Skip to main content
. Author manuscript; available in PMC: 2020 Sep 11.
Published in final edited form as: Blood Rev. 2019 Jul 16;37:100590. doi: 10.1016/j.blre.2019.100590

Fig. 2. The PHD2-HIF-VHL-EPO axis and its dysregulation.

Fig. 2.

(A) Scheme depicting the distinctive oxygen-sensing mechanism that regulates EPO transcription. In the presence of oxygen, PHD2 site-specifically hydroxylates HIF-2α, thereby targeting it for degradation by VHL. Little HIF-2α remains to bind the HRE of the EPO gene, so activation is modest. ARNT is the stable subunit of HIF-2.

(B) Loss-of-function mutations in PHD2, denoted by PHD2*, cause an increase in HIF-2α and increased (or inappropriately normal) EPO gene activation, designated erythrocytosis type 3 (ECYT3) in the OMIM classification.

(C) In gain-of-function mutations in HIF-2α, denoted by HIF-2α*, hydroxylation is deceased and VHL binding is reduced, leading to increased EPO gene activation, ECYT4.

(D) Loss-of-function mutations in VHL, denoted by VHL*, reduce binding to hydroxylated HIF-2α leading to increased EPO gene activation, ECYT2.

(E) A mutation in EPO, denoted by EPO* causes a frameshift that initiates excess production of EPO from a normally noncoding EPO mRNA, ECYT5.