Hsp90 Regulates a von Hippel Lindau-independent Hypoxia-inducible Factor-1α-degradative Pathway

HIF-1 alpha is a normally labile proangiogenic transcription factor that is stabilized and activated in hypoxia. Although the von Hippel Lindau (VHL) gene product, the ubiquitin ligase responsible for regulating HIF-1 alpha protein levels, efficiently targets HIF-1 alpha for rapid proteasome-dependent degradation under normoxia, HIF-1 alpha is resistant to the destabilizing effects of VHL under hypoxia. HIF-1 alpha also associates with the molecular chaperone Hsp90. To examine the role of Hsp90 in HIF-1 alpha function, we used renal carcinoma cell (RCC) lines that lack functional VHL and express stable HIF-1 alpha protein under normoxia. Geldanamycin (GA), an Hsp90 antagonist, promoted efficient ubiquitination…

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  National Cancer Institute