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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
46
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pubmed:dateCreated |
2005-11-15
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pubmed:abstractText |
Active NF-kappaB renders malignant hepatocytes refractory to the growth inhibitory and pro-apoptotic properties of transforming growth factorbeta1 (TGF-beta1). NF-kappaB counteracts TGF-beta1-induced apoptosis through up-regulation of downstream target genes, such as XIAP and Bcl-X(L), which in turn inhibit the intrinsic pathway of apoptosis. In addition, induction of NF-kappaB by TGF-beta1 inhibits JNK signaling, thereby attenuating TGF-beta1-induced cell death of normal hepatocytes. However, the mechanism involved in the negative cross-talk between the NF-kappaB and JNK pathways during TGF-beta1 signaling has not been determined. In this study, we have identified the XIAP gene as one of the critical mediators of NF-kappaB-mediated suppression of JNK signaling. We show that NF-kappaB plays a role in the up-regulation of XIAP gene expression in response to TGF-beta1 treatment and forms a TGF-beta1-inducible complex with TAK1. Furthermore, we show that the RING domain of XIAP mediates TAK1 polyubiquitination, which then targets this molecule for proteosomal degradation. Down-regulation of TAK1 protein expression inhibits TGF-beta1-mediated activation of JNK and apoptosis. Conversely, silencing of XIAP promotes persistent JNK activation and potentiates TGF-beta1-induced apoptosis. Collectively, our findings identify a novel mechanism for the regulation of JNK activity by NF-kappaB during TGF-beta1 signaling and raise the possibility that pharmacologic inhibition of the NF-kappaB/XIAP signaling pathway might selectively abolish the pro-oncogenic activity of TGF-beta1 in advanced hepatocellular carcinomas (HCCs) without affecting the pro-apoptotic effects of TGF-beta1 involved in normal liver homeostasis.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Anthracenes,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Glutathione Transferase,
http://linkedlifedata.com/resource/pubmed/chemical/Luciferases,
http://linkedlifedata.com/resource/pubmed/chemical/MAP Kinase Kinase 4,
http://linkedlifedata.com/resource/pubmed/chemical/MAP Kinase Kinase Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/MAP kinase kinase kinase 7,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase 8,
http://linkedlifedata.com/resource/pubmed/chemical/NF-kappa B,
http://linkedlifedata.com/resource/pubmed/chemical/Proteasome Endopeptidase Complex,
http://linkedlifedata.com/resource/pubmed/chemical/TGFB1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Tgfb1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Tgfb1 protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factor AP-1,
http://linkedlifedata.com/resource/pubmed/chemical/Transforming Growth Factor beta,
http://linkedlifedata.com/resource/pubmed/chemical/Transforming Growth Factor beta1,
http://linkedlifedata.com/resource/pubmed/chemical/Ubiquitin,
http://linkedlifedata.com/resource/pubmed/chemical/X-Linked Inhibitor of Apoptosis...,
http://linkedlifedata.com/resource/pubmed/chemical/anthra(1,9-cd)pyrazol-6(2H)-one,
http://linkedlifedata.com/resource/pubmed/chemical/bcl-X Protein
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
18
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pubmed:volume |
280
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
38599-608
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pubmed:dateRevised |
2011-11-2
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pubmed:meshHeading |
pubmed-meshheading:16157589-Animals,
pubmed-meshheading:16157589-Anthracenes,
pubmed-meshheading:16157589-Apoptosis,
pubmed-meshheading:16157589-Carcinoma, Hepatocellular,
pubmed-meshheading:16157589-Cell Death,
pubmed-meshheading:16157589-Cells, Cultured,
pubmed-meshheading:16157589-Dose-Response Relationship, Drug,
pubmed-meshheading:16157589-Down-Regulation,
pubmed-meshheading:16157589-Enzyme Activation,
pubmed-meshheading:16157589-Enzyme Inhibitors,
pubmed-meshheading:16157589-Gene Silencing,
pubmed-meshheading:16157589-Glutathione Transferase,
pubmed-meshheading:16157589-Hepatocytes,
pubmed-meshheading:16157589-Humans,
pubmed-meshheading:16157589-Immunoblotting,
pubmed-meshheading:16157589-Luciferases,
pubmed-meshheading:16157589-MAP Kinase Kinase 4,
pubmed-meshheading:16157589-MAP Kinase Kinase Kinases,
pubmed-meshheading:16157589-Male,
pubmed-meshheading:16157589-Mice,
pubmed-meshheading:16157589-Mitogen-Activated Protein Kinase 8,
pubmed-meshheading:16157589-Models, Biological,
pubmed-meshheading:16157589-NF-kappa B,
pubmed-meshheading:16157589-Proteasome Endopeptidase Complex,
pubmed-meshheading:16157589-Protein Binding,
pubmed-meshheading:16157589-Protein Structure, Tertiary,
pubmed-meshheading:16157589-Rats,
pubmed-meshheading:16157589-Rats, Sprague-Dawley,
pubmed-meshheading:16157589-Signal Transduction,
pubmed-meshheading:16157589-Time Factors,
pubmed-meshheading:16157589-Transcription Factor AP-1,
pubmed-meshheading:16157589-Transfection,
pubmed-meshheading:16157589-Transforming Growth Factor beta,
pubmed-meshheading:16157589-Transforming Growth Factor beta1,
pubmed-meshheading:16157589-Ubiquitin,
pubmed-meshheading:16157589-Up-Regulation,
pubmed-meshheading:16157589-X-Linked Inhibitor of Apoptosis Protein,
pubmed-meshheading:16157589-bcl-X Protein
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pubmed:year |
2005
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pubmed:articleTitle |
X-linked inhibitor of apoptosis (XIAP) inhibits c-Jun N-terminal kinase 1 (JNK1) activation by transforming growth factor beta1 (TGF-beta1) through ubiquitin-mediated proteosomal degradation of the TGF-beta1-activated kinase 1 (TAK1).
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pubmed:affiliation |
Department of Pharmacology, University of Tennessee Cancer Institute (UTCI), University of Tennessee Health Science Center, College of Medicine, University of Tennessee, Memphis, Tennessee 38163, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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