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

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