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CITED2 mediates the paradoxical responses of HIF-1alpha to proteasome inhibition
Cited 31 time in
Web of Science
Cited 33 time in Scopus
- Authors
- 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/*metabolism ; Cell Hypoxia ; Cells, Cultured ; Cysteine Proteinase Inhibitors/pharmacology ; DNA-Binding Proteins/*metabolism ; E1A-Associated p300 Protein/genetics/metabolism ; Erythropoietin/genetics ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism ; Immunoprecipitation ; Kidney/drug effects/metabolism ; Liver Neoplasms/drug therapy/genetics/*metabolism ; Leupeptins/pharmacology ; Proteasome Endopeptidase Complex/*antagonists & inhibitors/metabolism ; RNA, Messenger/genetics/metabolism ; Repressor Proteins/genetics/*metabolism ; Trans-Activators/*metabolism ; Transcription Factors/genetics/metabolism ; Ubiquitin/*metabolism ; Vascular 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
https://hdl.handle.net/10371/29017
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