Hypoxia-inducible factor: roles in development, physiology, and disease.

摘要

Multi-cellular organisms have evolved multiple mechanisms to respond to decreased oxygen levels (hypoxia). Healthy individuals typically encounter hypoxia at high altitudes, where at least three prominent physiological responses take place: neurotransmitter release by the carotid body to increase breathing; pulmonary vascular constriction to shunt blood to better oxygenated regions of the lung; and production of the hormone erythropoietin to enhance red blood cell mass and hemoglobin concentration in the blood. Hypoxia is also a feature of many diseases such as pulmonary hypertension, chronic obstructive pulmonary disease, sepsis, myocardial ischemia, and cancer.Although physiological responses to hypoxia at the organismal and tissue level have been appreciated for decades, the molecular and cellular biology of hypoxia have only been elucidated in the past 15 years. Notably, the discovery of the transcription factor hypoxia-inducible factor (HIF)-1, by Gregg Semenza and colleagues in the 1990s provideda molecular platform to investigate the mechanisms underlying responses to O_2 deprivation. HIF-1 was discovered as a nuclear factor bound to a cis-acting hypoxia response element in the 3' flanking region of the erythropoietin gene during hypoxia. Further biochemical purification experiments led to the identification of genes encoding the HIF-1alpha and HIF-1beta subunits. HIF-1alpha protein is only detectable under hypoxic conditions, while HIF-1beta subunit is constitutively stable. Subsequently, HIF-2alpha and HIF-3alpha were discovered, which show similar regulation in response to hypoxia.