Oxygen sensor model

Schematic showing a proposed model for the oxygen sensor mechanism of erythropoiesis. Under hypoxic conditions (upper left), both the alpha and beta subunits of HIF are stabilized, leading to subsequent erythropoietin (Epo) gene transcription via the aggregate effects of hepatic nuclear factor (HNF)-4, p300, and HIF-alpha and -beta. The Epo, once formed, binds to Epo receptors on committed erythroid precursor cells. Under normoxic conditions (upper middle), only the beta unit of HIF is fully expressed. The alpha unit undergoes proline hydroxylation (PH) in the presence of iron and oxygen. When hydroxylated HIF-alpha binds to the Von Hippel-Lindau protein (VHL), a ubiquitin ligase complex (UL) is activated, leading to ubiquitination and subsequent degradation of HIF-alpha via the proteasome, preventing the subsequent transcription of Epo. Mutations affecting proteins along this pathway have been associated with congenital erythrocytosis.