E27", "type": "Pathway", "trigger": { 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1762, 1770 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11441107_E28" }, { "role": "Cause", "ref_id": "PMID-11441107_T51" } ] }, { "id": "PMID-11441107_E32", "type": "Regulation", "trigger": { "text": [ "engagement" ], "offsets": [ [ 1839, 1849 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11441107_T52" } ] }, { "id": "PMID-11441107_E33", "type": "Pathway", "trigger": { "text": [ "signaling cascade" ], "offsets": [ [ 1956, 1973 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-11441107_T54" }, { "role": "Participant", "ref_id": "PMID-11441107_T55" } ] }, { "id": "PMID-11441107_E34", "type": "Pathway", "trigger": { "text": [ "signaling pathways" ], "offsets": [ [ 2067, 2085 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-11441107_T57" } ] }, { "id": "PMID-11441107_E35", "type": "Pathway", "trigger": { "text": [ "signaling pathways" ], "offsets": [ [ 2067, 2085 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-11441107_T58" } ] } ]

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[]

[ { "id": "PMID-11454693__text", "type": "abstract", "text": [ "Inhibition of promyelocytic leukemia (PML)/retinoic acid receptor-alpha and PML expression in acute promyelocytic leukemia cells by anti-PML peptide nucleic acid. \nThe fusion protein promyelocytic leukemia (PML)/retinoic acid receptor (RAR)alpha is tightly linked to the pathogenesis of acute promyelocytic leukemia (APL); hence, it represents a tumor-associated, transformation-related molecule. In this study, three anti-PML adamantyl-conjugated peptide nucleic acid (PNA) oligomers previously described as in vitro inhibitors of PML/RARalpha translation were combined and used to block PML/RARalpha synthesis in NB4 cells. Cationic liposomes were used to achieve sufficient delivery of PNAs into the cells. Upon treatment of cells with the liposome/PNA mixture, enhanced cellular uptake of PNA (approximately 5-fold compared with control) was obtained. Concomitantly, a substantial reduction (>90%) of the expression of PML/RARalpha was observed when all of the three PNAs were used together. This resulted in a dramatic effect on the number and viability of NB4 cells in culture after 48 h of treatment. This phenomenon was preceded by induction of apoptosis that could be observed 24 h after treatment. No sign of granulocytic differentiation was observed after treatment. These effects were also noted on other leukemic cell lines that express PML but not the fusion transcript. These results show that it is possible to deliver PNA into hematopoietic cells and obtain specific gene inhibition, and they suggest that a growth inhibitory effect on acute promyelocytic leukemia cells can be obtained through the block of PML/RARalpha and PML expression.\n" ], "offsets": [ [ 0, 1658 ] ] } ]

[ { "id": "PMID-11454693_T1", "type": "Gene_or_gene_product", "text": [ "promyelocytic leukemia" ], "offsets": [ [ 14, 36 ] ], "normalized": [] }, { "id": "PMID-11454693_T2", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 38, 41 ] ], "normalized": [] }, { "id": "PMID-11454693_T3", "type": "Gene_or_gene_product", "text": [ "retinoic acid receptor-alpha" ], "offsets": [ [ 43, 71 ] ], "normalized": [] }, { "id": "PMID-11454693_T4", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 76, 79 ] ], "normalized": [] }, { "id": "PMID-11454693_T5", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 137, 140 ] ], "normalized": [] }, { "id": "PMID-11454693_T6", "type": "Simple_chemical", "text": [ "peptide nucleic acid" ], "offsets": [ [ 141, 161 ] ], "normalized": [] }, { "id": "PMID-11454693_T7", "type": "Gene_or_gene_product", "text": [ "promyelocytic leukemia" ], "offsets": [ [ 183, 205 ] ], "normalized": [] }, { "id": "PMID-11454693_T8", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 207, 210 ] ], "normalized": [] }, { "id": "PMID-11454693_T9", "type": "Gene_or_gene_product", "text": [ "retinoic acid receptor (RAR)alpha" ], "offsets": [ [ 212, 245 ] ], "normalized": [] }, { "id": "PMID-11454693_T10", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 423, 426 ] ], "normalized": [] }, { "id": "PMID-11454693_T11", "type": "Simple_chemical", "text": [ "adamantyl" ], "offsets": [ [ 427, 436 ] ], "normalized": [] }, { "id": "PMID-11454693_T12", "type": "Simple_chemical", "text": [ "peptide nucleic acid" ], "offsets": [ [ 448, 468 ] ], "normalized": [] }, { "id": "PMID-11454693_T13", "type": "Simple_chemical", "text": [ "PNA" ], "offsets": [ [ 470, 473 ] ], "normalized": [] }, { "id": "PMID-11454693_T14", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 532, 535 ] ], "normalized": [] }, { "id": "PMID-11454693_T15", "type": "Gene_or_gene_product", "text": [ "RARalpha" ], "offsets": [ [ 536, 544 ] ], "normalized": [] }, { "id": "PMID-11454693_T16", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 589, 592 ] ], "normalized": [] }, { "id": "PMID-11454693_T17", "type": "Gene_or_gene_product", "text": [ "RARalpha" ], "offsets": [ [ 593, 601 ] ], "normalized": [] }, { "id": "PMID-11454693_T18", "type": "Simple_chemical", "text": [ "PNA" ], "offsets": [ [ 752, 755 ] ], "normalized": [] }, { "id": "PMID-11454693_T19", "type": "Simple_chemical", "text": [ "PNA" ], "offsets": [ [ 793, 796 ] ], "normalized": [] }, { "id": "PMID-11454693_T20", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 923, 926 ] ], "normalized": [] }, { "id": "PMID-11454693_T21", "type": "Gene_or_gene_product", "text": [ "RARalpha" ], "offsets": [ [ 927, 935 ] ], "normalized": [] }, { "id": "PMID-11454693_T22", "type": "Simple_chemical", "text": [ "PNAs" ], "offsets": [ [ 971, 975 ] ], "normalized": [] }, { "id": "PMID-11454693_T23", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 1350, 1353 ] ], "normalized": [] }, { "id": "PMID-11454693_T24", "type": "Simple_chemical", "text": [ "PNA" ], "offsets": [ [ 1435, 1438 ] ], "normalized": [] }, { "id": "PMID-11454693_T25", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 1625, 1628 ] ], "normalized": [] }, { "id": "PMID-11454693_T26", "type": "Gene_or_gene_product", "text": [ "RARalpha" ], "offsets": [ [ 1629, 1637 ] ], "normalized": [] }, { "id": "PMID-11454693_T27", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 1642, 1645 ] ], "normalized": [] } ]

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"deliver" ], "offsets": [ [ 1427, 1434 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11454693_T24" } ] }, { "id": "PMID-11454693_E25", "type": "Negative_regulation", "trigger": { "text": [ "block" ], "offsets": [ [ 1616, 1621 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11454693_E28" } ] }, { "id": "PMID-11454693_E26", "type": "Negative_regulation", "trigger": { "text": [ "block" ], "offsets": [ [ 1616, 1621 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11454693_E29" } ] }, { "id": "PMID-11454693_E27", "type": "Negative_regulation", "trigger": { "text": [ "block" ], "offsets": [ [ 1616, 1621 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11454693_E30" } ] }, { "id": "PMID-11454693_E28", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1646, 1656 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11454693_T25" } ] }, { "id": "PMID-11454693_E29", "type": "Gene_expression", "trigger": { "text": [ 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[]

[ { "id": "PMID-11470804__text", "type": "abstract", "text": [ "Molecular identification and characterization of two medium-chain acyl-CoA synthetases, MACS1 and the Sa gene product. \nIn this study, we identified and characterized two murine cDNAs encoding medium-chain acyl-CoA synthetase (MACS). One, designated MACS1, is a novel protein and the other the product of the Sa gene (Sa protein), which is preferentially expressed in spontaneously hypertensive rats. Based on the murine MACS1 sequence, we also identified the location and organization of the human MACS1 gene, showing that the human MACS1 and Sa genes are located in the opposite transcriptional direction within a 150-kilobase region on chromosome 16p13.1. Murine MACS1 and Sa protein were overexpressed in COS cells, purified to homogeneity, and characterized. Among C4-C16 fatty acids, MACS1 preferentially utilizes octanoate, whereas isobutyrate is the most preferred fatty acid among C2-C6 fatty acids for Sa protein. Like Sa gene transcript, MACS1 mRNA was detected mainly in the liver and kidney. Subcellular fractionation revealed that both MACS1 and Sa protein are localized in the mitochondrial matrix. (14)C-Fatty acid incorporation studies indicated that acyl-CoAs produced by MACS1 and Sa protein are utilized mainly for oxidation.\n" ], "offsets": [ [ 0, 1246 ] ] } ]

[ { "id": "PMID-11470804_T1", "type": "Gene_or_gene_product", "text": [ "medium-chain acyl-CoA synthetases" ], "offsets": [ [ 53, 86 ] ], "normalized": [] }, { "id": "PMID-11470804_T2", "type": "Gene_or_gene_product", "text": [ "MACS1" ], "offsets": [ [ 88, 93 ] ], "normalized": [] }, { "id": "PMID-11470804_T3", "type": "Gene_or_gene_product", "text": [ "Sa" ], "offsets": [ [ 102, 104 ] ], "normalized": [] }, { "id": "PMID-11470804_T4", "type": "Gene_or_gene_product", "text": [ "medium-chain acyl-CoA synthetase" ], "offsets": [ [ 193, 225 ] ], "normalized": [] }, { "id": "PMID-11470804_T5", "type": "Gene_or_gene_product", "text": [ "MACS" ], "offsets": [ [ 227, 231 ] ], "normalized": [] }, { "id": "PMID-11470804_T6", "type": "Gene_or_gene_product", "text": [ "MACS1" ], "offsets": [ [ 250, 255 ] ], "normalized": [] }, { "id": "PMID-11470804_T7", "type": "Gene_or_gene_product", "text": [ "Sa" ], "offsets": [ [ 309, 311 ] ], "normalized": [] }, { "id": "PMID-11470804_T8", "type": "Gene_or_gene_product", "text": [ "Sa" ], "offsets": [ [ 318, 320 ] ], "normalized": [] }, { "id": "PMID-11470804_T9", "type": "Gene_or_gene_product", "text": [ "MACS1" ], "offsets": [ [ 421, 426 ] ], "normalized": [] }, { "id": "PMID-11470804_T10", "type": "Gene_or_gene_product", "text": [ "MACS1" ], "offsets": [ [ 499, 504 ] ], "normalized": [] }, { "id": "PMID-11470804_T11", "type": "Gene_or_gene_product", "text": [ "MACS1" ], "offsets": [ [ 534, 539 ] ], "normalized": [] }, { "id": "PMID-11470804_T12", "type": "Gene_or_gene_product", "text": [ "Sa" ], "offsets": [ [ 544, 546 ] ], "normalized": [] }, { "id": "PMID-11470804_T13", "type": "Cellular_component", "text": [ "chromosome 16" ], "offsets": [ [ 639, 652 ] ], "normalized": [] }, { "id": "PMID-11470804_T14", "type": "Gene_or_gene_product", "text": [ "MACS1" ], "offsets": [ [ 666, 671 ] ], "normalized": [] }, { "id": "PMID-11470804_T15", "type": "Gene_or_gene_product", "text": [ "Sa" ], "offsets": [ [ 676, 678 ] ], "normalized": [] }, { "id": "PMID-11470804_T16", "type": "Simple_chemical", "text": [ "C4-C16 fatty acids" ], "offsets": [ [ 770, 788 ] ], "normalized": [] }, { "id": "PMID-11470804_T17", "type": "Gene_or_gene_product", "text": [ "MACS1" ], "offsets": [ [ 790, 795 ] ], "normalized": [] }, { "id": "PMID-11470804_T18", "type": "Simple_chemical", "text": [ "octanoate" ], "offsets": [ [ 820, 829 ] ], "normalized": [] }, { "id": "PMID-11470804_T19", "type": "Simple_chemical", "text": [ "isobutyrate" ], "offsets": [ [ 839, 850 ] ], "normalized": [] }, { "id": "PMID-11470804_T20", "type": "Simple_chemical", "text": [ "fatty acid" ], "offsets": [ [ 873, 883 ] ], "normalized": [] }, { "id": "PMID-11470804_T21", "type": "Simple_chemical", "text": [ "C2-C6 fatty acids" ], "offsets": [ [ 890, 907 ] ], "normalized": [] }, { "id": "PMID-11470804_T22", "type": "Gene_or_gene_product", "text": [ "Sa" ], "offsets": [ [ 912, 914 ] ], "normalized": [] }, { "id": "PMID-11470804_T23", "type": "Gene_or_gene_product", "text": [ "Sa" ], "offsets": [ [ 929, 931 ] ], "normalized": [] }, { "id": "PMID-11470804_T24", "type": "Gene_or_gene_product", "text": [ "MACS1" ], "offsets": [ [ 949, 954 ] ], "normalized": [] }, { "id": "PMID-11470804_T25", "type": "Cellular_component", "text": [ "Subcellular" ], "offsets": [ [ 1005, 1016 ] ], "normalized": [] }, { "id": "PMID-11470804_T26", "type": "Gene_or_gene_product", "text": [ "MACS1" ], "offsets": [ [ 1050, 1055 ] ], "normalized": [] }, { "id": "PMID-11470804_T27", "type": "Gene_or_gene_product", "text": [ "Sa" ], "offsets": [ [ 1060, 1062 ] ], "normalized": [] }, { "id": "PMID-11470804_T28", "type": "Cellular_component", "text": [ "mitochondrial matrix" ], "offsets": [ [ 1092, 1112 ] ], "normalized": [] }, { "id": "PMID-11470804_T29", "type": "Simple_chemical", "text": [ "(14)C-Fatty acid" ], "offsets": [ [ 1114, 1130 ] ], "normalized": [] }, { "id": "PMID-11470804_T30", "type": "Simple_chemical", "text": [ "acyl-CoAs" ], "offsets": [ [ 1168, 1177 ] ], "normalized": [] }, { "id": "PMID-11470804_T31", "type": "Gene_or_gene_product", "text": [ "MACS1" ], "offsets": [ [ 1190, 1195 ] ], "normalized": [] }, { "id": "PMID-11470804_T32", "type": "Gene_or_gene_product", "text": [ "Sa" ], "offsets": [ [ 1200, 1202 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-11483512__text", "type": "abstract", "text": [ "PIG-S and PIG-T, essential for GPI anchor attachment to proteins, form a complex with GAA1 and GPI8. \nMany eukaryotic cell surface proteins are anchored to the plasma membrane via glycosylphosphatidylinositol (GPI). The GPI transamidase mediates GPI anchoring in the endoplasmic reticulum, by replacing a protein's C-terminal GPI attachment signal peptide with a pre-assembled GPI. During this transamidation reaction, the GPI transamidase forms a carbonyl intermediate with a substrate protein. It was known that the GPI transamidase is a complex containing GAA1 and GPI8. Here, we report two new components of this enzyme: PIG-S and PIG-T. To determine roles for PIG-S and PIG-T, we disrupted these genes in mouse F9 cells by homologous recombination. PIG-S and PIG-T knockout cells were defective in transfer of GPI to proteins, particularly in formation of the carbonyl intermediates. We also demonstrate that PIG-S and PIG-T form a protein complex with GAA1 and GPI8, and that PIG-T maintains the complex by stabilizing the expression of GAA1 and GPI8. Saccharomyces cerevisiae Gpi16p (YHR188C) and Gpi17p (YDR434W) are orthologues of PIG-T and PIG-S, respectively.\n" ], "offsets": [ [ 0, 1171 ] ] } ]

[ { "id": "PMID-11483512_T1", "type": "Gene_or_gene_product", "text": [ "PIG-S" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMID-11483512_T2", "type": "Gene_or_gene_product", "text": [ "PIG-T" ], "offsets": [ [ 10, 15 ] ], "normalized": [] }, { "id": "PMID-11483512_T3", "type": "Simple_chemical", "text": [ "GPI" ], "offsets": [ [ 31, 34 ] ], "normalized": [] }, { "id": "PMID-11483512_T4", "type": "Gene_or_gene_product", "text": [ "GAA1" ], "offsets": [ [ 86, 90 ] ], "normalized": [] }, { "id": "PMID-11483512_T5", "type": "Gene_or_gene_product", "text": [ "GPI8" ], "offsets": [ [ 95, 99 ] ], "normalized": [] }, { "id": "PMID-11483512_T6", "type": "Cellular_component", "text": [ "cell surface" ], "offsets": [ [ 118, 130 ] ], "normalized": [] }, { "id": "PMID-11483512_T7", "type": "Cellular_component", "text": [ "plasma membrane" ], "offsets": [ [ 160, 175 ] ], "normalized": [] }, { "id": "PMID-11483512_T8", "type": "Simple_chemical", "text": [ "glycosylphosphatidylinositol" ], "offsets": [ [ 180, 208 ] ], "normalized": [] }, { "id": "PMID-11483512_T9", "type": "Simple_chemical", "text": [ "GPI" ], "offsets": [ [ 210, 213 ] ], "normalized": [] }, { "id": "PMID-11483512_T10", "type": "Complex", "text": [ "GPI transamidase" ], "offsets": [ [ 220, 236 ] ], "normalized": [] }, { "id": "PMID-11483512_T11", "type": "Simple_chemical", "text": [ "GPI" ], "offsets": [ [ 246, 249 ] ], "normalized": [] }, { "id": "PMID-11483512_T12", "type": "Cellular_component", "text": [ "endoplasmic reticulum" ], "offsets": [ [ 267, 288 ] ], "normalized": [] }, { "id": "PMID-11483512_T13", "type": "Simple_chemical", "text": [ "GPI" ], "offsets": [ [ 326, 329 ] ], "normalized": [] }, { "id": "PMID-11483512_T14", "type": "Simple_chemical", "text": [ "GPI" ], "offsets": [ [ 377, 380 ] ], "normalized": [] }, { "id": "PMID-11483512_T15", "type": "Complex", "text": [ "GPI transamidase" ], "offsets": [ [ 423, 439 ] ], "normalized": [] }, { "id": "PMID-11483512_T16", "type": "Simple_chemical", "text": [ "carbonyl" ], "offsets": [ [ 448, 456 ] ], "normalized": [] }, { "id": "PMID-11483512_T17", "type": "Complex", "text": [ "GPI transamidase" ], "offsets": [ [ 518, 534 ] ], "normalized": [] }, { "id": "PMID-11483512_T18", "type": "Gene_or_gene_product", "text": [ "GAA1" ], "offsets": [ [ 559, 563 ] ], "normalized": [] }, { "id": "PMID-11483512_T19", "type": "Gene_or_gene_product", "text": [ "GPI8" ], "offsets": [ [ 568, 572 ] ], "normalized": [] }, { "id": "PMID-11483512_T20", "type": "Gene_or_gene_product", "text": [ "PIG-S" ], "offsets": [ [ 625, 630 ] ], "normalized": [] }, { "id": "PMID-11483512_T21", "type": "Gene_or_gene_product", "text": [ "PIG-T" ], "offsets": [ [ 635, 640 ] ], "normalized": [] }, { "id": "PMID-11483512_T22", "type": "Gene_or_gene_product", "text": [ "PIG-S" ], "offsets": [ [ 665, 670 ] ], "normalized": [] }, { "id": "PMID-11483512_T23", "type": "Gene_or_gene_product", "text": [ "PIG-T" ], "offsets": [ [ 675, 680 ] ], "normalized": [] }, { "id": "PMID-11483512_T24", "type": "Gene_or_gene_product", "text": [ "PIG-S" ], "offsets": [ [ 754, 759 ] ], "normalized": [] }, { "id": "PMID-11483512_T25", "type": "Gene_or_gene_product", "text": [ "PIG-T" ], "offsets": [ [ 764, 769 ] ], "normalized": [] }, { "id": "PMID-11483512_T26", "type": "Simple_chemical", "text": [ "GPI" ], "offsets": [ [ 815, 818 ] ], "normalized": [] }, { "id": "PMID-11483512_T27", "type": "Simple_chemical", "text": [ "carbonyl" ], "offsets": [ [ 865, 873 ] ], "normalized": [] }, { "id": "PMID-11483512_T28", "type": "Gene_or_gene_product", "text": [ "PIG-S" ], "offsets": [ [ 914, 919 ] ], "normalized": [] }, { "id": "PMID-11483512_T29", "type": "Gene_or_gene_product", "text": [ "PIG-T" ], "offsets": [ [ 924, 929 ] ], "normalized": [] }, { "id": "PMID-11483512_T30", "type": "Gene_or_gene_product", "text": [ "GAA1" ], "offsets": [ [ 958, 962 ] ], "normalized": [] }, { "id": "PMID-11483512_T31", "type": "Gene_or_gene_product", "text": [ "GPI8" ], "offsets": [ [ 967, 971 ] ], "normalized": [] }, { "id": "PMID-11483512_T32", "type": "Gene_or_gene_product", "text": [ "PIG-T" ], "offsets": [ [ 982, 987 ] ], "normalized": [] }, { "id": "PMID-11483512_T33", "type": "Gene_or_gene_product", "text": [ "GAA1" ], "offsets": [ [ 1043, 1047 ] ], "normalized": [] }, { "id": "PMID-11483512_T34", "type": "Gene_or_gene_product", "text": [ "GPI8" ], "offsets": [ [ 1052, 1056 ] ], "normalized": [] }, { "id": "PMID-11483512_T35", "type": "Gene_or_gene_product", "text": [ "Gpi16p" ], "offsets": [ [ 1083, 1089 ] ], "normalized": [] }, { "id": "PMID-11483512_T36", "type": "Gene_or_gene_product", "text": [ "YHR188C" ], "offsets": [ [ 1091, 1098 ] ], "normalized": [] }, { "id": "PMID-11483512_T37", "type": "Gene_or_gene_product", "text": [ "Gpi17p" ], "offsets": [ [ 1104, 1110 ] ], "normalized": [] }, { "id": "PMID-11483512_T38", "type": "Gene_or_gene_product", "text": [ "YDR434W" ], "offsets": [ [ 1112, 1119 ] ], "normalized": [] }, { "id": "PMID-11483512_T39", "type": "Gene_or_gene_product", "text": [ "PIG-T" ], "offsets": [ [ 1140, 1145 ] ], "normalized": [] }, { "id": "PMID-11483512_T40", "type": "Gene_or_gene_product", "text": [ "PIG-S" ], "offsets": [ [ 1150, 1155 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-11485410__text", "type": "abstract", "text": [ "Disruption of NF-kappa B signaling and chemokine gene activation by retroviral mediated expression of IKK gamma/NEMO mutants. \nPhosphorylation of I kappa Bs--the cytoplasmic inhibitors of the NF-kappa B transcription factors--is the key event which triggers activation of the NF-kappa B cascade. Signal-mediated phosphorylation of I kappa B alpha is mediated by a multiprotein complex, the I kappa B kinase (IKK) complex, which is composed of at least three identified subunits. Two of these polypeptides, IKK alpha and IKK beta, also known as IKK1 and IKK2, are the catalytic subunits of the kinase complex and phosphorylate I kappa B alpha and I kappa B beta. The third component, NEMO/IKK gamma, does not exhibit kinase activity, but rather constitutes a regulatory subunit. In the present study, C-terminal truncated forms of IKK gamma--Delta C-IKK gamma 306 and Delta C-IKK gamma 261--were stably expressed in the myeloid cell line U937 by retroviral-mediated gene transfer. Overexpression of Delta C-IKK gamma resulted in a reduction in IKK kinase activity in vitro, a subsequent decrease in NF-kappa B DNA binding activity, and inhibition of chemokine gene induction in response to TNFalpha stimulation or paramyxovirus infection. This study demonstrates the efficacy of Delta C-IKK gamma as a repressor of IKK signaling and NF-kappa B activation and suggests a potential gene therapy approach to limit chronic inflammation due to chemokine hyperactivation.\n" ], "offsets": [ [ 0, 1465 ] ] } ]

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[ { "id": "PMID-11486005__text", "type": "abstract", "text": [ "Regulation of Snf1 kinase. Activation requires phosphorylation of threonine 210 by an upstream kinase as well as a distinct step mediated by the Snf4 subunit. \nThe yeast Snf1 kinase and its metazoan orthologues, the AMP-activated protein kinases, are activated in response to nutrient limitation. Activation requires the phosphorylation of a conserved threonine residue in the activation loop of the catalytic subunit. A phosphopeptide antibody was generated that specifically recognizes Snf1 protein that is phosphorylated in its activation loop on threonine 210. Using this reagent, we show that phosphorylation of threonine 210 correlates with Snf1 activity, since it is detected in cells subjected to glucose limitation but not in cells grown in abundant glucose. A Snf1 mutant completely lacking kinase activity was phosphorylated normally on threonine 210 in glucose-starved cells, eliminating the possibility that the threonine 210 modification is due to an autophosphorylation event. Cells lacking the Reg1 protein, a regulatory subunit for the Glc7 phosphatase, showed constitutive phosphorylation of Snf1 threonine 210. Exposure of cells to high concentrations of sodium chloride also induced phosphorylation of Snf1. Interestingly, Mig1, a downstream target of Snf1 kinase, is phosphorylated in glucose-stressed but not sodium-stressed cells. Finally, cells lacking the gamma subunit of the Snf1 kinase complex encoded by the SNF4 gene exhibited normal regulation of threonine 210 phosphorylation in response to glucose limitation but are unable to phosphorylate Mig1 efficiently. Our data indicate that activation of the Snf1 kinase complex involves two steps, one that requires a distinct upstream kinase and one that is mediated by the gamma subunit of the kinase itself.\n" ], "offsets": [ [ 0, 1786 ] ] } ]

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{ "id": "PMID-11486005_E10", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 509, 523 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11486005_T7" }, { "role": "Site", "ref_id": "PMID-11486005_T8" } ] }, { "id": "PMID-11486005_E11", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 598, 613 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-11486005_T9" }, { "role": "Theme", "ref_id": "PMID-11486005_T10" } ] }, { "id": "PMID-11486005_E12", "type": "Regulation", "trigger": { "text": [ "correlates" ], "offsets": [ [ 631, 641 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11486005_E11" }, { "role": "Theme", "ref_id": "PMID-11486005_T10" } ] }, { "id": "PMID-11486005_E13", "type": "Negative_regulation", "trigger": { "text": [ "limitation" ], "offsets": [ [ 713, 723 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11486005_T11" } ] }, { "id": "PMID-11486005_E14", "type": 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"PMID-11486005_E18", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1203, 1218 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11486005_T22" } ] }, { "id": "PMID-11486005_E19", "type": "Regulation", "trigger": { "text": [ "target" ], "offsets": [ [ 1262, 1268 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11486005_T23" }, { "role": "Cause", "ref_id": "PMID-11486005_T24" } ] }, { "id": "PMID-11486005_E20", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 1288, 1302 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11486005_T23" } ] }, { "id": "PMID-11486005_E21", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1464, 1474 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11486005_E22" } ] }, { "id": "PMID-11486005_E22", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1492, 1507 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-11486005_T29" }, { "role": "Theme", "ref_id": "PMID-11486005_T27" } ] }, { "id": "PMID-11486005_E23", "type": "Negative_regulation", "trigger": { "text": [ "limitation" ], "offsets": [ [ 1531, 1541 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11486005_T30" } ] }, { "id": "PMID-11486005_E24", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylate" ], "offsets": [ [ 1560, 1573 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11486005_T31" } ] }, { "id": "PMID-11486005_E25", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1615, 1625 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11486005_T32" } ] } ]

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[ { "id": "PMID-11562353__text", "type": "abstract", "text": [ "Mechanisms controlling differential promoter-occupancy by the yeast forkhead proteins Fkh1p and Fkh2p: implications for regulating the cell cycle and differentiation. \nThe roles of DNA and Mcm1p interactions in determining the overlapping and distinct functions of the yeast cell cycle regulatory transcription factors Fkh1p and Fkh2p were examined. Full-length recombinant Fkh1p and Fkh2p were purified and their binding to bona fide promoters examined in vitro. Each protein bound a variety of target promoters with similar specificity in vitro, consistent with the observation that these proteins bind common promoters in vivo. However, in vivo, the Fkh1p and Fkh2p occupied different target promoters to different extents, suggesting that each was primarily responsible for controlling a different set of genes. Additional in vitro studies provided a mechanistic explanation for this differential promoter-occupancy. Specifically, the Fkh2p, but not the Fkh1p, was capable of binding cooperatively with Mcm1p. The Mcm1p-Fkh2p cooperative binding was enhanced by, but did not require, the presence of a Mcm1p-binding site within a target promoter. Consistent with these data, Mcm1p was present at Fkh-controlled promoters in vivo regardless of whether they contained Mcm1p-binding sites, suggesting a role for Mcm1p at promoters not thought previously to be under Mcm1p control. Analysis of Fkh1p and Fkh2p binding to promoter targets in vivo by use of mutant strains indicated that the two proteins compete for promoter-occupancy at a number of target promoters. We postulate that Fkh1p and a stable Fkh2p/Mcm1p complex compete for binding to target promoters and that the levels and/or binding activity of Fkh1p, but not Fkh2p, are most limiting for promoter-occupancy in vivo. Interestingly, the in vitro DNA-binding assays, using a variety of promoter targets, revealed that bona fide Fkh target promoters contained two or more Fkh-binding sites that allowed the Fkh1p and Fkh2p proteins to form multiple protein-DNA complexes in vitro. Multiple Fkh-binding sites may be a distinguishing feature of bona fide Fkh promoters in yeast and other organisms.\n" ], "offsets": [ [ 0, 2160 ] ] } ]

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[ { "id": "PMID-11593391__text", "type": "abstract", "text": [ "Defects in transcription coupled repair interfere with expression of p90(MDM2) in response to ultraviolet light. \nUltraviolet (UV) irradiation transiently stabilizes p53 through a mechanism that may require a decrease in the activity of the ubiquitin ligase, p90(MDM2). Conversely, the recovery of low levels of p53 following UV exposure may depend on an increase in p90(MDM2). The level of p90(MDM2) is increased by UV light following the p53-dependent induction of an internal mdm2 promoter, P2. If this induction of mdm2 were critical for the recovery of low levels of p53 following UV exposure, defects in mdm2's transcription would result in a prolonged increase in p53. Cells defective in transcription coupled repair (TCR) maintain high levels of p53 for a prolonged period following UV exposure. Such cells also have defects in general transcription after UV irradiation. We investigated whether TCR-deficient cells express diminished levels of mdm2 mRNA and p90(MDM2) following UV exposure. We found that transcription of mdm2 was reduced in TCR-deficient cells. The uninducible mdm2 promoter, P1, was more sensitive to the inhibitory effects of UV irradiation than the P2 promoter. The decrease in transcription from the P1 promoter was sufficient to reduce the level of p90(MDM2) and correlated with a prolonged increase in p53. Thus, p53-independent transcription of mdm2 appears critical to p53's regulation.\n" ], "offsets": [ [ 0, 1422 ] ] } ]

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"PMID-11593391_E25", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 1040, 1047 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11593391_E24" } ] }, { "id": "PMID-11593391_E26", "type": "Positive_regulation", "trigger": { "text": [ "uninducible" ], "offsets": [ [ 1076, 1087 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11593391_T23" } ] }, { "id": "PMID-11593391_E27", "type": "Regulation", "trigger": { "text": [ "sensitive" ], "offsets": [ [ 1116, 1125 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11593391_E26" } ] }, { "id": "PMID-11593391_E28", "type": "Negative_regulation", "trigger": { "text": [ "reduce" ], "offsets": [ [ 1261, 1267 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11593391_T25" } ] }, { "id": "PMID-11593391_E29", "type": "Regulation", "trigger": { "text": [ "correlated" ], "offsets": [ [ 1295, 1305 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11593391_E30" } ] }, { "id": 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"offsets": [ [ 1410, 1420 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11593391_T29" } ] } ]

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[]

[ { "id": "PMID-11606759__text", "type": "abstract", "text": [ "Degradation of the kinesin Kip1p at anaphase onset is mediated by the anaphase-promoting complex and Cdc20p. \nKip1p of Saccharomyces cerevisiae is a bipolar kinesin in the conserved bimC kinesin subfamily that mediates mitotic spindle-pole separation. Here, we show that Kip1p is regulated immediately after anaphase initiation by its rapid degradation. Degradation required the ubiquitin protein ligase called the anaphase-promoting complex, the anaphase-promoting complex activating protein Cdc20, and a unique 43-aa sequence in Kip1p. Degradation also required import of Kip1p into the nucleus, but occurred independently of spindle association. A mutation that stabilized Kip1p impaired anaphase progression. The timing of degradation suggests that Kip1p functions primarily during spindle assembly and metaphase, and that Kip1p degradation facilitates structural changes in the mitotic spindle as anaphase progresses.\n" ], "offsets": [ [ 0, 923 ] ] } ]

[ { "id": "PMID-11606759_T1", "type": "Gene_or_gene_product", "text": [ "Kip1p" ], "offsets": [ [ 27, 32 ] ], "normalized": [] }, { "id": "PMID-11606759_T2", "type": "Complex", "text": [ "anaphase-promoting complex" ], "offsets": [ [ 70, 96 ] ], "normalized": [] }, { "id": "PMID-11606759_T3", "type": "Gene_or_gene_product", "text": [ "Cdc20p" ], "offsets": [ [ 101, 107 ] ], "normalized": [] }, { "id": "PMID-11606759_T4", "type": "Gene_or_gene_product", "text": [ "Kip1p" ], "offsets": [ [ 110, 115 ] ], "normalized": [] }, { "id": "PMID-11606759_T5", "type": "Gene_or_gene_product", "text": [ "bimC" ], "offsets": [ [ 182, 186 ] ], "normalized": [] }, { "id": "PMID-11606759_T6", "type": "Cellular_component", "text": [ "mitotic spindle" ], "offsets": [ [ 219, 234 ] ], "normalized": [] }, { "id": "PMID-11606759_T7", "type": "Cellular_component", "text": [ "pole" ], "offsets": [ [ 235, 239 ] ], "normalized": [] }, { "id": "PMID-11606759_T8", "type": "Gene_or_gene_product", "text": [ "Kip1p" ], "offsets": [ [ 271, 276 ] ], "normalized": [] }, { "id": "PMID-11606759_T9", "type": "Gene_or_gene_product", "text": [ "ubiquitin" ], "offsets": [ [ 379, 388 ] ], "normalized": [] }, { "id": "PMID-11606759_T10", "type": "Complex", "text": [ "anaphase-promoting complex" ], "offsets": [ [ 415, 441 ] ], "normalized": [] }, { "id": "PMID-11606759_T11", "type": "Complex", "text": [ "anaphase-promoting complex" ], "offsets": [ [ 447, 473 ] ], "normalized": [] }, { "id": "PMID-11606759_T12", "type": "Gene_or_gene_product", "text": [ "Cdc20" ], "offsets": [ [ 493, 498 ] ], "normalized": [] }, { "id": "PMID-11606759_T13", "type": "Gene_or_gene_product", "text": [ "Kip1p" ], "offsets": [ [ 531, 536 ] ], "normalized": [] }, { "id": "PMID-11606759_T14", "type": "Gene_or_gene_product", "text": [ "Kip1p" ], "offsets": [ [ 574, 579 ] ], "normalized": [] }, { "id": "PMID-11606759_T15", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 589, 596 ] ], "normalized": [] }, { "id": "PMID-11606759_T16", "type": "Cellular_component", "text": [ "spindle" ], "offsets": [ [ 628, 635 ] ], "normalized": [] }, { "id": "PMID-11606759_T17", "type": "Gene_or_gene_product", "text": [ "Kip1p" ], "offsets": [ [ 676, 681 ] ], "normalized": [] }, { "id": "PMID-11606759_T18", "type": "Gene_or_gene_product", "text": [ "Kip1p" ], "offsets": [ [ 753, 758 ] ], "normalized": [] }, { "id": "PMID-11606759_T19", "type": "Cellular_component", "text": [ "spindle" ], "offsets": [ [ 786, 793 ] ], "normalized": [] }, { "id": "PMID-11606759_T20", "type": "Gene_or_gene_product", "text": [ "Kip1p" ], "offsets": [ [ 827, 832 ] ], "normalized": [] }, { "id": "PMID-11606759_T21", "type": "Cellular_component", "text": [ "mitotic spindle" ], "offsets": [ [ 883, 898 ] ], "normalized": [] } ]

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[]

[]

[ { "id": "PMID-11677243__text", "type": "abstract", "text": [ "Cloning and expression of human core 1 beta1,3-galactosyltransferase. \nThe common core 1 O-glycan structure Galbeta1--> 3GalNAc-R is the precursor for many extended mucin-type O-glycan structures in animal cell surface and secreted glycoproteins. Core 1 is synthesized by the transfer of Gal from UDP-Gal to GalNAcalpha1-R by core 1 beta3-galactosyltransferase (core 1 beta3-Gal-T). Amino acid sequences from purified rat core 1 beta3-Gal-T (Ju, T., Cummings, R. D., and Canfield, W. M. (2002) J. Biol. Chem. 277, 169-177) were used to identify the core 1 beta3-Gal-T sequences in the human expressed sequence tag data bases. A 1794-bp human core 1 beta3-Gal-T cDNA sequence was determined by sequencing the expressed sequence tag and performing 5'-rapid amplification of cDNA ends. The core 1 beta3-Gal-T predicts a 363-amino acid type II transmembrane protein. Expression of both the full-length and epitope-tagged soluble forms of the putative enzyme in human 293T cells generated core 1 beta3-Gal-T activity that transferred galactose from UDP-Gal to GalNAcalpha1-O-phenyl, and a synthetic glycopeptide with Thr-linked GalNAc and the product was shown to have the core 1 structure. Northern analysis demonstrated widespread expression of core 1 beta3-Gal-T in tissues with a predominance in kidney, heart, placenta, and liver. Highly homologous cDNAs were identified and cloned from rat, mouse, Drosophila melanogaster, and Caenorhabditis elegans, suggesting that the enzyme is widely distributed in metazoans. The core 1 beta3-Gal-T sequence has minimal homology with conserved sequences found in previously described beta3-galactosyltransferases, suggesting this enzyme is only distantly related to the known beta3-galactosyltransferase family.\n" ], "offsets": [ [ 0, 1751 ] ] } ]

[ { "id": "PMID-11677243_T1", "type": "Gene_or_gene_product", "text": [ "core 1 beta1,3-galactosyltransferase" ], "offsets": [ [ 32, 68 ] ], "normalized": [] }, { "id": "PMID-11677243_T2", "type": "Simple_chemical", "text": [ "core 1 O-glycan" ], "offsets": [ [ 82, 97 ] ], "normalized": [] }, { "id": "PMID-11677243_T3", "type": "Simple_chemical", "text": [ "Galbeta1--> 3GalNAc-R" ], "offsets": [ [ 108, 129 ] ], "normalized": [] }, { "id": "PMID-11677243_T4", "type": "Simple_chemical", "text": [ "O-glycan" ], "offsets": [ [ 176, 184 ] ], "normalized": [] }, { "id": "PMID-11677243_T5", "type": "Cellular_component", "text": [ "cell surface" ], "offsets": [ [ 206, 218 ] ], "normalized": [] }, { "id": "PMID-11677243_T6", "type": "Simple_chemical", "text": [ "Core 1" ], "offsets": [ [ 247, 253 ] ], "normalized": [] }, { "id": "PMID-11677243_T7", "type": "Simple_chemical", "text": [ "Gal" ], "offsets": [ [ 288, 291 ] ], "normalized": [] }, { "id": "PMID-11677243_T8", "type": "Simple_chemical", "text": [ "UDP-Gal" ], "offsets": [ [ 297, 304 ] ], "normalized": [] }, { "id": "PMID-11677243_T9", "type": "Simple_chemical", "text": [ "GalNAcalpha1-R" ], "offsets": [ [ 308, 322 ] ], "normalized": [] }, { "id": "PMID-11677243_T10", "type": "Gene_or_gene_product", "text": [ "core 1 beta3-galactosyltransferase" ], "offsets": [ [ 326, 360 ] ], "normalized": [] }, { "id": "PMID-11677243_T11", "type": "Gene_or_gene_product", "text": [ "core 1 beta3-Gal-T" ], "offsets": [ [ 362, 380 ] ], "normalized": [] }, { "id": "PMID-11677243_T12", "type": "Gene_or_gene_product", "text": [ "core 1 beta3-Gal-T" ], "offsets": [ [ 422, 440 ] ], "normalized": [] }, { "id": "PMID-11677243_T13", "type": "Gene_or_gene_product", "text": [ "core 1 beta3-Gal-T" ], "offsets": [ [ 549, 567 ] ], "normalized": [] }, { "id": "PMID-11677243_T14", "type": "Gene_or_gene_product", "text": [ "core 1 beta3-Gal-T" ], "offsets": [ [ 642, 660 ] ], "normalized": [] }, { "id": "PMID-11677243_T15", "type": "Gene_or_gene_product", "text": [ "core 1 beta3-Gal-T" ], "offsets": [ [ 787, 805 ] ], "normalized": [] }, { "id": "PMID-11677243_T16", "type": "Cellular_component", "text": [ "transmembrane" ], "offsets": [ [ 840, 853 ] ], "normalized": [] }, { "id": "PMID-11677243_T17", "type": "Gene_or_gene_product", "text": [ "core 1 beta3-Gal-T" ], "offsets": [ [ 984, 1002 ] ], "normalized": [] }, { "id": "PMID-11677243_T18", "type": "Simple_chemical", "text": [ "galactose" ], "offsets": [ [ 1029, 1038 ] ], "normalized": [] }, { "id": "PMID-11677243_T19", "type": "Simple_chemical", "text": [ "UDP-Gal" ], "offsets": [ [ 1044, 1051 ] ], "normalized": [] }, { "id": "PMID-11677243_T20", "type": "Simple_chemical", "text": [ "GalNAcalpha1-O-phenyl" ], "offsets": [ [ 1055, 1076 ] ], "normalized": [] }, { "id": "PMID-11677243_T21", "type": "Simple_chemical", "text": [ "Thr" ], "offsets": [ [ 1112, 1115 ] ], "normalized": [] }, { "id": "PMID-11677243_T22", "type": "Simple_chemical", "text": [ "GalNAc" ], "offsets": [ [ 1123, 1129 ] ], "normalized": [] }, { "id": "PMID-11677243_T23", "type": "Simple_chemical", "text": [ "core 1" ], "offsets": [ [ 1168, 1174 ] ], "normalized": [] }, { "id": "PMID-11677243_T24", "type": "Gene_or_gene_product", "text": [ "core 1 beta3-Gal-T" ], "offsets": [ [ 1242, 1260 ] ], "normalized": [] }, { "id": "PMID-11677243_T25", "type": "Gene_or_gene_product", "text": [ "core 1 beta3-Gal-T" ], "offsets": [ [ 1519, 1537 ] ], "normalized": [] }, { "id": "PMID-11677243_T26", "type": "Gene_or_gene_product", "text": [ "beta3-galactosyltransferases" ], "offsets": [ [ 1623, 1651 ] ], "normalized": [] }, { "id": "PMID-11677243_T27", "type": "Gene_or_gene_product", "text": [ "beta3-galactosyltransferase" ], "offsets": [ [ 1715, 1742 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-11691836__text", "type": "abstract", "text": [ "Hierarchical phosphorylation of the translation inhibitor 4E-BP1. \nIn most instances, translation is regulated at the initiation phase, when a ribosome is recruited to the 5' end of an mRNA. The eIF4E-binding proteins (4E-BPs) interdict translation initiation by binding to the translation factor eIF4E, and preventing recruitment of the translation machinery to mRNA. The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity. We reported previously that phosphorylation of 4E-BP1 on Thr 37 and Thr 46 is relatively insensitive to serum deprivation and rapamycin treatment, and that phosphorylation of these residues is required for the subsequent phosphorylation of a set of unidentified serum-responsive sites. Here, using mass spectrometry, we identify the serum-responsive, rapamycin-sensitive sites as Ser 65 and Thr 70. Utilizing a novel combination of two-dimensional isoelectric focusing/SDS-PAGE and Western blotting with phosphospecific antibodies, we also establish the order of 4E-BP1 phosphorylation in vivo; phosphorylation of Thr 37/Thr 46 is followed by Thr 70 phosphorylation, and Ser 65 is phosphorylated last. Finally, we show that phosphorylation of Ser 65 and Thr 70 alone is insufficient to block binding to eIF4E, indicating that a combination of phosphorylation events is necessary to dissociate 4E-BP1 from eIF4E. \n" ], "offsets": [ [ 0, 1557 ] ] } ]

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512 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11691836_T9" } ] }, { "id": "PMID-11691836_E6", "type": "Positive_regulation", "trigger": { "text": [ "elicited" ], "offsets": [ [ 514, 522 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11691836_E5" } ] }, { "id": "PMID-11691836_E7", "type": "Positive_regulation", "trigger": { "text": [ "results" ], "offsets": [ [ 592, 599 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11691836_E5" }, { "role": "Theme", "ref_id": "PMID-11691836_E8" } ] }, { "id": "PMID-11691836_E8", "type": "Negative_regulation", "trigger": { "text": [ "abrogation" ], "offsets": [ [ 606, 616 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11691836_E9" } ] }, { "id": "PMID-11691836_E9", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 626, 633 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11691836_T10" }, { "role": "Theme", "ref_id": "PMID-11691836_T9" } ] }, { "id": "PMID-11691836_E10", "type": 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[ 1294, 1309 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-11691836_T21" }, { "role": "Theme", "ref_id": "PMID-11691836_T18" } ] }, { "id": "PMID-11691836_E23", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 1325, 1339 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-11691836_T22" }, { "role": "Theme", "ref_id": "PMID-11691836_T18" } ] }, { "id": "PMID-11691836_E24", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1368, 1383 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-11691836_T24" }, { "role": "Theme", "ref_id": "PMID-11691836_T18" } ] }, { "id": "PMID-11691836_E25", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1368, 1383 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-11691836_T23" }, { "role": "Theme", "ref_id": "PMID-11691836_T18" } ] }, { "id": "PMID-11691836_E26", "type": "Positive_regulation", "trigger": { "text": [ 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[ { "id": "PMID-11723111__text", "type": "abstract", "text": [ "Phosphorylation of eukaryotic initiation factor 4E markedly reduces its affinity for capped mRNA. \nIn eukaryotes, a key step in the initiation of translation is the binding of the eukaryotic initiation factor 4E (eIF4E) to the cap structure of the mRNA. Subsequent recruitment of several components, including the small ribosomal subunit, is thought to allow migration of initiation complexes and recognition of the initiation codon. Mitogens and cytokines stimulate the phosphorylation of eIF4E at Ser(209), but the functional consequences of this modification have remained a major unresolved question. Using fluorescence spectroscopy and surface plasmon resonance techniques, we show that phosphorylation of eIF4E markedly reduces its affinity for capped RNA, primarily due to an increased rate of dissociation. Variant eIF4E proteins harboring negatively charged acidic residues at position 209 also showed decreased binding to capped RNA. Furthermore, a basic residue at position 159 was shown to be essential for cap binding. Although eIF4E-binding protein 1 greatly stabilized binding of phosphorylated eIF4E to capped RNA, in the presence of eIF4E-binding protein 1 the phosphorylated form still dissociated faster compared with nonphopshorylated eIF4E. The implications of our findings for the mechanism of translation initiation are discussed. \n" ], "offsets": [ [ 0, 1355 ] ] } ]

[ { "id": "PMID-11723111_T1", "type": "Gene_or_gene_product", "text": [ "eukaryotic initiation factor 4E" ], "offsets": [ [ 19, 50 ] ], "normalized": [] }, { "id": "PMID-11723111_T2", "type": "Gene_or_gene_product", "text": [ "eukaryotic initiation factor 4E" ], "offsets": [ [ 180, 211 ] ], "normalized": [] }, { "id": "PMID-11723111_T3", "type": "Gene_or_gene_product", "text": [ "eIF4E" ], "offsets": [ [ 213, 218 ] ], "normalized": [] }, { "id": "PMID-11723111_T4", "type": "Cellular_component", "text": [ "small ribosomal subunit" ], "offsets": [ [ 314, 337 ] ], "normalized": [] }, { "id": "PMID-11723111_T5", "type": "Gene_or_gene_product", "text": [ "eIF4E" ], "offsets": [ [ 490, 495 ] ], "normalized": [] }, { "id": "PMID-11723111_T6", "type": "Simple_chemical", "text": [ "Ser(209)" ], "offsets": [ [ 499, 507 ] ], "normalized": [] }, { "id": "PMID-11723111_T7", "type": "Gene_or_gene_product", "text": [ "eIF4E" ], "offsets": [ [ 711, 716 ] ], "normalized": [] }, { "id": "PMID-11723111_T8", "type": "Gene_or_gene_product", "text": [ "eIF4E" ], "offsets": [ [ 823, 828 ] ], "normalized": [] }, { "id": "PMID-11723111_T9", "type": "Gene_or_gene_product", "text": [ "eIF4E-binding protein 1" ], "offsets": [ [ 1041, 1064 ] ], "normalized": [] }, { "id": "PMID-11723111_T10", "type": "Gene_or_gene_product", "text": [ "eIF4E" ], "offsets": [ [ 1110, 1115 ] ], "normalized": [] }, { "id": "PMID-11723111_T11", "type": "Gene_or_gene_product", "text": [ "eIF4E-binding protein 1" ], "offsets": [ [ 1150, 1173 ] ], "normalized": [] }, { "id": "PMID-11723111_T12", "type": "Gene_or_gene_product", "text": [ "eIF4E" ], "offsets": [ [ 1255, 1260 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-11726501__text", "type": "abstract", "text": [ "Bub3 interaction with Mad2, Mad3 and Cdc20 is mediated by WD40 repeats and does not require intact kinetochores. \nThe kinetochore checkpoint pathway, involving the Mad1, Mad2, Mad3, Bub1, Bub3 and Mps1 proteins, prevents anaphase entry and mitotic exit by inhibiting the anaphase promoting complex activator Cdc20 in response to monopolar attachment of sister kinetochores to spindle fibres. We show here that Cdc20, which had previously been shown to interact physically with Mad2 and Mad3, associates also with Bub3 and association is up-regulated upon checkpoint activation. Moreover, co-fractionation experiments suggest that Mad2, Mad3 and Bub3 may be concomitantly present in protein complexes with Cdc20. Formation of the Bub3-Cdc20 complex requires all kinetochore checkpoint proteins but, surprisingly, not intact kinetochores. Conversely, point mutations altering the conserved WD40 motifs of Bub3, which might be involved in the formation of a beta-propeller fold devoted to protein-protein interactions, disrupt its association with Mad2, Mad3 and Cdc20, as well as proper checkpoint response. We suggest that Bub3 could serve as a platform for interactions between kinetochore checkpoint proteins, and its association with Mad2, Mad3 and Cdc20 might be instrumental for checkpoint activation.\n" ], "offsets": [ [ 0, 1306 ] ] } ]

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"arguments": [ { "role": "Theme", "ref_id": "PMID-11726501_E12" } ] }, { "id": "PMID-11726501_E14", "type": "Binding", "trigger": { "text": [ "Formation" ], "offsets": [ [ 712, 721 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11726501_T26" } ] }, { "id": "PMID-11726501_E15", "type": "Regulation", "trigger": { "text": [ "altering" ], "offsets": [ [ 865, 873 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11726501_T30" } ] }, { "id": "PMID-11726501_E16", "type": "Negative_regulation", "trigger": { "text": [ "disrupt" ], "offsets": [ [ 1016, 1023 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11726501_E15" }, { "role": "Theme", "ref_id": "PMID-11726501_E19" } ] }, { "id": "PMID-11726501_E17", "type": "Negative_regulation", "trigger": { "text": [ "disrupt" ], "offsets": [ [ 1016, 1023 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11726501_E15" }, { "role": "Theme", "ref_id": "PMID-11726501_E20" } ] }, { "id": "PMID-11726501_E18", "type": 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[]

[]

[ { "id": "PMID-11729323__text", "type": "abstract", "text": [ "Phosphatidic acid-mediated mitogenic activation of mTOR signaling. \nThe mammalian target of rapamycin (mTOR) governs cell growth and proliferation by mediating the mitogen- and nutrient-dependent signal transduction that regulates messenger RNA translation. We identified phosphatidic acid (PA) as a critical component of mTOR signaling. In our study, mitogenic stimulation of mammalian cells led to a phospholipase D-dependent accumulation of cellular PA, which was required for activation of mTOR downstream effectors. PA directly interacted with the domain in mTOR that is targeted by rapamycin, and this interaction was positively correlated with mTOR's ability to activate downstream effectors. The involvement of PA in mTOR signaling reveals an important function of this lipid in signal transduction and protein synthesis, as well as a direct link between mTOR and mitogens. Furthermore, these studies suggest a potential mechanism for the in vivo actions of the immunosuppressant rapamycin. \n" ], "offsets": [ [ 0, 1000 ] ] } ]

[ { "id": "PMID-11729323_T1", "type": "Simple_chemical", "text": [ "Phosphatidic acid" ], "offsets": [ [ 0, 17 ] ], "normalized": [] }, { "id": "PMID-11729323_T2", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 51, 55 ] ], "normalized": [] }, { "id": "PMID-11729323_T3", "type": "Gene_or_gene_product", "text": [ "mammalian target of rapamycin" ], "offsets": [ [ 72, 101 ] ], "normalized": [] }, { "id": "PMID-11729323_T4", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 103, 107 ] ], "normalized": [] }, { "id": "PMID-11729323_T5", "type": "Simple_chemical", "text": [ "phosphatidic acid" ], "offsets": [ [ 272, 289 ] ], "normalized": [] }, { "id": "PMID-11729323_T6", "type": "Simple_chemical", "text": [ "PA" ], "offsets": [ [ 291, 293 ] ], "normalized": [] }, { "id": "PMID-11729323_T7", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 322, 326 ] ], "normalized": [] }, { "id": "PMID-11729323_T8", "type": "Gene_or_gene_product", "text": [ "phospholipase D" ], "offsets": [ [ 402, 417 ] ], "normalized": [] }, { "id": "PMID-11729323_T9", "type": "Simple_chemical", "text": [ "PA" ], "offsets": [ [ 453, 455 ] ], "normalized": [] }, { "id": "PMID-11729323_T10", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 494, 498 ] ], "normalized": [] }, { "id": "PMID-11729323_T11", "type": "Simple_chemical", "text": [ "PA" ], "offsets": [ [ 521, 523 ] ], "normalized": [] }, { "id": "PMID-11729323_T12", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 563, 567 ] ], "normalized": [] }, { "id": "PMID-11729323_T13", "type": "Simple_chemical", "text": [ "rapamycin" ], "offsets": [ [ 588, 597 ] ], "normalized": [] }, { "id": "PMID-11729323_T14", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 651, 655 ] ], "normalized": [] }, { "id": "PMID-11729323_T15", "type": "Simple_chemical", "text": [ "PA" ], "offsets": [ [ 719, 721 ] ], "normalized": [] }, { "id": "PMID-11729323_T16", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 725, 729 ] ], "normalized": [] }, { "id": "PMID-11729323_T17", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 863, 867 ] ], "normalized": [] }, { "id": "PMID-11729323_T18", "type": "Simple_chemical", "text": [ "rapamycin" ], "offsets": [ [ 988, 997 ] ], "normalized": [] } ]

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[ { "id": "PMID-11729323_1", "entity_ids": [ "PMID-11729323_T3", "PMID-11729323_T4" ] }, { "id": "PMID-11729323_2", "entity_ids": [ "PMID-11729323_T5", "PMID-11729323_T6" ] } ]

[]

[ { "id": "PMID-11751856__text", "type": "abstract", "text": [ "Negative regulation of toll-like receptor-mediated signaling by Tollip. \nToll-like receptor (TLR)-mediated recognition of pathogens represents one of the most important mechanisms of innate immunity and disease resistance. The adaptor protein Tollip was identified initially as an intermediate in interleukin (IL)-1 signaling. Here we report that Tollip also associates directly with TLR2 and TLR4 and plays an inhibitory role in TLR-mediated cell activation. Inhibition by Tollip is mediated through its ability to potently suppress the activity of IL-1 receptor-associated kinase (IRAK) after TLR activation. In addition, we show for the first time that Tollip is a bona fide substrate for IRAK and is phosphorylated by IRAK upon stimulation with lipopolysaccharide or IL-1. Negative regulation of TLR signaling by Tollip may therefore serve to limit the production of proinflammatory mediators during inflammation and infection.\n" ], "offsets": [ [ 0, 932 ] ] } ]

[ { "id": "PMID-11751856_T1", "type": "Gene_or_gene_product", "text": [ "toll-like receptor" ], "offsets": [ [ 23, 41 ] ], "normalized": [] }, { "id": "PMID-11751856_T2", "type": "Gene_or_gene_product", "text": [ "Tollip" ], "offsets": [ [ 64, 70 ] ], "normalized": [] }, { "id": "PMID-11751856_T3", "type": "Gene_or_gene_product", "text": [ "Toll-like receptor" ], "offsets": [ [ 73, 91 ] ], "normalized": [] }, { "id": "PMID-11751856_T4", "type": "Gene_or_gene_product", "text": [ "TLR" ], "offsets": [ [ 93, 96 ] ], "normalized": [] }, { "id": "PMID-11751856_T5", "type": "Gene_or_gene_product", "text": [ "Tollip" ], "offsets": [ [ 243, 249 ] ], "normalized": [] }, { "id": "PMID-11751856_T6", "type": "Gene_or_gene_product", "text": [ "interleukin (IL)-1" ], "offsets": [ [ 297, 315 ] ], "normalized": [] }, { "id": "PMID-11751856_T7", "type": "Gene_or_gene_product", "text": [ "Tollip" ], "offsets": [ [ 347, 353 ] ], "normalized": [] }, { "id": "PMID-11751856_T8", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 384, 388 ] ], "normalized": [] }, { "id": "PMID-11751856_T9", "type": "Gene_or_gene_product", "text": [ "TLR4" ], "offsets": [ [ 393, 397 ] ], "normalized": [] }, { "id": "PMID-11751856_T10", "type": "Gene_or_gene_product", "text": [ "TLR" ], "offsets": [ [ 430, 433 ] ], "normalized": [] }, { "id": "PMID-11751856_T11", "type": "Gene_or_gene_product", "text": [ "Tollip" ], "offsets": [ [ 474, 480 ] ], "normalized": [] }, { "id": "PMID-11751856_T12", "type": "Gene_or_gene_product", "text": [ "IL-1 receptor-associated kinase" ], "offsets": [ [ 550, 581 ] ], "normalized": [] }, { "id": "PMID-11751856_T13", "type": "Gene_or_gene_product", "text": [ "IRAK" ], "offsets": [ [ 583, 587 ] ], "normalized": [] }, { "id": "PMID-11751856_T14", "type": "Gene_or_gene_product", "text": [ "TLR" ], "offsets": [ [ 595, 598 ] ], "normalized": [] }, { "id": "PMID-11751856_T15", "type": "Gene_or_gene_product", "text": [ "Tollip" ], "offsets": [ [ 656, 662 ] ], "normalized": [] }, { "id": "PMID-11751856_T16", "type": "Gene_or_gene_product", "text": [ "IRAK" ], "offsets": [ [ 692, 696 ] ], "normalized": [] }, { "id": "PMID-11751856_T17", "type": "Gene_or_gene_product", "text": [ "IRAK" ], "offsets": [ [ 722, 726 ] ], "normalized": [] }, { "id": "PMID-11751856_T18", "type": "Simple_chemical", "text": [ "lipopolysaccharide" ], "offsets": [ [ 749, 767 ] ], "normalized": [] }, { "id": "PMID-11751856_T19", "type": "Gene_or_gene_product", "text": [ "IL-1" ], "offsets": [ [ 771, 775 ] ], "normalized": [] }, { "id": "PMID-11751856_T20", "type": "Gene_or_gene_product", "text": [ "TLR" ], "offsets": [ [ 800, 803 ] ], "normalized": [] }, { "id": "PMID-11751856_T21", "type": "Gene_or_gene_product", "text": [ "Tollip" ], "offsets": [ [ 817, 823 ] ], "normalized": [] } ]

[ { "id": "PMID-11751856_E1", "type": "Negative_regulation", "trigger": { "text": [ "Negative regulation" ], "offsets": [ [ 0, 19 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11751856_E3" }, { "role": "Cause", "ref_id": "PMID-11751856_T2" } ] }, { "id": "PMID-11751856_E2", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 42, 50 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11751856_T1" }, { "role": "Theme", "ref_id": "PMID-11751856_E3" } ] }, { "id": "PMID-11751856_E3", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 51, 60 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-11751856_T1" } ] }, { "id": "PMID-11751856_E4", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 316, 325 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-11751856_T6" } ] }, { "id": "PMID-11751856_E5", "type": "Regulation", "trigger": { "text": [ "associates" ], "offsets": [ [ 359, 369 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11751856_T7" }, { "role": "Theme", "ref_id": "PMID-11751856_T8" } ] }, { "id": "PMID-11751856_E6", "type": "Regulation", "trigger": { "text": [ "associates" ], "offsets": [ [ 359, 369 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11751856_T7" }, { "role": "Theme", "ref_id": "PMID-11751856_T9" } ] }, { "id": "PMID-11751856_E7", "type": "Negative_regulation", "trigger": { "text": [ "suppress" ], "offsets": [ [ 525, 533 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11751856_T12" } ] }, { "id": "PMID-11751856_E8", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 599, 609 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11751856_T14" } ] }, { "id": "PMID-11751856_E9", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 704, 718 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11751856_T17" }, { "role": "Theme", "ref_id": "PMID-11751856_T15" } ] }, { "id": "PMID-11751856_E10", "type": "Positive_regulation", "trigger": { "text": [ "stimulation" ], "offsets": [ [ 732, 743 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11751856_E9" }, { "role": "Cause", "ref_id": "PMID-11751856_T18" } ] }, { "id": "PMID-11751856_E11", "type": "Positive_regulation", "trigger": { "text": [ "stimulation" ], "offsets": [ [ 732, 743 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11751856_E9" }, { "role": "Cause", "ref_id": "PMID-11751856_T19" } ] }, { "id": "PMID-11751856_E12", "type": "Negative_regulation", "trigger": { "text": [ "Negative regulation" ], "offsets": [ [ 777, 796 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11751856_E13" }, { "role": "Cause", "ref_id": "PMID-11751856_T21" } ] }, { "id": "PMID-11751856_E13", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 804, 813 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-11751856_T20" } ] } ]

[ { "id": "PMID-11751856_1", "entity_ids": [ "PMID-11751856_T3", "PMID-11751856_T4" ] }, { "id": "PMID-11751856_2", "entity_ids": [ "PMID-11751856_T12", "PMID-11751856_T13" ] } ]

[]

[ { "id": "PMID-11801686__text", "type": "abstract", "text": [ "Chlamydial heat shock protein 60 activates macrophages and endothelial cells through Toll-like receptor 4 and MD2 in a MyD88-dependent pathway. \nActive inflammation and NF-kappaB activation contribute fundamentally to atherogenesis and plaque disruption. Accumulating evidence has implicated specific infectious agents including Chlamydia pneumoniae in the progression of atherogenesis. Chlamydial heat shock protein 60 (cHSP60) has been implicated in the induction of deleterious immune responses in human chlamydial infections and has been found to colocalize with infiltrating macrophages in atheroma lesions. cHSP60 might stimulate, enhance, and maintain innate immune and inflammatory responses and contribute to atherogenesis. In this study, we investigated the signaling mechanism of cHSP60. Recombinant cHSP60 rapidly activated NF-kappaB in human microvascular endothelial cells (EC) and in mouse macrophages, and induced human IL-8 promoter activity in EC. The inflammatory effect of cHSP60 was heat labile, thus excluding a role of contaminating LPS, and was blocked by specific anti-chlamydial HSP60 mAb. In human vascular EC which express Toll-like receptor 4 (TLR4) mRNA and protein, nonsignaling TLR4 constructs that act as dominant negative blocked cHSP60-mediated NF-kappaB activation. Furthermore, an anti-TLR4 Ab abolished cHSP60-induced cellular activation, whereas a control Ab had no effect. In 293 cells, cHSP60-mediated NF-kappaB activation required both TLR4 and MD2. A dominant-negative MyD88 construct also inhibited cHSP60-induced NF-kappaB activation. Collectively, our results indicate that cHSP60 is a potent inducer of vascular EC and macrophage inflammatory responses, which are very relevant to atherogenesis. The inflammatory effects are mediated through the innate immune receptor complex TLR4-MD2 and proceeds via the MyD88-dependent signaling pathway. These findings may help elucidate the mechanisms by which chronic asymptomatic chlamydial infection contribute to atherogenesis.\n" ], "offsets": [ [ 0, 2018 ] ] } ]

[ { "id": "PMID-11801686_T1", "type": "Gene_or_gene_product", "text": [ "heat shock protein 60" ], "offsets": [ [ 11, 32 ] ], "normalized": [] }, { "id": "PMID-11801686_T2", "type": "Gene_or_gene_product", "text": [ "Toll-like receptor 4" ], "offsets": [ [ 85, 105 ] ], "normalized": [] }, { "id": "PMID-11801686_T3", "type": "Gene_or_gene_product", "text": [ "MD2" ], "offsets": [ [ 110, 113 ] ], "normalized": [] }, { "id": "PMID-11801686_T4", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 119, 124 ] ], "normalized": [] }, { "id": "PMID-11801686_T5", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 169, 178 ] ], "normalized": [] }, { "id": "PMID-11801686_T6", "type": "Gene_or_gene_product", "text": [ "heat shock protein 60" ], "offsets": [ [ 398, 419 ] ], "normalized": [] }, { "id": "PMID-11801686_T7", "type": "Gene_or_gene_product", "text": [ "cHSP60" ], "offsets": [ [ 421, 427 ] ], "normalized": [] }, { "id": "PMID-11801686_T8", "type": "Gene_or_gene_product", "text": [ "cHSP60" ], "offsets": [ [ 613, 619 ] ], "normalized": [] }, { "id": "PMID-11801686_T9", "type": "Gene_or_gene_product", "text": [ "cHSP60" ], "offsets": [ [ 791, 797 ] ], "normalized": [] }, { "id": "PMID-11801686_T10", "type": "Gene_or_gene_product", "text": [ "cHSP60" ], "offsets": [ [ 811, 817 ] ], "normalized": [] }, { "id": "PMID-11801686_T11", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 836, 845 ] ], "normalized": [] }, { "id": "PMID-11801686_T12", "type": "Gene_or_gene_product", "text": [ "IL-8" ], "offsets": [ [ 936, 940 ] ], "normalized": [] }, { "id": "PMID-11801686_T13", "type": "Gene_or_gene_product", "text": [ "cHSP60" ], "offsets": [ [ 993, 999 ] ], "normalized": [] }, { "id": "PMID-11801686_T14", "type": "Simple_chemical", "text": [ "LPS" ], "offsets": [ [ 1056, 1059 ] ], "normalized": [] }, { "id": "PMID-11801686_T15", "type": "Gene_or_gene_product", "text": [ "HSP60" ], "offsets": [ [ 1105, 1110 ] ], "normalized": [] }, { "id": "PMID-11801686_T16", "type": "Gene_or_gene_product", "text": [ "Toll-like receptor 4" ], "offsets": [ [ 1151, 1171 ] ], "normalized": [] }, { "id": "PMID-11801686_T17", "type": "Gene_or_gene_product", "text": [ "TLR4" ], "offsets": [ [ 1173, 1177 ] ], "normalized": [] }, { "id": "PMID-11801686_T18", "type": "Gene_or_gene_product", "text": [ "TLR4" ], "offsets": [ [ 1210, 1214 ] ], "normalized": [] }, { "id": "PMID-11801686_T19", "type": "Gene_or_gene_product", "text": [ "cHSP60" ], "offsets": [ [ 1264, 1270 ] ], "normalized": [] }, { "id": "PMID-11801686_T20", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1280, 1289 ] ], "normalized": [] }, { "id": "PMID-11801686_T21", "type": "Gene_or_gene_product", "text": [ "TLR4" ], "offsets": [ [ 1323, 1327 ] ], "normalized": [] }, { "id": "PMID-11801686_T22", "type": "Gene_or_gene_product", "text": [ "cHSP60" ], "offsets": [ [ 1341, 1347 ] ], "normalized": [] }, { "id": "PMID-11801686_T23", "type": "Gene_or_gene_product", "text": [ "cHSP60" ], "offsets": [ [ 1427, 1433 ] ], "normalized": [] }, { "id": "PMID-11801686_T24", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1443, 1452 ] ], "normalized": [] }, { "id": "PMID-11801686_T25", "type": "Gene_or_gene_product", "text": [ "TLR4" ], "offsets": [ [ 1478, 1482 ] ], "normalized": [] }, { "id": "PMID-11801686_T26", "type": "Gene_or_gene_product", "text": [ "MD2" ], "offsets": [ [ 1487, 1490 ] ], "normalized": [] }, { "id": "PMID-11801686_T27", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 1512, 1517 ] ], "normalized": [] }, { "id": "PMID-11801686_T28", "type": "Gene_or_gene_product", "text": [ "cHSP60" ], "offsets": [ [ 1543, 1549 ] ], "normalized": [] }, { "id": "PMID-11801686_T29", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1558, 1567 ] ], "normalized": [] }, { "id": "PMID-11801686_T30", "type": "Gene_or_gene_product", "text": [ "cHSP60" ], "offsets": [ [ 1620, 1626 ] ], "normalized": [] }, { "id": "PMID-11801686_T31", "type": "Complex", "text": [ "TLR4-MD2" ], "offsets": [ [ 1824, 1832 ] ], "normalized": [] }, { "id": "PMID-11801686_T32", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 1854, 1859 ] ], "normalized": [] } ]

[ { "id": "PMID-11801686_E1", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 135, 142 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-11801686_T4" } ] }, { "id": "PMID-11801686_E2", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 179, 189 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11801686_T5" } ] }, { "id": "PMID-11801686_E3", "type": "Activation", "trigger": { "text": [ "activated" ], "offsets": [ [ 826, 835 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11801686_T11" }, { "role": "Cause", "ref_id": "PMID-11801686_T10" } ] }, { "id": "PMID-11801686_E4", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 922, 929 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11801686_T12" }, { "role": "Cause", "ref_id": "PMID-11801686_T10" } ] }, { "id": "PMID-11801686_E5", "type": "Gene_expression", "trigger": { "text": [ "express" ], "offsets": [ [ 1143, 1150 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11801686_T16" } ] }, { "id": "PMID-11801686_E6", "type": "Negative_regulation", "trigger": { "text": [ "blocked" ], "offsets": [ [ 1256, 1263 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11801686_E8" }, { "role": "Cause", "ref_id": "PMID-11801686_T18" } ] }, { "id": "PMID-11801686_E7", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1271, 1279 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11801686_T19" }, { "role": "Theme", "ref_id": "PMID-11801686_E8" } ] }, { "id": "PMID-11801686_E8", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1290, 1300 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11801686_T20" } ] }, { "id": "PMID-11801686_E9", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1434, 1442 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11801686_T23" }, { "role": "Theme", "ref_id": "PMID-11801686_E10" } ] }, { "id": "PMID-11801686_E10", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1453, 1463 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11801686_T24" } ] }, { "id": "PMID-11801686_E11", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 1464, 1472 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11801686_E10" }, { "role": "Cause", "ref_id": "PMID-11801686_T25" } ] }, { "id": "PMID-11801686_E12", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 1464, 1472 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11801686_E10" }, { "role": "Cause", "ref_id": "PMID-11801686_T26" } ] }, { "id": "PMID-11801686_E13", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 1533, 1542 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11801686_E15" }, { "role": "Cause", "ref_id": "PMID-11801686_T27" } ] }, { "id": "PMID-11801686_E14", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1550, 1557 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11801686_T28" }, { "role": "Theme", "ref_id": "PMID-11801686_E15" } ] }, { "id": "PMID-11801686_E15", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1568, 1578 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11801686_T29" } ] }, { "id": "PMID-11801686_E16", "type": "Pathway", "trigger": { "text": [ "signaling pathway" ], "offsets": [ [ 1870, 1887 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-11801686_T32" } ] } ]

[ { "id": "PMID-11801686_1", "entity_ids": [ "PMID-11801686_T6", "PMID-11801686_T7" ] }, { "id": "PMID-11801686_2", "entity_ids": [ "PMID-11801686_T16", "PMID-11801686_T17" ] } ]

[]

[ { "id": "PMID-11802770__text", "type": "abstract", "text": [ "Carnitine biosynthesis in mammals. \nCarnitine is indispensable for energy metabolism, since it enables activated fatty acids to enter the mitochondria, where they are broken down via beta-oxidation. Carnitine is probably present in all animal species, and in numerous micro-organisms and plants. In mammals, carnitine homoeostasis is maintained by endogenous synthesis, absorption from dietary sources and efficient tubular reabsorption by the kidney. This review aims to cover the current knowledge of the enzymological, molecular, metabolic and regulatory aspects of mammalian carnitine biosynthesis, with an emphasis on the human and rat.\n" ], "offsets": [ [ 0, 642 ] ] } ]

[ { "id": "PMID-11802770_T1", "type": "Simple_chemical", "text": [ "Carnitine" ], "offsets": [ [ 0, 9 ] ], "normalized": [] }, { "id": "PMID-11802770_T2", "type": "Simple_chemical", "text": [ "Carnitine" ], "offsets": [ [ 36, 45 ] ], "normalized": [] }, { "id": "PMID-11802770_T3", "type": "Simple_chemical", "text": [ "fatty acids" ], "offsets": [ [ 113, 124 ] ], "normalized": [] }, { "id": "PMID-11802770_T4", "type": "Cellular_component", "text": [ "mitochondria" ], "offsets": [ [ 138, 150 ] ], "normalized": [] }, { "id": "PMID-11802770_T5", "type": "Simple_chemical", "text": [ "Carnitine" ], "offsets": [ [ 199, 208 ] ], "normalized": [] }, { "id": "PMID-11802770_T6", "type": "Simple_chemical", "text": [ "carnitine" ], "offsets": [ [ 308, 317 ] ], "normalized": [] }, { "id": "PMID-11802770_T7", "type": "Simple_chemical", "text": [ "carnitine" ], "offsets": [ [ 579, 588 ] ], "normalized": [] } ]

[ { "id": "PMID-11802770_E1", "type": "Conversion", "trigger": { "text": [ "biosynthesis" ], "offsets": [ [ 10, 22 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-11802770_T1" } ] }, { "id": "PMID-11802770_E2", "type": "Activation", "trigger": { "text": [ "activated" ], "offsets": [ [ 103, 112 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11802770_T3" } ] }, { "id": "PMID-11802770_E3", "type": "Transport", "trigger": { "text": [ "enter" ], "offsets": [ [ 128, 133 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-11802770_T4" }, { "role": "Theme", "ref_id": "PMID-11802770_T3" } ] }, { "id": "PMID-11802770_E4", "type": "Regulation", "trigger": { "text": [ "broken down" ], "offsets": [ [ 167, 178 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11802770_E5" }, { "role": "Theme", "ref_id": "PMID-11802770_E2" } ] }, { "id": "PMID-11802770_E5", "type": "Pathway", "trigger": { "text": [ "beta-oxidation" ], "offsets": [ [ 183, 197 ] ] }, "arguments": [] }, { "id": "PMID-11802770_E6", "type": "Conversion", "trigger": { "text": [ "biosynthesis" ], "offsets": [ [ 589, 601 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-11802770_T7" } ] } ]

[]

[]

[ { "id": "PMID-11832211__text", "type": "abstract", "text": [ "Separase, polo kinase, the kinetochore protein Slk19, and Spo12 function in a network that controls Cdc14 localization during early anaphase. \nIn budding yeast, the phosphatase Cdc14, a key regulator of exit from mitosis, is released from its inhibitor Cfi1/Net1 in the nucleolus during anaphase. A signaling cascade, known as the mitotic exit network (MEN), controls this release. We have identified a regulatory network, the FEAR (Cdc fourteen early anaphase release) network that promotes Cdc14 release from the nucleolus during early anaphase. The FEAR network is comprised of the polo kinase Cdc5, the separase Esp1, the kinetochore-associated protein Slk19, and Spo12. We also show that the FEAR network initiates Cdc14 release from Cfi1/Net1 during early anaphase, and MEN maintains Cdc14 in the released state during late anaphase. We propose that one function of Cdc14 released by the FEAR network is to stimulate MEN activity.\n" ], "offsets": [ [ 0, 937 ] ] } ]

[ { "id": "PMID-11832211_T1", "type": "Gene_or_gene_product", "text": [ "Separase" ], "offsets": [ [ 0, 8 ] ], "normalized": [] }, { "id": "PMID-11832211_T2", "type": "Gene_or_gene_product", "text": [ "polo kinase" ], "offsets": [ [ 10, 21 ] ], "normalized": [] }, { "id": "PMID-11832211_T3", "type": "Cellular_component", "text": [ "kinetochore" ], "offsets": [ [ 27, 38 ] ], "normalized": [] }, { "id": "PMID-11832211_T4", "type": "Gene_or_gene_product", "text": [ "Slk19" ], "offsets": [ [ 47, 52 ] ], "normalized": [] }, { "id": "PMID-11832211_T5", "type": "Gene_or_gene_product", "text": [ "Spo12" ], "offsets": [ [ 58, 63 ] ], "normalized": [] }, { "id": "PMID-11832211_T6", "type": "Gene_or_gene_product", "text": [ "Cdc14" ], "offsets": [ [ 100, 105 ] ], "normalized": [] }, { "id": "PMID-11832211_T7", "type": "Gene_or_gene_product", "text": [ "Cdc14" ], "offsets": [ [ 177, 182 ] ], "normalized": [] }, { "id": "PMID-11832211_T8", "type": "Gene_or_gene_product", "text": [ "Cfi1" ], "offsets": [ [ 253, 257 ] ], "normalized": [] }, { "id": "PMID-11832211_T9", "type": "Gene_or_gene_product", "text": [ "Net1" ], "offsets": [ [ 258, 262 ] ], "normalized": [] }, { "id": "PMID-11832211_T10", "type": "Cellular_component", "text": [ "nucleolus" ], "offsets": [ [ 270, 279 ] ], "normalized": [] }, { "id": "PMID-11832211_T11", "type": "Gene_or_gene_product", "text": [ "Cdc" ], "offsets": [ [ 433, 436 ] ], "normalized": [] }, { "id": "PMID-11832211_T12", "type": "Gene_or_gene_product", "text": [ "Cdc14" ], "offsets": [ [ 492, 497 ] ], "normalized": [] }, { "id": "PMID-11832211_T13", "type": "Cellular_component", "text": [ "nucleolus" ], "offsets": [ [ 515, 524 ] ], "normalized": [] }, { "id": "PMID-11832211_T14", "type": "Gene_or_gene_product", "text": [ "polo kinase" ], "offsets": [ [ 585, 596 ] ], "normalized": [] }, { "id": "PMID-11832211_T15", "type": "Gene_or_gene_product", "text": [ "Cdc5" ], "offsets": [ [ 597, 601 ] ], "normalized": [] }, { "id": "PMID-11832211_T16", "type": "Gene_or_gene_product", "text": [ "separase" ], "offsets": [ [ 607, 615 ] ], "normalized": [] }, { "id": "PMID-11832211_T17", "type": "Gene_or_gene_product", "text": [ "Esp1" ], "offsets": [ [ 616, 620 ] ], "normalized": [] }, { "id": "PMID-11832211_T18", "type": "Cellular_component", "text": [ "kinetochore" ], "offsets": [ [ 626, 637 ] ], "normalized": [] }, { "id": "PMID-11832211_T19", "type": "Gene_or_gene_product", "text": [ "Slk19" ], "offsets": [ [ 657, 662 ] ], "normalized": [] }, { "id": "PMID-11832211_T20", "type": "Gene_or_gene_product", "text": [ "Spo12" ], "offsets": [ [ 668, 673 ] ], "normalized": [] }, { "id": "PMID-11832211_T21", "type": "Gene_or_gene_product", "text": [ "Cdc14" ], "offsets": [ [ 720, 725 ] ], "normalized": [] }, { "id": "PMID-11832211_T22", "type": "Gene_or_gene_product", "text": [ "Cfi1" ], "offsets": [ [ 739, 743 ] ], "normalized": [] }, { "id": "PMID-11832211_T23", "type": "Gene_or_gene_product", "text": [ "Net1" ], "offsets": [ [ 744, 748 ] ], "normalized": [] }, { "id": "PMID-11832211_T24", "type": "Gene_or_gene_product", "text": [ "Cdc14" ], "offsets": [ [ 790, 795 ] ], "normalized": [] }, { "id": "PMID-11832211_T25", "type": "Gene_or_gene_product", "text": [ "Cdc14" ], "offsets": [ [ 872, 877 ] ], "normalized": [] } ]

[ { "id": "PMID-11832211_E1", "type": "Regulation", "trigger": { "text": [ "controls" ], "offsets": [ [ 91, 99 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11832211_E5" }, { "role": "Cause", "ref_id": "PMID-11832211_T1" } ] }, { "id": "PMID-11832211_E2", "type": "Regulation", "trigger": { "text": [ "controls" ], "offsets": [ [ 91, 99 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11832211_E5" }, { "role": "Cause", "ref_id": "PMID-11832211_T2" } ] }, { "id": "PMID-11832211_E3", "type": "Regulation", "trigger": { "text": [ "controls" ], "offsets": [ [ 91, 99 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11832211_E5" }, { "role": "Cause", "ref_id": "PMID-11832211_T5" } ] }, { "id": "PMID-11832211_E4", "type": "Regulation", "trigger": { "text": [ "controls" ], "offsets": [ [ 91, 99 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11832211_E5" }, { "role": "Cause", "ref_id": "PMID-11832211_T4" } ] }, { "id": "PMID-11832211_E5", "type": "Localization", "trigger": { "text": [ "localization" ], "offsets": [ [ 106, 118 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11832211_T6" } ] }, { "id": "PMID-11832211_E6", "type": "Dissociation", "trigger": { "text": [ "released" ], "offsets": [ [ 225, 233 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-11832211_T7" } ] }, { "id": "PMID-11832211_E7", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 243, 252 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11832211_T8" }, { "role": "Theme", "ref_id": "PMID-11832211_T7" } ] }, { "id": "PMID-11832211_E8", "type": "Positive_regulation", "trigger": { "text": [ "promotes" ], "offsets": [ [ 483, 491 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11832211_E9" }, { "role": "Cause", "ref_id": "PMID-11832211_T11" } ] }, { "id": "PMID-11832211_E9", "type": "Transport", "trigger": { "text": [ "release" ], "offsets": [ [ 498, 505 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11832211_T12" }, { "role": "FromLoc", "ref_id": "PMID-11832211_T13" } ] }, { "id": "PMID-11832211_E10", "type": "Regulation", "trigger": { "text": [ "associated" ], "offsets": [ [ 638, 648 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11832211_T18" }, { "role": "Theme", "ref_id": "PMID-11832211_T19" } ] }, { "id": "PMID-11832211_E11", "type": "Positive_regulation", "trigger": { "text": [ "initiates" ], "offsets": [ [ 710, 719 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11832211_E12" } ] }, { "id": "PMID-11832211_E12", "type": "Dissociation", "trigger": { "text": [ "release" ], "offsets": [ [ 726, 733 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-11832211_T21" } ] }, { "id": "PMID-11832211_E13", "type": "Dissociation", "trigger": { "text": [ "released" ], "offsets": [ [ 878, 886 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-11832211_T25" } ] } ]

[ { "id": "PMID-11832211_1", "entity_ids": [ "PMID-11832211_T8", "PMID-11832211_T9" ] }, { "id": "PMID-11832211_2", "entity_ids": [ "PMID-11832211_T22", "PMID-11832211_T23" ] } ]

[]

[ { "id": "PMID-11836257__text", "type": "abstract", "text": [ "Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. \nRecent studies have initiated a paradigm shift in the understanding of the function of heat shock proteins (HSP). It is now clear that HSP can and do exit mammalian cells, interact with cells of the immune system, and exert immunoregulatory effects. We recently demonstrated that exogenously added HSP70 possesses potent cytokine activity, with the ability to bind with high affinity to the plasma membrane, elicit a rapid intracellular Ca(2+) flux, activate NF-kappaB, and up-regulate the expression of pro-inflammatory cytokines in human monocytes. Here for the first time, we report that HSP70-induced proinflammatory cytokine production is mediated via the MyD88/IRAK/NF-kappaB signal transduction pathway and that HSP70 utilizes both TLR2 (receptor for Gram-positive bacteria) and TLR4 (receptor for Gram-negative bacteria) to transduce its proinflammatory signal in a CD14-dependent fashion. These studies now pave the way for the development of highly effective pharmacological or molecular tools that will either up-regulate or suppress HSP70-induced functions in conditions where HSP70 effects are desirable (cancer) or disorders where HSP70 effects are undesirable (arthritis and arteriosclerosis).\n" ], "offsets": [ [ 0, 1322 ] ] } ]

[ { "id": "PMID-11836257_T1", "type": "Cellular_component", "text": [ "extracellular" ], "offsets": [ [ 46, 59 ] ], "normalized": [] }, { "id": "PMID-11836257_T2", "type": "Gene_or_gene_product", "text": [ "HSP70" ], "offsets": [ [ 60, 65 ] ], "normalized": [] }, { "id": "PMID-11836257_T3", "type": "Gene_or_gene_product", "text": [ "toll-like receptor (TLR) 2" ], "offsets": [ [ 75, 101 ] ], "normalized": [] }, { "id": "PMID-11836257_T4", "type": "Gene_or_gene_product", "text": [ "TLR4" ], "offsets": [ [ 106, 110 ] ], "normalized": [] }, { "id": "PMID-11836257_T5", "type": "Gene_or_gene_product", "text": [ "heat shock proteins" ], "offsets": [ [ 200, 219 ] ], "normalized": [] }, { "id": "PMID-11836257_T6", "type": "Gene_or_gene_product", "text": [ "HSP" ], "offsets": [ [ 221, 224 ] ], "normalized": [] }, { "id": "PMID-11836257_T7", "type": "Gene_or_gene_product", "text": [ "HSP" ], "offsets": [ [ 248, 251 ] ], "normalized": [] }, { "id": "PMID-11836257_T8", "type": "Gene_or_gene_product", "text": [ "HSP70" ], "offsets": [ [ 411, 416 ] ], "normalized": [] }, { "id": "PMID-11836257_T9", "type": "Cellular_component", "text": [ "plasma membrane" ], "offsets": [ [ 504, 519 ] ], "normalized": [] }, { "id": "PMID-11836257_T10", "type": "Cellular_component", "text": [ "intracellular" ], "offsets": [ [ 536, 549 ] ], "normalized": [] }, { "id": "PMID-11836257_T11", "type": "Simple_chemical", "text": [ "Ca(2+)" ], "offsets": [ [ 550, 556 ] ], "normalized": [] }, { "id": "PMID-11836257_T12", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 572, 581 ] ], "normalized": [] }, { "id": "PMID-11836257_T13", "type": "Gene_or_gene_product", "text": [ "HSP70" ], "offsets": [ [ 704, 709 ] ], "normalized": [] }, { "id": "PMID-11836257_T14", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 774, 779 ] ], "normalized": [] }, { "id": "PMID-11836257_T15", "type": "Gene_or_gene_product", "text": [ "IRAK" ], "offsets": [ [ 780, 784 ] ], "normalized": [] }, { "id": "PMID-11836257_T16", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 785, 794 ] ], "normalized": [] }, { "id": "PMID-11836257_T17", "type": "Gene_or_gene_product", "text": [ "HSP70" ], "offsets": [ [ 832, 837 ] ], "normalized": [] }, { "id": "PMID-11836257_T18", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 852, 856 ] ], "normalized": [] }, { "id": "PMID-11836257_T19", "type": "Gene_or_gene_product", "text": [ "TLR4" ], "offsets": [ [ 899, 903 ] ], "normalized": [] }, { "id": "PMID-11836257_T20", "type": "Gene_or_gene_product", "text": [ "CD14" ], "offsets": [ [ 987, 991 ] ], "normalized": [] }, { "id": "PMID-11836257_T21", "type": "Gene_or_gene_product", "text": [ "HSP70" ], "offsets": [ [ 1158, 1163 ] ], "normalized": [] }, { "id": "PMID-11836257_T22", "type": "Gene_or_gene_product", "text": [ "HSP70" ], "offsets": [ [ 1202, 1207 ] ], "normalized": [] }, { "id": "PMID-11836257_T23", "type": "Gene_or_gene_product", "text": [ "HSP70" ], "offsets": [ [ 1258, 1263 ] ], "normalized": [] } ]

[ { "id": "PMID-11836257_E1", "type": "Transport", "trigger": { "text": [ "exit" ], "offsets": [ [ 263, 267 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11836257_T7" } ] }, { "id": "PMID-11836257_E2", "type": "Binding", "trigger": { "text": [ "interact" ], "offsets": [ [ 285, 293 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11836257_T7" } ] }, { "id": "PMID-11836257_E3", "type": "Binding", "trigger": { "text": [ "bind" ], "offsets": [ [ 473, 477 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11836257_T8" } ] }, { "id": "PMID-11836257_E4", "type": "Positive_regulation", "trigger": { "text": [ "elicit" ], "offsets": [ [ 521, 527 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11836257_T8" }, { "role": "Theme", "ref_id": "PMID-11836257_E5" } ] }, { "id": "PMID-11836257_E5", "type": "Transport", "trigger": { "text": [ "flux" ], "offsets": [ [ 557, 561 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11836257_T11" } ] }, { "id": "PMID-11836257_E6", "type": "Activation", "trigger": { "text": [ "activate" ], "offsets": [ [ 563, 571 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11836257_T12" }, { "role": "Cause", "ref_id": "PMID-11836257_T8" } ] }, { "id": "PMID-11836257_E7", "type": "Pathway", "trigger": { "text": [ "signal transduction pathway" ], "offsets": [ [ 795, 822 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-11836257_T14" }, { "role": "Participant", "ref_id": "PMID-11836257_T15" }, { "role": "Participant", "ref_id": "PMID-11836257_T16" } ] }, { "id": "PMID-11836257_E8", "type": "Binding", "trigger": { "text": [ "utilizes" ], "offsets": [ [ 838, 846 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11836257_T17" }, { "role": "Theme", "ref_id": "PMID-11836257_T18" } ] }, { "id": "PMID-11836257_E9", "type": "Binding", "trigger": { "text": [ "utilizes" ], "offsets": [ [ 838, 846 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11836257_T17" }, { "role": "Theme", "ref_id": "PMID-11836257_T19" } ] }, { "id": "PMID-11836257_E10", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 992, 1001 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11836257_T20" }, { "role": "Theme", "ref_id": "PMID-11836257_E9" } ] }, { "id": "PMID-11836257_E11", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 992, 1001 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11836257_T20" }, { "role": "Theme", "ref_id": "PMID-11836257_E8" } ] } ]

[ { "id": "PMID-11836257_1", "entity_ids": [ "PMID-11836257_T5", "PMID-11836257_T6" ] } ]

[]

[ { "id": "PMID-11839797__text", "type": "abstract", "text": [ "Set2 is a nucleosomal histone H3-selective methyltransferase that mediates transcriptional repression. \nRecent studies of histone methylation have yielded fundamental new insights pertaining to the role of this modification in gene activation as well as in gene silencing. While a number of methylation sites are known to occur on histones, only limited information exists regarding the relevant enzymes that mediate these methylation events. We thus sought to identify native histone methyltransferase (HMT) activities from Saccharomyces cerevisiae. Here, we describe the biochemical purification and characterization of Set2, a novel HMT that is site-specific for lysine 36 (Lys36) of the H3 tail. Using an antiserum directed against Lys36 methylation in H3, we show that Set2, via its SET domain, is responsible for methylation at this site in vivo. Tethering of Set2 to a heterologous promoter reveals that Set2 represses transcription, and part of this repression is mediated through the HMT activity of the SET domain. These results suggest that Set2 and methylation at H3 Lys36 play a role in the repression of gene transcription.\n" ], "offsets": [ [ 0, 1138 ] ] } ]

[ { "id": "PMID-11839797_T1", "type": "Gene_or_gene_product", "text": [ "Set2" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-11839797_T2", "type": "Cellular_component", "text": [ "nucleosomal" ], "offsets": [ [ 10, 21 ] ], "normalized": [] }, { "id": "PMID-11839797_T3", "type": "Gene_or_gene_product", "text": [ "histone H3" ], "offsets": [ [ 22, 32 ] ], "normalized": [] }, { "id": "PMID-11839797_T4", "type": "Gene_or_gene_product", "text": [ "histone" ], "offsets": [ [ 122, 129 ] ], "normalized": [] }, { "id": "PMID-11839797_T5", "type": "Gene_or_gene_product", "text": [ "histones" ], "offsets": [ [ 331, 339 ] ], "normalized": [] }, { "id": "PMID-11839797_T6", "type": "Gene_or_gene_product", "text": [ "histone methyltransferase" ], "offsets": [ [ 477, 502 ] ], "normalized": [] }, { "id": "PMID-11839797_T7", "type": "Gene_or_gene_product", "text": [ "HMT" ], "offsets": [ [ 504, 507 ] ], "normalized": [] }, { "id": "PMID-11839797_T8", "type": "Gene_or_gene_product", "text": [ "Set2" ], "offsets": [ [ 622, 626 ] ], "normalized": [] }, { "id": "PMID-11839797_T9", "type": "Gene_or_gene_product", "text": [ "HMT" ], "offsets": [ [ 636, 639 ] ], "normalized": [] }, { "id": "PMID-11839797_T10", "type": "Simple_chemical", "text": [ "lysine 36" ], "offsets": [ [ 666, 675 ] ], "normalized": [] }, { "id": "PMID-11839797_T11", "type": "Simple_chemical", "text": [ "Lys36" ], "offsets": [ [ 677, 682 ] ], "normalized": [] }, { "id": "PMID-11839797_T12", "type": "Gene_or_gene_product", "text": [ "H3" ], "offsets": [ [ 691, 693 ] ], "normalized": [] }, { "id": "PMID-11839797_T13", "type": "Simple_chemical", "text": [ "Lys36" ], "offsets": [ [ 736, 741 ] ], "normalized": [] }, { "id": "PMID-11839797_T14", "type": "Gene_or_gene_product", "text": [ "H3" ], "offsets": [ [ 757, 759 ] ], "normalized": [] }, { "id": "PMID-11839797_T15", "type": "Gene_or_gene_product", "text": [ "Set2" ], "offsets": [ [ 774, 778 ] ], "normalized": [] }, { "id": "PMID-11839797_T16", "type": "Gene_or_gene_product", "text": [ "Set2" ], "offsets": [ [ 866, 870 ] ], "normalized": [] }, { "id": "PMID-11839797_T17", "type": "Gene_or_gene_product", "text": [ "Set2" ], "offsets": [ [ 911, 915 ] ], "normalized": [] }, { "id": "PMID-11839797_T18", "type": "Gene_or_gene_product", "text": [ "HMT" ], "offsets": [ [ 993, 996 ] ], "normalized": [] }, { "id": "PMID-11839797_T19", "type": "Gene_or_gene_product", "text": [ "Set2" ], "offsets": [ [ 1052, 1056 ] ], "normalized": [] }, { "id": "PMID-11839797_T20", "type": "Gene_or_gene_product", "text": [ "H3" ], "offsets": [ [ 1076, 1078 ] ], "normalized": [] }, { "id": "PMID-11839797_T21", "type": "Simple_chemical", "text": [ "Lys36" ], "offsets": [ [ 1079, 1084 ] ], "normalized": [] } ]

[ { "id": "PMID-11839797_E1", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 130, 141 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11839797_T4" } ] }, { "id": "PMID-11839797_E2", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 742, 753 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11839797_T14" }, { "role": "Site", "ref_id": "PMID-11839797_T13" } ] }, { "id": "PMID-11839797_E3", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 819, 830 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11839797_T15" }, { "role": "Theme", "ref_id": "PMID-11839797_T14" }, { "role": "Site", "ref_id": "PMID-11839797_T13" } ] }, { "id": "PMID-11839797_E4", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1061, 1072 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11839797_T20" }, { "role": "Site", "ref_id": "PMID-11839797_T21" } ] } ]

[ { "id": "PMID-11839797_1", "entity_ids": [ "PMID-11839797_T6", "PMID-11839797_T7" ] }, { "id": "PMID-11839797_2", "entity_ids": [ "PMID-11839797_T10", "PMID-11839797_T11" ] } ]

[]

[ { "id": "PMID-11847219__text", "type": "abstract", "text": [ "Up-regulation of prostaglandin E2 synthesis by interleukin-1beta in human orbital fibroblasts involves coordinate induction of prostaglandin-endoperoxide H synthase-2 and glutathione-dependent prostaglandin E2 synthase expression. \nProstaglandin E(2) (PGE(2)) production involves the activity of a multistep biosynthetic pathway. The terminal components of this cascade, two PGE(2) synthases (PGES), have very recently been identified as glutathione-dependent proteins. cPGES is cytoplasmic, apparently identical to the hsp90 chaperone, p23, and associates functionally with prostaglandin-endoperoxide H synthase-1 (PGHS-1), the constitutive cyclooxygenase. A second synthase, designated mPGES, is microsomal and can be regulated. Here we demonstrate that mPGES and PGHS-2 are expressed at very low levels in untreated human orbital fibroblasts. Interleukin (IL)-1beta treatment elicits high levels of PGHS-2 and mPGES expression. The induction of both enzymes occurs at the pretranslational level, is the consequence of enhanced gene promoter activities, and can be blocked by dexamethasone (10 nm). SC58125, a PGHS-2-selective inhibitor, could attenuate the induction of mPGES, suggesting a dependence of this enzyme on PGHS-2 activity. IL-1beta treatment activates p38 and ERK mitogen-activated protein kinases. Induction of both mPGES and PGHS-2 was susceptible to either chemical inhibition or molecular interruption of these pathways with dominant negative constructs. These results indicate that the induction of PGHS-2 and mPGES by IL-1beta underlies robust PGE(2) production in orbital fibroblasts.\n" ], "offsets": [ [ 0, 1608 ] ] } ]

[ { "id": "PMID-11847219_T1", "type": "Simple_chemical", "text": [ "prostaglandin E2" ], "offsets": [ [ 17, 33 ] ], "normalized": [] }, { "id": "PMID-11847219_T2", "type": "Gene_or_gene_product", "text": [ "interleukin-1beta" ], "offsets": [ [ 47, 64 ] ], "normalized": [] }, { "id": "PMID-11847219_T3", "type": "Gene_or_gene_product", "text": [ "prostaglandin-endoperoxide H synthase-2" ], "offsets": [ [ 127, 166 ] ], "normalized": [] }, { "id": "PMID-11847219_T4", "type": "Simple_chemical", "text": [ "glutathione" ], "offsets": [ [ 171, 182 ] ], "normalized": [] }, { "id": "PMID-11847219_T5", "type": "Gene_or_gene_product", "text": [ "prostaglandin E2 synthase" ], "offsets": [ [ 193, 218 ] ], "normalized": [] }, { "id": "PMID-11847219_T6", "type": "Simple_chemical", "text": [ "Prostaglandin E(2)" ], "offsets": [ [ 232, 250 ] ], "normalized": [] }, { "id": "PMID-11847219_T7", "type": "Simple_chemical", "text": [ "PGE(2)" ], "offsets": [ [ 252, 258 ] ], "normalized": [] }, { "id": "PMID-11847219_T8", "type": "Gene_or_gene_product", "text": [ "PGE(2) synthases" ], "offsets": [ [ 375, 391 ] ], "normalized": [] }, { "id": "PMID-11847219_T9", "type": "Gene_or_gene_product", "text": [ "PGES" ], "offsets": [ [ 393, 397 ] ], "normalized": [] }, { "id": "PMID-11847219_T10", "type": "Simple_chemical", "text": [ "glutathione" ], "offsets": [ [ 438, 449 ] ], "normalized": [] }, { "id": "PMID-11847219_T11", "type": "Gene_or_gene_product", "text": [ "cPGES" ], "offsets": [ [ 470, 475 ] ], "normalized": [] }, { "id": "PMID-11847219_T12", "type": "Cellular_component", "text": [ "cytoplasmic" ], "offsets": [ [ 479, 490 ] ], "normalized": [] }, { "id": "PMID-11847219_T13", "type": "Gene_or_gene_product", "text": [ "hsp90" ], "offsets": [ [ 520, 525 ] ], "normalized": [] }, { "id": "PMID-11847219_T14", "type": "Gene_or_gene_product", "text": [ "p23" ], "offsets": [ [ 537, 540 ] ], "normalized": [] }, { "id": "PMID-11847219_T15", "type": "Gene_or_gene_product", "text": [ "prostaglandin-endoperoxide H synthase-1" ], "offsets": [ [ 575, 614 ] ], "normalized": [] }, { "id": "PMID-11847219_T16", "type": "Gene_or_gene_product", "text": [ "PGHS-1" ], "offsets": [ [ 616, 622 ] ], "normalized": [] }, { "id": "PMID-11847219_T17", "type": "Gene_or_gene_product", "text": [ "cyclooxygenase" ], "offsets": [ [ 642, 656 ] ], "normalized": [] }, { "id": "PMID-11847219_T18", "type": "Gene_or_gene_product", "text": [ "mPGES" ], "offsets": [ [ 688, 693 ] ], "normalized": [] }, { "id": "PMID-11847219_T19", "type": "Gene_or_gene_product", "text": [ "mPGES" ], "offsets": [ [ 756, 761 ] ], "normalized": [] }, { "id": "PMID-11847219_T20", "type": "Gene_or_gene_product", "text": [ "PGHS-2" ], "offsets": [ [ 766, 772 ] ], "normalized": [] }, { "id": "PMID-11847219_T21", "type": "Gene_or_gene_product", "text": [ "Interleukin (IL)-1beta" ], "offsets": [ [ 846, 868 ] ], "normalized": [] }, { "id": "PMID-11847219_T22", "type": "Gene_or_gene_product", "text": [ "PGHS-2" ], "offsets": [ [ 902, 908 ] ], "normalized": [] }, { "id": "PMID-11847219_T23", "type": "Gene_or_gene_product", "text": [ "mPGES" ], "offsets": [ [ 913, 918 ] ], "normalized": [] }, { "id": "PMID-11847219_T24", "type": "Simple_chemical", "text": [ "dexamethasone" ], "offsets": [ [ 1078, 1091 ] ], "normalized": [] }, { "id": "PMID-11847219_T25", "type": "Simple_chemical", "text": [ "SC58125" ], "offsets": [ [ 1101, 1108 ] ], "normalized": [] }, { "id": "PMID-11847219_T26", "type": "Gene_or_gene_product", "text": [ "PGHS-2" ], "offsets": [ [ 1112, 1118 ] ], "normalized": [] }, { "id": "PMID-11847219_T27", "type": "Gene_or_gene_product", "text": [ "mPGES" ], "offsets": [ [ 1173, 1178 ] ], "normalized": [] }, { "id": "PMID-11847219_T28", "type": "Gene_or_gene_product", "text": [ "PGHS-2" ], "offsets": [ [ 1222, 1228 ] ], "normalized": [] }, { "id": "PMID-11847219_T29", "type": "Gene_or_gene_product", "text": [ "IL-1beta" ], "offsets": [ [ 1239, 1247 ] ], "normalized": [] }, { "id": "PMID-11847219_T30", "type": "Gene_or_gene_product", "text": [ "p38" ], "offsets": [ [ 1268, 1271 ] ], "normalized": [] }, { "id": "PMID-11847219_T31", "type": "Gene_or_gene_product", "text": [ "ERK" ], "offsets": [ [ 1276, 1279 ] ], "normalized": [] }, { "id": "PMID-11847219_T32", "type": "Gene_or_gene_product", "text": [ "mitogen-activated protein kinases" ], "offsets": [ [ 1280, 1313 ] ], "normalized": [] }, { "id": "PMID-11847219_T33", "type": "Gene_or_gene_product", "text": [ "mPGES" ], "offsets": [ [ 1333, 1338 ] ], "normalized": [] }, { "id": "PMID-11847219_T34", "type": "Gene_or_gene_product", "text": [ "PGHS-2" ], "offsets": [ [ 1343, 1349 ] ], "normalized": [] }, { "id": "PMID-11847219_T35", "type": "Gene_or_gene_product", "text": [ "PGHS-2" ], "offsets": [ [ 1520, 1526 ] ], "normalized": [] }, { "id": "PMID-11847219_T36", "type": "Gene_or_gene_product", "text": [ "mPGES" ], "offsets": [ [ 1531, 1536 ] ], "normalized": [] }, { "id": "PMID-11847219_T37", "type": "Gene_or_gene_product", "text": [ "IL-1beta" ], "offsets": [ [ 1540, 1548 ] ], "normalized": [] }, { "id": "PMID-11847219_T38", "type": "Simple_chemical", "text": [ "PGE(2)" ], "offsets": [ [ 1566, 1572 ] ], "normalized": [] } ]

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"trigger": { "text": [ "induction" ], "offsets": [ [ 114, 123 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11847219_T3" } ] }, { "id": "PMID-11847219_E6", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 183, 192 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11847219_T4" }, { "role": "Theme", "ref_id": "PMID-11847219_E7" } ] }, { "id": "PMID-11847219_E7", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 219, 229 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11847219_T5" } ] }, { "id": "PMID-11847219_E8", "type": "Conversion", "trigger": { "text": [ "production" ], "offsets": [ [ 260, 270 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-11847219_T6" } ] }, { "id": "PMID-11847219_E9", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 450, 459 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11847219_T10" }, { "role": "Theme", "ref_id": "PMID-11847219_T8" } ] }, { "id": "PMID-11847219_E10", "type": "Regulation", "trigger": { "text": [ "associates" ], "offsets": [ [ 546, 556 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11847219_T11" }, { "role": "Theme", "ref_id": "PMID-11847219_T15" } ] }, { "id": "PMID-11847219_E11", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 720, 729 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11847219_T18" } ] }, { "id": "PMID-11847219_E12", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 777, 786 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11847219_T19" } ] }, { "id": "PMID-11847219_E13", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 777, 786 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11847219_T20" } ] }, { "id": "PMID-11847219_E14", "type": "Positive_regulation", "trigger": { "text": [ "elicits" ], "offsets": [ [ 879, 886 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11847219_T21" }, { "role": "Theme", "ref_id": "PMID-11847219_E17" } ] }, { "id": "PMID-11847219_E15", "type": "Positive_regulation", "trigger": { "text": [ "elicits" ], "offsets": [ [ 879, 886 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11847219_T21" }, { "role": "Theme", "ref_id": "PMID-11847219_E16" } ] }, { "id": "PMID-11847219_E16", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 919, 929 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11847219_T22" } ] }, { "id": "PMID-11847219_E17", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 919, 929 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11847219_T23" } ] }, { "id": "PMID-11847219_E18", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 1129, 1138 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11847219_T25" }, { "role": "Theme", "ref_id": "PMID-11847219_T26" } ] }, { "id": "PMID-11847219_E19", "type": "Negative_regulation", "trigger": { "text": [ "attenuate" ], "offsets": [ [ 1146, 1155 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11847219_E20" }, { "role": "Cause", "ref_id": "PMID-11847219_T25" } ] }, { "id": "PMID-11847219_E20", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1160, 1169 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11847219_T27" } ] }, { "id": "PMID-11847219_E21", "type": "Positive_regulation", "trigger": { "text": [ "dependence" ], "offsets": [ [ 1193, 1203 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11847219_T28" }, { "role": "Theme", "ref_id": "PMID-11847219_T27" } ] }, { "id": "PMID-11847219_E22", "type": "Activation", "trigger": { "text": [ "activates" ], "offsets": [ [ 1258, 1267 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11847219_T29" }, { "role": "Theme", "ref_id": "PMID-11847219_T32" } ] }, { "id": "PMID-11847219_E23", "type": "Positive_regulation", "trigger": { "text": [ "Induction" ], "offsets": [ [ 1315, 1324 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11847219_T33" } ] }, { "id": "PMID-11847219_E24", "type": "Positive_regulation", "trigger": { "text": [ "Induction" ], "offsets": [ [ 1315, 1324 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11847219_T34" } ] }, { "id": "PMID-11847219_E25", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1507, 1516 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11847219_T37" }, { "role": "Theme", "ref_id": "PMID-11847219_T35" } ] }, { "id": "PMID-11847219_E26", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1507, 1516 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11847219_T37" }, { "role": "Theme", "ref_id": "PMID-11847219_T36" } ] }, { "id": "PMID-11847219_E27", "type": "Positive_regulation", "trigger": { "text": [ "underlies" ], "offsets": [ [ 1549, 1558 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11847219_E29" }, { "role": "Cause", "ref_id": "PMID-11847219_E25" } ] }, { "id": "PMID-11847219_E28", "type": "Positive_regulation", "trigger": { "text": [ "underlies" ], "offsets": [ [ 1549, 1558 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11847219_E29" }, { "role": "Cause", "ref_id": "PMID-11847219_E26" } ] }, { "id": "PMID-11847219_E29", "type": "Conversion", "trigger": { "text": [ "production" ], "offsets": [ [ 1573, 1583 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-11847219_T38" } ] } ]

[ { "id": "PMID-11847219_1", "entity_ids": [ "PMID-11847219_T6", "PMID-11847219_T7" ] }, { "id": "PMID-11847219_2", "entity_ids": [ "PMID-11847219_T8", "PMID-11847219_T9" ] }, { "id": "PMID-11847219_3", "entity_ids": [ "PMID-11847219_T15", "PMID-11847219_T16" ] } ]

[]

[ { "id": "PMID-11877380__text", "type": "abstract", "text": [ "Calcineurin-dependent regulation of Crz1p nuclear export requires Msn5p and a conserved calcineurin docking site. \nCalcineurin, a conserved Ca(2+)/calmodulin-regulated protein phosphatase, plays a crucial role in Ca(2+) signaling in a wide variety of cell types. In Saccharomyces cerevisiae, calcineurin positively regulates transcription in response to stress by dephosphorylating the transcription factor Crz1p/Tcn1p. Dephosphorylation promotes Crz1p nuclear localization in part by increasing the efficiency of its nuclear import. In this work, we show that calcineurin-dependent dephosphorylation of Crz1p also down-regulates its nuclear export. Using a genetic approach, we identify Msn5p as the exportin for Crz1p. In addition, we define the Crz1p nuclear export signal (NES) and show that it interacts with Msn5p in a phosphorylation-dependent manner. This indicates that calcineurin regulates Crz1p nuclear export by dephosphorylating and inactivating its NES. Finally, we define a motif in Crz1p, PIISIQ, similar to the PxIxIT docking site for calcineurin on the mammalian transcription factor NFAT, that mediates the in vivo interaction between calcineurin and Crz1p and is required for calcineurin-dependent regulation of Crz1p nuclear export and activity. Therefore, in yeast as in mammals, a docking site is required to target calcineurin to its substrate such that it can dephosphorylate it efficiently.\n" ], "offsets": [ [ 0, 1418 ] ] } ]

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[]

[ { "id": "PMID-11909531__text", "type": "abstract", "text": [ "Regulation of interleukin-1- and lipopolysaccharide-induced NF-kappaB activation by alternative splicing of MyD88. \nMyD88 is an adaptor protein that is involved in interleukin-1 receptor (IL-1R)- and Toll-like receptor (TLR)-induced activation of NF-kappaB. It is composed of a C-terminal Toll/IL-1R homology (TIR) domain and an N-terminal death domain (DD), which mediate the interaction of MyD88 with the IL-1R/TLR and the IL-1R-associated kinase (IRAK), respectively. The interaction of MyD88 with IRAK triggers IRAK phosphorylation, which is essential for its activation and downstream signaling ability. Both domains of MyD88 are separated by a small intermediate domain (ID) of unknown function. Here, we report the identification of a splice variant of MyD88, termed MyD88(S), which encodes for a protein lacking the ID. MyD88(S) is mainly expressed in the spleen and can be induced in monocytes upon LPS treatment. Although MyD88(S) still binds the IL-1R and IRAK, it is defective in its ability to induce IRAK phosphorylation and NF-kappaB activation. In contrast, MyD88(S) behaves as a dominant-negative inhibitor of IL-1- and LPS-, but not TNF-induced, NF-kappaB activation. These results implicate the ID of MyD88 in the phosphorylation of IRAK. Moreover, the regulated expression and antagonistic activity of MyD88(S) suggest an important role for alternative splicing of MyD88 in the regulation of the cellular response to IL-1 and LPS.\n" ], "offsets": [ [ 0, 1451 ] ] } ]

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"Toll-like receptor" ], "offsets": [ [ 200, 218 ] ], "normalized": [] }, { "id": "PMID-11909531_T9", "type": "Gene_or_gene_product", "text": [ "TLR" ], "offsets": [ [ 220, 223 ] ], "normalized": [] }, { "id": "PMID-11909531_T10", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 247, 256 ] ], "normalized": [] }, { "id": "PMID-11909531_T11", "type": "Gene_or_gene_product", "text": [ "Toll" ], "offsets": [ [ 289, 293 ] ], "normalized": [] }, { "id": "PMID-11909531_T12", "type": "Gene_or_gene_product", "text": [ "IL-1R" ], "offsets": [ [ 294, 299 ] ], "normalized": [] }, { "id": "PMID-11909531_T13", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 392, 397 ] ], "normalized": [] }, { "id": "PMID-11909531_T14", "type": "Gene_or_gene_product", "text": [ "IL-1R" ], "offsets": [ [ 407, 412 ] ], "normalized": [] }, { "id": "PMID-11909531_T15", "type": "Gene_or_gene_product", "text": [ "TLR" ], "offsets": [ [ 413, 416 ] ], "normalized": [] }, { "id": "PMID-11909531_T16", "type": "Gene_or_gene_product", "text": [ "IL-1R-associated kinase" ], "offsets": [ [ 425, 448 ] ], "normalized": [] }, { "id": "PMID-11909531_T17", "type": "Gene_or_gene_product", "text": [ "IRAK" ], "offsets": [ [ 450, 454 ] ], "normalized": [] }, { "id": "PMID-11909531_T18", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 490, 495 ] ], "normalized": [] }, { "id": "PMID-11909531_T19", "type": "Gene_or_gene_product", "text": [ "IRAK" ], "offsets": [ [ 501, 505 ] ], "normalized": [] }, { "id": "PMID-11909531_T20", "type": "Gene_or_gene_product", "text": [ "IRAK" ], "offsets": [ [ 515, 519 ] ], "normalized": [] }, { "id": "PMID-11909531_T21", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 625, 630 ] ], "normalized": [] }, { "id": "PMID-11909531_T22", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 760, 765 ] ], "normalized": [] }, { "id": "PMID-11909531_T23", "type": "Gene_or_gene_product", "text": [ "MyD88(S)" ], "offsets": [ [ 774, 782 ] ], "normalized": [] }, { "id": "PMID-11909531_T24", "type": "Gene_or_gene_product", "text": [ "MyD88(S)" ], "offsets": [ [ 828, 836 ] ], "normalized": [] }, { "id": "PMID-11909531_T25", "type": "Simple_chemical", "text": [ "LPS" ], "offsets": [ [ 908, 911 ] ], "normalized": [] }, { "id": "PMID-11909531_T26", "type": "Gene_or_gene_product", "text": [ "MyD88(S)" ], "offsets": [ [ 932, 940 ] ], "normalized": [] }, { "id": "PMID-11909531_T27", "type": "Gene_or_gene_product", "text": [ "IL-1R" ], "offsets": [ [ 957, 962 ] ], "normalized": [] }, { "id": "PMID-11909531_T28", "type": "Gene_or_gene_product", "text": [ "IRAK" ], "offsets": [ [ 967, 971 ] ], "normalized": [] }, { "id": "PMID-11909531_T29", "type": "Gene_or_gene_product", "text": [ "IRAK" ], "offsets": [ [ 1014, 1018 ] ], "normalized": [] }, { "id": "PMID-11909531_T30", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1039, 1048 ] ], "normalized": [] }, { "id": "PMID-11909531_T31", "type": "Gene_or_gene_product", "text": [ "MyD88(S)" ], "offsets": [ [ 1074, 1082 ] ], "normalized": [] }, { "id": "PMID-11909531_T32", "type": "Gene_or_gene_product", "text": [ "IL-1" ], "offsets": [ [ 1127, 1131 ] ], "normalized": [] }, { "id": "PMID-11909531_T33", "type": "Simple_chemical", "text": [ "LPS" ], "offsets": [ [ 1137, 1140 ] ], "normalized": [] }, { "id": "PMID-11909531_T34", "type": "Gene_or_gene_product", "text": [ "TNF" ], "offsets": [ [ 1151, 1154 ] ], "normalized": [] }, { "id": "PMID-11909531_T35", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1164, 1173 ] ], "normalized": [] }, { "id": "PMID-11909531_T36", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 1220, 1225 ] ], "normalized": [] }, { "id": "PMID-11909531_T37", "type": "Gene_or_gene_product", "text": [ "IRAK" ], "offsets": [ [ 1252, 1256 ] ], "normalized": [] }, { "id": "PMID-11909531_T38", "type": "Gene_or_gene_product", "text": [ "MyD88(S)" ], "offsets": [ [ 1322, 1330 ] ], "normalized": [] }, { "id": "PMID-11909531_T39", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 1385, 1390 ] ], "normalized": [] }, { "id": "PMID-11909531_T40", "type": "Gene_or_gene_product", "text": [ "IL-1" ], "offsets": [ [ 1437, 1441 ] ], "normalized": [] }, { "id": "PMID-11909531_T41", "type": "Simple_chemical", "text": [ "LPS" ], "offsets": [ [ 1446, 1449 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-11909979__text", "type": "abstract", "text": [ "MSK1 and MSK2 are required for the mitogen- and stress-induced phosphorylation of CREB and ATF1 in fibroblasts. \nUsing mouse knockouts for mitogen- and stress-activated protein kinase 1 (MSK1) and MSK2 and a double knockout of both MSK1 and MSK2, we show that these protein kinases are required for the stress-induced phosphorylation of transcription factors CREB and ATF1 in primary embryonic fibroblasts. In contrast mitogen-induced phosphorylation of CREB and ATF1 is greatly reduced but not totally abolished. The mitogen- and stress-induced phosphorylation of CREB at Ser133 has been linked to the transcription of several immediate early genes, including c-fos, junB, and egr1. The knockout of both MSK1 and MSK2 resulted in a 50% reduction in c-fos and junB gene transcription in response to anisomycin or UV-C radiation but only a small reduction in response to tetradecanoyl phorbol acetate or epidermal growth factor in fibroblasts. The transcription of egr1 in response to both mitogenic and stress stimuli, as well as stress-induced apoptosis, was unaffected in the MSK1/MSK2 double knockout.\n" ], "offsets": [ [ 0, 1105 ] ] } ]

[ { "id": "PMID-11909979_T1", "type": "Gene_or_gene_product", "text": [ "MSK1" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-11909979_T2", "type": "Gene_or_gene_product", "text": [ "MSK2" ], "offsets": [ [ 9, 13 ] ], "normalized": [] }, { "id": "PMID-11909979_T3", "type": "Gene_or_gene_product", "text": [ "CREB" ], "offsets": [ [ 82, 86 ] ], "normalized": [] }, { "id": "PMID-11909979_T4", "type": "Gene_or_gene_product", "text": [ "ATF1" ], "offsets": [ [ 91, 95 ] ], "normalized": [] }, { "id": "PMID-11909979_T5", "type": "Gene_or_gene_product", "text": [ "mitogen- and stress-activated protein kinase 1" ], "offsets": [ [ 139, 185 ] ], "normalized": [] }, { "id": "PMID-11909979_T6", "type": "Gene_or_gene_product", "text": [ "MSK1" ], "offsets": [ [ 187, 191 ] ], "normalized": [] }, { "id": "PMID-11909979_T7", "type": "Gene_or_gene_product", "text": [ "MSK2" ], "offsets": [ [ 197, 201 ] ], "normalized": [] }, { "id": "PMID-11909979_T8", "type": "Gene_or_gene_product", "text": [ "MSK1" ], "offsets": [ [ 232, 236 ] ], "normalized": [] }, { "id": "PMID-11909979_T9", "type": "Gene_or_gene_product", "text": [ "MSK2" ], "offsets": [ [ 241, 245 ] ], "normalized": [] }, { "id": "PMID-11909979_T10", "type": "Gene_or_gene_product", "text": [ "CREB" ], "offsets": [ [ 359, 363 ] ], "normalized": [] }, { "id": "PMID-11909979_T11", "type": "Gene_or_gene_product", "text": [ "ATF1" ], "offsets": [ [ 368, 372 ] ], "normalized": [] }, { "id": "PMID-11909979_T12", "type": "Gene_or_gene_product", "text": [ "CREB" ], "offsets": [ [ 454, 458 ] ], "normalized": [] }, { "id": "PMID-11909979_T13", "type": "Gene_or_gene_product", "text": [ "ATF1" ], "offsets": [ [ 463, 467 ] ], "normalized": [] }, { "id": "PMID-11909979_T14", "type": "Gene_or_gene_product", "text": [ "CREB" ], "offsets": [ [ 565, 569 ] ], "normalized": [] }, { "id": "PMID-11909979_T15", "type": "Simple_chemical", "text": [ "Ser133" ], "offsets": [ [ 573, 579 ] ], "normalized": [] }, { "id": "PMID-11909979_T16", "type": "Gene_or_gene_product", "text": [ "c-fos" ], "offsets": [ [ 661, 666 ] ], "normalized": [] }, { "id": "PMID-11909979_T17", "type": "Gene_or_gene_product", "text": [ "junB" ], "offsets": [ [ 668, 672 ] ], "normalized": [] }, { "id": "PMID-11909979_T18", "type": "Gene_or_gene_product", "text": [ "egr1" ], "offsets": [ [ 678, 682 ] ], "normalized": [] }, { "id": "PMID-11909979_T19", "type": "Gene_or_gene_product", "text": [ "MSK1" ], "offsets": [ [ 705, 709 ] ], "normalized": [] }, { "id": "PMID-11909979_T20", "type": "Gene_or_gene_product", "text": [ "MSK2" ], "offsets": [ [ 714, 718 ] ], "normalized": [] }, { "id": "PMID-11909979_T21", "type": "Gene_or_gene_product", "text": [ "c-fos" ], "offsets": [ [ 750, 755 ] ], "normalized": [] }, { "id": "PMID-11909979_T22", "type": "Gene_or_gene_product", "text": [ "junB" ], "offsets": [ [ 760, 764 ] ], "normalized": [] }, { "id": "PMID-11909979_T23", "type": "Simple_chemical", "text": [ "anisomycin" ], "offsets": [ [ 799, 809 ] ], "normalized": [] }, { "id": "PMID-11909979_T24", "type": "Simple_chemical", "text": [ "tetradecanoyl phorbol acetate" ], "offsets": [ [ 870, 899 ] ], "normalized": [] }, { "id": "PMID-11909979_T25", "type": "Gene_or_gene_product", "text": [ "epidermal growth factor" ], "offsets": [ [ 903, 926 ] ], "normalized": [] }, { "id": "PMID-11909979_T26", "type": "Gene_or_gene_product", "text": [ "egr1" ], "offsets": [ [ 964, 968 ] ], "normalized": [] }, { "id": "PMID-11909979_T27", "type": "Gene_or_gene_product", "text": [ "MSK1" ], "offsets": [ [ 1078, 1082 ] ], "normalized": [] }, { "id": "PMID-11909979_T28", "type": "Gene_or_gene_product", "text": [ "MSK2" ], "offsets": [ [ 1083, 1087 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-11959842__text", "type": "abstract", "text": [ "E2F mediates cell cycle-dependent transcriptional repression in vivo by recruitment of an HDAC1/mSin3B corepressor complex. \nDespite biochemical and genetic data suggesting that E2F and pRB (pocket protein) families regulate transcription via chromatin-modifying factors, the precise mechanisms underlying gene regulation by these protein families have not yet been defined in a physiological setting. In this study, we have investigated promoter occupancy in wild-type and pocket protein-deficient primary cells. We show that corepressor complexes consisting of histone deacetylase (HDAC1) and mSin3B were specifically recruited to endogenous E2F-regulated promoters in quiescent cells. These complexes dissociated from promoters once cells reached late G1, coincident with gene activation. Interestingly, recruitment of HDAC1 complexes to promoters depended absolutely on p107 and p130, and required an intact E2F-binding site. In contrast, mSin3B recruitment to certain promoters did not require p107 or p130, suggesting that recruitment of this corepressor can occur via E2F-dependent and -independent mechanisms. Remarkably, loss of pRB had no effect on HDAC1 or mSin3B recruitment. p107/p130 deficiency triggered a dramatic loss of E2F4 nuclear localization as well as transcriptional derepression, which is suggested by nucleosome mapping studies to be the result of localized hyperacetylation of nucleosomes proximal to E2F-binding sites. Taken together, these findings show that p130 escorts E2F4 into the nucleus and, together with corepressor complexes that contain mSin3B and/or HDAC1, directly represses transcription from target genes as cells withdraw from the cell cycle.\n" ], "offsets": [ [ 0, 1688 ] ] } ]

[ { "id": "PMID-11959842_T1", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 0, 3 ] ], "normalized": [] }, { "id": "PMID-11959842_T2", "type": "Complex", "text": [ "HDAC1/mSin3B" ], "offsets": [ [ 90, 102 ] ], "normalized": [] }, { "id": "PMID-11959842_T3", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 178, 181 ] ], "normalized": [] }, { "id": "PMID-11959842_T4", "type": "Gene_or_gene_product", "text": [ "pRB" ], "offsets": [ [ 186, 189 ] ], "normalized": [] }, { "id": "PMID-11959842_T5", "type": "Cellular_component", "text": [ "chromatin" ], "offsets": [ [ 243, 252 ] ], "normalized": [] }, { "id": "PMID-11959842_T6", "type": "Gene_or_gene_product", "text": [ "histone deacetylase" ], "offsets": [ [ 563, 582 ] ], "normalized": [] }, { "id": "PMID-11959842_T7", "type": "Gene_or_gene_product", "text": [ "HDAC1" ], "offsets": [ [ 584, 589 ] ], "normalized": [] }, { "id": "PMID-11959842_T8", "type": "Gene_or_gene_product", "text": [ "mSin3B" ], "offsets": [ [ 595, 601 ] ], "normalized": [] }, { "id": "PMID-11959842_T9", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 644, 647 ] ], "normalized": [] }, { "id": "PMID-11959842_T10", "type": "Complex", "text": [ "HDAC1 complexes" ], "offsets": [ [ 822, 837 ] ], "normalized": [] }, { "id": "PMID-11959842_T11", "type": "Gene_or_gene_product", "text": [ "p107" ], "offsets": [ [ 874, 878 ] ], "normalized": [] }, { "id": "PMID-11959842_T12", "type": "Gene_or_gene_product", "text": [ "p130" ], "offsets": [ [ 883, 887 ] ], "normalized": [] }, { "id": "PMID-11959842_T13", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 912, 915 ] ], "normalized": [] }, { "id": "PMID-11959842_T14", "type": "Gene_or_gene_product", "text": [ "mSin3B" ], "offsets": [ [ 943, 949 ] ], "normalized": [] }, { "id": "PMID-11959842_T15", "type": "Gene_or_gene_product", "text": [ "p107" ], "offsets": [ [ 999, 1003 ] ], "normalized": [] }, { "id": "PMID-11959842_T16", "type": "Gene_or_gene_product", "text": [ "p130" ], "offsets": [ [ 1007, 1011 ] ], "normalized": [] }, { "id": "PMID-11959842_T17", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1075, 1078 ] ], "normalized": [] }, { "id": "PMID-11959842_T18", "type": "Gene_or_gene_product", "text": [ "pRB" ], "offsets": [ [ 1138, 1141 ] ], "normalized": [] }, { "id": "PMID-11959842_T19", "type": "Gene_or_gene_product", "text": [ "HDAC1" ], "offsets": [ [ 1159, 1164 ] ], "normalized": [] }, { "id": "PMID-11959842_T20", "type": "Gene_or_gene_product", "text": [ "mSin3B" ], "offsets": [ [ 1168, 1174 ] ], "normalized": [] }, { "id": "PMID-11959842_T21", "type": "Gene_or_gene_product", "text": [ "p107" ], "offsets": [ [ 1188, 1192 ] ], "normalized": [] }, { "id": "PMID-11959842_T22", "type": "Gene_or_gene_product", "text": [ "p130" ], "offsets": [ [ 1193, 1197 ] ], "normalized": [] }, { "id": "PMID-11959842_T23", "type": "Gene_or_gene_product", "text": [ "E2F4" ], "offsets": [ [ 1238, 1242 ] ], "normalized": [] }, { "id": "PMID-11959842_T24", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 1243, 1250 ] ], "normalized": [] }, { "id": "PMID-11959842_T25", "type": "Cellular_component", "text": [ "nucleosome" ], "offsets": [ [ 1327, 1337 ] ], "normalized": [] }, { "id": "PMID-11959842_T26", "type": "Cellular_component", "text": [ "nucleosomes" ], "offsets": [ [ 1404, 1415 ] ], "normalized": [] }, { "id": "PMID-11959842_T27", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1428, 1431 ] ], "normalized": [] }, { "id": "PMID-11959842_T28", "type": "Gene_or_gene_product", "text": [ "p130" ], "offsets": [ [ 1488, 1492 ] ], "normalized": [] }, { "id": "PMID-11959842_T29", "type": "Gene_or_gene_product", "text": [ "E2F4" ], "offsets": [ [ 1501, 1505 ] ], "normalized": [] }, { "id": "PMID-11959842_T30", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 1515, 1522 ] ], "normalized": [] }, { "id": "PMID-11959842_T31", "type": "Gene_or_gene_product", "text": [ "mSin3B" ], "offsets": [ [ 1577, 1583 ] ], "normalized": [] }, { "id": "PMID-11959842_T32", "type": "Gene_or_gene_product", "text": [ "HDAC1" ], "offsets": [ [ 1591, 1596 ] ], "normalized": [] } ]

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"type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1079, 1088 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11959842_T17" }, { "role": "Theme", "ref_id": "PMID-11959842_E9" } ] }, { "id": "PMID-11959842_E16", "type": "Regulation", "trigger": { "text": [ "independent" ], "offsets": [ [ 1094, 1105 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11959842_T17" }, { "role": "Theme", "ref_id": "PMID-11959842_E9" } ] }, { "id": "PMID-11959842_E17", "type": "Inactivation", "trigger": { "text": [ "loss" ], "offsets": [ [ 1130, 1134 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11959842_T18" } ] }, { "id": "PMID-11959842_E18", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1149, 1155 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11959842_E17" }, { "role": "Theme", "ref_id": "PMID-11959842_E20" } ] }, { "id": "PMID-11959842_E19", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1149, 1155 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11959842_E17" }, { "role": "Theme", "ref_id": "PMID-11959842_E21" } ] }, { "id": "PMID-11959842_E20", "type": "Transport", "trigger": { "text": [ "recruitment" ], "offsets": [ [ 1175, 1186 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11959842_T19" } ] }, { "id": "PMID-11959842_E21", "type": "Transport", "trigger": { "text": [ "recruitment" ], "offsets": [ [ 1175, 1186 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11959842_T20" } ] }, { "id": "PMID-11959842_E22", "type": "Positive_regulation", "trigger": { "text": [ "triggered" ], "offsets": [ [ 1209, 1218 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11959842_E24" }, { "role": "Cause", "ref_id": "PMID-11959842_T21" } ] }, { "id": "PMID-11959842_E23", "type": "Positive_regulation", "trigger": { "text": [ "triggered" ], "offsets": [ [ 1209, 1218 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11959842_E24" }, { "role": "Cause", "ref_id": "PMID-11959842_T22" } ] }, { "id": "PMID-11959842_E24", "type": "Negative_regulation", "trigger": { "text": [ "loss" ], "offsets": [ [ 1230, 1234 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11959842_E25" } ] }, { "id": "PMID-11959842_E25", "type": "Localization", "trigger": { "text": [ "localization" ], "offsets": [ [ 1251, 1263 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-11959842_T24" }, { "role": "Theme", "ref_id": "PMID-11959842_T23" } ] }, { "id": "PMID-11959842_E26", "type": "Transport", "trigger": { "text": [ "escorts" ], "offsets": [ [ 1493, 1500 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11959842_T29" }, { "role": "ToLoc", "ref_id": "PMID-11959842_T30" } ] }, { "id": "PMID-11959842_E27", "type": "Positive_regulation", "trigger": { "text": [ "escorts" ], "offsets": [ [ 1493, 1500 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11959842_E26" }, { "role": "Cause", "ref_id": "PMID-11959842_T28" } ] }, { "id": "PMID-11959842_E28", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 1676, 1686 ] ] }, "arguments": [] } ]

[ { "id": "PMID-11959842_1", "entity_ids": [ "PMID-11959842_T6", "PMID-11959842_T7" ] } ]

[]

[ { "id": "PMID-11959850__text", "type": "abstract", "text": [ "Kinetic mechanism of activation of the Cdk2/cyclin A complex. Key role of the C-lobe of the Cdk. \nEukaryotic cell cycle progression is controlled by the ordered action of cyclin-dependent kinases, activation of which occurs through the binding of the cyclin to the Cdk followed by phosphorylation of a conserved threonine in the T-loop of the Cdk by Cdk-activating kinase (CAK). Despite our understanding of the structural changes, which occur upon Cdk/cyclin formation and activation, little is known about the dynamics of the molecular events involved. We have characterized the mechanism of Cdk2/cyclin A complex formation and activation at the molecular and dynamic level by rapid kinetics and demonstrate here that it is a two-step process. The first step involves the rapid association between the PSTAIRE helix of Cdk2 and helices 3 and 5 of the cyclin to yield an intermediate complex in which the threonine in the T-loop is not accessible for phosphorylation. Additional contacts between the C-lobe of the Cdk and the N-terminal helix of the cyclin then induce the isomerization of the Cdk into a fully mature form by promoting the exposure of the T-loop for phosphorylation by CAK and the formation of the substrate binding site. This conformational change is selective for the cyclin partner.\n" ], "offsets": [ [ 0, 1304 ] ] } ]

[ { "id": "PMID-11959850_T1", "type": "Complex", "text": [ "Cdk2/cyclin A" ], "offsets": [ [ 39, 52 ] ], "normalized": [] }, { "id": "PMID-11959850_T2", "type": "Gene_or_gene_product", "text": [ "Cdk" ], "offsets": [ [ 92, 95 ] ], "normalized": [] }, { "id": "PMID-11959850_T3", "type": "Gene_or_gene_product", "text": [ "cyclin-dependent kinases" ], "offsets": [ [ 171, 195 ] ], "normalized": [] }, { "id": "PMID-11959850_T4", "type": "Gene_or_gene_product", "text": [ "cyclin" ], "offsets": [ [ 251, 257 ] ], "normalized": [] }, { "id": "PMID-11959850_T5", "type": "Gene_or_gene_product", "text": [ "Cdk" ], "offsets": [ [ 265, 268 ] ], "normalized": [] }, { "id": "PMID-11959850_T6", "type": "Simple_chemical", "text": [ "threonine" ], "offsets": [ [ 312, 321 ] ], "normalized": [] }, { "id": "PMID-11959850_T7", "type": "Gene_or_gene_product", "text": [ "Cdk" ], "offsets": [ [ 343, 346 ] ], "normalized": [] }, { "id": "PMID-11959850_T8", "type": "Gene_or_gene_product", "text": [ "Cdk-activating kinase" ], "offsets": [ [ 350, 371 ] ], "normalized": [] }, { "id": "PMID-11959850_T9", "type": "Gene_or_gene_product", "text": [ "CAK" ], "offsets": [ [ 373, 376 ] ], "normalized": [] }, { "id": "PMID-11959850_T10", "type": "Complex", "text": [ "Cdk/cyclin" ], "offsets": [ [ 449, 459 ] ], "normalized": [] }, { "id": "PMID-11959850_T11", "type": "Complex", "text": [ "Cdk2/cyclin A" ], "offsets": [ [ 594, 607 ] ], "normalized": [] }, { "id": "PMID-11959850_T12", "type": "Gene_or_gene_product", "text": [ "Cdk2" ], "offsets": [ [ 821, 825 ] ], "normalized": [] }, { "id": "PMID-11959850_T13", "type": "Gene_or_gene_product", "text": [ "cyclin" ], "offsets": [ [ 853, 859 ] ], "normalized": [] }, { "id": "PMID-11959850_T14", "type": "Simple_chemical", "text": [ "threonine" ], "offsets": [ [ 906, 915 ] ], "normalized": [] }, { "id": "PMID-11959850_T15", "type": "Gene_or_gene_product", "text": [ "Cdk" ], "offsets": [ [ 1015, 1018 ] ], "normalized": [] }, { "id": "PMID-11959850_T16", "type": "Gene_or_gene_product", "text": [ "cyclin" ], "offsets": [ [ 1051, 1057 ] ], "normalized": [] }, { "id": "PMID-11959850_T17", "type": "Gene_or_gene_product", "text": [ "Cdk" ], "offsets": [ [ 1095, 1098 ] ], "normalized": [] }, { "id": "PMID-11959850_T18", "type": "Gene_or_gene_product", "text": [ "CAK" ], "offsets": [ [ 1187, 1190 ] ], "normalized": [] }, { "id": "PMID-11959850_T19", "type": "Gene_or_gene_product", "text": [ "cyclin" ], "offsets": [ [ 1288, 1294 ] ], "normalized": [] } ]

[ { "id": "PMID-11959850_E1", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 21, 31 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11959850_T1" } ] }, { "id": "PMID-11959850_E2", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 109, 119 ] ] }, "arguments": [] }, { "id": "PMID-11959850_E3", "type": "Regulation", "trigger": { "text": [ "controlled" ], "offsets": [ [ 135, 145 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11959850_E2" }, { "role": "Cause", "ref_id": "PMID-11959850_E5" } ] }, { "id": "PMID-11959850_E4", "type": "Regulation", "trigger": { "text": [ "controlled" ], "offsets": [ [ 135, 145 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11959850_E2" }, { "role": "Cause", "ref_id": "PMID-11959850_E6" } ] }, { "id": "PMID-11959850_E5", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 197, 207 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11959850_T3" }, { "role": "Cause", "ref_id": "PMID-11959850_E7" } ] }, { "id": "PMID-11959850_E6", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 197, 207 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11959850_T3" }, { "role": "Cause", "ref_id": "PMID-11959850_E8" } ] }, { "id": "PMID-11959850_E7", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 236, 243 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11959850_T4" }, { "role": "Theme", "ref_id": "PMID-11959850_T5" } ] }, { "id": "PMID-11959850_E8", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 281, 296 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-11959850_T6" }, { "role": "Theme", "ref_id": "PMID-11959850_T7" }, { "role": "Cause", "ref_id": "PMID-11959850_T8" } ] }, { "id": "PMID-11959850_E9", "type": "Binding", "trigger": { "text": [ "formation" ], "offsets": [ [ 460, 469 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11959850_T10" } ] }, { "id": "PMID-11959850_E10", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 474, 484 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11959850_T10" } ] }, { "id": "PMID-11959850_E11", "type": "Binding", "trigger": { "text": [ "complex formation" ], "offsets": [ [ 608, 625 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11959850_T11" } ] }, { "id": "PMID-11959850_E12", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 630, 640 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11959850_T11" } ] }, { "id": "PMID-11959850_E13", "type": "Binding", "trigger": { "text": [ "association" ], "offsets": [ [ 780, 791 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11959850_T12" }, { "role": "Theme", "ref_id": "PMID-11959850_T13" } ] }, { "id": "PMID-11959850_E14", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 952, 967 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-11959850_T14" }, { "role": "Theme", "ref_id": "PMID-11959850_T12" } ] }, { "id": "PMID-11959850_E15", "type": "Binding", "trigger": { "text": [ "contacts" ], "offsets": [ [ 980, 988 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11959850_T15" }, { "role": "Theme", "ref_id": "PMID-11959850_T16" } ] }, { "id": "PMID-11959850_E16", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 1063, 1069 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11959850_E17" }, { "role": "Cause", "ref_id": "PMID-11959850_E18" } ] }, { "id": "PMID-11959850_E17", "type": "Binding", "trigger": { "text": [ "isomerization" ], "offsets": [ [ 1074, 1087 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11959850_T17" } ] }, { "id": "PMID-11959850_E18", "type": "Positive_regulation", "trigger": { "text": [ "promoting" ], "offsets": [ [ 1127, 1136 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11959850_E19" }, { "role": "Cause", "ref_id": "PMID-11959850_E15" } ] }, { "id": "PMID-11959850_E19", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1168, 1183 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11959850_T17" }, { "role": "Cause", "ref_id": "PMID-11959850_T18" } ] } ]

[ { "id": "PMID-11959850_1", "entity_ids": [ "PMID-11959850_T8", "PMID-11959850_T9" ] } ]

[]

[ { "id": "PMID-11971008__text", "type": "abstract", "text": [ "Divergence of apoptosis-inducing and preventing signals in bacteria-faced macrophages through myeloid differentiation factor 88 and IL-1 receptor-associated kinase members. \nThe induction of apoptosis in host cells is a common strategy by which pathogenic bacteria interfere with the host immune response. The Yersinia enterocolitica outer protein P (YopP) inhibits activation of transcription factor NF-kappa B in macrophages, which suppresses NF-kappa B-dependent antiapoptotic activities. The simultaneous initiation of proapoptotic signaling by yersiniae infection or LPS treatment results in macrophage apoptosis. In this study, we used YopP as a tool to dissect survival- and death-inducing pathways in bacteria-faced macrophages. We cotransfected J774A.1 macrophages with expression plasmids for YopP and dominant-negative mutants of signal transmitters of the NF-kappa B cascade downstream from the LPS receptor complex. Dominant-negative myeloid differentiation factor 88 (MyD88) or IL-1R-associated kinase (IRAK) 2 diminished LPS-induced apoptosis in YopP-transfected macrophages, suggesting implication of MyD88 and IRAK2 in signaling cell death. In contrast, dominant-negative IRAK1 and TNFR-associated factor 6 (TRAF6) did not provide protection, but augmented LPS-mediated apoptosis in the absence of YopP, which indicates roles of IRAK1 and TRAF6 in the antiapoptotic signal relay of the NF-kappa B cascade. The distinct functions of IRAK members in macrophage survival were reflected by opposing effects of dominant-negative IRAK1 and IRAK2 on Y. enterocolitica-mediated apoptosis. Yersiniae- and LPS-dependent cell death were substantially attenuated by a specific caspase-8 inhibitory peptide or by dominant negative Fas-associated death domain protein (FADD). This suggests, that Yersinia-induced apoptosis involves a proapoptotic signal relay through MyD88 and IRAK2, which potentially targets the Fas-associated death domain protein/caspase-8 apoptotic pathway, whereas IRAK1 and TRAF6 counteract the bacteria-induced cytotoxic response by signaling macrophage survival.\n" ], "offsets": [ [ 0, 2092 ] ] } ]

[ { "id": "PMID-11971008_T1", "type": "Gene_or_gene_product", "text": [ "myeloid differentiation factor 88" ], "offsets": [ [ 94, 127 ] ], "normalized": [] }, { "id": "PMID-11971008_T2", "type": "Gene_or_gene_product", "text": [ "IL-1 receptor-associated kinase" ], "offsets": [ [ 132, 163 ] ], "normalized": [] }, { "id": "PMID-11971008_T3", "type": "Gene_or_gene_product", "text": [ "outer protein P" ], "offsets": [ [ 334, 349 ] ], "normalized": [] }, { "id": "PMID-11971008_T4", "type": "Gene_or_gene_product", "text": [ "YopP" ], "offsets": [ [ 351, 355 ] ], "normalized": [] }, { "id": "PMID-11971008_T5", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 401, 411 ] ], "normalized": [] }, { "id": "PMID-11971008_T6", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 445, 455 ] ], "normalized": [] }, { "id": "PMID-11971008_T7", "type": "Simple_chemical", "text": [ "LPS" ], "offsets": [ [ 572, 575 ] ], "normalized": [] }, { "id": "PMID-11971008_T8", "type": "Gene_or_gene_product", "text": [ "YopP" ], "offsets": [ [ 642, 646 ] ], "normalized": [] }, { "id": "PMID-11971008_T9", "type": "Gene_or_gene_product", "text": [ "YopP" ], "offsets": [ [ 803, 807 ] ], "normalized": [] }, { "id": "PMID-11971008_T10", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 868, 878 ] ], "normalized": [] }, { "id": "PMID-11971008_T11", "type": "Complex", "text": [ "LPS receptor" ], "offsets": [ [ 907, 919 ] ], "normalized": [] }, { "id": "PMID-11971008_T12", "type": "Gene_or_gene_product", "text": [ "myeloid differentiation factor 88" ], "offsets": [ [ 947, 980 ] ], "normalized": [] }, { "id": "PMID-11971008_T13", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 982, 987 ] ], "normalized": [] }, { "id": "PMID-11971008_T14", "type": "Gene_or_gene_product", "text": [ "IL-1R-associated kinase (IRAK) 2" ], "offsets": [ [ 992, 1024 ] ], "normalized": [] }, { "id": "PMID-11971008_T15", "type": "Simple_chemical", "text": [ "LPS" ], "offsets": [ [ 1036, 1039 ] ], "normalized": [] }, { "id": "PMID-11971008_T16", "type": "Gene_or_gene_product", "text": [ "YopP" ], "offsets": [ [ 1061, 1065 ] ], "normalized": [] }, { "id": "PMID-11971008_T17", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 1117, 1122 ] ], "normalized": [] }, { "id": "PMID-11971008_T18", "type": "Gene_or_gene_product", "text": [ "IRAK2" ], "offsets": [ [ 1127, 1132 ] ], "normalized": [] }, { "id": "PMID-11971008_T19", "type": "Gene_or_gene_product", "text": [ "IRAK1" ], "offsets": [ [ 1189, 1194 ] ], "normalized": [] }, { "id": "PMID-11971008_T20", "type": "Gene_or_gene_product", "text": [ "TNFR-associated factor 6" ], "offsets": [ [ 1199, 1223 ] ], "normalized": [] }, { "id": "PMID-11971008_T21", "type": "Gene_or_gene_product", "text": [ "TRAF6" ], "offsets": [ [ 1225, 1230 ] ], "normalized": [] }, { "id": "PMID-11971008_T22", "type": "Simple_chemical", "text": [ "LPS" ], "offsets": [ [ 1274, 1277 ] ], "normalized": [] }, { "id": "PMID-11971008_T23", "type": "Gene_or_gene_product", "text": [ "YopP" ], "offsets": [ [ 1315, 1319 ] ], "normalized": [] }, { "id": "PMID-11971008_T24", "type": "Gene_or_gene_product", "text": [ "IRAK1" ], "offsets": [ [ 1346, 1351 ] ], "normalized": [] }, { "id": "PMID-11971008_T25", "type": "Gene_or_gene_product", "text": [ "TRAF6" ], "offsets": [ [ 1356, 1361 ] ], "normalized": [] }, { "id": "PMID-11971008_T26", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 1403, 1413 ] ], "normalized": [] }, { "id": "PMID-11971008_T27", "type": "Gene_or_gene_product", "text": [ "IRAK" ], "offsets": [ [ 1449, 1453 ] ], "normalized": [] }, { "id": "PMID-11971008_T28", "type": "Gene_or_gene_product", "text": [ "IRAK1" ], "offsets": [ [ 1541, 1546 ] ], "normalized": [] }, { "id": "PMID-11971008_T29", "type": "Gene_or_gene_product", "text": [ "IRAK2" ], "offsets": [ [ 1551, 1556 ] ], "normalized": [] }, { "id": "PMID-11971008_T30", "type": "Simple_chemical", "text": [ "LPS" ], "offsets": [ [ 1613, 1616 ] ], "normalized": [] }, { "id": "PMID-11971008_T31", "type": "Gene_or_gene_product", "text": [ "caspase-8" ], "offsets": [ [ 1682, 1691 ] ], "normalized": [] }, { "id": "PMID-11971008_T32", "type": "Gene_or_gene_product", "text": [ "Fas-associated death domain protein" ], "offsets": [ [ 1735, 1770 ] ], "normalized": [] }, { "id": "PMID-11971008_T33", "type": "Gene_or_gene_product", "text": [ "FADD" ], "offsets": [ [ 1772, 1776 ] ], "normalized": [] }, { "id": "PMID-11971008_T34", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 1871, 1876 ] ], "normalized": [] }, { "id": "PMID-11971008_T35", "type": "Gene_or_gene_product", "text": [ "IRAK2" ], "offsets": [ [ 1881, 1886 ] ], "normalized": [] }, { "id": "PMID-11971008_T36", "type": "Gene_or_gene_product", "text": [ "Fas-associated death domain protein" ], "offsets": [ [ 1918, 1953 ] ], "normalized": [] }, { "id": "PMID-11971008_T37", "type": "Gene_or_gene_product", "text": [ "caspase-8" ], "offsets": [ [ 1954, 1963 ] ], "normalized": [] }, { "id": "PMID-11971008_T38", "type": "Gene_or_gene_product", "text": [ "IRAK1" ], "offsets": [ [ 1991, 1996 ] ], "normalized": [] }, { "id": "PMID-11971008_T39", "type": "Gene_or_gene_product", "text": [ "TRAF6" ], "offsets": [ [ 2001, 2006 ] ], "normalized": [] } ]

[ { "id": "PMID-11971008_E1", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 14, 23 ] ] }, "arguments": [] }, { "id": "PMID-11971008_E2", "type": "Positive_regulation", "trigger": { "text": [ "inducing" ], "offsets": [ [ 24, 32 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11971008_E1" } ] }, { "id": "PMID-11971008_E3", "type": "Negative_regulation", "trigger": { "text": [ "preventing" ], "offsets": [ [ 37, 47 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11971008_E1" } ] }, { "id": "PMID-11971008_E4", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 178, 187 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11971008_E5" } ] }, { "id": "PMID-11971008_E5", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 191, 200 ] ] }, "arguments": [] }, { "id": "PMID-11971008_E6", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 357, 365 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11971008_T3" }, { "role": "Theme", "ref_id": "PMID-11971008_E7" } ] }, { "id": "PMID-11971008_E7", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 366, 376 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11971008_T5" } ] }, { "id": "PMID-11971008_E8", "type": "Positive_regulation", "trigger": { "text": [ "results" ], "offsets": [ [ 586, 593 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11971008_T7" }, { "role": "Theme", "ref_id": "PMID-11971008_E9" } ] }, { "id": "PMID-11971008_E9", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 608, 617 ] ] }, "arguments": [] }, { "id": "PMID-11971008_E10", "type": "Pathway", "trigger": { "text": [ "cascade" ], "offsets": [ [ 879, 886 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-11971008_T10" } ] }, { "id": "PMID-11971008_E11", "type": "Negative_regulation", "trigger": { "text": [ "diminished" ], "offsets": [ [ 1025, 1035 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11971008_E14" }, { "role": "Cause", "ref_id": "PMID-11971008_T14" } ] }, { "id": "PMID-11971008_E12", "type": "Negative_regulation", "trigger": { "text": [ "diminished" ], "offsets": [ [ 1025, 1035 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11971008_E14" }, { "role": "Cause", "ref_id": "PMID-11971008_T12" } ] }, { "id": "PMID-11971008_E13", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1040, 1047 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11971008_T15" }, { "role": "Theme", "ref_id": "PMID-11971008_E14" } ] }, { "id": "PMID-11971008_E14", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 1048, 1057 ] ] }, "arguments": [] }, { "id": "PMID-11971008_E15", "type": "Pathway", "trigger": { "text": [ "cell death" ], "offsets": [ [ 1146, 1156 ] ] }, "arguments": [] }, { "id": "PMID-11971008_E16", "type": "Positive_regulation", "trigger": { "text": [ "augmented" ], "offsets": [ [ 1264, 1273 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11971008_E18" } ] }, { "id": "PMID-11971008_E17", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1278, 1286 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11971008_T22" }, { "role": "Theme", "ref_id": "PMID-11971008_E18" } ] }, { "id": "PMID-11971008_E18", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 1287, 1296 ] ] }, "arguments": [] }, { "id": "PMID-11971008_E19", "type": "Pathway", "trigger": { "text": [ "cascade" ], "offsets": [ [ 1414, 1421 ] ] }, "arguments": [] }, { "id": "PMID-11971008_E20", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 1512, 1519 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11971008_E23" }, { "role": "Cause", "ref_id": "PMID-11971008_T28" } ] }, { "id": "PMID-11971008_E21", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 1512, 1519 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11971008_E23" }, { "role": "Cause", "ref_id": "PMID-11971008_T29" } ] }, { "id": "PMID-11971008_E22", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1578, 1586 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11971008_E23" } ] }, { "id": "PMID-11971008_E23", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 1587, 1596 ] ] }, "arguments": [] }, { "id": "PMID-11971008_E24", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1617, 1626 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11971008_T30" }, { "role": "Theme", "ref_id": "PMID-11971008_E25" } ] }, { "id": "PMID-11971008_E25", "type": "Pathway", "trigger": { "text": [ "cell death" ], "offsets": [ [ 1627, 1637 ] ] }, "arguments": [] }, { "id": "PMID-11971008_E26", "type": "Negative_regulation", "trigger": { "text": [ "attenuated" ], "offsets": [ [ 1657, 1667 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-11971008_T32" }, { "role": "Theme", "ref_id": "PMID-11971008_E25" } ] }, { "id": "PMID-11971008_E27", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 1816, 1825 ] ] }, "arguments": [] }, { "id": "PMID-11971008_E28", "type": "Regulation", "trigger": { "text": [ "targets" ], "offsets": [ [ 1906, 1913 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11971008_E29" } ] }, { "id": "PMID-11971008_E29", "type": "Pathway", "trigger": { "text": [ "apoptotic pathway" ], "offsets": [ [ 1964, 1981 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-11971008_T36" }, { "role": "Participant", "ref_id": "PMID-11971008_T37" } ] } ]

[ { "id": "PMID-11971008_1", "entity_ids": [ "PMID-11971008_T4", "PMID-11971008_T3" ] }, { "id": "PMID-11971008_2", "entity_ids": [ "PMID-11971008_T13", "PMID-11971008_T12" ] }, { "id": "PMID-11971008_3", "entity_ids": [ "PMID-11971008_T20", "PMID-11971008_T21" ] }, { "id": "PMID-11971008_4", "entity_ids": [ "PMID-11971008_T32", "PMID-11971008_T33" ] } ]

[]

[ { "id": "PMID-11994509__text", "type": "abstract", "text": [ "Glycosylphosphatidylinositol-anchored mucin-like glycoproteins isolated from Trypanosoma cruzi trypomastigotes induce in vivo leukocyte recruitment dependent on MCP-1 production by IFN-gamma-primed-macrophages. \nGlycosylphosphatidylinositol-anchored mucin-like glycoproteins from Trypanosoma cruzi trypomastigotes (tGPI-mucins) activate macrophages in vitro to produce proinflammatory cytokines, chemokines, and nitric oxide. These effects of tGPI-mucins may be important in the ensuing immune response to T. cruzi. Here, we have sought evidence for a role of tGPI-mucins in mediating leukocyte recruitment in vivo. tGPI-mucins are highly effective in promoting cell recruitment in the pleural cavity of mice primed with IFN-gamma-inducing agents but not in naive mice. Maximal recruitment was observed at a dose between 250 and 1250 ng tGPI-mucins. There was a significant elevation in the levels of MCP-1 in the pleural cavity of primed animals injected with tGPI-mucins, and in vivo neutralization of MCP-1 abolished leukocyte recruitment. Pretreatment with anti-MIP-1alpha or anti-RANTES had no effect on the recruitment induced by tGPI-mucins. MCP-1 immunoreactivity was detected in pleural macrophages, and macrophages produced MCP-1 in vitro, especially after priming with IFN-gamma. Finally, tGPI-mucins induced significant leukocyte recruitment in primed C3H/HeJ but not in TLR2-deficient mice. Together, our results suggest that T. cruzi-derived GPI-mucins in conjunction with IFN-gamma may drive tissue chemokine production and inflammation and bear a significant role in the pathogenesis of Chagas disease.\n" ], "offsets": [ [ 0, 1619 ] ] } ]

[ { "id": "PMID-11994509_T1", "type": "Gene_or_gene_product", "text": [ "Glycosylphosphatidylinositol-anchored mucin-like glycoproteins" ], "offsets": [ [ 0, 62 ] ], "normalized": [] }, { "id": "PMID-11994509_T2", "type": "Gene_or_gene_product", "text": [ "MCP-1" ], "offsets": [ [ 161, 166 ] ], "normalized": [] }, { "id": "PMID-11994509_T3", "type": "Gene_or_gene_product", "text": [ "IFN-gamma" ], "offsets": [ [ 181, 190 ] ], "normalized": [] }, { "id": "PMID-11994509_T4", "type": "Gene_or_gene_product", "text": [ "Glycosylphosphatidylinositol-anchored mucin-like glycoproteins" ], "offsets": [ [ 212, 274 ] ], "normalized": [] }, { "id": "PMID-11994509_T5", "type": "Gene_or_gene_product", "text": [ "tGPI-mucins" ], "offsets": [ [ 315, 326 ] ], "normalized": [] }, { "id": "PMID-11994509_T6", "type": "Simple_chemical", "text": [ "nitric oxide" ], "offsets": [ [ 412, 424 ] ], "normalized": [] }, { "id": "PMID-11994509_T7", "type": "Gene_or_gene_product", "text": [ "tGPI-mucins" ], "offsets": [ [ 443, 454 ] ], "normalized": [] }, { "id": "PMID-11994509_T8", "type": "Gene_or_gene_product", "text": [ "tGPI-mucins" ], "offsets": [ [ 560, 571 ] ], "normalized": [] }, { "id": "PMID-11994509_T9", "type": "Gene_or_gene_product", "text": [ "tGPI-mucins" ], "offsets": [ [ 616, 627 ] ], "normalized": [] }, { "id": "PMID-11994509_T10", "type": "Gene_or_gene_product", "text": [ "IFN-gamma" ], "offsets": [ [ 721, 730 ] ], "normalized": [] }, { "id": "PMID-11994509_T11", "type": "Gene_or_gene_product", "text": [ "tGPI-mucins" ], "offsets": [ [ 837, 848 ] ], "normalized": [] }, { "id": "PMID-11994509_T12", "type": "Gene_or_gene_product", "text": [ "MCP-1" ], "offsets": [ [ 901, 906 ] ], "normalized": [] }, { "id": "PMID-11994509_T13", "type": "Gene_or_gene_product", "text": [ "tGPI-mucins" ], "offsets": [ [ 961, 972 ] ], "normalized": [] }, { "id": "PMID-11994509_T14", "type": "Gene_or_gene_product", "text": [ "MCP-1" ], "offsets": [ [ 1004, 1009 ] ], "normalized": [] }, { "id": "PMID-11994509_T15", "type": "Gene_or_gene_product", "text": [ "MIP-1alpha" ], "offsets": [ [ 1066, 1076 ] ], "normalized": [] }, { "id": "PMID-11994509_T16", "type": "Gene_or_gene_product", "text": [ "RANTES" ], "offsets": [ [ 1085, 1091 ] ], "normalized": [] }, { "id": "PMID-11994509_T17", "type": "Gene_or_gene_product", "text": [ "tGPI-mucins" ], "offsets": [ [ 1136, 1147 ] ], "normalized": [] }, { "id": "PMID-11994509_T18", "type": "Gene_or_gene_product", "text": [ "MCP-1" ], "offsets": [ [ 1149, 1154 ] ], "normalized": [] }, { "id": "PMID-11994509_T19", "type": "Gene_or_gene_product", "text": [ "MCP-1" ], "offsets": [ [ 1234, 1239 ] ], "normalized": [] }, { "id": "PMID-11994509_T20", "type": "Gene_or_gene_product", "text": [ "IFN-gamma" ], "offsets": [ [ 1280, 1289 ] ], "normalized": [] }, { "id": "PMID-11994509_T21", "type": "Gene_or_gene_product", "text": [ "tGPI-mucins" ], "offsets": [ [ 1300, 1311 ] ], "normalized": [] }, { "id": "PMID-11994509_T22", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 1383, 1387 ] ], "normalized": [] }, { "id": "PMID-11994509_T23", "type": "Gene_or_gene_product", "text": [ "GPI-mucins" ], "offsets": [ [ 1456, 1466 ] ], "normalized": [] }, { "id": "PMID-11994509_T24", "type": "Gene_or_gene_product", "text": [ "IFN-gamma" ], "offsets": [ [ 1487, 1496 ] ], "normalized": [] } ]

[ { "id": "PMID-11994509_E1", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 167, 177 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11994509_T2" } ] }, { "id": "PMID-11994509_E2", "type": "Conversion", "trigger": { "text": [ "produce" ], "offsets": [ [ 361, 368 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-11994509_T6" } ] }, { "id": "PMID-11994509_E3", "type": "Positive_regulation", "trigger": { "text": [ "elevation" ], "offsets": [ [ 874, 883 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-11994509_T12" } ] } ]

[ { "id": "PMID-11994509_1", "entity_ids": [ "PMID-11994509_T5", "PMID-11994509_T4" ] } ]

[]

[ { "id": "PMID-12015078__text", "type": "abstract", "text": [ "[Study of the effects of quercetin on PML gene and protein expression and localization in leukemia cells]. \nOBJECTIVE: To investigate PML gene and protein expression and localization in leukemia cell lines. METHODS: Cell morphology was assayed by Wright and fluorescence stain, PML mRNA expression by RT-PCR, and PML protein localization by immunofluorescence. RESULTS: (1) Differentiation was observed by morphology in NB4 and HL-60 cells after treatment with all-trans retinoic acid (ATRA) while K562 cells did not show. Apoptosis was found in each cell line after treatment with quercetin. (2) After treatment with ATRA, the fusion protein disappeared and PML protein resumed in NB4 cells, while in HL-60 and K562 cells there was no difference from control cells. After treatment with quercetin, the fusion protein disappeared in NB4 cells, then degraded, and so did in HL-60 cells and K562 cells. (3) The expression of PML mRNA had no change in all the three cell lines after treatment with ATRA or quercetin. CONCLUSION: PML plays a role of differentiation and apoptosis induction in leukemia cells at the translational level. PML in POD plays a role of apoptosis induction and growth control of leukemia cells.\n" ], "offsets": [ [ 0, 1217 ] ] } ]

[ { "id": "PMID-12015078_T1", "type": "Simple_chemical", "text": [ "quercetin" ], "offsets": [ [ 25, 34 ] ], "normalized": [] }, { "id": "PMID-12015078_T2", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 38, 41 ] ], "normalized": [] }, { "id": "PMID-12015078_T3", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 134, 137 ] ], "normalized": [] }, { "id": "PMID-12015078_T4", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 278, 281 ] ], "normalized": [] }, { "id": "PMID-12015078_T5", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 313, 316 ] ], "normalized": [] }, { "id": "PMID-12015078_T6", "type": "Simple_chemical", "text": [ "all-trans retinoic acid" ], "offsets": [ [ 461, 484 ] ], "normalized": [] }, { "id": "PMID-12015078_T7", "type": "Simple_chemical", "text": [ "ATRA" ], "offsets": [ [ 486, 490 ] ], "normalized": [] }, { "id": "PMID-12015078_T8", "type": "Simple_chemical", "text": [ "quercetin" ], "offsets": [ [ 582, 591 ] ], "normalized": [] }, { "id": "PMID-12015078_T9", "type": "Simple_chemical", "text": [ "ATRA" ], "offsets": [ [ 618, 622 ] ], "normalized": [] }, { "id": "PMID-12015078_T10", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 659, 662 ] ], "normalized": [] }, { "id": "PMID-12015078_T11", "type": "Simple_chemical", "text": [ "quercetin" ], "offsets": [ [ 788, 797 ] ], "normalized": [] }, { "id": "PMID-12015078_T12", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 923, 926 ] ], "normalized": [] }, { "id": "PMID-12015078_T13", "type": "Simple_chemical", "text": [ "ATRA" ], "offsets": [ [ 995, 999 ] ], "normalized": [] }, { "id": "PMID-12015078_T14", "type": "Simple_chemical", "text": [ "quercetin" ], "offsets": [ [ 1003, 1012 ] ], "normalized": [] }, { "id": "PMID-12015078_T15", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 1026, 1029 ] ], "normalized": [] }, { "id": "PMID-12015078_T16", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 1132, 1135 ] ], "normalized": [] } ]

[ { "id": "PMID-12015078_E1", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 14, 21 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12015078_T1" }, { "role": "Theme", "ref_id": "PMID-12015078_E3" } ] }, { "id": "PMID-12015078_E2", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 14, 21 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12015078_T1" }, { "role": "Theme", "ref_id": "PMID-12015078_E4" } ] }, { "id": "PMID-12015078_E3", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 59, 69 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12015078_T2" } ] }, { "id": "PMID-12015078_E4", "type": "Localization", "trigger": { "text": [ "localization" ], "offsets": [ [ 74, 86 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12015078_T2" } ] }, { "id": "PMID-12015078_E5", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 155, 165 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12015078_T3" } ] }, { "id": "PMID-12015078_E6", "type": "Localization", "trigger": { "text": [ "localization" ], "offsets": [ [ 170, 182 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12015078_T3" } ] }, { "id": "PMID-12015078_E7", "type": "Transcription", "trigger": { "text": [ "mRNA expression" ], "offsets": [ [ 282, 297 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12015078_T4" } ] }, { "id": "PMID-12015078_E8", "type": "Localization", "trigger": { "text": [ "localization" ], "offsets": [ [ 325, 337 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12015078_T5" } ] }, { "id": "PMID-12015078_E9", "type": "Pathway", "trigger": { "text": [ "Apoptosis" ], "offsets": [ [ 523, 532 ] ] }, "arguments": [] }, { "id": "PMID-12015078_E10", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 909, 919 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12015078_T12" } ] }, { "id": "PMID-12015078_E11", "type": "Regulation", "trigger": { "text": [ "change" ], "offsets": [ [ 939, 945 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12015078_E10" } ] }, { "id": "PMID-12015078_E12", "type": "Regulation", "trigger": { "text": [ "plays a role" ], "offsets": [ [ 1030, 1042 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12015078_T15" }, { "role": "Theme", "ref_id": "PMID-12015078_E14" } ] }, { "id": "PMID-12015078_E13", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 1066, 1075 ] ] }, "arguments": [] }, { "id": "PMID-12015078_E14", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1076, 1085 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12015078_E13" } ] }, { "id": "PMID-12015078_E15", "type": "Regulation", "trigger": { "text": [ "plays a role" ], "offsets": [ [ 1143, 1155 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12015078_T16" }, { "role": "Theme", "ref_id": "PMID-12015078_E17" } ] }, { "id": "PMID-12015078_E16", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 1159, 1168 ] ] }, "arguments": [] }, { "id": "PMID-12015078_E17", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1169, 1178 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12015078_E16" } ] } ]

[]

[]

[ { "id": "PMID-12015319__text", "type": "abstract", "text": [ "A 63-base pair DNA segment containing an Sp1 site but not a canonical E2F site can confer growth-dependent and E2F-mediated transcriptional stimulation of the human ASK gene encoding the regulatory subunit for human Cdc7-related kinase. \nCdc7-Dbf4 kinase complexes, conserved widely in eukaryotes, play essential roles in initiation and progression of the S phase. Cdc7 kinase activity fluctuates during cell cycle, and this is mainly the result of oscillation of expression of the Dbf4 subunit. Therefore, it is crucial to understand the mechanisms of regulation of Dbf4 expression. We have isolated and characterized the promoter region of the human ASK gene encoding Dbf4-related regulatory subunit for human Cdc7 kinase. We have identified a 63-base pair ASK promoter segment, which is sufficient for mediating growth stimulation. This minimal promoter segment (MP), containing an Sp1 site but no canonical E2F site, can be activated by ectopic E2F expression as well. Within the 63-base pair region, the Sp1 site as well as other elements are essential for stimulation by growth signals and by E2F, whereas an AT-rich sequence proximal to the coding region may serve as an element required for suppression in quiescence. Gel shift assays in the presence of an antibody demonstrate the presence of E2F1 in the protein-DNA complexes generated on the MP segment. However, the complex formation on MP was not competed by a DHFR promoter fragment, known to bind to E2F, nor by a consensus E2F binding oligonucleotide. Gel shift assays with point mutant MP fragments indicate that a non-canonical E2F site in the middle of this segment is critical for generation of the E2F complex. Our results suggest that E2F regulates the ASK promoter through an atypical mode of recognition of the target site.\n" ], "offsets": [ [ 0, 1798 ] ] } ]

[ { "id": "PMID-12015319_T1", "type": "Gene_or_gene_product", "text": [ "Sp1" ], "offsets": [ [ 41, 44 ] ], "normalized": [] }, { "id": "PMID-12015319_T2", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 70, 73 ] ], "normalized": [] }, { "id": "PMID-12015319_T3", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 111, 114 ] ], "normalized": [] }, { "id": "PMID-12015319_T4", "type": "Gene_or_gene_product", "text": [ "ASK" ], "offsets": [ [ 165, 168 ] ], "normalized": [] }, { "id": "PMID-12015319_T5", "type": "Gene_or_gene_product", "text": [ "Cdc7-related kinase" ], "offsets": [ [ 216, 235 ] ], "normalized": [] }, { "id": "PMID-12015319_T6", "type": "Complex", "text": [ "Cdc7-Dbf4" ], "offsets": [ [ 238, 247 ] ], "normalized": [] }, { "id": "PMID-12015319_T7", "type": "Gene_or_gene_product", "text": [ "Cdc7" ], "offsets": [ [ 365, 369 ] ], "normalized": [] }, { "id": "PMID-12015319_T8", "type": "Gene_or_gene_product", "text": [ "Dbf4" ], "offsets": [ [ 482, 486 ] ], "normalized": [] }, { "id": "PMID-12015319_T9", "type": "Gene_or_gene_product", "text": [ "Dbf4" ], "offsets": [ [ 567, 571 ] ], "normalized": [] }, { "id": "PMID-12015319_T10", "type": "Gene_or_gene_product", "text": [ "ASK" ], "offsets": [ [ 652, 655 ] ], "normalized": [] }, { "id": "PMID-12015319_T11", "type": "Gene_or_gene_product", "text": [ "Dbf4" ], "offsets": [ [ 670, 674 ] ], "normalized": [] }, { "id": "PMID-12015319_T12", "type": "Gene_or_gene_product", "text": [ "Cdc7" ], "offsets": [ [ 712, 716 ] ], "normalized": [] }, { "id": "PMID-12015319_T13", "type": "Gene_or_gene_product", "text": [ "ASK" ], "offsets": [ [ 759, 762 ] ], "normalized": [] }, { "id": "PMID-12015319_T14", "type": "Gene_or_gene_product", "text": [ "Sp1" ], "offsets": [ [ 885, 888 ] ], "normalized": [] }, { "id": "PMID-12015319_T15", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 911, 914 ] ], "normalized": [] }, { "id": "PMID-12015319_T16", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 949, 952 ] ], "normalized": [] }, { "id": "PMID-12015319_T17", "type": "Gene_or_gene_product", "text": [ "Sp1" ], "offsets": [ [ 1009, 1012 ] ], "normalized": [] }, { "id": "PMID-12015319_T18", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1099, 1102 ] ], "normalized": [] }, { "id": "PMID-12015319_T19", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 1302, 1306 ] ], "normalized": [] }, { "id": "PMID-12015319_T20", "type": "Gene_or_gene_product", "text": [ "DHFR" ], "offsets": [ [ 1424, 1428 ] ], "normalized": [] }, { "id": "PMID-12015319_T21", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1465, 1468 ] ], "normalized": [] }, { "id": "PMID-12015319_T22", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1489, 1492 ] ], "normalized": [] }, { "id": "PMID-12015319_T23", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1596, 1599 ] ], "normalized": [] }, { "id": "PMID-12015319_T24", "type": "Complex", "text": [ "E2F complex" ], "offsets": [ [ 1669, 1680 ] ], "normalized": [] }, { "id": "PMID-12015319_T25", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1707, 1710 ] ], "normalized": [] }, { "id": "PMID-12015319_T26", "type": "Gene_or_gene_product", "text": [ "ASK" ], "offsets": [ [ 1725, 1728 ] ], "normalized": [] } ]

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[]

[]

[ { "id": "PMID-12080070__text", "type": "abstract", "text": [ "The turn motif is a phosphorylation switch that regulates the binding of Hsp70 to protein kinase C. \nHeat shock proteins play central roles in ensuring the correct folding and maturation of cellular proteins. Here we show that the heat shock protein Hsp70 has a novel role in prolonging the lifetime of activated protein kinase C. We identified Hsp70 in a screen for binding partners for the carboxyl terminus of protein kinase C. Co-immunoprecipitation experiments revealed that Hsp70 specifically binds the unphosphorylated turn motif (Thr(641) in protein kinase C beta II), one of three priming sites phosphorylated during the maturation of protein kinase C family members. The interaction of Hsp70 with protein kinase C can be abolished in vivo by co-expression of fusion proteins encoding the carboxyl terminus of protein kinase C or the carboxyl terminus of Hsp70. Pulse-chase experiments reveal that Hsp70 does not regulate the maturation of protein kinase C: the rate of processing by phosphorylation is the same in the presence or absence of disrupting constructs. Rather, Hsp70 prolongs the lifetime of mature protein kinase C; disruption of the interaction promotes the accumulation of matured and then dephosphorylated protein kinase C in the detergent-insoluble fraction of cells. Furthermore, studies with K562 cells reveal that disruption of the interaction with Hsp70 slows the protein kinase C beta II-mediated recovery of cells from PMA-induced growth arrest. Last, we show that other members of the AGC superfamily (Akt/protein kinase B and protein kinase A) also bind Hsp70 via their unphosphorylated turn motifs. Our data are consistent with a model in which Hsp70 binds the dephosphorylated carboxyl terminus of mature protein kinase C, thus stabilizing the protein and allowing re-phosphorylation of the enzyme. Disruption of this interaction prevents re-phosphorylation and targets the enzyme for down-regulation. \n" ], "offsets": [ [ 0, 1939 ] ] } ]

[ { "id": "PMID-12080070_T1", "type": "Gene_or_gene_product", "text": [ "Hsp70" ], "offsets": [ [ 73, 78 ] ], "normalized": [] }, { "id": "PMID-12080070_T2", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 82, 98 ] ], "normalized": [] }, { "id": "PMID-12080070_T3", "type": "Gene_or_gene_product", "text": [ "Hsp70" ], "offsets": [ [ 250, 255 ] ], "normalized": [] }, { "id": "PMID-12080070_T4", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 313, 329 ] ], "normalized": [] }, { "id": "PMID-12080070_T5", "type": "Gene_or_gene_product", "text": [ "Hsp70" ], "offsets": [ [ 345, 350 ] ], "normalized": [] }, { "id": "PMID-12080070_T6", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 413, 429 ] ], "normalized": [] }, { "id": "PMID-12080070_T7", "type": "Gene_or_gene_product", "text": [ "Hsp70" ], "offsets": [ [ 480, 485 ] ], "normalized": [] }, { "id": "PMID-12080070_T8", "type": "Simple_chemical", "text": [ "Thr(641)" ], "offsets": [ [ 538, 546 ] ], "normalized": [] }, { "id": "PMID-12080070_T9", "type": "Gene_or_gene_product", "text": [ "protein kinase C beta II" ], "offsets": [ [ 550, 574 ] ], "normalized": [] }, { "id": "PMID-12080070_T10", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 644, 660 ] ], "normalized": [] }, { "id": "PMID-12080070_T11", "type": "Gene_or_gene_product", "text": [ "Hsp70" ], "offsets": [ [ 696, 701 ] ], "normalized": [] }, { "id": "PMID-12080070_T12", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 707, 723 ] ], "normalized": [] }, { "id": "PMID-12080070_T13", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 819, 835 ] ], "normalized": [] }, { "id": "PMID-12080070_T14", "type": "Gene_or_gene_product", "text": [ "Hsp70" ], "offsets": [ [ 864, 869 ] ], "normalized": [] }, { "id": "PMID-12080070_T15", "type": "Gene_or_gene_product", "text": [ "Hsp70" ], "offsets": [ [ 907, 912 ] ], "normalized": [] }, { "id": "PMID-12080070_T16", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 949, 965 ] ], "normalized": [] }, { "id": "PMID-12080070_T17", "type": "Gene_or_gene_product", "text": [ "Hsp70" ], "offsets": [ [ 1082, 1087 ] ], "normalized": [] }, { "id": "PMID-12080070_T18", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 1120, 1136 ] ], "normalized": [] }, { "id": "PMID-12080070_T19", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 1231, 1247 ] ], "normalized": [] }, { "id": "PMID-12080070_T20", "type": "Gene_or_gene_product", "text": [ "Hsp70" ], "offsets": [ [ 1378, 1383 ] ], "normalized": [] }, { "id": "PMID-12080070_T21", "type": "Gene_or_gene_product", "text": [ "protein kinase C beta II" ], "offsets": [ [ 1394, 1418 ] ], "normalized": [] }, { "id": "PMID-12080070_T22", "type": "Gene_or_gene_product", "text": [ "AGC" ], "offsets": [ [ 1518, 1521 ] ], "normalized": [] }, { "id": "PMID-12080070_T23", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 1535, 1538 ] ], "normalized": [] }, { "id": "PMID-12080070_T24", "type": "Gene_or_gene_product", "text": [ "protein kinase B" ], "offsets": [ [ 1539, 1555 ] ], "normalized": [] }, { "id": "PMID-12080070_T25", "type": "Gene_or_gene_product", "text": [ "protein kinase A" ], "offsets": [ [ 1560, 1576 ] ], "normalized": [] }, { "id": "PMID-12080070_T26", "type": "Gene_or_gene_product", "text": [ "Hsp70" ], "offsets": [ [ 1588, 1593 ] ], "normalized": [] }, { "id": "PMID-12080070_T27", "type": "Gene_or_gene_product", "text": [ "Hsp70" ], "offsets": [ [ 1680, 1685 ] ], "normalized": [] }, { "id": "PMID-12080070_T28", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 1741, 1757 ] ], "normalized": [] } ]

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[ { "role": "Theme", "ref_id": "PMID-12080070_T4" } ] }, { "id": "PMID-12080070_E6", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 367, 374 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_T6" }, { "role": "Theme", "ref_id": "PMID-12080070_T5" } ] }, { "id": "PMID-12080070_E7", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 499, 504 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_T9" }, { "role": "Theme", "ref_id": "PMID-12080070_T7" } ] }, { "id": "PMID-12080070_E8", "type": "Phosphorylation", "trigger": { "text": [ "unphosphorylated" ], "offsets": [ [ 509, 525 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-12080070_T8" }, { "role": "Theme", "ref_id": "PMID-12080070_T9" } ] }, { "id": "PMID-12080070_E9", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 604, 618 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_T10" }, { "role": "Site", "ref_id": "PMID-12080070_T8" } ] }, { "id": "PMID-12080070_E10", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 681, 692 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_T11" }, { "role": "Theme", "ref_id": "PMID-12080070_T12" } ] }, { "id": "PMID-12080070_E11", "type": "Negative_regulation", "trigger": { "text": [ "abolished" ], "offsets": [ [ 731, 740 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_E10" }, { "role": "Cause", "ref_id": "PMID-12080070_E13" } ] }, { "id": "PMID-12080070_E12", "type": "Negative_regulation", "trigger": { "text": [ "abolished" ], "offsets": [ [ 731, 740 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_E10" }, { "role": "Cause", "ref_id": "PMID-12080070_E14" } ] }, { "id": "PMID-12080070_E13", "type": "Gene_expression", "trigger": { "text": [ "co-expression" ], "offsets": [ [ 752, 765 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_T13" } ] }, { "id": "PMID-12080070_E14", "type": "Gene_expression", "trigger": { "text": [ "co-expression" ], "offsets": [ [ 752, 765 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_T14" } ] }, { "id": "PMID-12080070_E15", "type": "Regulation", "trigger": { "text": [ "regulate" ], "offsets": [ [ 922, 930 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12080070_T15" }, { "role": "Theme", "ref_id": "PMID-12080070_T16" } ] }, { "id": "PMID-12080070_E16", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 993, 1008 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_T16" } ] }, { "id": "PMID-12080070_E17", "type": "Positive_regulation", "trigger": { "text": [ "prolongs" ], "offsets": [ [ 1088, 1096 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12080070_T17" }, { "role": "Theme", "ref_id": "PMID-12080070_T18" } ] }, { "id": "PMID-12080070_E18", "type": "Negative_regulation", "trigger": { "text": [ "disruption" ], "offsets": [ [ 1138, 1148 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_E19" } ] }, { "id": "PMID-12080070_E19", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1156, 1167 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_T18" }, { "role": "Theme", "ref_id": "PMID-12080070_T17" } ] }, { "id": "PMID-12080070_E20", "type": "Positive_regulation", "trigger": { "text": [ "promotes" ], "offsets": [ [ 1168, 1176 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12080070_E18" }, { "role": "Theme", "ref_id": "PMID-12080070_E21" } ] }, { "id": "PMID-12080070_E21", "type": "Positive_regulation", "trigger": { "text": [ "accumulation" ], "offsets": [ [ 1181, 1193 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_T19" } ] }, { "id": "PMID-12080070_E22", "type": "Dephosphorylation", "trigger": { "text": [ "dephosphorylated" ], "offsets": [ [ 1214, 1230 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_T19" } ] }, { "id": "PMID-12080070_E23", "type": "Negative_regulation", "trigger": { "text": [ "disruption" ], "offsets": [ [ 1343, 1353 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_E24" } ] }, { "id": "PMID-12080070_E24", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1361, 1372 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_T20" } ] }, { "id": "PMID-12080070_E25", "type": "Negative_regulation", "trigger": { "text": [ "slows" ], "offsets": [ [ 1384, 1389 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12080070_E23" }, { "role": "Theme", "ref_id": "PMID-12080070_T21" } ] }, { "id": "PMID-12080070_E26", "type": "Binding", "trigger": { "text": [ "bind" ], "offsets": [ [ 1583, 1587 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_T26" }, { "role": "Theme", "ref_id": "PMID-12080070_T24" } ] }, { "id": "PMID-12080070_E27", "type": "Binding", "trigger": { "text": [ "bind" ], "offsets": [ [ 1583, 1587 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_T26" }, { "role": "Theme", "ref_id": "PMID-12080070_T25" } ] }, { "id": "PMID-12080070_E28", "type": "Phosphorylation", "trigger": { "text": [ "unphosphorylated" ], "offsets": [ [ 1604, 1620 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_T24" } ] }, { "id": "PMID-12080070_E29", "type": "Phosphorylation", "trigger": { "text": [ "unphosphorylated" ], "offsets": [ [ 1604, 1620 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_T25" } ] }, { "id": "PMID-12080070_E30", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 1686, 1691 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_T28" }, { "role": "Theme", "ref_id": "PMID-12080070_T27" } ] }, { "id": "PMID-12080070_E31", "type": "Dephosphorylation", "trigger": { "text": [ "dephosphorylated" ], "offsets": [ [ 1696, 1712 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_T28" } ] }, { "id": "PMID-12080070_E32", "type": "Regulation", "trigger": { "text": [ "stabilizing" ], "offsets": [ [ 1764, 1775 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_T28" }, { "role": "Cause", "ref_id": "PMID-12080070_E30" } ] }, { "id": "PMID-12080070_E33", "type": "Positive_regulation", "trigger": { "text": [ "allowing" ], "offsets": [ [ 1792, 1800 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12080070_E30" }, { "role": "Theme", "ref_id": "PMID-12080070_E34" } ] }, { "id": "PMID-12080070_E34", "type": "Phosphorylation", "trigger": { "text": [ "re-phosphorylation" ], "offsets": [ [ 1801, 1819 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_T28" } ] }, { "id": "PMID-12080070_E35", "type": "Negative_regulation", "trigger": { "text": [ "Disruption" ], "offsets": [ [ 1835, 1845 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_E36" } ] }, { "id": "PMID-12080070_E36", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1854, 1865 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_T28" }, { "role": "Theme", "ref_id": "PMID-12080070_T27" } ] }, { "id": "PMID-12080070_E37", "type": "Negative_regulation", "trigger": { "text": [ "prevents" ], "offsets": [ [ 1866, 1874 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_E38" }, { "role": "Cause", "ref_id": "PMID-12080070_E35" } ] }, { "id": "PMID-12080070_E38", "type": "Phosphorylation", "trigger": { "text": [ "re-phosphorylation" ], "offsets": [ [ 1875, 1893 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_T28" } ] }, { "id": "PMID-12080070_E39", "type": "Positive_regulation", "trigger": { "text": [ "targets" ], "offsets": [ [ 1898, 1905 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_E40" }, { "role": "Cause", "ref_id": "PMID-12080070_E35" } ] }, { "id": "PMID-12080070_E40", "type": "Negative_regulation", "trigger": { "text": [ "down-regulation" ], "offsets": [ [ 1921, 1936 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12080070_T28" } ] } ]

[ { "id": "PMID-12080070_1", "entity_ids": [ "PMID-12080070_T23", "PMID-12080070_T24" ] } ]

[]

[ { "id": "PMID-12084455__text", "type": "abstract", "text": [ "Homeostatic control of uridine and the role of uridine phosphorylase: a biological and clinical update. \nUridine, a pyrimidine nucleoside essential for the synthesis of RNA and bio-membranes, is a crucial element in the regulation of normal physiological processes as well as pathological states. The biological effects of uridine have been associated with the regulation of the cardio-circulatory system, at the reproduction level, with both peripheral and central nervous system modulation and with the functionality of the respiratory system. Furthermore, uridine plays a role at the clinical level in modulating the cytotoxic effects of fluoropyrimidines in both normal and neoplastic tissues. The concentration of uridine in plasma and tissues is tightly regulated by cellular transport mechanisms and by the activity of uridine phosphorylase (UPase), responsible for the reversible phosphorolysis of uridine to uracil. We have recently completed several studies designed to define the mechanisms regulating UPase expression and better characterize the multiple biological effects of uridine. Immunohistochemical analysis and co-purification studies have revealed the association of UPase with the cytoskeleton and the cellular membrane. The characterization of the promoter region of UPase has indicated a direct regulation of its expression by the tumor suppressor gene p53. The evaluation of human surgical specimens has shown elevated UPase activity in tumor tissue compared to paired normal tissue.\n" ], "offsets": [ [ 0, 1509 ] ] } ]

[ { "id": "PMID-12084455_T1", "type": "Simple_chemical", "text": [ "uridine" ], "offsets": [ [ 23, 30 ] ], "normalized": [] }, { "id": "PMID-12084455_T2", "type": "Gene_or_gene_product", "text": [ "uridine phosphorylase" ], "offsets": [ [ 47, 68 ] ], "normalized": [] }, { "id": "PMID-12084455_T3", "type": "Simple_chemical", "text": [ "Uridine" ], "offsets": [ [ 105, 112 ] ], "normalized": [] }, { "id": "PMID-12084455_T4", "type": "Simple_chemical", "text": [ "pyrimidine nucleoside" ], "offsets": [ [ 116, 137 ] ], "normalized": [] }, { "id": "PMID-12084455_T5", "type": "Cellular_component", "text": [ "bio-membranes" ], "offsets": [ [ 177, 190 ] ], "normalized": [] }, { "id": "PMID-12084455_T6", "type": "Simple_chemical", "text": [ "uridine" ], "offsets": [ [ 323, 330 ] ], "normalized": [] }, { "id": "PMID-12084455_T7", "type": "Simple_chemical", "text": [ "uridine" ], "offsets": [ [ 559, 566 ] ], "normalized": [] }, { "id": "PMID-12084455_T8", "type": "Simple_chemical", "text": [ "fluoropyrimidines" ], "offsets": [ [ 641, 658 ] ], "normalized": [] }, { "id": "PMID-12084455_T9", "type": "Simple_chemical", "text": [ "uridine" ], "offsets": [ [ 719, 726 ] ], "normalized": [] }, { "id": "PMID-12084455_T10", "type": "Gene_or_gene_product", "text": [ "uridine phosphorylase" ], "offsets": [ [ 826, 847 ] ], "normalized": [] }, { "id": "PMID-12084455_T11", "type": "Gene_or_gene_product", "text": [ "UPase" ], "offsets": [ [ 849, 854 ] ], "normalized": [] }, { "id": "PMID-12084455_T12", "type": "Simple_chemical", "text": [ "uridine" ], "offsets": [ [ 906, 913 ] ], "normalized": [] }, { "id": "PMID-12084455_T13", "type": "Simple_chemical", "text": [ "uracil" ], "offsets": [ [ 917, 923 ] ], "normalized": [] }, { "id": "PMID-12084455_T14", "type": "Gene_or_gene_product", "text": [ "UPase" ], "offsets": [ [ 1013, 1018 ] ], "normalized": [] }, { "id": "PMID-12084455_T15", "type": "Simple_chemical", "text": [ "uridine" ], "offsets": [ [ 1089, 1096 ] ], "normalized": [] }, { "id": "PMID-12084455_T16", "type": "Gene_or_gene_product", "text": [ "UPase" ], "offsets": [ [ 1188, 1193 ] ], "normalized": [] }, { "id": "PMID-12084455_T17", "type": "Cellular_component", "text": [ "cytoskeleton" ], "offsets": [ [ 1203, 1215 ] ], "normalized": [] }, { "id": "PMID-12084455_T18", "type": "Cellular_component", "text": [ "cellular membrane" ], "offsets": [ [ 1224, 1241 ] ], "normalized": [] }, { "id": "PMID-12084455_T19", "type": "Gene_or_gene_product", "text": [ "UPase" ], "offsets": [ [ 1290, 1295 ] ], "normalized": [] }, { "id": "PMID-12084455_T20", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1377, 1380 ] ], "normalized": [] }, { "id": "PMID-12084455_T21", "type": "Gene_or_gene_product", "text": [ "UPase" ], "offsets": [ [ 1444, 1449 ] ], "normalized": [] } ]

[ { "id": "PMID-12084455_E1", "type": "Regulation", "trigger": { "text": [ "control" ], "offsets": [ [ 12, 19 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12084455_T1" } ] }, { "id": "PMID-12084455_E2", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 760, 769 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12084455_T9" }, { "role": "Cause", "ref_id": "PMID-12084455_T11" } ] }, { "id": "PMID-12084455_E3", "type": "Positive_regulation", "trigger": { "text": [ "responsible" ], "offsets": [ [ 857, 868 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12084455_T11" }, { "role": "Theme", "ref_id": "PMID-12084455_E4" } ] }, { "id": "PMID-12084455_E4", "type": "Conversion", "trigger": { "text": [ "phosphorolysis" ], "offsets": [ [ 888, 902 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12084455_T12" }, { "role": "Product", "ref_id": "PMID-12084455_T13" } ] }, { "id": "PMID-12084455_E5", "type": "Regulation", "trigger": { "text": [ "regulating" ], "offsets": [ [ 1002, 1012 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12084455_E6" } ] }, { "id": "PMID-12084455_E6", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1019, 1029 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12084455_T14" } ] }, { "id": "PMID-12084455_E7", "type": "Regulation", "trigger": { "text": [ "association" ], "offsets": [ [ 1173, 1184 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12084455_T16" }, { "role": "Theme", "ref_id": "PMID-12084455_T17" } ] }, { "id": "PMID-12084455_E8", "type": "Regulation", "trigger": { "text": [ "association" ], "offsets": [ [ 1173, 1184 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12084455_T16" }, { "role": "Theme", "ref_id": "PMID-12084455_T18" } ] }, { "id": "PMID-12084455_E9", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1319, 1329 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12084455_E10" }, { "role": "Cause", "ref_id": "PMID-12084455_T20" } ] }, { "id": "PMID-12084455_E10", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1337, 1347 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12084455_T19" } ] }, { "id": "PMID-12084455_E11", "type": "Positive_regulation", "trigger": { "text": [ "elevated" ], "offsets": [ [ 1435, 1443 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12084455_T21" } ] } ]

[ { "id": "PMID-12084455_1", "entity_ids": [ "PMID-12084455_T10", "PMID-12084455_T11" ] } ]

[]

[ { "id": "PMID-12119352__text", "type": "abstract", "text": [ "Potential role of phosphatidylinositol 3 kinase, rather than DNA-dependent protein kinase, in CpG DNA-induced immune activation. \nUnmethylated CpG motifs present in bacterial DNA stimulate a strong innate immune response. There is evidence that DNA-dependent protein kinase (DNA-PK) mediates CpG signaling. Specifically, wortmannin (an inhibitor of phosphatidylinositol 3 kinase [PI3]-kinases including DNA-PK) interferes with CpG-dependent cell activation, and DNA-PK knockout (KO) mice fail to respond to CpG stimulation. Current studies establish that wortmannin actually inhibits the uptake and colocalization of CpG DNA with toll-like receptor (TLR)-9 in endocytic vesicles, thereby preventing CpG-induced activation of the NF-kappaB signaling cascade. We find that DNA-PK is not involved in this process, since three strains of DNA-PK KO mice responded normally to CpG DNA. These results support a model in which CpG signaling is mediated through TLR-9 but not DNA-PK, and suggest that wortmannin-sensitive member(s) of the PI3-kinase family play a critical role in shuttling CpG DNA to TLR-9.\n" ], "offsets": [ [ 0, 1100 ] ] } ]

[ { "id": "PMID-12119352_T1", "type": "Gene_or_gene_product", "text": [ "phosphatidylinositol 3 kinase" ], "offsets": [ [ 18, 47 ] ], "normalized": [] }, { "id": "PMID-12119352_T2", "type": "Complex", "text": [ "DNA-dependent protein kinase" ], "offsets": [ [ 61, 89 ] ], "normalized": [] }, { "id": "PMID-12119352_T3", "type": "Complex", "text": [ "DNA-dependent protein kinase" ], "offsets": [ [ 245, 273 ] ], "normalized": [] }, { "id": "PMID-12119352_T4", "type": "Complex", "text": [ "DNA-PK" ], "offsets": [ [ 275, 281 ] ], "normalized": [] }, { "id": "PMID-12119352_T5", "type": "Simple_chemical", "text": [ "wortmannin" ], "offsets": [ [ 321, 331 ] ], "normalized": [] }, { "id": "PMID-12119352_T6", "type": "Gene_or_gene_product", "text": [ "phosphatidylinositol 3 kinase [PI3]-kinases" ], "offsets": [ [ 349, 392 ] ], "normalized": [] }, { "id": "PMID-12119352_T7", "type": "Complex", "text": [ "DNA-PK" ], "offsets": [ [ 403, 409 ] ], "normalized": [] }, { "id": "PMID-12119352_T8", "type": "Complex", "text": [ "DNA-PK" ], "offsets": [ [ 462, 468 ] ], "normalized": [] }, { "id": "PMID-12119352_T9", "type": "Simple_chemical", "text": [ "wortmannin" ], "offsets": [ [ 555, 565 ] ], "normalized": [] }, { "id": "PMID-12119352_T10", "type": "Gene_or_gene_product", "text": [ "toll-like receptor (TLR)-9" ], "offsets": [ [ 630, 656 ] ], "normalized": [] }, { "id": "PMID-12119352_T11", "type": "Cellular_component", "text": [ "vesicles" ], "offsets": [ [ 670, 678 ] ], "normalized": [] }, { "id": "PMID-12119352_T12", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 729, 738 ] ], "normalized": [] }, { "id": "PMID-12119352_T13", "type": "Complex", "text": [ "DNA-PK" ], "offsets": [ [ 771, 777 ] ], "normalized": [] }, { "id": "PMID-12119352_T14", "type": "Complex", "text": [ "DNA-PK" ], "offsets": [ [ 834, 840 ] ], "normalized": [] }, { "id": "PMID-12119352_T15", "type": "Gene_or_gene_product", "text": [ "TLR-9" ], "offsets": [ [ 953, 958 ] ], "normalized": [] }, { "id": "PMID-12119352_T16", "type": "Complex", "text": [ "DNA-PK" ], "offsets": [ [ 967, 973 ] ], "normalized": [] }, { "id": "PMID-12119352_T17", "type": "Simple_chemical", "text": [ "wortmannin" ], "offsets": [ [ 992, 1002 ] ], "normalized": [] }, { "id": "PMID-12119352_T18", "type": "Gene_or_gene_product", "text": [ "PI3-kinase" ], "offsets": [ [ 1030, 1040 ] ], "normalized": [] }, { "id": "PMID-12119352_T19", "type": "Gene_or_gene_product", "text": [ "TLR-9" ], "offsets": [ [ 1093, 1098 ] ], "normalized": [] } ]

[ { "id": "PMID-12119352_E1", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 336, 345 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12119352_T5" }, { "role": "Theme", "ref_id": "PMID-12119352_T6" } ] }, { "id": "PMID-12119352_E2", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 336, 345 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12119352_T5" }, { "role": "Theme", "ref_id": "PMID-12119352_T7" } ] }, { "id": "PMID-12119352_E3", "type": "Negative_regulation", "trigger": { "text": [ "preventing" ], "offsets": [ [ 688, 698 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12119352_E4" } ] }, { "id": "PMID-12119352_E4", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 711, 721 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12119352_E5" } ] }, { "id": "PMID-12119352_E5", "type": "Pathway", "trigger": { "text": [ "signaling cascade" ], "offsets": [ [ 739, 756 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-12119352_T12" } ] }, { "id": "PMID-12119352_E6", "type": "Regulation", "trigger": { "text": [ "sensitive" ], "offsets": [ [ 1003, 1012 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12119352_T17" }, { "role": "Theme", "ref_id": "PMID-12119352_T18" } ] } ]

[ { "id": "PMID-12119352_1", "entity_ids": [ "PMID-12119352_T3", "PMID-12119352_T4" ] } ]

[]

[ { "id": "PMID-12138177__text", "type": "abstract", "text": [ "Transcriptional regulation of the mdm2 oncogene by p53 requires TRRAP acetyltransferase complexes. \nThe p53 tumor suppressor regulates the cellular response to genetic damage through its function as a sequence-specific transcription factor. Among the most well-characterized transcriptional targets of p53 is the mdm2 oncogene. Activation of mdm2 is critical in the p53 pathway because the mdm2 protein marks p53 for proteosome-mediated degradation, thereby providing a negative-feedback loop. Here we show that the ATM-related TRRAP protein functionally cooperates with p53 to activate mdm2 transcription. TRRAP is a component of several multiprotein acetyltransferase complexes implicated in both transcriptional regulation and DNA repair. In support of a role for these complexes in mdm2 expression, we show that transactivation of the mdm2 gene is augmented by pharmacological inhibition of cellular deacetylases. In vitro analysis demonstrates that p53 directly binds to a TRRAP domain previously shown to be an activator docking site. Furthermore, transfection of cells with antisense TRRAP blocks p53-dependent transcription of mdm2. Finally, using chromatin immunoprecipitation, we demonstrate direct p53-dependent recruitment of TRRAP to the mdm2 promoter, followed by increased histone acetylation. These findings suggest a model in which p53 directly recruits a TRRAP/acetyltransferase complex to the mdm2 gene to activate transcription. In addition, this study defines a novel biochemical mechanism utilized by the p53 tumor suppressor to regulate gene expression.\n" ], "offsets": [ [ 0, 1577 ] ] } ]

[ { "id": "PMID-12138177_T1", "type": "Gene_or_gene_product", "text": [ "mdm2" ], "offsets": [ [ 34, 38 ] ], "normalized": [] }, { "id": "PMID-12138177_T2", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 51, 54 ] ], "normalized": [] }, { "id": "PMID-12138177_T3", "type": "Complex", "text": [ "TRRAP acetyltransferase" ], "offsets": [ [ 64, 87 ] ], "normalized": [] }, { "id": "PMID-12138177_T4", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 104, 107 ] ], "normalized": [] }, { "id": "PMID-12138177_T5", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 302, 305 ] ], "normalized": [] }, { "id": "PMID-12138177_T6", "type": "Gene_or_gene_product", "text": [ "mdm2" ], "offsets": [ [ 313, 317 ] ], "normalized": [] }, { "id": "PMID-12138177_T7", "type": "Gene_or_gene_product", "text": [ "mdm2" ], "offsets": [ [ 342, 346 ] ], "normalized": [] }, { "id": "PMID-12138177_T8", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 366, 369 ] ], "normalized": [] }, { "id": "PMID-12138177_T9", "type": "Gene_or_gene_product", "text": [ "mdm2" ], "offsets": [ [ 390, 394 ] ], "normalized": [] }, { "id": "PMID-12138177_T10", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 409, 412 ] ], "normalized": [] }, { "id": "PMID-12138177_T11", "type": "Gene_or_gene_product", "text": [ "TRRAP" ], "offsets": [ [ 528, 533 ] ], "normalized": [] }, { "id": "PMID-12138177_T12", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 571, 574 ] ], "normalized": [] }, { "id": "PMID-12138177_T13", "type": "Gene_or_gene_product", "text": [ "mdm2" ], "offsets": [ [ 587, 591 ] ], "normalized": [] }, { "id": "PMID-12138177_T14", "type": "Gene_or_gene_product", "text": [ "TRRAP" ], "offsets": [ [ 607, 612 ] ], "normalized": [] }, { "id": "PMID-12138177_T15", "type": "Gene_or_gene_product", "text": [ "mdm2" ], "offsets": [ [ 786, 790 ] ], "normalized": [] }, { "id": "PMID-12138177_T16", "type": "Gene_or_gene_product", "text": [ "mdm2" ], "offsets": [ [ 839, 843 ] ], "normalized": [] }, { "id": "PMID-12138177_T17", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 954, 957 ] ], "normalized": [] }, { "id": "PMID-12138177_T18", "type": "Gene_or_gene_product", "text": [ "TRRAP" ], "offsets": [ [ 978, 983 ] ], "normalized": [] }, { "id": "PMID-12138177_T19", "type": "Gene_or_gene_product", "text": [ "TRRAP" ], "offsets": [ [ 1091, 1096 ] ], "normalized": [] }, { "id": "PMID-12138177_T20", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1104, 1107 ] ], "normalized": [] }, { "id": "PMID-12138177_T21", "type": "Gene_or_gene_product", "text": [ "mdm2" ], "offsets": [ [ 1135, 1139 ] ], "normalized": [] }, { "id": "PMID-12138177_T22", "type": "Cellular_component", "text": [ "chromatin" ], "offsets": [ [ 1156, 1165 ] ], "normalized": [] }, { "id": "PMID-12138177_T23", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1209, 1212 ] ], "normalized": [] }, { "id": "PMID-12138177_T24", "type": "Gene_or_gene_product", "text": [ "TRRAP" ], "offsets": [ [ 1238, 1243 ] ], "normalized": [] }, { "id": "PMID-12138177_T25", "type": "Gene_or_gene_product", "text": [ "mdm2" ], "offsets": [ [ 1251, 1255 ] ], "normalized": [] }, { "id": "PMID-12138177_T26", "type": "Gene_or_gene_product", "text": [ "histone" ], "offsets": [ [ 1288, 1295 ] ], "normalized": [] }, { "id": "PMID-12138177_T27", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1349, 1352 ] ], "normalized": [] }, { "id": "PMID-12138177_T28", "type": "Complex", "text": [ "TRRAP/acetyltransferase" ], "offsets": [ [ 1373, 1396 ] ], "normalized": [] }, { "id": "PMID-12138177_T29", "type": "Gene_or_gene_product", "text": [ "mdm2" ], "offsets": [ [ 1412, 1416 ] ], "normalized": [] }, { "id": "PMID-12138177_T30", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1527, 1530 ] ], "normalized": [] } ]

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"ref_id": "PMID-12138177_E8" } ] }, { "id": "PMID-12138177_E10", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 592, 605 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12138177_T13" } ] }, { "id": "PMID-12138177_E11", "type": "Positive_regulation", "trigger": { "text": [ "implicated" ], "offsets": [ [ 680, 690 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12138177_E12" }, { "role": "Cause", "ref_id": "PMID-12138177_T14" } ] }, { "id": "PMID-12138177_E12", "type": "Pathway", "trigger": { "text": [ "DNA repair" ], "offsets": [ [ 730, 740 ] ] }, "arguments": [] }, { "id": "PMID-12138177_E13", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 791, 801 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12138177_T15" } ] }, { "id": "PMID-12138177_E14", "type": "Positive_regulation", "trigger": { "text": [ "transactivation" ], "offsets": [ [ 816, 831 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12138177_T16" } ] }, { "id": "PMID-12138177_E15", "type": "Positive_regulation", "trigger": { "text": [ "augmented" ], "offsets": [ [ 852, 861 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12138177_E14" } ] }, { "id": "PMID-12138177_E16", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 967, 972 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12138177_T17" }, { "role": "Theme", "ref_id": "PMID-12138177_T18" } ] }, { "id": "PMID-12138177_E17", "type": "Negative_regulation", "trigger": { "text": [ "blocks" ], "offsets": [ [ 1097, 1103 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12138177_E19" } ] }, { "id": "PMID-12138177_E18", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1108, 1117 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12138177_T20" }, { "role": "Theme", "ref_id": "PMID-12138177_E19" } ] }, { "id": "PMID-12138177_E19", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 1118, 1131 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12138177_T21" } ] }, { "id": "PMID-12138177_E20", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1213, 1222 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12138177_T23" }, { "role": "Theme", "ref_id": "PMID-12138177_E21" } ] }, { "id": "PMID-12138177_E21", "type": "Transport", "trigger": { "text": [ "recruitment" ], "offsets": [ [ 1223, 1234 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12138177_T24" } ] }, { "id": "PMID-12138177_E22", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1278, 1287 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12138177_E23" } ] }, { "id": "PMID-12138177_E23", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 1296, 1307 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12138177_T26" } ] }, { "id": "PMID-12138177_E24", "type": "Transport", "trigger": { "text": [ "recruits" ], "offsets": [ [ 1362, 1370 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12138177_T28" } ] }, { "id": "PMID-12138177_E25", "type": "Regulation", "trigger": { "text": [ "recruits" ], "offsets": [ [ 1362, 1370 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12138177_T27" }, { "role": "Theme", "ref_id": "PMID-12138177_E24" } ] } ]

[]

[]

[ { "id": "PMID-12231510__text", "type": "abstract", "text": [ "The FKBP12-rapamycin-associated protein (FRAP) is a CLIP-170 kinase. \nCLIP-170/Restin belongs to a family of conserved microtubule (MT)-associated proteins, which are important for MT organization and functions. CLIP-170 is a phosphoprotein and phosphorylation is thought to regulate the binding of CLIP-170 to MTs. However, little is known about the kinase(s) involved. In this study, we show that FKBP12-rapamycin-associated protein (FRAP, also called mTOR/RAFT) interacts with CLIP-170. CLIP-170 is phosphorylated in vivo at multiple sites, including rapamycin-sensitive and -insensitive sites, and is phosphorylated by FRAP in vitro at the rapamycin-sensitive sites. In addition, rapamycin inhibited the ability of CLIP-170 to bind to MTs. Our observations suggest that multiple CLIP-170 kinases are involved in positive and negative control of CLIP-170, and FRAP is a CLIP-170 kinase positively regulating the MT-binding behavior of CLIP-170. \n" ], "offsets": [ [ 0, 949 ] ] } ]

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[ { "id": "PMID-12231510_1", "entity_ids": [ "PMID-12231510_T1", "PMID-12231510_T2" ] }, { "id": "PMID-12231510_2", "entity_ids": [ "PMID-12231510_T4", "PMID-12231510_T5" ] }, { "id": "PMID-12231510_3", "entity_ids": [ "PMID-12231510_T6", "PMID-12231510_T7" ] }, { "id": "PMID-12231510_4", "entity_ids": [ "PMID-12231510_T12", "PMID-12231510_T13", "PMID-12231510_T14", "PMID-12231510_T15" ] } ]

[]

[ { "id": "PMID-12368233__text", "type": "abstract", "text": [ "Opposing regulatory roles of E2F in human telomerase reverse transcriptase (hTERT) gene expression in human tumor and normal somatic cells. \nTelomerase activity is closely correlated with cellular proliferative activity in human tissues. Human cells with high proliferative potential, such as tumor cells or stem cells, exhibit telomerase activity, whereas most normal human somatic cells do not. Telomerase activity is tightly regulated by the expression of its catalytic subunit human telomerase reverse transcriptase (hTERT). Through an expression cloning approach, we identified E2F-1 as a repressor of the hTERT gene in human tumor cells. Ectopic expression of E2F-1 repressed hTERT promoter activity by inhibiting Sp1 activation of the hTERT promoter. In contrast to the repressor function of E2F-1 in human tumor cells, we demonstrated that E2F-1 is an activator of the hTERT gene in normal human somatic cells. Ectopically expressed E2F-1 activated the hTERT promoter through a noncanonical DNA binding site. E2F-1, E2F-2, and E2F-3 (but not E2F-4 and E2F-5) repressed hTERT promoter activity in human tumor cells, whereas they activated it in normal somatic cells. These contrasting effects of E2F transcription factors on the hTERT promoter could underlie the paradoxical biological activities of E2F, which can both promote and inhibit cellular proliferation and tumorigenesis.\n" ], "offsets": [ [ 0, 1389 ] ] } ]

[ { "id": "PMID-12368233_T1", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 29, 32 ] ], "normalized": [] }, { "id": "PMID-12368233_T2", "type": "Gene_or_gene_product", "text": [ "human telomerase reverse transcriptase" ], "offsets": [ [ 36, 74 ] ], "normalized": [] }, { "id": "PMID-12368233_T3", "type": "Gene_or_gene_product", "text": [ "hTERT" ], "offsets": [ [ 76, 81 ] ], "normalized": [] }, { "id": "PMID-12368233_T4", "type": "Complex", "text": [ "Telomerase" ], "offsets": [ [ 141, 151 ] ], "normalized": [] }, { "id": "PMID-12368233_T5", "type": "Complex", "text": [ "telomerase" ], "offsets": [ [ 328, 338 ] ], "normalized": [] }, { "id": "PMID-12368233_T6", "type": "Complex", "text": [ "Telomerase" ], "offsets": [ [ 397, 407 ] ], "normalized": [] }, { "id": "PMID-12368233_T7", "type": "Gene_or_gene_product", "text": [ "human telomerase reverse transcriptase" ], "offsets": [ [ 481, 519 ] ], "normalized": [] }, { "id": "PMID-12368233_T8", "type": "Gene_or_gene_product", "text": [ "hTERT" ], "offsets": [ [ 521, 526 ] ], "normalized": [] }, { "id": "PMID-12368233_T9", "type": "Gene_or_gene_product", "text": [ "E2F-1" ], "offsets": [ [ 583, 588 ] ], "normalized": [] }, { "id": "PMID-12368233_T10", "type": "Gene_or_gene_product", "text": [ "hTERT" ], "offsets": [ [ 611, 616 ] ], "normalized": [] }, { "id": "PMID-12368233_T11", "type": "Gene_or_gene_product", "text": [ "E2F-1" ], "offsets": [ [ 666, 671 ] ], "normalized": [] }, { "id": "PMID-12368233_T12", "type": "Gene_or_gene_product", "text": [ "hTERT" ], "offsets": [ [ 682, 687 ] ], "normalized": [] }, { "id": "PMID-12368233_T13", "type": "Gene_or_gene_product", "text": [ "Sp1" ], "offsets": [ [ 720, 723 ] ], "normalized": [] }, { "id": "PMID-12368233_T14", "type": "Gene_or_gene_product", "text": [ "hTERT" ], "offsets": [ [ 742, 747 ] ], "normalized": [] }, { "id": "PMID-12368233_T15", "type": "Gene_or_gene_product", "text": [ "E2F-1" ], "offsets": [ [ 799, 804 ] ], "normalized": [] }, { "id": "PMID-12368233_T16", "type": "Gene_or_gene_product", "text": [ "E2F-1" ], "offsets": [ [ 848, 853 ] ], "normalized": [] }, { "id": "PMID-12368233_T17", "type": "Gene_or_gene_product", "text": [ "hTERT" ], "offsets": [ [ 877, 882 ] ], "normalized": [] }, { "id": "PMID-12368233_T18", "type": "Gene_or_gene_product", "text": [ "E2F-1" ], "offsets": [ [ 941, 946 ] ], "normalized": [] }, { "id": "PMID-12368233_T19", "type": "Gene_or_gene_product", "text": [ "hTERT" ], "offsets": [ [ 961, 966 ] ], "normalized": [] }, { "id": "PMID-12368233_T20", "type": "Gene_or_gene_product", "text": [ "E2F-1" ], "offsets": [ [ 1017, 1022 ] ], "normalized": [] }, { "id": "PMID-12368233_T21", "type": "Gene_or_gene_product", "text": [ "E2F-2" ], "offsets": [ [ 1024, 1029 ] ], "normalized": [] }, { "id": "PMID-12368233_T22", "type": "Gene_or_gene_product", "text": [ "E2F-3" ], "offsets": [ [ 1035, 1040 ] ], "normalized": [] }, { "id": "PMID-12368233_T23", "type": "Gene_or_gene_product", "text": [ "E2F-4" ], "offsets": [ [ 1050, 1055 ] ], "normalized": [] }, { "id": "PMID-12368233_T24", "type": "Gene_or_gene_product", "text": [ "E2F-5" ], "offsets": [ [ 1060, 1065 ] ], "normalized": [] }, { "id": "PMID-12368233_T25", "type": "Gene_or_gene_product", "text": [ "hTERT" ], "offsets": [ [ 1077, 1082 ] ], "normalized": [] }, { "id": "PMID-12368233_T26", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1203, 1206 ] ], "normalized": [] }, { "id": "PMID-12368233_T27", "type": "Gene_or_gene_product", "text": [ "hTERT" ], "offsets": [ [ 1236, 1241 ] ], "normalized": [] }, { "id": "PMID-12368233_T28", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1307, 1310 ] ], "normalized": [] } ]

[ { "id": "PMID-12368233_E1", "type": "Negative_regulation", "trigger": { "text": [ "Opposing" ], "offsets": [ [ 0, 8 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12368233_E2" } ] }, { "id": "PMID-12368233_E2", "type": "Regulation", "trigger": { "text": [ "regulatory roles" ], "offsets": [ [ 9, 25 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12368233_T1" } ] }, { "id": "PMID-12368233_E3", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 88, 98 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12368233_T3" } ] }, { "id": "PMID-12368233_E4", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 428, 437 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12368233_T6" }, { "role": "Cause", "ref_id": "PMID-12368233_E5" } ] }, { "id": "PMID-12368233_E5", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 445, 455 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12368233_T8" } ] }, { "id": "PMID-12368233_E6", "type": "Negative_regulation", "trigger": { "text": [ "repressor" ], "offsets": [ [ 594, 603 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12368233_T10" }, { "role": "Cause", "ref_id": "PMID-12368233_T9" } ] }, { "id": "PMID-12368233_E7", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 652, 662 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12368233_T11" } ] }, { "id": "PMID-12368233_E8", "type": "Negative_regulation", "trigger": { "text": [ "repressed" ], "offsets": [ [ 672, 681 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12368233_T12" }, { "role": "Cause", "ref_id": "PMID-12368233_E9" } ] }, { "id": "PMID-12368233_E9", "type": "Negative_regulation", "trigger": { "text": [ "inhibiting" ], "offsets": [ [ 709, 719 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12368233_E7" }, { "role": "Theme", "ref_id": "PMID-12368233_E10" } ] }, { "id": "PMID-12368233_E10", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 724, 734 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12368233_T13" } ] }, { "id": "PMID-12368233_E11", "type": "Negative_regulation", "trigger": { "text": [ "repressor" ], "offsets": [ [ 777, 786 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12368233_T15" } ] }, { "id": "PMID-12368233_E12", "type": "Activation", "trigger": { "text": [ "activator" ], "offsets": [ [ 860, 869 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12368233_T16" }, { "role": "Theme", "ref_id": "PMID-12368233_T17" } ] }, { "id": "PMID-12368233_E13", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 931, 940 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12368233_T18" } ] }, { "id": "PMID-12368233_E14", "type": "Activation", "trigger": { "text": [ "activated" ], "offsets": [ [ 947, 956 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12368233_T19" }, { "role": "Cause", "ref_id": "PMID-12368233_E13" } ] }, { "id": "PMID-12368233_E15", "type": "Negative_regulation", "trigger": { "text": [ "repressed" ], "offsets": [ [ 1067, 1076 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12368233_T25" }, { "role": "Cause", "ref_id": "PMID-12368233_T20" } ] }, { "id": "PMID-12368233_E16", "type": "Negative_regulation", "trigger": { "text": [ "repressed" ], "offsets": [ [ 1067, 1076 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12368233_T25" }, { "role": "Cause", "ref_id": "PMID-12368233_T21" } ] }, { "id": "PMID-12368233_E17", "type": "Negative_regulation", "trigger": { "text": [ "repressed" ], "offsets": [ [ 1067, 1076 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12368233_T25" }, { "role": "Cause", "ref_id": "PMID-12368233_T22" } ] }, { "id": "PMID-12368233_E18", "type": "Activation", "trigger": { "text": [ "activated" ], "offsets": [ [ 1136, 1145 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12368233_T25" }, { "role": "Cause", "ref_id": "PMID-12368233_T20" } ] }, { "id": "PMID-12368233_E19", "type": "Activation", "trigger": { "text": [ "activated" ], "offsets": [ [ 1136, 1145 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12368233_T25" }, { "role": "Cause", "ref_id": "PMID-12368233_T21" } ] }, { "id": "PMID-12368233_E20", "type": "Activation", "trigger": { "text": [ "activated" ], "offsets": [ [ 1136, 1145 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12368233_T25" }, { "role": "Cause", "ref_id": "PMID-12368233_T22" } ] }, { "id": "PMID-12368233_E21", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 1192, 1199 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12368233_T27" }, { "role": "Cause", "ref_id": "PMID-12368233_T26" } ] } ]

[ { "id": "PMID-12368233_1", "entity_ids": [ "PMID-12368233_T2", "PMID-12368233_T3" ] }, { "id": "PMID-12368233_2", "entity_ids": [ "PMID-12368233_T7", "PMID-12368233_T8" ] } ]

[]

[ { "id": "PMID-12402045__text", "type": "abstract", "text": [ "The Doc1 subunit is a processivity factor for the anaphase-promoting complex. \nUbiquitin-mediated proteolysis of securin and mitotic cyclins is essential for exit from mitosis. The final step in ubiquitination of these and other proteins is catalysed by the anaphase-promoting complex (APC), a multi-subunit ubiquitin-protein ligase (E3). Little is known about the molecular reaction resulting in APC-dependent substrate ubiquitination or the role of individual APC subunits in the reaction. Using a well-defined in vitro system, we show that highly purified APC from Saccharomyces cerevisiae ubiquitinates a model cyclin substrate in a processive manner. Analysis of mutant APC lacking the Doc1/Apc10 subunit (APC(doc1 Delta)) indicates that Doc1 is required for processivity. The specific molecular defect in APC(doc1 Delta) is identified by a large increase in apparent K(M) for the cyclin substrate relative to the wild-type enzyme. This suggests that Doc1 stimulates processivity by limiting substrate dissociation. Addition of recombinant Doc1 to APC(doc1 Delta) fully restores enzyme function. Doc1-related domains are found in mechanistically distinct ubiquitin-ligase enzymes and may generally stimulate ubiquitination by contributing to substrate-enzyme affinity.\n" ], "offsets": [ [ 0, 1274 ] ] } ]

[ { "id": "PMID-12402045_T1", "type": "Gene_or_gene_product", "text": [ "Doc1" ], "offsets": [ [ 4, 8 ] ], "normalized": [] }, { "id": "PMID-12402045_T2", "type": "Complex", "text": [ "anaphase-promoting complex" ], "offsets": [ [ 50, 76 ] ], "normalized": [] }, { "id": "PMID-12402045_T3", "type": "Gene_or_gene_product", "text": [ "Ubiquitin" ], "offsets": [ [ 79, 88 ] ], "normalized": [] }, { "id": "PMID-12402045_T4", "type": "Gene_or_gene_product", "text": [ "securin" ], "offsets": [ [ 113, 120 ] ], "normalized": [] }, { "id": "PMID-12402045_T5", "type": "Gene_or_gene_product", "text": [ "cyclins" ], "offsets": [ [ 133, 140 ] ], "normalized": [] }, { "id": "PMID-12402045_T6", "type": "Complex", "text": [ "anaphase-promoting complex" ], "offsets": [ [ 258, 284 ] ], "normalized": [] }, { "id": "PMID-12402045_T7", "type": "Complex", "text": [ "APC" ], "offsets": [ [ 286, 289 ] ], "normalized": [] }, { "id": "PMID-12402045_T8", "type": "Gene_or_gene_product", "text": [ "ubiquitin" ], "offsets": [ [ 308, 317 ] ], "normalized": [] }, { "id": "PMID-12402045_T9", "type": "Complex", "text": [ "APC" ], "offsets": [ [ 397, 400 ] ], "normalized": [] }, { "id": "PMID-12402045_T10", "type": "Complex", "text": [ "APC" ], "offsets": [ [ 462, 465 ] ], "normalized": [] }, { "id": "PMID-12402045_T11", "type": "Complex", "text": [ "APC" ], "offsets": [ [ 559, 562 ] ], "normalized": [] }, { "id": "PMID-12402045_T12", "type": "Gene_or_gene_product", "text": [ "cyclin" ], "offsets": [ [ 615, 621 ] ], "normalized": [] }, { "id": "PMID-12402045_T13", "type": "Complex", "text": [ "APC" ], "offsets": [ [ 675, 678 ] ], "normalized": [] }, { "id": "PMID-12402045_T14", "type": "Gene_or_gene_product", "text": [ "Doc1" ], "offsets": [ [ 691, 695 ] ], "normalized": [] }, { "id": "PMID-12402045_T15", "type": "Gene_or_gene_product", "text": [ "Apc10" ], "offsets": [ [ 696, 701 ] ], "normalized": [] }, { "id": "PMID-12402045_T16", "type": "Complex", "text": [ "APC(doc1 Delta)" ], "offsets": [ [ 711, 726 ] ], "normalized": [] }, { "id": "PMID-12402045_T17", "type": "Gene_or_gene_product", "text": [ "Doc1" ], "offsets": [ [ 743, 747 ] ], "normalized": [] }, { "id": "PMID-12402045_T18", "type": "Complex", "text": [ "APC(doc1 Delta)" ], "offsets": [ [ 811, 826 ] ], "normalized": [] }, { "id": "PMID-12402045_T19", "type": "Gene_or_gene_product", "text": [ "cyclin" ], "offsets": [ [ 886, 892 ] ], "normalized": [] }, { "id": "PMID-12402045_T20", "type": "Gene_or_gene_product", "text": [ "Doc1" ], "offsets": [ [ 956, 960 ] ], "normalized": [] }, { "id": "PMID-12402045_T21", "type": "Gene_or_gene_product", "text": [ "Doc1" ], "offsets": [ [ 1045, 1049 ] ], "normalized": [] }, { "id": "PMID-12402045_T22", "type": "Complex", "text": [ "APC(doc1 Delta)" ], "offsets": [ [ 1053, 1068 ] ], "normalized": [] }, { "id": "PMID-12402045_T23", "type": "Gene_or_gene_product", "text": [ "Doc1" ], "offsets": [ [ 1101, 1105 ] ], "normalized": [] }, { "id": "PMID-12402045_T24", "type": "Gene_or_gene_product", "text": [ "ubiquitin" ], "offsets": [ [ 1160, 1169 ] ], "normalized": [] } ]

[ { "id": "PMID-12402045_E1", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 89, 97 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12402045_T3" }, { "role": "Theme", "ref_id": "PMID-12402045_E3" } ] }, { "id": "PMID-12402045_E2", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 89, 97 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12402045_T3" }, { "role": "Theme", "ref_id": "PMID-12402045_E4" } ] }, { "id": "PMID-12402045_E3", "type": "Degradation", "trigger": { "text": [ "proteolysis" ], "offsets": [ [ 98, 109 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12402045_T4" } ] }, { "id": "PMID-12402045_E4", "type": "Degradation", "trigger": { "text": [ "proteolysis" ], "offsets": [ [ 98, 109 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12402045_T5" } ] }, { "id": "PMID-12402045_E5", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 195, 209 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12402045_T4" } ] }, { "id": "PMID-12402045_E6", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 195, 209 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12402045_T5" } ] }, { "id": "PMID-12402045_E7", "type": "Positive_regulation", "trigger": { "text": [ "catalysed" ], "offsets": [ [ 241, 250 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12402045_T6" }, { "role": "Theme", "ref_id": "PMID-12402045_E5" } ] }, { "id": "PMID-12402045_E8", "type": "Positive_regulation", "trigger": { "text": [ "catalysed" ], "offsets": [ [ 241, 250 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12402045_T8" }, { "role": "Theme", "ref_id": "PMID-12402045_E5" } ] }, { "id": "PMID-12402045_E9", "type": "Positive_regulation", "trigger": { "text": [ "catalysed" ], "offsets": [ [ 241, 250 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12402045_T6" }, { "role": "Theme", "ref_id": "PMID-12402045_E6" } ] }, { "id": "PMID-12402045_E10", "type": "Positive_regulation", "trigger": { "text": [ "catalysed" ], "offsets": [ [ 241, 250 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12402045_T8" }, { "role": "Theme", "ref_id": "PMID-12402045_E6" } ] } ]

[ { "id": "PMID-12402045_1", "entity_ids": [ "PMID-12402045_T6", "PMID-12402045_T7" ] }, { "id": "PMID-12402045_2", "entity_ids": [ "PMID-12402045_T14", "PMID-12402045_T15" ] } ]

[]

[ { "id": "PMID-12410835__text", "type": "abstract", "text": [ "Regulation of the yeast Rlm1 transcription factor by the Mpk1 cell wall integrity MAP kinase. \nThe Mpk1 MAP kinase of the Saccharomyces cerevisiae cell wall integrity signalling pathway phosphorylates and activates the Rlm1 transcription factor in response to cell wall stress. Rlm1 is related to mammalian MEF2 isoforms, and shares a similar DNA-binding specificity. Signalling through Rlm1 regulates the expression of at least 25 genes, most of which have been implicated in cell wall biogenesis. We report here the transcriptional induction by agents of cell wall stress of a set of lacZ reporter plasmids derived from several Rlm1-responsive genes. Analysis of substitution mutations at putative Mpk1 phosphorylation sites within Rlm1 revealed that Ser427 and Thr439 are important for its stress-induced transcriptional activation of these reporter plasmids. Assessment of Rlm1 activation potency when fused to a heterologous DNA-binding domain showed that the identified seryl and threonyl residues are necessary for the Rlm1 transcriptional activation function independently of its DNA binding. We also demonstrate that a MAP kinase docking site, shown recently to mediate activation of MEF2A and MEF2C, is conserved in Rlm1 and is required for its ability to mediate transcriptional activation in response to agents that induce cell wall stress. Finally, intracellular localization analyses show that Rlm1 resides in the nucleus regardless of its activation and phosphorylation status. Together these observations support the inference that Mpk1 regulates the Rlm1 transcriptional activation function by phosphorylation of Ser427 and Thr439.\n" ], "offsets": [ [ 0, 1649 ] ] } ]

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[]

[]

[ { "id": "PMID-12455995__text", "type": "abstract", "text": [ "GTPase-activating proteins for Cdc42. \nThe Rho-type GTPase, Cdc42, has been implicated in a variety of functions in the yeast life cycle, including septin organization for cytokinesis, pheromone response, and haploid invasive growth. A group of proteins called GTPase-activating proteins (GAPs) catalyze the hydrolysis of GTP to GDP, thereby inactivating Cdc42. At the time this study began, there was one known GAP, Bem3, and one putative GAP, Rga1, for Cdc42. We identified another putative GAP for Cdc42 and named it Rga2 (Rho GTPase-activating protein 2). We confirmed by genetic and biochemical criteria that Rga1, Rga2, and Bem3 act as GAPs for Cdc42. A detailed characterization of Rga1, Rga2, and Bem3 suggested that they regulate different subsets of Cdc42 function. In particular, deletion of the individual GAPs conferred different phenotypes. For example, deletion of RGA1, but not RGA2 or BEM3, caused hyperinvasive growth. Furthermore, overproduction or loss of Rga1 and Rga2, but not Bem3, affected the two-hybrid interaction of Cdc42 with Ste20, a p21-activated kinase (PAK) kinase required for haploid invasive growth. These results suggest Rga1, and possibly Rga2, facilitate the interaction of Cdc42 with Ste20 to mediate signaling in the haploid invasive growth pathway. Deletion of BEM3 resulted in cells with severe morphological defects not observed in rga1delta or rga2delta strains. These data suggest that Bem3 and, to a lesser extent, Rga1 and Rga2 facilitate the role of Cdc42 in septin organization. Thus, it appears that the GAPs play a role in modulating specific aspects of Cdc42 function. Alternatively, the different phenotypes could reflect quantitative rather than qualitative differences in GAP activity in the mutant strains.\n" ], "offsets": [ [ 0, 1764 ] ] } ]

[ { "id": "PMID-12455995_T1", "type": "Gene_or_gene_product", "text": [ "GTPase-activating proteins" ], "offsets": [ [ 0, 26 ] ], "normalized": [] }, { "id": "PMID-12455995_T2", "type": "Gene_or_gene_product", "text": [ "Cdc42" ], "offsets": [ [ 31, 36 ] ], "normalized": [] }, { "id": "PMID-12455995_T3", "type": "Gene_or_gene_product", "text": [ "Rho" ], "offsets": [ [ 43, 46 ] ], "normalized": [] }, { "id": "PMID-12455995_T4", "type": "Gene_or_gene_product", "text": [ "Cdc42" ], "offsets": [ [ 60, 65 ] ], "normalized": [] }, { "id": "PMID-12455995_T5", "type": "Gene_or_gene_product", "text": [ "septin" ], "offsets": [ [ 148, 154 ] ], "normalized": [] }, { "id": "PMID-12455995_T6", "type": "Gene_or_gene_product", "text": [ "GTPase-activating proteins" ], "offsets": [ [ 261, 287 ] ], "normalized": [] }, { "id": "PMID-12455995_T7", "type": "Gene_or_gene_product", "text": [ "GAPs" ], "offsets": [ [ 289, 293 ] ], "normalized": [] }, { "id": "PMID-12455995_T8", "type": "Simple_chemical", "text": [ "GTP" ], "offsets": [ [ 322, 325 ] ], "normalized": [] }, { "id": "PMID-12455995_T9", "type": "Simple_chemical", "text": [ "GDP" ], "offsets": [ [ 329, 332 ] ], "normalized": [] }, { "id": "PMID-12455995_T10", "type": "Gene_or_gene_product", "text": [ "Cdc42" ], "offsets": [ [ 355, 360 ] ], "normalized": [] }, { "id": "PMID-12455995_T11", "type": "Gene_or_gene_product", "text": [ "GAP" ], "offsets": [ [ 412, 415 ] ], "normalized": [] }, { "id": "PMID-12455995_T12", "type": "Gene_or_gene_product", "text": [ "Bem3" ], "offsets": [ [ 417, 421 ] ], "normalized": [] }, { "id": "PMID-12455995_T13", "type": "Gene_or_gene_product", "text": [ "GAP" ], "offsets": [ [ 440, 443 ] ], "normalized": [] }, { "id": "PMID-12455995_T14", "type": "Gene_or_gene_product", "text": [ "Rga1" ], "offsets": [ [ 445, 449 ] ], "normalized": [] }, { "id": "PMID-12455995_T15", "type": "Gene_or_gene_product", "text": [ "Cdc42" ], "offsets": [ [ 455, 460 ] ], "normalized": [] }, { "id": "PMID-12455995_T16", "type": "Gene_or_gene_product", "text": [ "GAP" ], "offsets": [ [ 493, 496 ] ], "normalized": [] }, { "id": "PMID-12455995_T17", "type": "Gene_or_gene_product", "text": [ "Cdc42" ], "offsets": [ [ 501, 506 ] ], "normalized": [] }, { "id": "PMID-12455995_T18", "type": "Gene_or_gene_product", "text": [ "Rga2" ], "offsets": [ [ 520, 524 ] ], "normalized": [] }, { "id": "PMID-12455995_T19", "type": "Gene_or_gene_product", "text": [ "Rho GTPase-activating protein 2" ], "offsets": [ [ 526, 557 ] ], "normalized": [] }, { "id": "PMID-12455995_T20", "type": "Gene_or_gene_product", "text": [ "Rga1" ], "offsets": [ [ 614, 618 ] ], "normalized": [] }, { "id": "PMID-12455995_T21", "type": "Gene_or_gene_product", "text": [ "Rga2" ], "offsets": [ [ 620, 624 ] ], "normalized": [] }, { "id": "PMID-12455995_T22", "type": "Gene_or_gene_product", "text": [ "Bem3" ], "offsets": [ [ 630, 634 ] ], "normalized": [] }, { "id": "PMID-12455995_T23", "type": "Gene_or_gene_product", "text": [ "GAPs" ], "offsets": [ [ 642, 646 ] ], "normalized": [] }, { "id": "PMID-12455995_T24", "type": "Gene_or_gene_product", "text": [ "Cdc42" ], "offsets": [ [ 651, 656 ] ], "normalized": [] }, { "id": "PMID-12455995_T25", "type": "Gene_or_gene_product", "text": [ "Rga1" ], "offsets": [ [ 689, 693 ] ], "normalized": [] }, { "id": "PMID-12455995_T26", "type": "Gene_or_gene_product", "text": [ "Rga2" ], "offsets": [ [ 695, 699 ] ], "normalized": [] }, { "id": "PMID-12455995_T27", "type": "Gene_or_gene_product", "text": [ "Bem3" ], "offsets": [ [ 705, 709 ] ], "normalized": [] }, { "id": "PMID-12455995_T28", "type": "Gene_or_gene_product", "text": [ "Cdc42" ], "offsets": [ [ 760, 765 ] ], "normalized": [] }, { "id": "PMID-12455995_T29", "type": "Gene_or_gene_product", "text": [ "GAPs" ], "offsets": [ [ 818, 822 ] ], "normalized": [] }, { "id": "PMID-12455995_T30", "type": "Gene_or_gene_product", "text": [ "RGA1" ], "offsets": [ [ 880, 884 ] ], "normalized": [] }, { "id": "PMID-12455995_T31", "type": "Gene_or_gene_product", "text": [ "RGA2" ], "offsets": [ [ 894, 898 ] ], "normalized": [] }, { "id": "PMID-12455995_T32", "type": "Gene_or_gene_product", "text": [ "BEM3" ], "offsets": [ [ 902, 906 ] ], "normalized": [] }, { "id": "PMID-12455995_T33", "type": "Gene_or_gene_product", "text": [ "Rga1" ], "offsets": [ [ 976, 980 ] ], "normalized": [] }, { "id": "PMID-12455995_T34", "type": "Gene_or_gene_product", "text": [ "Rga2" ], "offsets": [ [ 985, 989 ] ], "normalized": [] }, { "id": "PMID-12455995_T35", "type": "Gene_or_gene_product", "text": [ "Bem3" ], "offsets": [ [ 999, 1003 ] ], "normalized": [] }, { "id": "PMID-12455995_T36", "type": "Gene_or_gene_product", "text": [ "Cdc42" ], "offsets": [ [ 1044, 1049 ] ], "normalized": [] }, { "id": "PMID-12455995_T37", "type": "Gene_or_gene_product", "text": [ "Ste20" ], "offsets": [ [ 1055, 1060 ] ], "normalized": [] }, { "id": "PMID-12455995_T38", "type": "Gene_or_gene_product", "text": [ "p21-activated kinase (PAK) kinase" ], "offsets": [ [ 1064, 1097 ] ], "normalized": [] }, { "id": "PMID-12455995_T39", "type": "Gene_or_gene_product", "text": [ "Rga1" ], "offsets": [ [ 1158, 1162 ] ], "normalized": [] }, { "id": "PMID-12455995_T40", "type": "Gene_or_gene_product", "text": [ "Rga2" ], "offsets": [ [ 1177, 1181 ] ], "normalized": [] }, { "id": "PMID-12455995_T41", "type": "Gene_or_gene_product", "text": [ "Cdc42" ], "offsets": [ [ 1213, 1218 ] ], "normalized": [] }, { "id": "PMID-12455995_T42", "type": "Gene_or_gene_product", "text": [ "Ste20" ], "offsets": [ [ 1224, 1229 ] ], "normalized": [] }, { "id": "PMID-12455995_T43", "type": "Gene_or_gene_product", "text": [ "BEM3" ], "offsets": [ [ 1303, 1307 ] ], "normalized": [] }, { "id": "PMID-12455995_T44", "type": "Gene_or_gene_product", "text": [ "rga1" ], "offsets": [ [ 1376, 1380 ] ], "normalized": [] }, { "id": "PMID-12455995_T45", "type": "Gene_or_gene_product", "text": [ "rga2" ], "offsets": [ [ 1389, 1393 ] ], "normalized": [] }, { "id": "PMID-12455995_T46", "type": "Gene_or_gene_product", "text": [ "Bem3" ], "offsets": [ [ 1432, 1436 ] ], "normalized": [] }, { "id": "PMID-12455995_T47", "type": "Gene_or_gene_product", "text": [ "Rga1" ], "offsets": [ [ 1462, 1466 ] ], "normalized": [] }, { "id": "PMID-12455995_T48", "type": "Gene_or_gene_product", "text": [ "Rga2" ], "offsets": [ [ 1471, 1475 ] ], "normalized": [] }, { "id": "PMID-12455995_T49", "type": "Gene_or_gene_product", "text": [ "Cdc42" ], "offsets": [ [ 1499, 1504 ] ], "normalized": [] }, { "id": "PMID-12455995_T50", "type": "Gene_or_gene_product", "text": [ "septin" ], "offsets": [ [ 1508, 1514 ] ], "normalized": [] }, { "id": "PMID-12455995_T51", "type": "Gene_or_gene_product", "text": [ "GAPs" ], "offsets": [ [ 1555, 1559 ] ], "normalized": [] }, { "id": "PMID-12455995_T52", "type": "Gene_or_gene_product", "text": [ "Cdc42" ], "offsets": [ [ 1606, 1611 ] ], "normalized": [] }, { "id": "PMID-12455995_T53", "type": "Gene_or_gene_product", "text": [ "GAP" ], "offsets": [ [ 1728, 1731 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-12459251__text", "type": "abstract", "text": [ "Linking cyclins to transcriptional control. \nCell cycle activation is coordinated by D-type cyclins which are rate limiting and essential for the progression through the G1 phase of the cell cycle. D-type cyclins bind to and activate the cyclin-dependent kinases Cdk4 and Cdk6, which in turn phosphorylate their downstream target, the retinoblastoma protein Rb. Upon Rb phosphorylation, the E2F transcription factors activate the expression of S-phase genes and thereby induce cell cycle progression. The raise of cyclin D levels in early G1 also serves to titrate Kip/Cip proteins away from cyclinE/Cdk2 complexes, further accelerating cell cycle progression. Therefore, cyclin D plays essential roles in the response to mitogens, transmitting their signal to the Rb/E2F pathway. Surprisingly, cyclin D1-deficient animals are viable and have developmental abnormalities limited to restricted tissues, such as retina, the nervous system and breast epithelium. This observation, combined with several other studies, have raised the possibility that cyclin D1 may have new activities that are unrelated to its function as a cdk regulatory subunit and as regulator of Rb. Effectively, cyclin D has been reported to have transcriptional functions since it interacts with several transcription factors to regulate their activity. Most often, this effect does not rely on the kinase function of Cdk4, indicating that this function is probably independent of cell cycle progression. Further extending its role in gene regulation, cyclin D interacts with histone acetylases such as P/CAF or NcoA/SRC1a but also with components of the transcriptional machinery such as TAF(II)250. Therefore, these studies suggest that the functions of cyclin D might need to be reevaluated. They have established a new cdk-independent role of cyclin D1 as a transcriptional regulator, indicating that cyclin D1 can act via two different mechanisms, as a cdk activator it regulates cell cycle progression and as a transcriptional regulator, it modulates the activity of transcription factors.\n" ], "offsets": [ [ 0, 2067 ] ] } ]

[ { "id": "PMID-12459251_T1", "type": "Gene_or_gene_product", "text": [ "cyclins" ], "offsets": [ [ 8, 15 ] ], "normalized": [] }, { "id": "PMID-12459251_T2", "type": "Gene_or_gene_product", "text": [ "D-type cyclins" ], "offsets": [ [ 85, 99 ] ], "normalized": [] }, { "id": "PMID-12459251_T3", "type": "Gene_or_gene_product", "text": [ "D-type cyclins" ], "offsets": [ [ 198, 212 ] ], "normalized": [] }, { "id": "PMID-12459251_T4", "type": "Gene_or_gene_product", "text": [ "cyclin-dependent kinases" ], "offsets": [ [ 238, 262 ] ], "normalized": [] }, { "id": "PMID-12459251_T5", "type": "Gene_or_gene_product", "text": [ "Cdk4" ], "offsets": [ [ 263, 267 ] ], "normalized": [] }, { "id": "PMID-12459251_T6", "type": "Gene_or_gene_product", "text": [ "Cdk6" ], "offsets": [ [ 272, 276 ] ], "normalized": [] }, { "id": "PMID-12459251_T7", "type": "Gene_or_gene_product", "text": [ "retinoblastoma protein" ], "offsets": [ [ 335, 357 ] ], "normalized": [] }, { "id": "PMID-12459251_T8", "type": "Gene_or_gene_product", "text": [ "Rb" ], "offsets": [ [ 358, 360 ] ], "normalized": [] }, { "id": "PMID-12459251_T9", "type": "Gene_or_gene_product", "text": [ "Rb" ], "offsets": [ [ 367, 369 ] ], "normalized": [] }, { "id": "PMID-12459251_T10", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 391, 394 ] ], "normalized": [] }, { "id": "PMID-12459251_T11", "type": "Gene_or_gene_product", "text": [ "cyclin D" ], "offsets": [ [ 514, 522 ] ], "normalized": [] }, { "id": "PMID-12459251_T12", "type": "Gene_or_gene_product", "text": [ "Kip/Cip" ], "offsets": [ [ 565, 572 ] ], "normalized": [] }, { "id": "PMID-12459251_T13", "type": "Complex", "text": [ "cyclinE/Cdk2" ], "offsets": [ [ 592, 604 ] ], "normalized": [] }, { "id": "PMID-12459251_T14", "type": "Gene_or_gene_product", "text": [ "cyclin D" ], "offsets": [ [ 672, 680 ] ], "normalized": [] }, { "id": "PMID-12459251_T15", "type": "Gene_or_gene_product", "text": [ "Rb" ], "offsets": [ [ 765, 767 ] ], "normalized": [] }, { "id": "PMID-12459251_T16", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 768, 771 ] ], "normalized": [] }, { "id": "PMID-12459251_T17", "type": "Gene_or_gene_product", "text": [ "cyclin D1" ], "offsets": [ [ 795, 804 ] ], "normalized": [] }, { "id": "PMID-12459251_T18", "type": "Gene_or_gene_product", "text": [ "cyclin D1" ], "offsets": [ [ 1048, 1057 ] ], "normalized": [] }, { "id": "PMID-12459251_T19", "type": "Gene_or_gene_product", "text": [ "cdk" ], "offsets": [ [ 1122, 1125 ] ], "normalized": [] }, { "id": "PMID-12459251_T20", "type": "Gene_or_gene_product", "text": [ "Rb" ], "offsets": [ [ 1165, 1167 ] ], "normalized": [] }, { "id": "PMID-12459251_T21", "type": "Gene_or_gene_product", "text": [ "cyclin D" ], "offsets": [ [ 1182, 1190 ] ], "normalized": [] }, { "id": "PMID-12459251_T22", "type": "Gene_or_gene_product", "text": [ "Cdk4" ], "offsets": [ [ 1389, 1393 ] ], "normalized": [] }, { "id": "PMID-12459251_T23", "type": "Gene_or_gene_product", "text": [ "cyclin D" ], "offsets": [ [ 1523, 1531 ] ], "normalized": [] }, { "id": "PMID-12459251_T24", "type": "Gene_or_gene_product", "text": [ "histone acetylases" ], "offsets": [ [ 1547, 1565 ] ], "normalized": [] }, { "id": "PMID-12459251_T25", "type": "Gene_or_gene_product", "text": [ "P/CAF" ], "offsets": [ [ 1574, 1579 ] ], "normalized": [] }, { "id": "PMID-12459251_T26", "type": "Gene_or_gene_product", "text": [ "NcoA" ], "offsets": [ [ 1583, 1587 ] ], "normalized": [] }, { "id": "PMID-12459251_T27", "type": "Gene_or_gene_product", "text": [ "SRC1a" ], "offsets": [ [ 1588, 1593 ] ], "normalized": [] }, { "id": "PMID-12459251_T28", "type": "Gene_or_gene_product", "text": [ "TAF(II)250" ], "offsets": [ [ 1660, 1670 ] ], "normalized": [] }, { "id": "PMID-12459251_T29", "type": "Gene_or_gene_product", "text": [ "cyclin D" ], "offsets": [ [ 1727, 1735 ] ], "normalized": [] }, { "id": "PMID-12459251_T30", "type": "Gene_or_gene_product", "text": [ "cdk" ], "offsets": [ [ 1794, 1797 ] ], "normalized": [] }, { "id": "PMID-12459251_T31", "type": "Gene_or_gene_product", "text": [ "cyclin D1" ], "offsets": [ [ 1818, 1827 ] ], "normalized": [] }, { "id": "PMID-12459251_T32", "type": "Gene_or_gene_product", "text": [ "cyclin D1" ], "offsets": [ [ 1876, 1885 ] ], "normalized": [] }, { "id": "PMID-12459251_T33", "type": "Gene_or_gene_product", "text": [ "cdk" ], "offsets": [ [ 1929, 1932 ] ], "normalized": [] } ]

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"phosphorylation" ], "offsets": [ [ 370, 385 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12459251_T9" } ] }, { "id": "PMID-12459251_E11", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 470, 476 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12459251_E12" }, { "role": "Cause", "ref_id": "PMID-12459251_T10" } ] }, { "id": "PMID-12459251_E12", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 477, 487 ] ] }, "arguments": [] }, { "id": "PMID-12459251_E13", "type": "Positive_regulation", "trigger": { "text": [ "raise" ], "offsets": [ [ 505, 510 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12459251_T11" } ] }, { "id": "PMID-12459251_E14", "type": "Positive_regulation", "trigger": { "text": [ "accelerating" ], "offsets": [ [ 624, 636 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12459251_E15" } ] }, { "id": "PMID-12459251_E15", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 637, 647 ] ] }, "arguments": [] }, { "id": "PMID-12459251_E16", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 772, 779 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-12459251_T15" }, { "role": "Participant", "ref_id": "PMID-12459251_T16" } ] }, { "id": "PMID-12459251_E17", "type": "Regulation", "trigger": { "text": [ "independent" ], "offsets": [ [ 1437, 1448 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12459251_E18" }, { "role": "Theme", "ref_id": "PMID-12459251_T22" } ] }, { "id": "PMID-12459251_E18", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 1452, 1462 ] ] }, "arguments": [] }, { "id": "PMID-12459251_E19", "type": "Binding", "trigger": { "text": [ "interacts" ], "offsets": [ [ 1532, 1541 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12459251_T23" }, { "role": "Theme", "ref_id": "PMID-12459251_T24" } ] }, { "id": "PMID-12459251_E20", "type": "Binding", "trigger": { "text": [ 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"offsets": [ [ 1933, 1942 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12459251_T33" } ] }, { "id": "PMID-12459251_E25", "type": "Positive_regulation", "trigger": { "text": [ "regulates" ], "offsets": [ [ 1946, 1955 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12459251_E26" }, { "role": "Cause", "ref_id": "PMID-12459251_T33" } ] }, { "id": "PMID-12459251_E26", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 1956, 1966 ] ] }, "arguments": [] } ]

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[]

[ { "id": "PMID-12482958__text", "type": "abstract", "text": [ "The transformation suppressor Pdcd4 is a novel eukaryotic translation initiation factor 4A binding protein that inhibits translation. \nPdcd4 is a novel transformation suppressor that inhibits tumor promoter-induced neoplastic transformation and the activation of AP-1-dependent transcription required for transformation. A yeast two-hybrid analysis revealed that Pdcd4 associates with the eukaryotic translation initiation factors eIF4AI and eIF4AII. Immunofluorescent confocal microscopy showed that Pdcd4 colocalizes with eIF4A in the cytoplasm. eIF4A is an ATP-dependent RNA helicase needed to unwind 5' mRNA secondary structure. Recombinant Pdcd4 specifically inhibited the helicase activity of eIF4A and eIF4F. In vivo translation assays showed that Pdcd4 inhibited cap-dependent but not internal ribosome entry site (IRES)-dependent translation. In contrast, Pdcd4(D418A), a mutant inactivated for binding to eIF4A, failed to inhibit cap-dependent or IRES-dependent translation or AP-1 transactivation. Recombinant Pdcd4 prevented eIF4A from binding to the C-terminal region of eIF4G (amino acids 1040 to 1560) but not to the middle region of eIF4G(amino acids 635 to 1039). In addition, both Pdcd4 and Pdcd4(D418A) bound to the middle region of eIF4G. The mechanism by which Pdcd4 inhibits translation thus appears to involve inhibition of eIF4A helicase, interference with eIF4A association-dissociation from eIF4G, and inhibition of eIF4A binding to the C-terminal domain of eIF4G. Pdcd4 binding to eIF4A is linked to its transformation-suppressing activity, as Pdcd4-eIF4A binding and consequent inhibition of translation are required for Pdcd4 transrepression of AP-1. \n" ], "offsets": [ [ 0, 1681 ] ] } ]

[ { "id": "PMID-12482958_T1", "type": "Gene_or_gene_product", "text": [ "Pdcd4" ], "offsets": [ [ 30, 35 ] ], "normalized": [] }, { "id": "PMID-12482958_T2", "type": "Gene_or_gene_product", "text": [ "eukaryotic translation initiation factor 4A" ], "offsets": [ [ 47, 90 ] ], "normalized": [] }, { "id": "PMID-12482958_T3", "type": "Gene_or_gene_product", "text": [ "Pdcd4" ], "offsets": [ [ 135, 140 ] ], "normalized": [] }, { "id": "PMID-12482958_T4", "type": "Gene_or_gene_product", "text": [ "AP-1" ], "offsets": [ [ 263, 267 ] ], "normalized": [] }, { "id": "PMID-12482958_T5", "type": "Gene_or_gene_product", "text": [ "Pdcd4" ], "offsets": [ [ 363, 368 ] ], "normalized": [] }, { "id": "PMID-12482958_T6", "type": "Gene_or_gene_product", "text": [ "eIF4AI" ], "offsets": [ [ 431, 437 ] ], "normalized": [] }, { "id": "PMID-12482958_T7", "type": "Gene_or_gene_product", "text": [ "eIF4AII" ], "offsets": [ [ 442, 449 ] ], "normalized": [] }, { "id": "PMID-12482958_T8", "type": 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"normalized": [] }, { "id": "PMID-12482958_T31", "type": "Gene_or_gene_product", "text": [ "eIF4G" ], "offsets": [ [ 1252, 1257 ] ], "normalized": [] }, { "id": "PMID-12482958_T32", "type": "Gene_or_gene_product", "text": [ "Pdcd4" ], "offsets": [ [ 1282, 1287 ] ], "normalized": [] }, { "id": "PMID-12482958_T33", "type": "Gene_or_gene_product", "text": [ "eIF4A" ], "offsets": [ [ 1347, 1352 ] ], "normalized": [] }, { "id": "PMID-12482958_T34", "type": "Gene_or_gene_product", "text": [ "eIF4A" ], "offsets": [ [ 1381, 1386 ] ], "normalized": [] }, { "id": "PMID-12482958_T35", "type": "Gene_or_gene_product", "text": [ "eIF4G" ], "offsets": [ [ 1417, 1422 ] ], "normalized": [] }, { "id": "PMID-12482958_T36", "type": "Gene_or_gene_product", "text": [ "eIF4A" ], "offsets": [ [ 1442, 1447 ] ], "normalized": [] }, { "id": "PMID-12482958_T37", "type": "Gene_or_gene_product", "text": [ "eIF4G" ], "offsets": [ [ 1484, 1489 ] ], "normalized": [] }, { "id": "PMID-12482958_T38", "type": 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[]

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[ { "id": "PMID-12511557__text", "type": "abstract", "text": [ "The tuberin-hamartin complex negatively regulates beta-catenin signaling activity. \nTuberous sclerosis complex (TSC) is characterized by the formation of hamartomas in multiple organs resulting from mutations in the TSC1 or TSC2 gene. Their protein products, hamartin and tuberin, respectively, form a functional complex that affects cell growth, differentiation, and proliferation. Several lines of evidence, including renal tumors derived from TSC2+/- animals, suggest that the loss or inhibition of tuberin is associated with up-regulation of cyclin D1. As cyclin D1 can be regulated through the canonical Wnt/beta-catenin signaling pathway, we hypothesize that the cell proliferative effects of hamartin and tuberin are partly mediated through beta-catenin. In this study, total beta-catenin protein levels were found to be elevated in the TSC2-related renal tumors. Ectopic expression of hamartin and wild-type tuberin, but not mutant tuberin, reduced beta-catenin steady-state levels and its half-life. The TSC1-TSC2 complex also inhibited Wnt-1 stimulated Tcf/LEF luciferase reporter activity. This inhibition was eliminated by constitutively active beta-catenin but not by Disheveled, suggesting that hamartin and tuberin function at the level of the beta-catenin degradation complex. Indeed, hamartin and tuberin co-immunoprecipitated with glycogen synthase kinase 3 beta and Axin, components of this complex in a Wnt-1-dependent manner. Our data suggest that hamartin and tuberin negatively regulate beta-catenin stability and activity by participating in the beta-catenin degradation complex. \n" ], "offsets": [ [ 0, 1605 ] ] } ]

[ { "id": "PMID-12511557_T1", "type": "Complex", "text": [ "tuberin-hamartin" ], "offsets": [ [ 4, 20 ] ], "normalized": [] }, { "id": "PMID-12511557_T2", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 50, 62 ] ], "normalized": [] }, { "id": "PMID-12511557_T3", "type": "Gene_or_gene_product", "text": [ "TSC1" ], "offsets": [ [ 216, 220 ] ], "normalized": [] }, { "id": "PMID-12511557_T4", "type": "Gene_or_gene_product", "text": [ "TSC2" ], "offsets": [ [ 224, 228 ] ], "normalized": [] }, { "id": "PMID-12511557_T5", "type": "Gene_or_gene_product", "text": [ "hamartin" ], "offsets": [ [ 259, 267 ] ], "normalized": [] }, { "id": "PMID-12511557_T6", "type": "Gene_or_gene_product", "text": [ "tuberin" ], "offsets": [ [ 272, 279 ] ], "normalized": [] }, { "id": "PMID-12511557_T7", "type": "Gene_or_gene_product", "text": [ "TSC2" ], "offsets": [ [ 446, 450 ] ], "normalized": [] }, { "id": "PMID-12511557_T8", "type": "Gene_or_gene_product", "text": [ "tuberin" ], "offsets": [ [ 502, 509 ] ], "normalized": [] }, { "id": "PMID-12511557_T9", "type": "Gene_or_gene_product", "text": [ "cyclin D1" ], "offsets": [ [ 546, 555 ] ], "normalized": [] }, { "id": "PMID-12511557_T10", "type": "Gene_or_gene_product", "text": [ "cyclin D1" ], "offsets": [ [ 560, 569 ] ], "normalized": [] }, { "id": "PMID-12511557_T11", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 609, 612 ] ], "normalized": [] }, { "id": "PMID-12511557_T12", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 613, 625 ] ], "normalized": [] }, { "id": "PMID-12511557_T13", "type": "Gene_or_gene_product", "text": [ "hamartin" ], "offsets": [ [ 699, 707 ] ], "normalized": [] }, { "id": "PMID-12511557_T14", "type": "Gene_or_gene_product", "text": [ "tuberin" ], "offsets": [ [ 712, 719 ] ], "normalized": [] }, { "id": "PMID-12511557_T15", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 748, 760 ] ], "normalized": [] }, { "id": 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], "offsets": [ [ 1046, 1051 ] ], "normalized": [] }, { "id": "PMID-12511557_T24", "type": "Gene_or_gene_product", "text": [ "Tcf" ], "offsets": [ [ 1063, 1066 ] ], "normalized": [] }, { "id": "PMID-12511557_T25", "type": "Gene_or_gene_product", "text": [ "LEF" ], "offsets": [ [ 1067, 1070 ] ], "normalized": [] }, { "id": "PMID-12511557_T26", "type": "Gene_or_gene_product", "text": [ "luciferase" ], "offsets": [ [ 1071, 1081 ] ], "normalized": [] }, { "id": "PMID-12511557_T27", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 1157, 1169 ] ], "normalized": [] }, { "id": "PMID-12511557_T28", "type": "Gene_or_gene_product", "text": [ "Disheveled" ], "offsets": [ [ 1181, 1191 ] ], "normalized": [] }, { "id": "PMID-12511557_T29", "type": "Gene_or_gene_product", "text": [ "hamartin" ], "offsets": [ [ 1209, 1217 ] ], "normalized": [] }, { "id": "PMID-12511557_T30", "type": "Gene_or_gene_product", "text": [ "tuberin" ], "offsets": [ [ 1222, 1229 ] ], "normalized": [] 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"PMID-12511557_T40" } ] } ]

[]

[]

[ { "id": "PMID-12551923__text", "type": "abstract", "text": [ "Phosphorylation of Raf-1 by p21-activated kinase 1 and Src regulates Raf-1 autoinhibition. \nExposure of cells to mitogens or growth factors stimulates Raf-1 activity through a complex mechanism that involves binding to active Ras, phosphorylation on multiple residues, and protein-protein interactions. Recently it was shown that the amino terminus of Raf-1 contains an autoregulatory domain that can inhibit its activity in Xenopus oocytes. In the present work we show that expression of the Raf-1 autoinhibitory domain blocks extracellular signal-regulated kinase 2 activation by the Raf-1 catalytic domain in mammalian cells. We also show that phosphorylation of Raf-1 on serine 338 by PAK1 and tyrosines 340 and 341 by Src relieves autoinhibition and that this occurs through a specific decrease in the binding of the Raf-1 regulatory domain to its catalytic domain. In addition, we demonstrate that phosphorylation of threonine 491 and serine 494, two phosphorylation sites in the catalytic domain that are required for Raf-1 activation, is unlikely to regulate autoinhibition. These results demonstrate that the autoinhibitory domain of Raf-1 is functional in mammalian cells and that its interaction with the Raf-1 catalytic domain is regulated by phosphorylation of serine 338 and tyrosines 340 and 341.\n" ], "offsets": [ [ 0, 1312 ] ] } ]

[ { "id": "PMID-12551923_T1", "type": "Gene_or_gene_product", "text": [ "Raf-1" ], "offsets": [ [ 19, 24 ] ], "normalized": [] }, { "id": "PMID-12551923_T2", "type": "Gene_or_gene_product", "text": [ "p21-activated kinase 1" ], "offsets": [ [ 28, 50 ] ], "normalized": [] }, { "id": "PMID-12551923_T3", "type": "Gene_or_gene_product", "text": [ "Src" ], "offsets": [ [ 55, 58 ] ], "normalized": [] }, { "id": "PMID-12551923_T4", "type": "Gene_or_gene_product", "text": [ "Raf-1" ], "offsets": [ [ 69, 74 ] ], "normalized": [] }, { "id": "PMID-12551923_T5", "type": "Gene_or_gene_product", "text": [ "Raf-1" ], "offsets": [ [ 151, 156 ] ], "normalized": [] }, { "id": "PMID-12551923_T6", "type": "Gene_or_gene_product", "text": [ "Ras" ], "offsets": [ [ 226, 229 ] ], "normalized": [] }, { "id": "PMID-12551923_T7", "type": "Gene_or_gene_product", "text": [ "Raf-1" ], "offsets": [ [ 352, 357 ] ], "normalized": [] }, { "id": "PMID-12551923_T8", "type": "Gene_or_gene_product", "text": [ "Raf-1" ], "offsets": [ [ 493, 498 ] ], "normalized": [] }, { "id": "PMID-12551923_T9", "type": "Gene_or_gene_product", "text": [ "extracellular signal-regulated kinase 2" ], "offsets": [ [ 528, 567 ] ], "normalized": [] }, { "id": "PMID-12551923_T10", "type": "Gene_or_gene_product", "text": [ "Raf-1" ], "offsets": [ [ 586, 591 ] ], "normalized": [] }, { "id": "PMID-12551923_T11", "type": "Gene_or_gene_product", "text": [ "Raf-1" ], "offsets": [ [ 666, 671 ] ], "normalized": [] }, { "id": "PMID-12551923_T12", "type": "Simple_chemical", "text": [ "serine 338" ], "offsets": [ [ 675, 685 ] ], "normalized": [] }, { "id": "PMID-12551923_T13", "type": "Gene_or_gene_product", "text": [ "PAK1" ], "offsets": [ [ 689, 693 ] ], "normalized": [] }, { "id": "PMID-12551923_T14", "type": "Simple_chemical", "text": [ "tyrosines 340" ], "offsets": [ [ 698, 711 ] ], "normalized": [] }, { "id": "PMID-12551923_T15", "type": "Simple_chemical", "text": [ "341" ], "offsets": [ [ 716, 719 ] ], "normalized": [] }, { "id": "PMID-12551923_T16", "type": "Gene_or_gene_product", "text": [ "Src" ], "offsets": [ [ 723, 726 ] ], "normalized": [] }, { "id": "PMID-12551923_T17", "type": "Gene_or_gene_product", "text": [ "Raf-1" ], "offsets": [ [ 822, 827 ] ], "normalized": [] }, { "id": "PMID-12551923_T18", "type": "Simple_chemical", "text": [ "threonine 491" ], "offsets": [ [ 923, 936 ] ], "normalized": [] }, { "id": "PMID-12551923_T19", "type": "Simple_chemical", "text": [ "serine 494" ], "offsets": [ [ 941, 951 ] ], "normalized": [] }, { "id": "PMID-12551923_T20", "type": "Gene_or_gene_product", "text": [ "Raf-1" ], "offsets": [ [ 1025, 1030 ] ], "normalized": [] }, { "id": "PMID-12551923_T21", "type": "Gene_or_gene_product", "text": [ "Raf-1" ], "offsets": [ [ 1143, 1148 ] ], "normalized": [] }, { "id": "PMID-12551923_T22", "type": "Gene_or_gene_product", "text": [ "Raf-1" ], "offsets": [ [ 1216, 1221 ] ], "normalized": [] }, { "id": "PMID-12551923_T23", "type": "Simple_chemical", "text": [ "serine 338" ], "offsets": [ [ 1274, 1284 ] ], "normalized": [] }, { "id": "PMID-12551923_T24", "type": "Simple_chemical", "text": [ "tyrosines 340" ], "offsets": [ [ 1289, 1302 ] ], "normalized": [] }, { "id": "PMID-12551923_T25", "type": "Simple_chemical", "text": [ "341" ], "offsets": [ [ 1307, 1310 ] ], "normalized": [] } ]

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"PMID-12551923_E5", "type": "Negative_regulation", "trigger": { "text": [ "autoinhibition" ], "offsets": [ [ 75, 89 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_T4" }, { "role": "Cause", "ref_id": "PMID-12551923_T4" } ] }, { "id": "PMID-12551923_E6", "type": "Positive_regulation", "trigger": { "text": [ "stimulates" ], "offsets": [ [ 140, 150 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_T5" }, { "role": "Cause", "ref_id": "PMID-12551923_E7" } ] }, { "id": "PMID-12551923_E7", "type": "Positive_regulation", "trigger": { "text": [ "involves" ], "offsets": [ [ 199, 207 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_E8" } ] }, { "id": "PMID-12551923_E8", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 208, 215 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_T6" } ] }, { "id": "PMID-12551923_E9", "type": "Activation", "trigger": { "text": [ "active" ], "offsets": [ [ 219, 225 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_T6" } ] }, { "id": "PMID-12551923_E10", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 401, 408 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_T7" }, { "role": "Cause", "ref_id": "PMID-12551923_T7" } ] }, { "id": "PMID-12551923_E11", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 475, 485 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_T8" } ] }, { "id": "PMID-12551923_E12", "type": "Negative_regulation", "trigger": { "text": [ "blocks" ], "offsets": [ [ 521, 527 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_E13" }, { "role": "Cause", "ref_id": "PMID-12551923_E11" } ] }, { "id": "PMID-12551923_E13", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 568, 578 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_T9" }, { "role": "Cause", "ref_id": "PMID-12551923_T10" } ] }, { "id": "PMID-12551923_E14", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 647, 662 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_T11" }, { "role": "Site", "ref_id": "PMID-12551923_T12" }, { "role": "Cause", "ref_id": "PMID-12551923_T13" } ] }, { "id": "PMID-12551923_E15", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 647, 662 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12551923_T16" }, { "role": "Theme", "ref_id": "PMID-12551923_T11" }, { "role": "Site", "ref_id": "PMID-12551923_T14" } ] }, { "id": "PMID-12551923_E16", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 647, 662 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12551923_T16" }, { "role": "Theme", "ref_id": "PMID-12551923_T11" }, { "role": "Site", "ref_id": "PMID-12551923_T15" } ] }, { "id": "PMID-12551923_E17", "type": "Negative_regulation", "trigger": { "text": [ "relieves" ], "offsets": [ [ 727, 735 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_E20" }, { "role": "Cause", "ref_id": "PMID-12551923_E15" } ] }, { "id": "PMID-12551923_E18", "type": "Negative_regulation", "trigger": { "text": [ "relieves" ], "offsets": [ [ 727, 735 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_E20" }, { "role": "Cause", "ref_id": "PMID-12551923_E14" } ] }, { "id": "PMID-12551923_E19", "type": "Negative_regulation", "trigger": { "text": [ "relieves" ], "offsets": [ [ 727, 735 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_E20" }, { "role": "Cause", "ref_id": "PMID-12551923_E16" } ] }, { "id": "PMID-12551923_E20", "type": "Negative_regulation", "trigger": { "text": [ "autoinhibition" ], "offsets": [ [ 736, 750 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_T11" } ] }, { "id": "PMID-12551923_E21", "type": "Negative_regulation", "trigger": { "text": [ "decrease" ], "offsets": [ [ 791, 799 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_E24" }, { "role": "Cause", "ref_id": "PMID-12551923_E17" } ] }, { "id": "PMID-12551923_E22", "type": "Negative_regulation", "trigger": { "text": [ "decrease" ], "offsets": [ [ 791, 799 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_E24" }, { "role": "Cause", "ref_id": "PMID-12551923_E18" } ] }, { "id": "PMID-12551923_E23", "type": "Negative_regulation", "trigger": { "text": [ "decrease" ], "offsets": [ [ 791, 799 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_E24" }, { "role": "Cause", "ref_id": "PMID-12551923_E19" } ] }, { "id": "PMID-12551923_E24", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 807, 814 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_T17" } ] }, { "id": "PMID-12551923_E25", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 904, 919 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_T11" }, { "role": "Site", "ref_id": "PMID-12551923_T18" } ] }, { "id": "PMID-12551923_E26", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 904, 919 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_T11" }, { "role": "Site", "ref_id": "PMID-12551923_T19" } ] }, { "id": "PMID-12551923_E27", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 1012, 1020 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_E29" }, { "role": "Cause", "ref_id": "PMID-12551923_E25" } ] }, { "id": "PMID-12551923_E28", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 1012, 1020 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_E29" }, { "role": "Cause", "ref_id": "PMID-12551923_E26" } ] }, { "id": "PMID-12551923_E29", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1031, 1041 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_T20" } ] }, { "id": "PMID-12551923_E30", "type": "Regulation", "trigger": { "text": [ "regulate" ], "offsets": [ [ 1058, 1066 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_E32" }, { "role": "Cause", "ref_id": "PMID-12551923_E25" } ] }, { "id": "PMID-12551923_E31", "type": "Regulation", "trigger": { "text": [ "regulate" ], "offsets": [ [ 1058, 1066 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_E32" }, { "role": "Cause", "ref_id": "PMID-12551923_E26" } ] }, { "id": "PMID-12551923_E32", "type": "Negative_regulation", "trigger": { "text": [ "autoinhibition" ], "offsets": [ [ 1067, 1081 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_T11" }, { "role": "Cause", "ref_id": "PMID-12551923_T11" } ] }, { "id": "PMID-12551923_E33", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1195, 1206 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_T22" }, { "role": "Theme", "ref_id": "PMID-12551923_T21" } ] }, { "id": "PMID-12551923_E34", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 1242, 1251 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12551923_E37" }, { "role": "Theme", "ref_id": "PMID-12551923_E33" } ] }, { "id": "PMID-12551923_E35", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 1242, 1251 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12551923_E38" }, { "role": "Theme", "ref_id": "PMID-12551923_E33" } ] }, { "id": "PMID-12551923_E36", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 1242, 1251 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12551923_E39" }, { "role": "Theme", "ref_id": "PMID-12551923_E33" } ] }, { "id": "PMID-12551923_E37", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1255, 1270 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_T22" }, { "role": "Site", "ref_id": "PMID-12551923_T23" } ] }, { "id": "PMID-12551923_E38", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1255, 1270 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_T22" }, { "role": "Site", "ref_id": "PMID-12551923_T24" } ] }, { "id": "PMID-12551923_E39", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1255, 1270 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12551923_T22" }, { "role": "Site", "ref_id": "PMID-12551923_T25" } ] } ]

[]

[]

[ { "id": "PMID-12586352__text", "type": "abstract", "text": [ "Structure-function analysis of the A20-binding inhibitor of NF-kappa B activation, ABIN-1. \nNuclear factor kappa B (NF-kappa B)-dependent gene expression plays an important role in numerous cellular processes including stress responses, inflammation and cell proliferation. Therefore, the activity of this transcription factor needs to be tightly regulated. Among others, the NF-kappa B-dependent zinc finger protein A20 is involved in the negative feedback regulation of NF-kappa B activation in response to tumor necrosis factor (TNF). We previously demonstrated that A20 can interact with A20-binding inhibitors of NF-kappa B activation (ABINs), which have the potential to inhibit TNF-induced activation of NF-kappa B upon overexpression. The ABIN proteins were therefore proposed to mediate the NF-kappa B inhibiting function of A20. Here we demonstrate the presence of a short homologous region in ABINs and I kappa B kinase gamma, the regulatory subunit of the I kappa B kinase complex. Site-specific mutagenesis of this region abolished the NF-kappa B inhibiting function of ABIN-1, without affecting the interaction with A20. Furthermore, coexpression of these ABIN-1 mutants interfered in a dominant negative manner with the NF-kappa B inhibiting function of ABIN-1, whereas the A20-mediated inhibition was unaffected. These results suggest that A20 and ABIN-1 probably act independently of their mutual interaction.\n" ], "offsets": [ [ 0, 1427 ] ] } ]

[ { "id": "PMID-12586352_T1", "type": "Gene_or_gene_product", "text": [ "A20-binding inhibitor of NF-kappa B activation" ], "offsets": [ [ 35, 81 ] ], "normalized": [] }, { "id": "PMID-12586352_T2", "type": "Gene_or_gene_product", "text": [ "ABIN-1" ], "offsets": [ [ 83, 89 ] ], "normalized": [] }, { "id": "PMID-12586352_T3", "type": "Complex", "text": [ "Nuclear factor kappa B" ], "offsets": [ [ 92, 114 ] ], "normalized": [] }, { "id": "PMID-12586352_T4", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 116, 126 ] ], "normalized": [] }, { "id": "PMID-12586352_T5", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 376, 386 ] ], "normalized": [] }, { "id": "PMID-12586352_T6", "type": "Simple_chemical", "text": [ "zinc" ], "offsets": [ [ 397, 401 ] ], "normalized": [] }, { "id": "PMID-12586352_T7", "type": "Gene_or_gene_product", "text": [ "A20" ], "offsets": [ [ 417, 420 ] ], "normalized": [] }, { "id": "PMID-12586352_T8", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 472, 482 ] ], "normalized": [] }, { "id": "PMID-12586352_T9", "type": "Gene_or_gene_product", "text": [ "tumor necrosis factor" ], "offsets": [ [ 509, 530 ] ], "normalized": [] }, { "id": "PMID-12586352_T10", "type": "Gene_or_gene_product", "text": [ "TNF" ], "offsets": [ [ 532, 535 ] ], "normalized": [] }, { "id": "PMID-12586352_T11", "type": "Gene_or_gene_product", "text": [ "A20" ], "offsets": [ [ 570, 573 ] ], "normalized": [] }, { "id": "PMID-12586352_T12", "type": "Gene_or_gene_product", "text": [ "A20-binding inhibitors of NF-kappa B activation" ], "offsets": [ [ 592, 639 ] ], "normalized": [] }, { "id": "PMID-12586352_T13", "type": "Gene_or_gene_product", "text": [ "ABINs" ], "offsets": [ [ 641, 646 ] ], "normalized": [] }, { "id": "PMID-12586352_T14", "type": "Gene_or_gene_product", "text": [ "TNF" ], "offsets": [ [ 685, 688 ] ], "normalized": [] }, { "id": "PMID-12586352_T15", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 711, 721 ] ], "normalized": [] }, { "id": "PMID-12586352_T16", "type": "Gene_or_gene_product", "text": [ "ABIN" ], "offsets": [ [ 747, 751 ] ], "normalized": [] }, { "id": "PMID-12586352_T17", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 800, 810 ] ], "normalized": [] }, { "id": "PMID-12586352_T18", "type": "Gene_or_gene_product", "text": [ "A20" ], "offsets": [ [ 834, 837 ] ], "normalized": [] }, { "id": "PMID-12586352_T19", "type": "Gene_or_gene_product", "text": [ "ABINs" ], "offsets": [ [ 904, 909 ] ], "normalized": [] }, { "id": "PMID-12586352_T20", "type": "Gene_or_gene_product", "text": [ "I kappa B kinase gamma" ], "offsets": [ [ 914, 936 ] ], "normalized": [] }, { "id": "PMID-12586352_T21", "type": "Complex", "text": [ "I kappa B kinase" ], "offsets": [ [ 968, 984 ] ], "normalized": [] }, { "id": "PMID-12586352_T22", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 1049, 1059 ] ], "normalized": [] }, { "id": "PMID-12586352_T23", "type": "Gene_or_gene_product", "text": [ "ABIN-1" ], "offsets": [ [ 1083, 1089 ] ], "normalized": [] }, { "id": "PMID-12586352_T24", "type": "Gene_or_gene_product", "text": [ "A20" ], "offsets": [ [ 1130, 1133 ] ], "normalized": [] }, { "id": "PMID-12586352_T25", "type": "Gene_or_gene_product", "text": [ "ABIN-1" ], "offsets": [ [ 1170, 1176 ] ], "normalized": [] }, { "id": "PMID-12586352_T26", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 1235, 1245 ] ], "normalized": [] }, { "id": "PMID-12586352_T27", "type": "Gene_or_gene_product", "text": [ "ABIN-1" ], "offsets": [ [ 1269, 1275 ] ], "normalized": [] }, { "id": "PMID-12586352_T28", "type": "Gene_or_gene_product", "text": [ "A20" ], "offsets": [ [ 1289, 1292 ] ], "normalized": [] }, { "id": "PMID-12586352_T29", "type": "Gene_or_gene_product", "text": [ "A20" ], "offsets": [ [ 1356, 1359 ] ], "normalized": [] }, { "id": "PMID-12586352_T30", "type": "Gene_or_gene_product", "text": [ "ABIN-1" ], "offsets": [ [ 1364, 1370 ] ], "normalized": [] } ]

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[ { "id": "PMID-12586352_1", "entity_ids": [ "PMID-12586352_T3", "PMID-12586352_T4" ] }, { "id": "PMID-12586352_2", "entity_ids": [ "PMID-12586352_T9", "PMID-12586352_T10" ] }, { "id": "PMID-12586352_3", "entity_ids": [ "PMID-12586352_T12", "PMID-12586352_T13" ] } ]

[]

[ { "id": "PMID-12588975__text", "type": "abstract", "text": [ "The C terminus of initiation factor 4E-binding protein 1 contains multiple regulatory features that influence its function and phosphorylation. \nEukaryotic initiation factor 4E (eIF4E) binds the mRNA cap structure and forms eIF4F complexes that recruit 40S subunits to the mRNA. Formation of eIF4F is blocked by eIF4E-binding proteins such as 4E-BP1, which interacts with eIF4E via a motif in the center of its 118-residue sequence. 4E-BP1 plays key roles in cell proliferation, growth, and survival. Binding of 4E-BP1 to eIF4E is regulated by hierarchical multisite phosphorylation. Here we demonstrate that three different features in the C terminus of 4E-BP1 play distinct roles in regulating its phosphorylation and function. Firstly, we identify a new phosphorylation site in its C terminus (S101). A serine or glutamate at this position is required for efficient phosphorylation at Ser65. A second C-terminal site, S112, directly affects binding of 4E-BP1 to eIF4E without influencing phosphorylation of other sites. Thirdly, a conserved C-terminal motif influences phosphorylation of multiple residues, including rapamycin-insensitive sites. These relatively long-range effects are surprising given the reportedly unstructured nature of 4E-BP1 and may imply that phosphorylation of 4E-BP1 and/or binding to eIF4E induces a more-ordered structure. 4E-BP2 and -3 lack phosphorylatable residues corresponding to both S101 and S112. However, in 4E-BP3, replacement of the alanine at the position corresponding to S112 by serine or glutamate did not confer the ability to be released from eIF4E in response to insulin. \n" ], "offsets": [ [ 0, 1622 ] ] } ]

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"PMID-12588975_T12" } ] }, { "id": "PMID-12588975_E19", "type": "Regulation", "trigger": { "text": [ "affects" ], "offsets": [ [ 936, 943 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12588975_T17" }, { "role": "Theme", "ref_id": "PMID-12588975_E20" } ] }, { "id": "PMID-12588975_E20", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 944, 951 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12588975_T19" }, { "role": "Theme", "ref_id": "PMID-12588975_T18" } ] }, { "id": "PMID-12588975_E21", "type": "Regulation", "trigger": { "text": [ "influencing" ], "offsets": [ [ 979, 990 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12588975_E22" }, { "role": "Cause", "ref_id": "PMID-12588975_T17" } ] }, { "id": "PMID-12588975_E22", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 991, 1006 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12588975_T18" } ] }, { "id": "PMID-12588975_E23", "type": 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"Theme", "ref_id": "PMID-12588975_E33" } ] }, { "id": "PMID-12588975_E32", "type": "Dissociation", "trigger": { "text": [ "released" ], "offsets": [ [ 1577, 1585 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-12588975_T28" }, { "role": "Product", "ref_id": "PMID-12588975_T33" } ] }, { "id": "PMID-12588975_E33", "type": "Positive_regulation", "trigger": { "text": [ "response" ], "offsets": [ [ 1600, 1608 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12588975_T34" }, { "role": "Theme", "ref_id": "PMID-12588975_E32" } ] } ]

[ { "id": "PMID-12588975_1", "entity_ids": [ "PMID-12588975_T2", "PMID-12588975_T3" ] } ]

[]

[ { "id": "PMID-12611887__text", "type": "abstract", "text": [ "Regulation of the cyclin D3 promoter by E2F1. \nWe have previously demonstrated that ectopic expression of E2F1 is sufficient to drive quiescent cells into S phase and that E2F1 expression can contribute to oncogenic transformation. Key target genes in this process include master regulators of the cell cycle, such as cyclin E, which regulates G(1) progression, and cyclin A, which is required for the initiation of DNA synthesis. In the present work, we present novel evidence that a second G(1) cyclin, cyclin D3, is also potently activated by E2F1. First, an estrogen receptor-E2F1 fusion protein (ER-E2F1) potently activates the endogenous cyclin D3 mRNA upon treatment with 4-hydroxytamoxifen, which induces nuclear accumulation of the otherwise cytosolic fusion protein. Furthermore, trans-activation of cyclin D3 by ER-E2F1 occurs even in the presence of the protein synthesis inhibitor cycloheximide and thus appears direct. Second, all of the growth-stimulatory members of the E2F family (E2F1, -2, and -3A) potently activate a cyclin D3 promoter reporter, whereas growth-restraining members of the family (E2F4, -5, and -6) have little effect. Third, recombinant E2F1 binds with high affinity to the cyclin D3 promoter in vitro. Fourth, chromatin immunoprecipitation assays demonstrate that endogenous E2F1 is associated with the cyclin D3 promoter in vivo. Finally, mapping experiments localize the essential E2F regulatory element of the cyclin D3 promoter to a noncanonical E2F site in the promoter between nucleotides -143 and -135 relative to the initiating methionine codon. We conclude that in addition to cyclins E and A, E2F family members can also activate one member of the D-type cyclins, further contributing to the ability of the stimulatory E2F family members to drive cellular proliferation.\n" ], "offsets": [ [ 0, 1818 ] ] } ]

[ { "id": "PMID-12611887_T1", "type": "Gene_or_gene_product", "text": [ "cyclin D3" ], "offsets": [ [ 18, 27 ] ], "normalized": [] }, { "id": "PMID-12611887_T2", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 40, 44 ] ], "normalized": [] }, { "id": "PMID-12611887_T3", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 106, 110 ] ], "normalized": [] }, { "id": "PMID-12611887_T4", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 172, 176 ] ], "normalized": [] }, { "id": "PMID-12611887_T5", "type": "Gene_or_gene_product", "text": [ "cyclin E" ], "offsets": [ [ 318, 326 ] ], "normalized": [] }, { "id": "PMID-12611887_T6", "type": "Gene_or_gene_product", "text": [ "cyclin A" ], "offsets": [ [ 366, 374 ] ], "normalized": [] }, { "id": "PMID-12611887_T7", "type": "Gene_or_gene_product", "text": [ "cyclin" ], "offsets": [ [ 497, 503 ] ], "normalized": [] }, { "id": "PMID-12611887_T8", "type": "Gene_or_gene_product", "text": [ "cyclin D3" ], "offsets": [ [ 505, 514 ] ], "normalized": [] }, { "id": "PMID-12611887_T9", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 546, 550 ] ], "normalized": [] }, { "id": "PMID-12611887_T10", "type": "Gene_or_gene_product", "text": [ "estrogen receptor-E2F1" ], "offsets": [ [ 562, 584 ] ], "normalized": [] }, { "id": "PMID-12611887_T11", "type": "Gene_or_gene_product", "text": [ "ER-E2F1" ], "offsets": [ [ 601, 608 ] ], "normalized": [] }, { "id": "PMID-12611887_T12", "type": "Gene_or_gene_product", "text": [ "cyclin D3" ], "offsets": [ [ 644, 653 ] ], "normalized": [] }, { "id": "PMID-12611887_T13", "type": "Simple_chemical", "text": [ "4-hydroxytamoxifen" ], "offsets": [ [ 679, 697 ] ], "normalized": [] }, { "id": "PMID-12611887_T14", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 713, 720 ] ], "normalized": [] }, { "id": "PMID-12611887_T15", "type": "Cellular_component", "text": [ "cytosolic" ], "offsets": [ [ 751, 760 ] ], "normalized": [] }, { "id": "PMID-12611887_T16", "type": "Gene_or_gene_product", "text": [ "cyclin D3" ], "offsets": [ [ 810, 819 ] ], "normalized": [] }, { "id": "PMID-12611887_T17", "type": "Gene_or_gene_product", "text": [ "ER-E2F1" ], "offsets": [ [ 823, 830 ] ], "normalized": [] }, { "id": "PMID-12611887_T18", "type": "Simple_chemical", "text": [ "cycloheximide" ], "offsets": [ [ 894, 907 ] ], "normalized": [] }, { "id": "PMID-12611887_T19", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 986, 989 ] ], "normalized": [] }, { "id": "PMID-12611887_T20", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 998, 1002 ] ], "normalized": [] }, { "id": "PMID-12611887_T21", "type": "Gene_or_gene_product", "text": [ "-2" ], "offsets": [ [ 1004, 1006 ] ], "normalized": [] }, { "id": "PMID-12611887_T22", "type": "Gene_or_gene_product", "text": [ "-3A" ], "offsets": [ [ 1012, 1015 ] ], "normalized": [] }, { "id": "PMID-12611887_T23", "type": "Gene_or_gene_product", "text": [ "cyclin D3" ], "offsets": [ [ 1037, 1046 ] ], "normalized": [] }, { "id": "PMID-12611887_T24", "type": "Gene_or_gene_product", "text": [ "E2F4" ], "offsets": [ [ 1116, 1120 ] ], "normalized": [] }, { "id": "PMID-12611887_T25", "type": "Gene_or_gene_product", "text": [ "-5" ], "offsets": [ [ 1122, 1124 ] ], "normalized": [] }, { "id": "PMID-12611887_T26", "type": "Gene_or_gene_product", "text": [ "-6" ], "offsets": [ [ 1130, 1132 ] ], "normalized": [] }, { "id": "PMID-12611887_T27", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 1173, 1177 ] ], "normalized": [] }, { "id": "PMID-12611887_T28", "type": "Gene_or_gene_product", "text": [ "cyclin D3" ], "offsets": [ [ 1210, 1219 ] ], "normalized": [] }, { "id": "PMID-12611887_T29", "type": "Cellular_component", "text": [ "chromatin" ], "offsets": [ [ 1247, 1256 ] ], "normalized": [] }, { "id": "PMID-12611887_T30", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 1312, 1316 ] ], "normalized": [] }, { "id": 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[ { "id": "PMID-12616480__text", "type": "abstract", "text": [ "Phosphatidylinositol 3-kinase is involved in Toll-like receptor 4-mediated cytokine expression in mouse macrophages. \nRecent evidence suggests a role for phosphatidylinositol (PI) 3-kinase in various inflammatory responses. In this study, the consequences of LPS-induced PI 3-kinase activation on cytokine and chemokine expression and the intracellular mechanisms of inflammatory activation were examined in mouse macrophages. LPS stimulation induced a complex formation between PI 3-kinase and myeloid differentiation factor 88 (MyD88), which was followed by an induction of IL-1beta, tumor necrosis factor-alpha (TNF-alpha) and macrophage inflammatory protein (MIP)-2. The induction of IL-1beta, but not of MIP-2 or TNF-alpha, was blocked by the PI 3-kinase inhibitors LY294002 and wortmannin. The nuclear factor-kappaB (NF-kappaB) inhibitor pyrrolidinedithiocarbamate (PDTC) blocked the induction of IL-1beta and TNF-alpha, but had no effect on MIP-2 expression. Inhibition of PI 3-kinase decreased the LPS-induced transcriptional activity of NF-kappaB, but it had no effect on the nuclear DNA binding activity of NF-kappaB. These findings suggest that, while NF-kappaB nuclear localization and DNA binding are necessary, they are not sufficient for transcriptional activation of the IL-1beta gene in the absence of PI 3-kinase activity. Taken together, our results demonstrate that activation of Toll-like receptor (TLR)-4 results in PI 3-kinase-MyD88 complex formation, and that PI 3-kinase activity selectively leads to cytokine induction downstream of TLR4.\n" ], "offsets": [ [ 0, 1565 ] ] } ]

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"type": "Gene_or_gene_product", "text": [ "PI 3-kinase" ], "offsets": [ [ 479, 490 ] ], "normalized": [] }, { "id": "PMID-12616480_T9", "type": "Gene_or_gene_product", "text": [ "myeloid differentiation factor 88" ], "offsets": [ [ 495, 528 ] ], "normalized": [] }, { "id": "PMID-12616480_T10", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 530, 535 ] ], "normalized": [] }, { "id": "PMID-12616480_T11", "type": "Gene_or_gene_product", "text": [ "IL-1beta" ], "offsets": [ [ 576, 584 ] ], "normalized": [] }, { "id": "PMID-12616480_T12", "type": "Gene_or_gene_product", "text": [ "tumor necrosis factor-alpha" ], "offsets": [ [ 586, 613 ] ], "normalized": [] }, { "id": "PMID-12616480_T13", "type": "Gene_or_gene_product", "text": [ "TNF-alpha" ], "offsets": [ [ 615, 624 ] ], "normalized": [] }, { "id": "PMID-12616480_T14", "type": "Gene_or_gene_product", "text": [ "macrophage inflammatory protein (MIP)-2" ], "offsets": [ [ 630, 669 ] ], "normalized": [] }, { "id": "PMID-12616480_T15", "type": "Gene_or_gene_product", "text": [ "IL-1beta" ], "offsets": [ [ 688, 696 ] ], "normalized": [] }, { "id": "PMID-12616480_T16", "type": "Gene_or_gene_product", "text": [ "MIP-2" ], "offsets": [ [ 709, 714 ] ], "normalized": [] }, { "id": "PMID-12616480_T17", "type": "Gene_or_gene_product", "text": [ "TNF-alpha" ], "offsets": [ [ 718, 727 ] ], "normalized": [] }, { "id": "PMID-12616480_T18", "type": "Gene_or_gene_product", "text": [ "PI 3-kinase" ], "offsets": [ [ 748, 759 ] ], "normalized": [] }, { "id": "PMID-12616480_T19", "type": "Simple_chemical", "text": [ "LY294002" ], "offsets": [ [ 771, 779 ] ], "normalized": [] }, { "id": "PMID-12616480_T20", "type": "Simple_chemical", "text": [ "wortmannin" ], "offsets": [ [ 784, 794 ] ], "normalized": [] }, { "id": "PMID-12616480_T21", "type": "Complex", "text": [ "nuclear factor-kappaB" ], "offsets": [ [ 800, 821 ] ], "normalized": [] }, { "id": "PMID-12616480_T22", "type": "Complex", "text": [ "NF-kappaB" ], 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[]

[ { "id": "PMID-12618428__text", "type": "abstract", "text": [ "14-3-3beta is a p90 ribosomal S6 kinase (RSK) isoform 1-binding protein that negatively regulates RSK kinase activity. \np90 ribosomal S6 kinase 1 (RSK1) is a serine/threonine kinase that is activated by extracellular signal-related kinases 1/2 and phosphoinositide-dependent protein kinase 1 upon mitogen stimulation. Under basal conditions, RSK1 is located in the cytosol and upon stimulation, RSK1 translocates to the plasma membrane where it is fully activated. The ability of RSK1 to bind the adapter protein 14-3-3beta was investigated because RSK1 contains several putative 14-3-3-binding motifs. We demonstrate that RSK1 specifically and directly binds 14-3-3beta. This interaction was dependent on phosphorylation of serine 154 within the motif RLSKEV of RSK1. Binding of RSK1 to 14-3-3beta was maximal under basal conditions and decreased significantly upon mitogen stimulation. After 5 min of serum stimulation, a portion of 14-3-3beta and RSK1 translocated to the membrane fraction, and immunofluorescence studies demonstrated colocalization of RSK1 and 14-3-3beta at the plasma membrane in vivo. Incubation of recombinant RSK1 with 14-3-3beta decreased RSK1 kinase activity by approximately 50%. Mutation of RSK1 serine 154 increased both basal and serum-stimulated RSK activity. In addition, the epidermal growth factor response of RSK1S154A was enhanced compared with wild type RSK. The amount of RSK1S154A was significantly increased in the membrane fraction under basal conditions. Increased phosphorylation of two sites essential for RSK1 kinase activity (Ser(380) and Ser(363)) in RSK1S154A compared with RSK1 wild type, demonstrated that 14-3-3 interferes with RSK1 phosphorylation. These data suggest that 14-3-3beta binding negatively regulates RSK1 activity to maintain signal specificity and that association/dissociation of the 14-3-3beta-RSK1 complex is likely to be important for mitogen-mediated RSK1 activation. \n" ], "offsets": [ [ 0, 1941 ] ] } ]

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"Gene_or_gene_product", "text": [ "extracellular signal-related kinases 1/2" ], "offsets": [ [ 203, 243 ] ], "normalized": [] }, { "id": "PMID-12618428_T9", "type": "Gene_or_gene_product", "text": [ "phosphoinositide-dependent protein kinase 1" ], "offsets": [ [ 248, 291 ] ], "normalized": [] }, { "id": "PMID-12618428_T10", "type": "Gene_or_gene_product", "text": [ "RSK1" ], "offsets": [ [ 342, 346 ] ], "normalized": [] }, { "id": "PMID-12618428_T11", "type": "Cellular_component", "text": [ "cytosol" ], "offsets": [ [ 365, 372 ] ], "normalized": [] }, { "id": "PMID-12618428_T12", "type": "Gene_or_gene_product", "text": [ "RSK1" ], "offsets": [ [ 395, 399 ] ], "normalized": [] }, { "id": "PMID-12618428_T13", "type": "Cellular_component", "text": [ "plasma membrane" ], "offsets": [ [ 420, 435 ] ], "normalized": [] }, { "id": "PMID-12618428_T14", "type": "Gene_or_gene_product", "text": [ "RSK1" ], "offsets": [ [ 480, 484 ] ], "normalized": [] }, { "id": "PMID-12618428_T15", "type": "Gene_or_gene_product", "text": [ "14-3-3beta" ], "offsets": [ [ 513, 523 ] ], "normalized": [] }, { "id": "PMID-12618428_T16", "type": "Gene_or_gene_product", "text": [ "RSK1" ], "offsets": [ [ 549, 553 ] ], "normalized": [] }, { "id": "PMID-12618428_T17", "type": "Gene_or_gene_product", "text": [ "14-3-3" ], "offsets": [ [ 580, 586 ] ], "normalized": [] }, { "id": "PMID-12618428_T18", "type": "Gene_or_gene_product", "text": [ "RSK1" ], "offsets": [ [ 623, 627 ] ], "normalized": [] }, { "id": "PMID-12618428_T19", "type": "Gene_or_gene_product", "text": [ "14-3-3beta" ], "offsets": [ [ 660, 670 ] ], "normalized": [] }, { "id": "PMID-12618428_T20", "type": "Simple_chemical", "text": [ "serine 154" ], "offsets": [ [ 725, 735 ] ], "normalized": [] }, { "id": "PMID-12618428_T21", "type": "Gene_or_gene_product", "text": [ "RSK1" ], "offsets": [ [ 763, 767 ] ], "normalized": [] }, { "id": "PMID-12618428_T22", "type": "Gene_or_gene_product", "text": [ "RSK1" ], "offsets": [ [ 780, 784 ] ], "normalized": [] }, { "id": "PMID-12618428_T23", "type": "Gene_or_gene_product", "text": [ "14-3-3beta" ], "offsets": [ [ 788, 798 ] ], "normalized": [] }, { "id": "PMID-12618428_T24", "type": "Gene_or_gene_product", "text": [ "14-3-3beta" ], "offsets": [ [ 935, 945 ] ], "normalized": [] }, { "id": "PMID-12618428_T25", "type": "Gene_or_gene_product", "text": [ "RSK1" ], "offsets": [ [ 950, 954 ] ], "normalized": [] }, { "id": "PMID-12618428_T26", "type": "Cellular_component", "text": [ "membrane" ], "offsets": [ [ 975, 983 ] ], "normalized": [] }, { "id": "PMID-12618428_T27", "type": "Gene_or_gene_product", "text": [ "RSK1" ], "offsets": [ [ 1056, 1060 ] ], "normalized": [] }, { "id": "PMID-12618428_T28", "type": "Gene_or_gene_product", "text": [ "14-3-3beta" ], "offsets": [ [ 1065, 1075 ] ], "normalized": [] }, { "id": "PMID-12618428_T29", "type": "Cellular_component", "text": [ "plasma membrane" ], "offsets": [ [ 1083, 1098 ] ], "normalized": [] }, { "id": "PMID-12618428_T30", "type": "Gene_or_gene_product", "text": [ "RSK1" ], "offsets": [ [ 1134, 1138 ] ], "normalized": [] }, { "id": "PMID-12618428_T31", "type": "Gene_or_gene_product", "text": [ "14-3-3beta" ], "offsets": [ [ 1144, 1154 ] ], "normalized": [] }, { "id": "PMID-12618428_T32", "type": "Gene_or_gene_product", "text": [ "RSK1" ], "offsets": [ [ 1165, 1169 ] ], "normalized": [] }, { "id": "PMID-12618428_T33", "type": "Gene_or_gene_product", "text": [ "RSK1" ], "offsets": [ [ 1220, 1224 ] ], "normalized": [] }, { "id": "PMID-12618428_T34", "type": "Simple_chemical", "text": [ "serine 154" ], "offsets": [ [ 1225, 1235 ] ], "normalized": [] }, { "id": "PMID-12618428_T35", "type": "Gene_or_gene_product", "text": [ "RSK" ], "offsets": [ [ 1278, 1281 ] ], "normalized": [] }, { "id": "PMID-12618428_T36", "type": "Gene_or_gene_product", "text": [ "RSK1S154A" ], "offsets": [ [ 1345, 1354 ] ], "normalized": [] }, { "id": "PMID-12618428_T37", "type": "Gene_or_gene_product", "text": [ "RSK" ], "offsets": [ [ 1392, 1395 ] ], "normalized": [] }, { "id": "PMID-12618428_T38", "type": "Gene_or_gene_product", "text": [ "RSK1S154A" ], "offsets": [ [ 1411, 1420 ] ], "normalized": [] }, { "id": "PMID-12618428_T39", "type": "Cellular_component", "text": [ "membrane" ], "offsets": [ [ 1456, 1464 ] ], "normalized": [] }, { "id": "PMID-12618428_T40", "type": "Gene_or_gene_product", "text": [ "RSK1" ], "offsets": [ [ 1551, 1555 ] ], "normalized": [] }, { "id": "PMID-12618428_T41", "type": "Simple_chemical", "text": [ "Ser(380)" ], "offsets": [ [ 1573, 1581 ] ], "normalized": [] }, { "id": "PMID-12618428_T42", "type": "Simple_chemical", "text": [ "Ser(363)" ], "offsets": [ [ 1586, 1594 ] ], "normalized": [] }, { "id": "PMID-12618428_T43", "type": "Gene_or_gene_product", "text": [ "RSK1S154A" ], "offsets": [ [ 1599, 1608 ] ], "normalized": [] }, { "id": "PMID-12618428_T44", "type": "Gene_or_gene_product", "text": [ "RSK1" ], "offsets": [ [ 1623, 1627 ] ], "normalized": [] }, { "id": "PMID-12618428_T45", 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"offsets": [ [ 1820, 1831 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-12618428_T49" } ] }, { "id": "PMID-12618428_E36", "type": "Dissociation", "trigger": { "text": [ "dissociation" ], "offsets": [ [ 1832, 1844 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12618428_T49" } ] }, { "id": "PMID-12618428_E37", "type": "Regulation", "trigger": { "text": [ "important" ], "offsets": [ [ 1892, 1901 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12618428_E35" }, { "role": "Theme", "ref_id": "PMID-12618428_E40" } ] }, { "id": "PMID-12618428_E38", "type": "Regulation", "trigger": { "text": [ "important" ], "offsets": [ [ 1892, 1901 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12618428_E36" }, { "role": "Theme", "ref_id": "PMID-12618428_E40" } ] }, { "id": "PMID-12618428_E39", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1914, 1922 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12618428_E40" } ] }, { "id": "PMID-12618428_E40", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1928, 1938 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12618428_T50" } ] } ]

[ { "id": "PMID-12618428_1", "entity_ids": [ "PMID-12618428_T4", "PMID-12618428_T5" ] } ]

[]

[ { "id": "PMID-12625370__text", "type": "abstract", "text": [ "E2F1 activates the human p53 promoter and overcomes the repressive effect of hepatitis B viral X protein (Hbx) on the p53 promoter. \nThe functional effect of the interaction of E2F1 and hepatitis B virus X protein (HBx) on the promoter of human p53 gene was studied using chloramphenicol acetyl transferase (CAT) assay. E2F1 activated the p53 promoter through E2F1 binding site. As previously reported, HBx repressed the p53 promoter through E-box. When E2F1 was cotransfected with HBx, E2F1 overcame the repressive effect of HBx on the p53 promoter through the E2F1 site. However, in the thymidine kinase (tk) heterologous promoter system with the E2F1 binding sites, cotransfection of E2F1 and HBx showed a strong synergistic activation. An in vitro interaction assay showed that E2F1 and HBx physically bind with each other. Analyses of the interaction domain with the GAL4 fusion protein showed that the pRb-binding domain of E2F1 was necessary for the functional interaction of these two proteins. Taken together, these results imply the functional inhibitory action of E2F1 on the HBV life cycle and HBV-mediated hepatocellular carcinogenesis (HCC). Therefore, the normal or enhanced function of E2F1 gene would be important in controlling the HBx function in HCC.\n" ], "offsets": [ [ 0, 1271 ] ] } ]

[ { "id": "PMID-12625370_T1", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-12625370_T2", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 25, 28 ] ], "normalized": [] }, { "id": "PMID-12625370_T3", "type": "Gene_or_gene_product", "text": [ "hepatitis B viral X protein" ], "offsets": [ [ 77, 104 ] ], "normalized": [] }, { "id": "PMID-12625370_T4", "type": "Gene_or_gene_product", "text": [ "Hbx" ], "offsets": [ [ 106, 109 ] ], "normalized": [] }, { "id": "PMID-12625370_T5", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 118, 121 ] ], "normalized": [] }, { "id": "PMID-12625370_T6", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 177, 181 ] ], "normalized": [] }, { "id": "PMID-12625370_T7", "type": "Gene_or_gene_product", "text": [ "hepatitis B virus X protein" ], "offsets": [ [ 186, 213 ] ], "normalized": [] }, { "id": "PMID-12625370_T8", "type": "Gene_or_gene_product", "text": [ "HBx" ], "offsets": [ [ 215, 218 ] ], "normalized": [] }, { "id": "PMID-12625370_T9", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 245, 248 ] ], "normalized": [] }, { "id": "PMID-12625370_T10", "type": "Gene_or_gene_product", "text": [ "chloramphenicol acetyl transferase" ], "offsets": [ [ 272, 306 ] ], "normalized": [] }, { "id": "PMID-12625370_T11", "type": "Gene_or_gene_product", "text": [ "CAT" ], "offsets": [ [ 308, 311 ] ], "normalized": [] }, { "id": "PMID-12625370_T12", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 320, 324 ] ], "normalized": [] }, { "id": "PMID-12625370_T13", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 339, 342 ] ], "normalized": [] }, { "id": "PMID-12625370_T14", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 360, 364 ] ], "normalized": [] }, { "id": "PMID-12625370_T15", "type": "Gene_or_gene_product", "text": [ "HBx" ], "offsets": [ [ 403, 406 ] ], "normalized": [] }, { "id": "PMID-12625370_T16", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 421, 424 ] ], "normalized": [] }, { "id": "PMID-12625370_T17", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 454, 458 ] ], "normalized": [] }, { "id": "PMID-12625370_T18", "type": "Gene_or_gene_product", "text": [ "HBx" ], "offsets": [ [ 482, 485 ] ], "normalized": [] }, { "id": "PMID-12625370_T19", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 487, 491 ] ], "normalized": [] }, { "id": "PMID-12625370_T20", "type": "Gene_or_gene_product", "text": [ "HBx" ], "offsets": [ [ 526, 529 ] ], "normalized": [] }, { "id": "PMID-12625370_T21", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 537, 540 ] ], "normalized": [] }, { "id": "PMID-12625370_T22", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 562, 566 ] ], "normalized": [] }, { "id": "PMID-12625370_T23", "type": "Gene_or_gene_product", "text": [ "thymidine kinase" ], "offsets": [ [ 589, 605 ] ], "normalized": [] }, { "id": "PMID-12625370_T24", "type": "Gene_or_gene_product", "text": [ "tk" ], "offsets": [ [ 607, 609 ] ], "normalized": [] }, { "id": "PMID-12625370_T25", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 649, 653 ] ], "normalized": [] }, { "id": "PMID-12625370_T26", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 687, 691 ] ], "normalized": [] }, { "id": "PMID-12625370_T27", "type": "Gene_or_gene_product", "text": [ "HBx" ], "offsets": [ [ 696, 699 ] ], "normalized": [] }, { "id": "PMID-12625370_T28", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 782, 786 ] ], "normalized": [] }, { "id": "PMID-12625370_T29", "type": "Gene_or_gene_product", "text": [ "HBx" ], "offsets": [ [ 791, 794 ] ], "normalized": [] }, { "id": "PMID-12625370_T30", "type": "Gene_or_gene_product", "text": [ "GAL4" ], "offsets": [ [ 872, 876 ] ], "normalized": [] }, { "id": "PMID-12625370_T31", "type": "Gene_or_gene_product", "text": [ "pRb" ], "offsets": [ [ 908, 911 ] ], "normalized": [] }, { "id": "PMID-12625370_T32", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 930, 934 ] ], "normalized": [] }, { "id": "PMID-12625370_T33", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 1075, 1079 ] ], "normalized": [] }, { "id": "PMID-12625370_T34", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 1202, 1206 ] ], "normalized": [] }, { "id": "PMID-12625370_T35", "type": "Gene_or_gene_product", "text": [ "HBx" ], "offsets": [ [ 1250, 1253 ] ], "normalized": [] } ]

[ { "id": "PMID-12625370_E1", "type": "Activation", "trigger": { "text": [ "activates" ], "offsets": [ [ 5, 14 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12625370_T2" }, { "role": "Cause", "ref_id": "PMID-12625370_T1" } ] }, { "id": "PMID-12625370_E2", "type": "Negative_regulation", "trigger": { "text": [ "overcomes" ], "offsets": [ [ 42, 51 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12625370_E4" }, { "role": "Cause", "ref_id": "PMID-12625370_T1" } ] }, { "id": "PMID-12625370_E3", "type": "Negative_regulation", "trigger": { "text": [ "repressive" ], "offsets": [ [ 56, 66 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12625370_E4" } ] }, { "id": "PMID-12625370_E4", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 67, 73 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12625370_T3" }, { "role": "Theme", "ref_id": "PMID-12625370_T5" } ] }, { "id": "PMID-12625370_E5", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 148, 154 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12625370_E6" }, { "role": "Theme", "ref_id": "PMID-12625370_T9" } ] }, { "id": "PMID-12625370_E6", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 162, 173 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12625370_T6" }, { "role": "Theme", "ref_id": "PMID-12625370_T7" } ] }, { "id": "PMID-12625370_E7", "type": "Activation", "trigger": { "text": [ "activated" ], "offsets": [ [ 325, 334 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12625370_T12" }, { "role": "Theme", "ref_id": "PMID-12625370_T13" } ] }, { "id": "PMID-12625370_E8", "type": "Negative_regulation", "trigger": { "text": [ "repressed" ], "offsets": [ [ 407, 416 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12625370_T15" }, { "role": "Theme", "ref_id": "PMID-12625370_T16" } ] }, { "id": "PMID-12625370_E9", "type": "Negative_regulation", "trigger": { "text": [ "overcame" ], "offsets": [ [ 492, 500 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12625370_T19" }, { "role": "Theme", "ref_id": "PMID-12625370_E11" } ] }, { "id": "PMID-12625370_E10", "type": "Negative_regulation", "trigger": { "text": [ "repressive" ], "offsets": [ [ 505, 515 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12625370_E11" } ] }, { "id": "PMID-12625370_E11", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 516, 522 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12625370_T20" }, { "role": "Theme", "ref_id": "PMID-12625370_T21" } ] }, { "id": "PMID-12625370_E12", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 728, 738 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12625370_T27" } ] }, { "id": "PMID-12625370_E13", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 728, 738 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12625370_T26" } ] }, { "id": "PMID-12625370_E14", "type": "Binding", "trigger": { "text": [ "bind" ], "offsets": [ [ 806, 810 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12625370_T29" }, { "role": "Theme", "ref_id": "PMID-12625370_T28" } ] }, { "id": "PMID-12625370_E15", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 912, 919 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12625370_T31" } ] }, { "id": "PMID-12625370_E16", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 1181, 1189 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12625370_T34" } ] }, { "id": "PMID-12625370_E17", "type": "Positive_regulation", "trigger": { "text": [ "important" ], "offsets": [ [ 1221, 1230 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12625370_E18" }, { "role": "Cause", "ref_id": "PMID-12625370_E16" } ] }, { "id": "PMID-12625370_E18", "type": "Regulation", "trigger": { "text": [ "controlling" ], "offsets": [ [ 1234, 1245 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12625370_T35" } ] } ]

[ { "id": "PMID-12625370_1", "entity_ids": [ "PMID-12625370_T3", "PMID-12625370_T4" ] }, { "id": "PMID-12625370_2", "entity_ids": [ "PMID-12625370_T7", "PMID-12625370_T8" ] }, { "id": "PMID-12625370_3", "entity_ids": [ "PMID-12625370_T10", "PMID-12625370_T11" ] }, { "id": "PMID-12625370_4", "entity_ids": [ "PMID-12625370_T23", "PMID-12625370_T24" ] } ]

[]

[ { "id": "PMID-12636916__text", "type": "abstract", "text": [ "Phosphorylation-dependent regulation of septin dynamics during the cell cycle. \nSeptins are GTPases involved in cytokinesis. In yeast, they form a ring at the cleavage site. Using FRAP, we show that septins are mobile within the ring at bud emergence and telophase and are immobile during S, G2, and M phases. Immobilization of the septins is dependent on both Cla4, a PAK-like kinase, and Gin4, a septin-dependent kinase that can phosphorylate the septin Shs1/Sep7. Induction of septin ring dynamics in telophase is triggered by the translocation of Rts1, a kinetochore-associated regulatory subunit of PP2A phosphatase, to the bud neck and correlates with Rts1-dependent dephosphorylation of Shs1. In rts1-Delta cells, the actomyosin ring contracts properly but cytokinesis fails. Together our results implicate septins in a late step of cytokinesis and indicate that proper regulation of septin dynamics, possibly through the control of their phosphorylation state, is required for the completion of cytokinesis.\n" ], "offsets": [ [ 0, 1016 ] ] } ]

[ { "id": "PMID-12636916_T1", "type": "Gene_or_gene_product", "text": [ "septin" ], "offsets": [ [ 40, 46 ] ], "normalized": [] }, { "id": "PMID-12636916_T2", "type": "Gene_or_gene_product", "text": [ "Septins" ], "offsets": [ [ 80, 87 ] ], "normalized": [] }, { "id": "PMID-12636916_T3", "type": "Gene_or_gene_product", "text": [ "septins" ], "offsets": [ [ 199, 206 ] ], "normalized": [] }, { "id": "PMID-12636916_T4", "type": "Cellular_component", "text": [ "bud" ], "offsets": [ [ 237, 240 ] ], "normalized": [] }, { "id": "PMID-12636916_T5", "type": "Gene_or_gene_product", "text": [ "septins" ], "offsets": [ [ 332, 339 ] ], "normalized": [] }, { "id": "PMID-12636916_T6", "type": "Gene_or_gene_product", "text": [ "Cla4" ], "offsets": [ [ 361, 365 ] ], "normalized": [] }, { "id": "PMID-12636916_T7", "type": "Gene_or_gene_product", "text": [ "PAK-like kinase" ], "offsets": [ [ 369, 384 ] ], "normalized": [] }, { "id": "PMID-12636916_T8", "type": "Gene_or_gene_product", "text": [ "Gin4" ], "offsets": [ [ 390, 394 ] ], "normalized": [] }, { "id": "PMID-12636916_T9", "type": "Gene_or_gene_product", "text": [ "septin" ], "offsets": [ [ 398, 404 ] ], "normalized": [] }, { "id": "PMID-12636916_T10", "type": "Gene_or_gene_product", "text": [ "septin" ], "offsets": [ [ 449, 455 ] ], "normalized": [] }, { "id": "PMID-12636916_T11", "type": "Gene_or_gene_product", "text": [ "Shs1" ], "offsets": [ [ 456, 460 ] ], "normalized": [] }, { "id": "PMID-12636916_T12", "type": "Gene_or_gene_product", "text": [ "Sep7" ], "offsets": [ [ 461, 465 ] ], "normalized": [] }, { "id": "PMID-12636916_T13", "type": "Gene_or_gene_product", "text": [ "septin" ], "offsets": [ [ 480, 486 ] ], "normalized": [] }, { "id": "PMID-12636916_T14", "type": "Gene_or_gene_product", "text": [ "Rts1" ], "offsets": [ [ 551, 555 ] ], "normalized": [] }, { "id": "PMID-12636916_T15", "type": "Cellular_component", "text": [ "kinetochore" ], "offsets": [ [ 559, 570 ] ], "normalized": [] }, { "id": "PMID-12636916_T16", "type": "Complex", "text": [ "PP2A" ], "offsets": [ [ 604, 608 ] ], "normalized": [] }, { "id": "PMID-12636916_T17", "type": "Cellular_component", "text": [ "bud neck" ], "offsets": [ [ 629, 637 ] ], "normalized": [] }, { "id": "PMID-12636916_T18", "type": "Gene_or_gene_product", "text": [ "Rts1" ], "offsets": [ [ 658, 662 ] ], "normalized": [] }, { "id": "PMID-12636916_T19", "type": "Gene_or_gene_product", "text": [ "Shs1" ], "offsets": [ [ 694, 698 ] ], "normalized": [] }, { "id": "PMID-12636916_T20", "type": "Gene_or_gene_product", "text": [ "rts1" ], "offsets": [ [ 703, 707 ] ], "normalized": [] }, { "id": "PMID-12636916_T21", "type": "Complex", "text": [ "actomyosin" ], "offsets": [ [ 725, 735 ] ], "normalized": [] }, { "id": "PMID-12636916_T22", "type": "Gene_or_gene_product", "text": [ "septins" ], "offsets": [ [ 814, 821 ] ], "normalized": [] }, { "id": "PMID-12636916_T23", "type": "Gene_or_gene_product", "text": [ "septin" ], "offsets": [ [ 891, 897 ] ], "normalized": [] } ]

[ { "id": "PMID-12636916_E1", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 16, 25 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12636916_E2" } ] }, { "id": "PMID-12636916_E2", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 26, 36 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12636916_T1" } ] }, { "id": "PMID-12636916_E3", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 67, 77 ] ] }, "arguments": [] }, { "id": "PMID-12636916_E4", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 405, 414 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12636916_T9" }, { "role": "Theme", "ref_id": "PMID-12636916_T8" } ] }, { "id": "PMID-12636916_E5", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylate" ], "offsets": [ [ 431, 444 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12636916_T8" }, { "role": "Theme", "ref_id": "PMID-12636916_T10" } ] }, { "id": "PMID-12636916_E6", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylate" ], "offsets": [ [ 431, 444 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12636916_T8" }, { "role": "Theme", "ref_id": "PMID-12636916_T11" } ] }, { "id": "PMID-12636916_E7", "type": "Positive_regulation", "trigger": { "text": [ "Induction" ], "offsets": [ [ 467, 476 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12636916_T13" } ] }, { "id": "PMID-12636916_E8", "type": "Positive_regulation", "trigger": { "text": [ "triggered" ], "offsets": [ [ 517, 526 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12636916_E7" }, { "role": "Cause", "ref_id": "PMID-12636916_E9" } ] }, { "id": "PMID-12636916_E9", "type": "Transport", "trigger": { "text": [ "translocation" ], "offsets": [ [ 534, 547 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12636916_T14" }, { "role": "ToLoc", "ref_id": "PMID-12636916_T17" } ] }, { "id": "PMID-12636916_E10", "type": "Regulation", "trigger": { "text": [ "associated" ], "offsets": [ [ 571, 581 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12636916_T15" }, { "role": "Theme", "ref_id": "PMID-12636916_E11" } ] }, { "id": "PMID-12636916_E11", "type": "Regulation", "trigger": { "text": [ "regulatory" ], "offsets": [ [ 582, 592 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12636916_T14" }, { "role": "Theme", "ref_id": "PMID-12636916_T16" } ] }, { "id": "PMID-12636916_E12", "type": "Regulation", "trigger": { "text": [ "correlates" ], "offsets": [ [ 642, 652 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12636916_E7" }, { "role": "Theme", "ref_id": "PMID-12636916_E14" } ] }, { "id": "PMID-12636916_E13", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 663, 672 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12636916_T18" }, { "role": "Theme", "ref_id": "PMID-12636916_E14" } ] }, { "id": "PMID-12636916_E14", "type": "Dephosphorylation", "trigger": { "text": [ "dephosphorylation" ], "offsets": [ [ 673, 690 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12636916_T19" } ] }, { "id": "PMID-12636916_E15", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 877, 887 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12636916_T23" } ] } ]

[ { "id": "PMID-12636916_1", "entity_ids": [ "PMID-12636916_T11", "PMID-12636916_T12" ] } ]

[]

[ { "id": "PMID-12642668__text", "type": "abstract", "text": [ "The role of disulfide bonds in the assembly and function of MD-2. \nMD-2 is a secreted glycoprotein that binds to the extracellular domain of Toll-like receptor 4 (TLR4) and is required for the activation of TLR4 by lipopolysaccharide (LPS). The protein contains seven Cys residues and consists of a heterogeneous collection of disulfide-linked oligomers. To investigate the role of sulfhydryls in MD-2 structure and function, we created 17 single and multiple Cys substitution mutants. All of the MD-2 mutant proteins, including one totally lacking Cys residues, were secreted and stable. SDSPAGE analyses indicated that most Cys residues could participate in oligomer formation and that no single Cys residue was required for oligomerization. Of the single Cys substitutions, only C95S and C105S failed to confer LPS responsiveness on TLR4 when mutant and TLR4 were cotransfected into cells expressing an NF-kappaB reporter plasmid. Surprisingly, substitution of both C95 and C105 partially restored activity. Structural analyses revealed that C95 and C105 formed an intrachain disulfide bond, whereas C95 by itself produced an inactive dimer. In contrast to the cotransfection experiments, only WT MD-2 conferred responsiveness to LPS when secreted proteins were added directly to TLR4 reporter cells. Our data are consistent with a model in which most, possibly all sulfhydryls lie on the surface of a stable MD-2 core structure where they form both intra- and interchain disulfide bridges. These disulfide bonds produce a heterogeneous array of oligomers, including some species that can form an active complex with TLR4.\n" ], "offsets": [ [ 0, 1626 ] ] } ]

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[ { "id": "PMID-12642668_1", "entity_ids": [ "PMID-12642668_T4", "PMID-12642668_T5" ] }, { "id": "PMID-12642668_2", "entity_ids": [ "PMID-12642668_T7", "PMID-12642668_T8" ] } ]

[]

[ { "id": "PMID-12663670__text", "type": "abstract", "text": [ "The activation of c-Jun NH2-terminal kinase (JNK) by DNA-damaging agents serves to promote drug resistance via activating transcription factor 2 (ATF2)-dependent enhanced DNA repair. \nThe activating transcription factor 2 (ATF2) is a member of the ATF/cAMP-response element-binding protein family of basic-leucine zipper proteins involved in cellular stress response. The transcription potential of ATF2 is enhanced markedly by NH2-terminal phosphorylation by c-Jun NH2-terminal kinase (JNK) and mediates stress responses including DNA-damaging events. We have observed that four DNA-damaging agents (cisplatin, actinomycin D, MMS, and etoposide), but not the cisplatin isomer, transplatin, which does not readily damage DNA, strongly activate JNK, p38, and extracellular signal-regulated kinase (ERK), and strongly increase phosphorylation and ATF2-dependent transcriptional activity. Selective inhibition studies with PD98059, SB202190, SP600125, and the dominant negative JNK indicate that activation of JNK but not p38 kinase or ERK kinase is required for the phosphorylation and transcriptional activation of ATF2. Stable expression of ATF2 in human breast carcinoma BT474 cells increases transcriptional activity and confers resistance to the four DNA-damaging agents, but not to transplatin. Conversely, stable expression of a dominant negative ATF2 (dnATF2) quantitatively blocks phosphorylation of endogenous ATF2 leading to a marked decrease in transcriptional activity by endogenous ATF2 and a markedly increased sensitivity to the four agents as judged by decreased cell viability. Similarly, application of SB202190 at 50 micro m or SP600125 inhibited JNK activity, blocked transactivation, and sensitized parental cells to the four DNA-damaging drugs. Moreover, the wild type ATF2-expressing clones exhibited rapid DNA repair after treatment with the four DNA-damaging agents but not transplatin. Conversely, expression of dnATF2 quantitatively blocks DNA repair. These results indicate that JNK-dependent phosphorylation of ATF2 plays an important role in the drug resistance phenotype likely by mediating enhanced DNA repair by a p53-independent mechanism. JNK may be a rational target for sensitizing tumor cells to DNA-damaging chemotherapy agents.\n" ], "offsets": [ [ 0, 2267 ] ] } ]

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"normalized": [] }, { "id": "PMID-12663670_T8", "type": "Simple_chemical", "text": [ "leucine" ], "offsets": [ [ 306, 313 ] ], "normalized": [] }, { "id": "PMID-12663670_T9", "type": "Gene_or_gene_product", "text": [ "ATF2" ], "offsets": [ [ 399, 403 ] ], "normalized": [] }, { "id": "PMID-12663670_T10", "type": "Gene_or_gene_product", "text": [ "c-Jun NH2-terminal kinase" ], "offsets": [ [ 460, 485 ] ], "normalized": [] }, { "id": "PMID-12663670_T11", "type": "Gene_or_gene_product", "text": [ "JNK" ], "offsets": [ [ 487, 490 ] ], "normalized": [] }, { "id": "PMID-12663670_T12", "type": "Simple_chemical", "text": [ "cisplatin" ], "offsets": [ [ 601, 610 ] ], "normalized": [] }, { "id": "PMID-12663670_T13", "type": "Simple_chemical", "text": [ "actinomycin D" ], "offsets": [ [ 612, 625 ] ], "normalized": [] }, { "id": "PMID-12663670_T14", "type": "Simple_chemical", "text": [ "MMS" ], "offsets": [ [ 627, 630 ] ], "normalized": [] }, { "id": "PMID-12663670_T15", "type": "Simple_chemical", "text": [ "etoposide" ], "offsets": [ [ 636, 645 ] ], "normalized": [] }, { "id": "PMID-12663670_T16", "type": "Simple_chemical", "text": [ "cisplatin" ], "offsets": [ [ 660, 669 ] ], "normalized": [] }, { "id": "PMID-12663670_T17", "type": "Simple_chemical", "text": [ "transplatin" ], "offsets": [ [ 678, 689 ] ], "normalized": [] }, { "id": "PMID-12663670_T18", "type": "Gene_or_gene_product", "text": [ "JNK" ], "offsets": [ [ 744, 747 ] ], "normalized": [] }, { "id": "PMID-12663670_T19", "type": "Gene_or_gene_product", "text": [ "p38" ], "offsets": [ [ 749, 752 ] ], "normalized": [] }, { "id": "PMID-12663670_T20", "type": "Gene_or_gene_product", "text": [ "extracellular signal-regulated kinase" ], "offsets": [ [ 758, 795 ] ], "normalized": [] }, { "id": "PMID-12663670_T21", "type": "Gene_or_gene_product", "text": [ "ERK" ], "offsets": [ [ 797, 800 ] ], "normalized": [] }, { "id": "PMID-12663670_T22", "type": "Gene_or_gene_product", "text": [ "ATF2" ], "offsets": [ [ 845, 849 ] ], "normalized": [] }, { "id": "PMID-12663670_T23", "type": "Simple_chemical", "text": [ "PD98059" ], "offsets": [ [ 920, 927 ] ], "normalized": [] }, { "id": "PMID-12663670_T24", "type": "Simple_chemical", "text": [ "SB202190" ], "offsets": [ [ 929, 937 ] ], "normalized": [] }, { "id": "PMID-12663670_T25", "type": "Simple_chemical", "text": [ "SP600125" ], "offsets": [ [ 939, 947 ] ], "normalized": [] }, { "id": "PMID-12663670_T26", "type": "Gene_or_gene_product", "text": [ "JNK" ], "offsets": [ [ 975, 978 ] ], "normalized": [] }, { "id": "PMID-12663670_T27", "type": "Gene_or_gene_product", "text": [ "JNK" ], "offsets": [ [ 1007, 1010 ] ], "normalized": [] }, { "id": "PMID-12663670_T28", "type": "Gene_or_gene_product", "text": [ "p38" ], "offsets": [ [ 1019, 1022 ] ], "normalized": [] }, { "id": "PMID-12663670_T29", "type": "Gene_or_gene_product", "text": [ "ERK" ], "offsets": [ [ 1033, 1036 ] ], "normalized": [] }, { "id": "PMID-12663670_T30", "type": "Gene_or_gene_product", "text": [ "ATF2" ], "offsets": [ [ 1114, 1118 ] ], "normalized": [] }, { "id": "PMID-12663670_T31", "type": "Gene_or_gene_product", "text": [ "ATF2" ], "offsets": [ [ 1141, 1145 ] ], "normalized": [] }, { "id": "PMID-12663670_T32", "type": "Simple_chemical", "text": [ "transplatin" ], "offsets": [ [ 1286, 1297 ] ], "normalized": [] }, { "id": "PMID-12663670_T33", "type": "Gene_or_gene_product", "text": [ "ATF2" ], "offsets": [ [ 1352, 1356 ] ], "normalized": [] }, { "id": "PMID-12663670_T34", "type": "Gene_or_gene_product", "text": [ "dnATF2" ], "offsets": [ [ 1358, 1364 ] ], "normalized": [] }, { "id": "PMID-12663670_T35", "type": "Gene_or_gene_product", "text": [ "ATF2" ], "offsets": [ [ 1418, 1422 ] ], "normalized": [] }, { "id": "PMID-12663670_T36", "type": "Gene_or_gene_product", "text": [ "ATF2" ], "offsets": [ [ 1494, 1498 ] ], "normalized": [] }, { "id": "PMID-12663670_T37", "type": "Simple_chemical", "text": [ "SB202190" ], "offsets": [ [ 1620, 1628 ] ], "normalized": [] }, { "id": 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"ref_id": "PMID-12663670_E14" } ] }, { "id": "PMID-12663670_E18", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1064, 1079 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12663670_T30" } ] }, { "id": "PMID-12663670_E19", "type": "Positive_regulation", "trigger": { "text": [ "transcriptional activation" ], "offsets": [ [ 1084, 1110 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12663670_T30" } ] }, { "id": "PMID-12663670_E20", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1127, 1137 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12663670_T31" } ] }, { "id": "PMID-12663670_E21", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1318, 1328 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12663670_T33" } ] }, { "id": "PMID-12663670_E22", "type": "Negative_regulation", "trigger": { "text": [ "blocks" ], "offsets": [ [ 1381, 1387 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12663670_E23" }, { "role": "Cause", "ref_id": "PMID-12663670_E21" } ] }, { "id": "PMID-12663670_E23", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1388, 1403 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12663670_T35" } ] }, { "id": "PMID-12663670_E24", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 1655, 1664 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12663670_T39" }, { "role": "Cause", "ref_id": "PMID-12663670_T37" } ] }, { "id": "PMID-12663670_E25", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 1655, 1664 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12663670_T39" }, { "role": "Cause", "ref_id": "PMID-12663670_T38" } ] }, { "id": "PMID-12663670_E26", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1923, 1933 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12663670_T42" } ] }, { "id": "PMID-12663670_E27", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 2010, 2019 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12663670_T43" }, { "role": "Theme", "ref_id": "PMID-12663670_E28" } ] }, { "id": "PMID-12663670_E28", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 2020, 2035 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12663670_T44" } ] } ]

[ { "id": "PMID-12663670_1", "entity_ids": [ "PMID-12663670_T1", "PMID-12663670_T2" ] }, { "id": "PMID-12663670_2", "entity_ids": [ "PMID-12663670_T3", "PMID-12663670_T4" ] }, { "id": "PMID-12663670_3", "entity_ids": [ "PMID-12663670_T5", "PMID-12663670_T6" ] }, { "id": "PMID-12663670_4", "entity_ids": [ "PMID-12663670_T10", "PMID-12663670_T11" ] }, { "id": "PMID-12663670_5", "entity_ids": [ "PMID-12663670_T20", "PMID-12663670_T21" ] }, { "id": "PMID-12663670_6", "entity_ids": [ "PMID-12663670_T33", "PMID-12663670_T34" ] } ]

[]

[ { "id": "PMID-12665581__text", "type": "abstract", "text": [ "NPAT expression is regulated by E2F and is essential for cell cycle progression. \nNPAT is an in vivo substrate of cyclin E-Cdk2 kinase and is thought to play a critical role in coordinated transcriptional activation of histone genes during the G(1)/S-phase transition and in S-phase entry in mammalian cells. Here we show that NPAT transcription is up-regulated at the G(1)/S-phase boundary in growth-stimulated cells and that the NPAT promoter responds to activation by E2F proteins. We demonstrate that endogenous E2F proteins interact with the promoter of the NPAT gene in vivo and that induced expression of E2F1 stimulates NPAT mRNA expression, supporting the idea that the expression of NPAT is regulated by E2F. Consistently, we find that the E2F sites in the NPAT promoter are required for its activation during the G(1)/S-phase transition. Moreover, we show that the expression of NPAT accelerates S-phase entry in cells released from quiescence. The inhibition of NPAT expression by small interfering RNA duplexes impedes cell cycle progression and histone gene expression in tissue culture cells. Thus, NPAT is an important E2F target that is required for cell cycle progression in mammalian cells. As NPAT is involved in the regulation of S-phase-specific histone gene transcription, our findings indicate that NPAT links E2F to the activation of S-phase-specific histone gene transcription.\n" ], "offsets": [ [ 0, 1404 ] ] } ]

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"PMID-12665581_E6" }, { "role": "Cause", "ref_id": "PMID-12665581_T3" } ] }, { "id": "PMID-12665581_E6", "type": "Regulation", "trigger": { "text": [ "coordinated" ], "offsets": [ [ 177, 188 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12665581_E7" } ] }, { "id": "PMID-12665581_E7", "type": "Positive_regulation", "trigger": { "text": [ "transcriptional activation" ], "offsets": [ [ 189, 215 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12665581_T5" } ] }, { "id": "PMID-12665581_E8", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 332, 345 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12665581_T6" } ] }, { "id": "PMID-12665581_E9", "type": "Positive_regulation", "trigger": { "text": [ "up-regulated" ], "offsets": [ [ 349, 361 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12665581_E8" } ] }, { "id": "PMID-12665581_E10", "type": "Binding", "trigger": { "text": [ "interact" ], "offsets": [ [ 529, 537 ] ] }, 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"role": "Theme", "ref_id": "PMID-12665581_T17" } ] }, { "id": "PMID-12665581_E20", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 960, 970 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12665581_E21" } ] }, { "id": "PMID-12665581_E21", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 979, 989 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12665581_T18" } ] }, { "id": "PMID-12665581_E22", "type": "Negative_regulation", "trigger": { "text": [ "impedes" ], "offsets": [ [ 1024, 1031 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12665581_E20" }, { "role": "Theme", "ref_id": "PMID-12665581_E24" } ] }, { "id": "PMID-12665581_E23", "type": "Negative_regulation", "trigger": { "text": [ "impedes" ], "offsets": [ [ 1024, 1031 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12665581_E20" }, { "role": "Theme", "ref_id": "PMID-12665581_E25" } ] }, { "id": "PMID-12665581_E24", "type": 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"PMID-12665581_E34" } ] }, { "id": "PMID-12665581_E34", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 1389, 1402 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12665581_T26" } ] } ]

[]

[]

[ { "id": "PMID-12667410__text", "type": "abstract", "text": [ "Effects of red orpiment on cell morphology and expression of PML mRNA and protein in NB4 and HL-60 cells. \nOBJECTIVE: To investigate the effects of red orpiment on cell morphology, expression of promyelocytic leukemia (PML) mRNA and its protein localization in NB4 and HL-60 cell lines. METHODS: Cell morphology was assayed by Wright's staining and fluorescence staining, while PML mRNA expression was determined by RT-PCR. PML protein localization by evaluated by immunofluorescence staining. RESULTS: The typical apoptosis was found in NB4 and HL-60 cells after treatment with red orpiment. The fusion protein was no longer observed in NB4 cells, PML protein was relocated, and then degraded. In HL-60 cells, PML protein underwent a similar progress. The expression of promyelocytic leukemia (PML) mRNA was not changed in the treated cells. CONCLUSION: Red orpiment inhibits the proliferation of leukemia cells by inducing them to undergo apoptosis.\n" ], "offsets": [ [ 0, 952 ] ] } ]

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