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. Author manuscript; available in PMC: 2015 Jan 1.
Published in final edited form as: Blood Cells Mol Dis. 2013 Aug 28;52(1):35–45. doi: 10.1016/j.bcmd.2013.07.016

Figure 6.

Figure 6

Proposed mechanism for divergent expression of HIF-target genes according to iron status. Upper panel: With non-mutated VHL and normal iron status in normoxia, the alpha subunits of HIF are degraded in the proteasome after prolyl hydroxylation through the action of PHD2. Middle panel: The homozygous VHLR200W mutation causes impaired recognition of hydroxylated alpha-subunits of HIF, leading to increased levels of the alpha subunits of HIF and increased transcription of HIF target genes under normoxia. Lower panel: The addition of iron deficiency leads to a further increase in HIF-1α through impaired function of PHD2, but a decrease in HIF-2α because of reduced translation of HIF-2α through the interaction of iron responsive protein (IRP) with an iron response element in the 5’ untranslated region of HIF-2α mRNA.