Fig. 1.

The Hypoxia adaptive response system. Under normoxic conditions, hypoxia-inducible factor α (HIF-α) subunits are hydroxylated by prolyl hydroxylase (PHD) at specific proline residues (prolines 402 and 564 for HIF-1α and prolines 405 and 531 for HIF-2α). Hydroxylated HIFs are recognized by the von Hippel–Lindau (VHL) protein, leading to ubiquitinilation and proteasomal degradation. PHD activity is inhibited by hypoxia, allowing the nuclear translocation of HIF-α, where it dimerizes with HIF-1β to activate transcription of hypoxia target genes