Regulation of Mammalian O<sub>2</sub>Homeostasis by Hypoxia-Inducible Factor 1

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  • Gregg L. Semenza
    Institute for Genetic Medicine, Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-3914,

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<jats:p>▪ Abstract  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 O<jats:sub>2</jats:sub>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 O<jats:sub>2</jats:sub>delivery or allow metabolic adaptation to reduced O<jats:sub>2</jats:sub>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 O<jats:sub>2</jats:sub>homeostasis that plays essential roles in cellular and systemic physiology, development, and pathophysiology.</jats:p>

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