Regulation of Gene Expression by the Hypoxia-Inducible Factors

Two step model for the induction of HIF-1a and HIF-2a function. There are two major steps required for the hypoxic induction of HIF-1α and HIF-2α activity: i) inhibition of the oxygen-dependent prolyl-4-hydroxylation in the ODD to prevent the association with the pVHL–E3-ubiquitin-ligase complex (VHL), and ii) subsequent destruction by the ubiquitin (Ub) proteasome pathway, and inhibition of the oxygen-dependent asparaginyl hydroxylation in the CAD to permit association with CBP/p300, subsequent assembly of the transcriptional co-activator complex, and transcription of HIF-α target genes. The prolyl-4-hydroxylases (PHDs) and asparaginyl hydroxlase (FIH-1) function independently, with HIF-α currently as their only known substrate.