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Fig. 1. Regulation of hypoxia-inducible factor (HIF) activity in response to cellular oxygen level. Two independent hydroxylation pathways regulate HIF activity in response to cellular oxygen level. In normoxia, oxygen availability enables hydroxylation of proline (P) residues of the HIF- oxygen-dependent degradation domain via prolyl hydroxylase domain (PHD) enzymes. This prolyl hydroxylation allows binding of the von Hippel-Lindau (VHL) E3 ligase, leading to ubiquitylation and proteasomal degradation of HIF- subunits. Oxygen availability also enables hydroxylation of asparagine (N) residues of the C-terminal transactivation domain (C-TAD), blocking interaction with the transcriptional co-activator p300/CBP (CREB binding protein). This event is governed by an asparaginyl hydroxylase termed factor-inhibiting HIF (FIH). As a consequence, in the presence of oxygen, active PHDs and FIH result in inactivation of HIF, and thus HIF-mediated gene transcription is blocked. In hypoxia, the PHD and FIH enzymes are inactive and the lack of hydroxylation results in stable HIF- and an active C-TAD, which is able to form a DNA-binding heterodimer with the constitutive present HIF-ß subunit and recruit the co-activator p300/CBP. Lack of oxygen and thus inactive PHD and FIH enzymes result in active HIF, which enables hypoxia-dependent gene expression of, for example, erythropoietin (EPO) and vascular endothelial growth factor (VEGF). Reproduced with permission from Masson and Ratcliffe (2003).

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