HIF

Hypoxia-inducible factor (HIF) is a transcription factor that coordinates the cellular response to low oxygen. It is a heterodimer made up of an oxygen-regulated alpha subunit (HIF-1α, HIF-2α, or HIF-3α) and a constitutively expressed beta subunit (ARNT, HIF-β). The alpha subunits determine the activity of the complex and vary in tissue distribution and target genes.

Regulation of HIF activity is primarily oxygen-dependent. In normal oxygen conditions, prolyl hydroxylases (PHD1–3) hydroxylate specific proline residues on HIF-α, enabling recognition by the VHL E3 ubiquitin ligase and subsequent proteasomal degradation. Hypoxia inhibits PHD activity, leading to stabilization of HIF-α, which then dimerizes with ARNT, binds to hypoxia-responsive elements in DNA, and activates transcription of target genes. An additional regulator, factor inhibiting HIF (FIH), can hydroxylate an asparagine residue on HIF-α to prevent recruitment of coactivators; under low oxygen this inhibition is relieved, enhancing transcriptional activity.

HIF-1α and HIF-2α have overlapping but distinct sets of target genes. HIF-1 often promotes glycolysis and angiogenesis-related genes, while HIF-2 can selectively regulate erythropoiesis and other pathways; HIF-3α is thought to act mainly as a negative regulator in some contexts. The beta subunit ARNT is shared among HIF family members and serves as the DNA-binding partner.

Physiological roles include adaptation to hypoxia during development, metabolism, angiogenesis, and wound healing. Pathologically, aberrant HIF signaling is linked to cancer progression, ischemic diseases, and inherited conditions such as von Hippel–Lindau disease and clear cell renal cell carcinoma, where VHL mutations stabilize HIF. Because of its central role in oxygen sensing, the HIF pathway is a target of therapeutic research in cancer and ischemia management.