How Cells Sense Oxygen

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Science  20 Apr 2001:
Vol. 292, Issue 5516, pp. 393
DOI: 10.1126/science.292.5516.393f

Mammalian cells are exquisitely sensitive to changes in oxygen concentration. When oxygen becomes limiting (hypoxia), the cells increase the transcription of genes that enhance oxygen delivery or that facilitate metabolic adjustment to reduced oxygen availability. This adaptive response is mediated by hypoxia-inducible factor (HIF), which is stable under hypoxic conditions but is degraded in the presence of oxygen by a ubiquitin ligase containing the von Hippel-Lindau (VHL) tumor suppressor protein. Ivan et al. (p. 464) and Jaakkola et al. (p. 468) have found that VHL binds to a specific domain of the HIF-1 subunit only when a conserved proline in that domain is hydroxylated (see the Perspective by Zhu and Bunn). The enzymes that catalyze prolyl hydroxylation require oxygen as a substrate, which suggests that this protein modification plays a key role in cellular oxygen sensing. This discovery could open up new therapeutic possibilities for the many diseases in which hypoxia plays a crucial role, including cancer, ischemic heart disease, hypertension, and stroke.

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