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CITED2 mediates the paradoxical responses of HIF-1alpha to proteasome inhibition
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Shin, D. H. | - |
dc.contributor.author | Li, S. H. | - |
dc.contributor.author | Chun, Y. S. | - |
dc.contributor.author | Huang, L. E. | - |
dc.contributor.author | Kim, M. S. | - |
dc.contributor.author | Park, J. W. | - |
dc.date.accessioned | 2010-01-08T08:04:07Z | - |
dc.date.available | 2010-01-08T08:04:07Z | - |
dc.date.issued | 2007-10-02 | - |
dc.identifier.citation | Oncogene. 2008 Mar 20;27(13):1939-44. Epub 2007 Oct 1. | en |
dc.identifier.issn | 1476-5594 (Electronic) | - |
dc.identifier.uri | http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17906695 | - |
dc.identifier.uri | https://hdl.handle.net/10371/29017 | - |
dc.description.abstract | 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. | en |
dc.language.iso | en | en |
dc.publisher | Nature Publishing Group | en |
dc.subject | Carcinoma, Hepatocellular/drug therapy/genetics/*metabolism | en |
dc.subject | Cell Hypoxia | en |
dc.subject | Cells, Cultured | en |
dc.subject | Cysteine Proteinase Inhibitors/pharmacology | en |
dc.subject | DNA-Binding Proteins/*metabolism | en |
dc.subject | E1A-Associated p300 Protein/genetics/metabolism | en |
dc.subject | Erythropoietin/genetics | en |
dc.subject | Humans | en |
dc.subject | Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism | en |
dc.subject | Immunoprecipitation | en |
dc.subject | Kidney/drug effects/metabolism | en |
dc.subject | Liver Neoplasms/drug therapy/genetics/*metabolism | en |
dc.subject | Leupeptins/pharmacology | en |
dc.subject | Proteasome Endopeptidase Complex/*antagonists & inhibitors/metabolism | en |
dc.subject | RNA, Messenger/genetics/metabolism | en |
dc.subject | Repressor Proteins/genetics/*metabolism | en |
dc.subject | Trans-Activators/*metabolism | en |
dc.subject | Transcription Factors/genetics/metabolism | en |
dc.subject | Ubiquitin/*metabolism | en |
dc.subject | Vascular Endothelial Growth Factor A/genetics | en |
dc.title | CITED2 mediates the paradoxical responses of HIF-1alpha to proteasome inhibition | en |
dc.type | Article | en |
dc.identifier.doi | 10.1038/sj.onc.1210826 | - |
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