Regulation of Gene Expression by the Hypoxia-Inducible Factors

Many molecular and physiological responses to hypoxia in mammals are controlled by the transcription factors Hypoxia-Inducible Factor-1alpha (HIF-1alpha) and HIF-2alpha. Their ability to promote the transcription of hypoxia-inducible genes is mediated by protein stability and regulation of a C-terminal transactivation domain. Oxygen-dependent hydroxylation of conserved proline and asparagine residues in HIF-alpha are required for targeting HIF-alpha to proteasomes for destruction, and for inhibiting its capacity for CBP/p300-dependent transactivation, respectively. In hypoxia, the O2 required for prolyl and asparaginyl hydroxylation is limiting, and HIF-alpha is thus stabilized and competent for transcription. Because these proteins participate in angiogenesis, glycolysis, programmed cell death, cancer, and ischemia, HIF-alpha and its mediators are attractive therapeutic targets.