Figure 2.

Regulation of HIF-α subunits by O₂ availability and other intracellular metabolites. In oxygen replete cells, the HIF-prolyl hydroxylases (PHDs) are active, resulting in the hydroxylation of proline residues in HIF-α and their targeted degradation via the pVHL-proteosome pathway. “Factor-inhibiting HIF” (FIH) hydroxylation of an asparagine residue in the C-terminus of the HIF-α subunit, blocks p300 co-factor recruitment. This results in the inactivation of HIF-α subunit transcriptional activity. All of these processes are inhibited when O₂ levels decrease or cells exhibit increased levels of reactive oxygen species (ROS) and other metabolites such as fumerate, succinate, and nitric oxide (NO). Here, the HIF-α subunits are stabilized, they recruit co-activators such as p300, and activate HIF target genes, as described in Figure 1.