Hypoxia-inducible factor 1-alpha (HIF-1α) and Hypoxia-inducible factor 2-alpha (HIF-2α) (HIF-1α; HIF-2α)

Hypoxia-inducible factor 1-alpha and 2-alpha are closely related subunits of transcription factors that play central roles in cellular adaptation to low oxygen, or hypoxic, environments. Both proteins heterodimerize with HIF-1β (ARNT), forming complexes that bind specific DNA sequences known as hypoxia response elements (HREs) and activate the transcription of numerous genes involved in processes such as erythropoiesis, angiogenesis, metabolic adaptation to hypoxia, and cell survival. HIF-1α primarily regulates genes involved in glycolysis and acute response to hypoxia, while HIF-2α controls genes associated with erythropoiesis, angiogenesis, and longer-term oxygen sensing. Their dysregulation is implicated in tumor growth and progression, particularly in cancers with altered oxygen sensing such as clear cell renal cell carcinoma, where HIF-2α, in particular, is a recognized therapeutic target. Many small-molecule inhibitors are in clinical or preclinical development, and HIFs are used as biomarkers for hypoxic tumor microenvironments, disease aggressiveness, and response to therapy

Other names

HIF-1 alphaHIF1AHIF-2 alphaEPAS1Endothelial PAS domain-containing protein 1HIF-alphaHIF-αHypoxia-inducible factor alpha subunits

Inhibition of HIF-α dimerization with HIF-1β (ARNT) Promoting protein degradation of HIF-α Inhibiting transcriptional activity or DNA binding Inhibiting synthesis or accumulation of HIF-α subunits Competing for hypoxia-response element (HRE) DNA binding