Figure 1.

The degradation, stabilization, and transcriptional function of HIF. Under normoxic condition, with Fe²⁺ as a cofactor and oxygen and 2-oxoglutaric acid (2-OG) as substrates, PHD and FIH hydroxylate HIF-α at the site of two proline residues and an asparagine residue in ODDD, respectively, accompanied by the generation of carbon dioxide and succinic acid as by-products. The prolyl hydroxylated HIF-α is preferentially recognized and ubiquitinated by VCB-Cul2 E3 ligase complex and is then targeted to proteasome for degradation. Meanwhile, hydroxylation of the asparagine residue of HIF-α prevents its recruitment and binding to coactivator p300 and CBP. Under hypoxic stress, the hydroxylation reaction of PHD and FIH is inhibited. The VCB-Cul2 E3 ligase complexes are not able to recognize and ubiquitinate HIF-α, leading to the stabilization and accumulation of HIF-α. HIF-α then translocates into the nucleus, heterodimerizes with HIF-β, and recruits coactivator p300 and CBP to specifically bind to the hypoxia response elements (HRE) of target genes, resulting in gene transcription.