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CITED2 mediates the paradoxical responses of HIF-1alpha to proteasome inhibition

Cited 25 time in Web of Science Cited 27 time in Scopus
Authors
Shin, D. H.; Li, S. H.; Chun, Y. S.; Huang, L. E.; Kim, M. S.; Park, J. W.
Issue Date
2007-10-02
Publisher
Nature Publishing Group
Citation
Oncogene. 2008 Mar 20;27(13):1939-44. Epub 2007 Oct 1.
Keywords
Carcinoma, Hepatocellular/drug therapy/genetics/*metabolismCell HypoxiaCells, CulturedCysteine Proteinase Inhibitors/pharmacologyDNA-Binding Proteins/*metabolismE1A-Associated p300 Protein/genetics/metabolismErythropoietin/geneticsHumansHypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolismImmunoprecipitationKidney/drug effects/metabolismLiver Neoplasms/drug therapy/genetics/*metabolismLeupeptins/pharmacologyProteasome Endopeptidase Complex/*antagonists & inhibitors/metabolismRNA, Messenger/genetics/metabolismRepressor Proteins/genetics/*metabolismTrans-Activators/*metabolismTranscription Factors/genetics/metabolismUbiquitin/*metabolismVascular Endothelial Growth Factor A/genetics
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.
ISSN
1476-5594 (Electronic)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17906695

http://hdl.handle.net/10371/29017
DOI
https://doi.org/10.1038/sj.onc.1210826
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College of Medicine/School of Medicine (의과대학/대학원)Pharmacology (약리학전공)Journal Papers (저널논문_약리학전공)
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