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HIF/HIF Prolyl-hydroxylase

HIFs are basic pleiotropic helix-loop-helix transcription factors that belong to the PAS (PER/aryl hydrocarbon receptor nuclear translocator [ARNT]/single minded) family of transcription factors. They consist of two subunits, an oxygen-sensitive a-subunit and a constitutively expressed b-subunit, which is often referred to as the ARNT. HIF-1 and HIF-2, the most extensively studied HIF transcription factors, facilitate oxygen delivery and cellular adaptation to hypoxia by regulating a wide spectrum of hypoxia responses such as angiogenesis, anaerobic glucose metabolism, mitochondrial biogenesis, and others. Under hypoxic conditions, HIF-prolyl hydroxylation is reduced, HIF-a is no longer degraded and translocates to the nucleus where it heterodimerizes with HIF-b and activates gene transcription. Oxygen-dependent hydroxylation of HIF-a is carried out by PHD1, PHD2, and PHD3, which function as oxygen sensors in the HIF pathway. The PHD/HIF axis is a critically important oxygen-sensing pathway that mediates tissue adaptation to low oxygen environments primarily through the transcriptional regulation of gene expression. The PHD/HIF pathway stimulate erythropoiesis through direct effects on the bone marrow via stimulation of EPO receptor expression, hemoglobin synthesis, and modulation of stem cell maintenance, lineage differentiation, and maturation.

References

1.Haase VH. Hemodial Int. 2017;21 Suppl 1(Suppl 1):S110–S124.