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Hypoxia-inducible factors (HIFs) are transcription factors that respond to changes in available oxygen in the cellular environment, specifically to a decrease in oxygen or hypoxia.
HIF-1α regulates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia.
The importance of understanding how cells react to oxygen was made evident by the 2019 Nobel Prize in Physiology or Medicine. This was jointly awarded to William G. Kaelin Jr., Sir Peter J. Ratcliffe, and Gregg L. Semenza for their work on how cells sense oxygen availability.
Under normoxic conditions, HIF-1α is hydroxylated by oxygen-sensing HIF-1α-specific prolyl hydroxylases (PHD1–3). Hydroxylation triggers poly-ubiquitination of HIF-1α, which targets it for proteosomal degradation by an E3 ubiquitin ligase – the von Hippel-Lindau protein (pVHL) complex. HIF-1α subunits are also substrates for an asparaginyl hydroxylase, FIH-1 (factor inhibiting HIF-1α).
FIH-1 also senses oxygen, and hydroxylation by FIH-1 disrupts a critical interaction between HIF-1α subunits and co-activators such as p300/CBP, impairing HIF transcriptional activity. Hypoxia and TCA cycle intermediates inhibit hydroxylation, stabilizing the protein and allowing interaction with co-activators, resulting in transcription of target genes.
Regulation of HIF-1α stability can also be mediated by an oxygen-independent pathway. In the cytoplasm, HIF-1α is bound to heat-shock protein 90 (Hsp90), leading to enhanced HIF-1α stability. Displacement if Hsp90 by inhibitors allows RACK (receptor of activated protein C kinase) to bind and recruit ubiquitin ligase machinery, leading to HIF-1α degradation.