HIF‐1‐dependent transcriptional activity is required for oxygen‐mediated HIF‐1α degradation

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Abstract
Hypoxia-inducible factor-1α (HIF-1α) plays a central role in oxygen homeostasis. In normoxia, HIF-1α is a short lived protein, whereas hypoxia rapidly increases HIF-1α protein levels by relaxing its ubiquitin–proteasome-dependent degradation. In this study, we show that the p42/p44 MAP kinase cascade, known to phosphorylate HIF-1α, does not modulate the degradation/stabilization profile of HIF-1α. However, we present evidence that the rate of HIF-1α degradation depends on the duration of hypoxic stress. We demonstrate that degradation of HIF-1α is suppressed by: (i) inhibiting general transcription with actinomycin D or (ii) specifically blocking HIF-1-dependent transcriptional activity. In keeping with these findings, we postulate that HIF-1α is targetted to the proteasome via a HIF-1α proteasome targetting factor (HPTF) which expression is directly under the control of HIF-1-mediated transcriptional activity. Although HPTF is not yet molecularly identified, it is clearly distinct from the von Hippel–Lindau protein (pVHL).