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. 2020 Sep 18;9:F1000 Faculty Rev-1153. [Version 1] doi: 10.12688/f1000research.26648.1

Figure 2. Regulation of endogenous erythropoietin (EPO) gene transcription by the oxygen-sensitive hypoxia-inducible factor (HIF) pathway.

Figure 2.

The HIF transcription factor heterodimer (HIFα–HIFβ) activates the EPO gene and numerous other genes that promote tissue oxygen delivery. At high oxygen concentrations, prolyl hydroxylase (PHD) enzymes hydroxylate the HIFα subunit, targeting it for ubiquitination by the von Hippel–Lindau protein (pVHL) ubiquitin ligase complex followed by proteasomal degradation. Under hypoxia, PHD enzymes are inactive, thereby stabilizing HIF, which activates transcription of EPO and other target genes involved in tissue oxygen delivery. PHD inhibitors (PHIs) such as roxadustat and vadadustat stabilize HIFα and are under investigation for treating anemia associated with chronic renal failure. PDGFβ, platelet-derived growth factor beta; SLC40A1, solute carrier family 40 member 1; TF, Transferrin; VEGF-A, vascular endothelial growth factor A.