Fig. 5.
Activation of hypoxia-inducible factor (HIF)–dependent gene expression via prolyl hydroxylase inhibition. Under hypoxic conditions (blue arrows), HIF-α and the constitutively expressed HIF-β bind and translocate into the cell nucleus. After binding to the DNA hypoxia response promoter element, the HIF heterodimer induces expression of hypoxia-sensitive genes. Under normoxic conditions (red arrows), prolyl hydroxylases (PHDs) hydroxylate HIF-α and thereby mark it for proteasomal degradation, effectively inhibiting HIF-dependent gene expression. Prevention of proteasomal HIF-α degradation using prolyl hydroxylase inhibitors, for example, FG-2216,144 activates hypoxia-activated signaling pathways even under normoxic conditions.