How Cells Sense Oxygen

Abstract

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. and Jaakkola et al. have found that VHL binds to a specific domain of the HIF-1 subunit only when a conserved proline in that domain is hydroxylated. 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. Zhu and Bunn write a perspective on the data. M. Ivan, K. Kondo, H. Yang, W. Kim, J. Valiando, M. Ohh, A. Salic, J. M. Asara, W. S. Lane, W. G. Kaelin Jr., HIFα targeted for VHL-mediated destruction by proline hydroxylation: Implications for O 2 sensing. Science 292 , 464-468 (2001). [Abstract] [Full Text] P. Jaakkola, D. R. Mole, Y.-M. Tian, M. I. Wilson, J. Gielbert, S. J. Gaskell, A. von Kriegsheim, H. F. Hebestreit, M. Mukherji, C. J. Schofield, P. H. Maxwell, C. W. Pugh, P. J. Ratcliffe, Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O 2 -regulated prolyl hydroxylation. Science 292 , 468-472 (2001). [Abstract] [Full Text] H. Zhu, H. F. Bunn, How do cells sense oxygen? Science 292 , 449-451 (2001). [Full Text]