Figure 1. HIF-1 regulates the balance between O₂ supply and demand.

In well-oxygenated cells, prolyl hydroxylase domain (PHD) proteins use O₂ and α-ketoglutarate (αKG) to hydroxylate HIF-1α, which is then bound by VHL, ubiquitylated, and degraded by the proteasome. Under hypoxic conditions, the hydroxylation reaction is inhibited and HIF-1α accumulates and regulates cell proliferation directly or dimerizes with HIF-1β to activate the transcription of hundreds of target genes, many of which encode enzymes and transporters that control cell metabolism. Red and blue arrows indicate reactions that are favored in aerobic and hypoxic conditions, respectively.