Under normal oxygen levels, HIF-α is hydroxylated by prolyl hydroxylase domain enzymes (PHDs), marking it for ubiquitination and proteasomal degradation by the von Hippel-Lindau (VHL) tumor suppressor protein. In hypoxic conditions, the activity of PHDs is inhibited, leading to the stabilization and accumulation of HIF-α, which then dimerizes with HIF-β to activate target gene transcription.
