Abstract
In the presence of oxygen and iron, hypoxia-inducible factor (HIF-1α) is rapidly degraded via the prolyl hydroxylases (PHD)/VHL pathways. Given striking similarities between p53 and HIF-1α regulation, we previously suggested that HIF-1 transcriptionally initiates its own degradation and therefore inhibitors of transcription must induce HIF-1α. Under normoxia, while inducing p53, inhibitors of transcription did not induce HIF-1α. Under hypoxia or low iron (DFX), inhibitors of transcription dramatically super-induced HIF-1α. Removal of inhibitors resulted in outburst of the HIF-1-dependent transcription followed by depletion of HIF-1α. Although hypoxia/DFX induced PHD3, we excluded the PHD/VHL pathway in the regulation of HIF-1α under hypoxia/DFX. The transcription-dependent degradation of HIF-1α under hypoxia occurs via the proteasome and is accelerated by protein acetylation. Thus, HIF-1α is regulated by two distinct mechanisms. Under normoxia, HIF-1α 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-1α accumulates and transcriptionally activates its own degradation that is independent from the PHD/VHL pathway.
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Demidenko, Z., Rapisarda, A., Garayoa, M. et al. Accumulation of hypoxia-inducible factor-1α is limited by transcription-dependent depletion. Oncogene 24, 4829–4838 (2005). https://doi.org/10.1038/sj.onc.1208636
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DOI: https://doi.org/10.1038/sj.onc.1208636
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