The complexity of HIF activation. This schema illustrates the numerous levels of regulation of the HIF pathway at both normoxia and hypoxia. The red dotted line indicates regulatory pathways for HIF stabilization and transcription of hypoxia-regulatable genes even at normal tissue oxygen. Note the 3 different prolyl hydroxylases, and 3 different HIF-α and HIF-β subunits. PHD indicates prolyl hydroxylase; HIF-α, hypoxia inducible factor α subunit; VHL, von Hipple Lindau protein; FIH, factor inhibiting HIFs; HIF-β, hypoxia inducible factor β subunit, or ARNT (aryl hydrocarbon receptor nuclear translocator); HSP90, heat shock protein 90; RACK1, receptor of activated kinase 1; p53, tumor suppressor protein 53; CBP/p300, CREB binding protein; and HRE, hypoxia regulatory element.