Module 4: Figure HIF activation
Activation of the hypoxia-inducible factor (HIF).
1. At the normal oxygen tension of blood, the hypoxia-inducible factor 1α (HIF-1α) isoform is constantly being degraded by a process that is driven by O2, which activates the O2-sensitive prolyl hydroxylase domain (PHD2) protein and factor inhibiting HIF-1 (FIH). These two proteins hydroxylate HIF-1α. 2. Two of these hydroxy groups provide binding sites for the von Hippel–Lindau (VHL) protein, which is a component of the E3 ubiquitin ligase complex. 3. Ubiquitinated HIF-1α is degraded by the proteasome. 4. At low O2 tensions, PHD2 and FIH are inactive. 5. HIF-1α is free to associated with HIF-1β to form a heterodimer. 6. The heterodimer translocates into the nucleus to initiate the transcription of genes such as vascular endothelial growth factor A (VEGF-A) that function in angiogenesis.