HIF-1-dependent transcriptional activity is required for oxygen-mediated HIF-1 alpha degradation

Hypoxia-inducible factor-1 alpha (HIF-1 alpha) plays a central role in oxyg en homeostasis. In normoxia, HIF-1 alpha. is a short lived protein, whereas hypoxia rapidly increases HIF-1 alpha protein levels by relaxing its ubiqu itin-proteasome-dependcnt degradation. In this study, we show that the p42/ p44 MAP kinase cascade, known to phosphorylate HIF-1 alpha, does not modula te the degradation/stabilization profile of HIF-1 alpha. E-Iovrever, we pre sent evidence that the rate of HIF-1 alpha degradation depends on the durat ion of hypoxic stress. Wc demonstrate that degradation of HIF-1 alpha is su ppressed by: (i) inhibiting general transcription with actinomycin D or (ii ) specifically blocking HIF-1-dependent transcriptional activity. In keepin g with these findings, we postulate that HIF-1 alpha is targetted to the pr oteasome via a HIF-1 alpha. proteasome targetting factor (HPTF) which expre ssion is directly under the control of HIF-1-mediated transcriptional activ ity, Although HPTF is not set molecularly identified, it is clearly distinc t from the von Hippel-Lindau protein (pVHL.), (C) 2001 Federation of Europe an Biochemical Societies. Published by Elsevier Science B,V, All rights res erved.