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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
13
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pubmed:dateCreated |
2008-3-20
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pubmed:abstractText |
Hypoxia-inducible factor-1alpha (HIF-1alpha) is destabilized via the ubiquitin-proteasome system. Thus HIF-1alpha expression is robustly upregulated by proteasome inhibition, but paradoxically its activity is reduced. In the present study, we investigated the mechanism underlying the paradoxical response of HIF-1alpha to proteasome inhibition. In both Hep3B and HEK293 cells, a proteasome inhibitor MG132 noticeably attenuated hypoxic induction of erythropoietin and VEGF mRNAs. MG132 inactivated HIF-1alpha C-terminal transactivation domain (CAD), independently of factor inhibiting HIF-1 (FIH) and inhibited p300 recruitment by HIF-1alpha. We next tested the possibility that CITED2 is involved in the HIF-1 inactivation. CITED2 was found to be degraded via the ubiquitin-proteasome system and thus was stabilized by proteasome inhibition. Both the activity and the p300 binding of HIF-1alpha were inhibited by CITED2 expression and recovered by CITED2 siRNA in the presence of MG132. These results suggest that CITED2 is stabilized by proteasome inhibition and inactivates HIF-1 by interfering with the HIF-1alpha-p300 interaction. This may be an important mode-of-action for proteasome inhibition-based cancer therapy.
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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/CITED2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Cysteine Proteinase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/E1A-Associated p300 Protein,
http://linkedlifedata.com/resource/pubmed/chemical/EP300 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Erythropoietin,
http://linkedlifedata.com/resource/pubmed/chemical/HIF1A protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/HIF1AN protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Hypoxia-Inducible Factor 1, alpha...,
http://linkedlifedata.com/resource/pubmed/chemical/Leupeptins,
http://linkedlifedata.com/resource/pubmed/chemical/Mixed Function Oxygenases,
http://linkedlifedata.com/resource/pubmed/chemical/Proteasome Endopeptidase Complex,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Repressor Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Trans-Activators,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Ubiquitin,
http://linkedlifedata.com/resource/pubmed/chemical/VEGFA protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Vascular Endothelial Growth Factor A,
http://linkedlifedata.com/resource/pubmed/chemical/benzyloxycarbonylleucyl-leucyl-leuci...
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
1476-5594
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
20
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pubmed:volume |
27
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1939-44
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:17906695-Carcinoma, Hepatocellular,
pubmed-meshheading:17906695-Cell Hypoxia,
pubmed-meshheading:17906695-Cells, Cultured,
pubmed-meshheading:17906695-Cysteine Proteinase Inhibitors,
pubmed-meshheading:17906695-DNA-Binding Proteins,
pubmed-meshheading:17906695-E1A-Associated p300 Protein,
pubmed-meshheading:17906695-Erythropoietin,
pubmed-meshheading:17906695-Humans,
pubmed-meshheading:17906695-Hypoxia-Inducible Factor 1, alpha Subunit,
pubmed-meshheading:17906695-Immunoprecipitation,
pubmed-meshheading:17906695-Kidney,
pubmed-meshheading:17906695-Leupeptins,
pubmed-meshheading:17906695-Liver Neoplasms,
pubmed-meshheading:17906695-Mixed Function Oxygenases,
pubmed-meshheading:17906695-Proteasome Endopeptidase Complex,
pubmed-meshheading:17906695-RNA, Messenger,
pubmed-meshheading:17906695-Repressor Proteins,
pubmed-meshheading:17906695-Trans-Activators,
pubmed-meshheading:17906695-Transcription Factors,
pubmed-meshheading:17906695-Ubiquitin,
pubmed-meshheading:17906695-Vascular Endothelial Growth Factor A
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pubmed:year |
2008
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pubmed:articleTitle |
CITED2 mediates the paradoxical responses of HIF-1alpha to proteasome inhibition.
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pubmed:affiliation |
Department of Pharmacology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul, Korea.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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