Regulation of Gene Expression by the Hypoxia-Inducible Factors

Oxygen dependent degradation of HIF-1a and HIF-2a. In normoxia, a specific proline within HIF-1α (P⁵⁶⁴, or P⁵³¹ in HIF-2α) is hydroxylated by O₂-, 2-oxoglutarate-, ascorbate-, and Fe²⁺-dependent HIF-α prolyl-4-hydroxylases (PHDs). This targets the HIF-α protein for association with the von Hippel-Lindau protein (pVHL) that serves as the HIF-α recognition component of an E3 ubiquitin ligase complex (VHL) also containing elongins B and C, cullin 2, and Rbx 1 and results in degradation of HIF-α protein via the ubiquitin proteasome pathway. In hypoxia, the required O₂ for prolyl-4-hydroxylase activity is deficient. As a result, HIF-α protein is not degraded because the prolyl-4-hydroxylation required for targeting by the VHL complex is inhibited.