Accumulation of hypoxia-inducible factor-1α is limited by transcription-dependent depletion

In the presence of oxygen and iron, hypoxia- inducible factor (HIF-1 alpha) is rapidly degraded via the prolyl hydroxylases (PHD)/VHL pathways. Given striking similarities between p53 and HIF-1 alpha regulation, we previously suggested that HIF-1 transcriptionally initiates its own degradation and therefore inhibitors of transcription must induce HIF-1 alpha. Under normoxia, while inducing p53, inhibitors of transcription did not induce HIF-1 alpha. Under hypoxia or low iron (DFX), inhibitors of transcription dramatically super- induced HIF-1 alpha. Removal of inhibitors resulted in outburst of the HIF-1-dependent transcription followed by depletion of HIF-1 alpha. Although hypoxia/ DFX induced PHD3, we excluded the PHD/VHL pathway in the regulation of HIF-1 alpha under hypoxia/DFX. The transcription-dependent degradation of HIF-1 alpha under hypoxia occurs via the proteasome and is accelerated by protein acetylation. Thus, HIF-1 alpha is regulated by two distinct mechanisms. Under normoxia, HIF-1 alpha is degraded via the classic PHD/VHL pathway, is expressed at low levels and therefore does not activate the feedback loop. But under hypoxia, HIF-1 alpha accumulates and transcriptionally activates its own degradation that is independent from the PHD/VHL pathway.