Mammalian cells are able to sense prolonged decreases in oxygen concentration (hypoxia) through a conserved hypoxic response pathway. This pathway facilitates adaptation to hypoxia-induced physiological stress by regulating changes in gene expression, and is also critical for the execution of many physiological events, including formation of blood vessels during embryogenesis, and pathophysiological processes such as tumorigenesis. A family of hypoxia-inducible transcription factors (HIFs) lies at the heart of this adaptive pathway. HIF proteins are activated by a decrease in the concentration of molecular oxygen (O2), which results in the induced expression of downstream target genes that mediate adaptation and survival of cells and the whole organism.

Until recently, the means by which cells sense alterations in oxygen tension and subsequently induce changes in HIF activity remained obscure. The first inkling of an oxygen sensing pathway in higher organisms came last year with the discovery of a family of oxygen-dependent enzymes responsible for the modulation of HIF sta-