Regulation of mammalian O₂ homeostasis by hypoxia-inducible factor 1

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic-helix-loop-helix-PAS transcription factor consisting of HIF-1α and HIF-1β subunits. HIF-1α expression and HIF-1 transcriptional activity increase exponentially as cellular O₂ concentration is decreased. Several dozen target genes that are transactivated by HIF-1 have been identified, including those encoding erythropoietin, glucose transporters, glycolytic enzymes, and vascular endothelial growth factor. The products of these genes either increase O₂ delivery or allow metabolic adaptation to reduced O₂ availability. HIF-1 is required for cardiac and vascular development and embryonic survival. In fetal and postnatal life, HIF-1 is required for a variety of physiological responses to chronic hypoxia. HIF-1 expression is increased in tumor cells by multiple mechanisms and may mediate adaptation to hypoxia that is critical for tumor progression. HIF-1 thus appears to function as a master regulator of O₂ homeostasis that plays essential roles in cellular and systemic physiology, development, and pathophysiology.