Regulation of Oxygen Homeostasis by Hypoxia-Inducible Factor 1

Gregg L. Semenza Vascular Program, Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, and Departments of Pediatrics, Medicine, Oncology, and Radiation Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, gsemenza{at}jhmi.edu Metazoan organisms are dependent on a continuous supply of O 2 for survival. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that regulates oxygen homeostasis and plays key roles in development, physiology, and disease. HIF-1 activity is induced in response to continuous hypoxia, intermittent hypoxia, growth factor stimulation, and Ca 2+ signaling. HIF-1 mediates adaptive responses to hypoxia, including erythropoiesis, angiogenesis, and metabolic reprogramming. In each case, HIF-1 regulates the expression of multiple genes encoding key components of the response pathway. HIF-1 also mediates maladaptive responses to chronic continuous and intermittent hypoxia, which underlie the development of pulmonary and systemic hypertension, respectively.