Figure 1.

Regulation of HIF-α via VHL-dependent ubiquitylation and proteasomal degradation. (A) Alpha subunits of the Hypoxia Inducible Factors (HIFs) are constitutively expressed but are tightly regulated. Under normal oxygen availability, HIF-α subunits are hydroxylated at specific proline residues via the activity of Proline Hydroxylases (PDHs), which target HIF-α for degradation via VHL- dependent recognition and ubiquitination. (B) Under low oxygen availability, however, PDH-dependent hydroxylation of proline residues in HIF-α is absent; as a result, recognition via VHL and subsequent HIF-α degradation is inhibited. Consequently, HIF-α subunits are stabilized, accumulate, and translocate to the nucleus, forming heterodimeric complexes with HIF-1β subunits. This complex interacts with the (HIF Response Element) HRE in DNA to induce the expression of HIF target genes that regulate angiogenesis, cell growth, cell cycle progression, cell proliferation, glycolysis, and apoptosis to maintain cell growth and survival under hypoxic conditions.