Figure 1. Overview of HIF regulation.

Under normoxia hydroxylation of hypoxia-inducible factor (HIF)-α subunits by prolyl-4-hydroxylases is required for binding to the pVHL-E3-ubiquitin ligase complex, which poly-ubiquitinates HIF-α and targets it for proteasomal degradation. When prolyl-4-hydroxylation is inhibited HIFα is stabilized and translocates to the nucleus where it heterodimerizes with HIF-β. HIF-α/β heterodimers bind to the HIF consensus binding site RCGTG and regulate transcription of HIF target genes, for example, EPO, VEGF, and GLUT-1. Factor-inhibiting-HIF (FIH) is an asparagines hydroxylase that modulates cofactor recruitment to the HIF transcriptional complex through oxygen-dependent asparagines hydroxylation of the HIF-α carboxy-terminal transactivation domain. FIH also modulates the cross talk between Notch and HIF pathways through Notch ICD hydroxylation.³⁴ Non-canonical HIF signaling occurs through functional interaction with other proteins, such as the Notch intracellular domain (for a more complete overview of HIF-α-interacting proteins see Wenger et al.¹²). Nitric oxide, reactive oxygen species, the Krebs cycle metabolites succinate and fumarate, cobalt chloride, and iron chelators such as desferrioxamine are known to inhibit HIF prolyl-4-hydroxylases in the presence of oxygen. Asn, asparagine; CoCl₂, cobalt chloride; EPO, erythropoietin; Fe²⁺, ferrous iron; GLUT-1, glucose transporter 1; HRE, hypoxia response element; NO, nitric oxide; Notch ICD, Notch intracellular domain; VEGF, vascular endothelial growth factor; ROS, reactive oxygen species.