Oxygen sensing and response to hypoxia by mammalian cells.

Cells are able to sense reduced oxygen tension and modulate the expression of specific genes in order to adapt to hypoxic conditions. In the carotid body and pulmonary neuroepithelial bodies a heme-containing nicotinamide-adenine dinucleotide phosphate oxidase-coupled potassium channel serves as an oxygen sensor. Membrane depolarization triggers an increase in intracellular calcium levels and cellular responses. Hemoproteins may also sense oxygen In non-depolarizable cells. Hypoxia signal transduction involves protein phosphorylation and is affected by cellular redox state. Src, Ras, Raf and MAP kinases have been implicated in some systems involving hypoxia signal transduction. Gene products that are induced by hypoxia include cytokines, metabolic enzymes, transcription factors, cellular redox regulators and protective proteins. Study of hypoxic activation of erythropoietin gene transcription identified a hypoxia-inducible enhancer and transcription factor HIF-1 (hypoxia-inducible factor 1). Recent evidence suggests that HIF-1 may regulate transcription of hypoxia-inducible genes in a variety of cell types in cooperation with other transcription factors and may play an important role in coupling signal transduction pathways to the transcriptional activation of hypoxia inducible genes.