HIF-1 alpha pathway

Hypoxia-indicible 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.

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Oxygen-dependent pathway

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.

Oxygen-independent pathway

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.