S-Space College of Medicine/School of Medicine (의과대학/대학원) Pharmacology (약리학전공) Journal Papers (저널논문_약리학전공)
CITED2 mediates the paradoxical responses of HIF-1alpha to proteasome inhibition
- Shin, D. H.; Li, S. H.; Chun, Y. S.; Huang, L. E.; Kim, M. S.; Park, J. W.
- Issue Date
- Nature Publishing Group
- Oncogene. 2008 Mar 20;27(13):1939-44. Epub 2007 Oct 1.
- 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
- 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.
- 1476-5594 (Electronic)
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