CITED2 mediates the paradoxical responses of HIF-1alpha to proteasome inhibition.
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.
Mesh Terms:
Carcinoma, Hepatocellular, Cell Hypoxia, Cells, Cultured, Cysteine Proteinase Inhibitors, DNA-Binding Proteins, E1A-Associated p300 Protein, Erythropoietin, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Immunoprecipitation, Kidney, Leupeptins, Liver Neoplasms, Mixed Function Oxygenases, Proteasome Endopeptidase Complex, Proteasome Inhibitors, RNA, Messenger, Repressor Proteins, Trans-Activators, Transcription Factors, Ubiquitin, Vascular Endothelial Growth Factor A
Carcinoma, Hepatocellular, Cell Hypoxia, Cells, Cultured, Cysteine Proteinase Inhibitors, DNA-Binding Proteins, E1A-Associated p300 Protein, Erythropoietin, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Immunoprecipitation, Kidney, Leupeptins, Liver Neoplasms, Mixed Function Oxygenases, Proteasome Endopeptidase Complex, Proteasome Inhibitors, RNA, Messenger, Repressor Proteins, Trans-Activators, Transcription Factors, Ubiquitin, Vascular Endothelial Growth Factor A
Oncogene
Date: Mar. 20, 2008
PubMed ID: 17906695
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