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Science 302 (5652): 1975-1978

Copyright © 2003 by the American Association for the Advancement of Science

Redistribution of Intracellular Oxygen in Hypoxia by Nitric Oxide: Effect on HIF1{alpha}

Thilo Hagen,1 Cormac T. Taylor,2 Francis Lam,1 Salvador Moncada1*

Abstract: Cells exposed to low oxygen concentrations respond by initiating defense mechanisms, including the stabilization of hypoxia-inducible factor (HIF) 1{alpha}, a transcription factor that upregulates genes such as those involved in glycolysis and angiogenesis. Nitric oxide and other inhibitors of mitochondrial respiration prevent the stabilization of HIF1{alpha} during hypoxia. In studies of cultured cells, we show that this effect is a result of an increase in prolyl hydroxylase–dependent degradation of HIF1{alpha}. With the use of Renilla luciferase to detect intracellular oxygen concentrations, we also demonstrate that, upon inhibition of mitochondrial respiration in hypoxia, oxygen is redistributed toward nonrespiratory oxygen-dependent targets such as prolyl hydroxylases so that they do not register hypoxia. Thus, the signaling consequences of hypoxia may be profoundly modified by nitric oxide.

1 Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.
2 Conway Institute for Biomedical and Biochemical Research, University College Dublin 4, Belfield, Dublin, Ireland.

* To whom correspondence should be addressed. E-mail: s.moncada{at}ucl.ac.uk

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Inhibition of cellular respiration by endogenously produced carbon monoxide.
G. D'Amico, F. Lam, T. Hagen, and S. Moncada (2006)
J. Cell Sci. 119, 2291-2298
   Abstract »    Full Text »    PDF »
Adventures in vascular biology: a tale of two mediators.
S. Moncada (2006)
Phil Trans R Soc B 361, 735-759
   Abstract »    Full Text »    PDF »
Persistent S-Nitrosation of Complex I and Other Mitochondrial Membrane Proteins by S-Nitrosothiols but Not Nitric Oxide or Peroxynitrite: IMPLICATIONS FOR THE INTERACTION OF NITRIC OXIDE WITH MITOCHONDRIA.
C. C. Dahm, K. Moore, and M. P. Murphy (2006)
J. Biol. Chem. 281, 10056-10065
   Abstract »    Full Text »    PDF »
Mitochondria as signaling organelles in the vascular endothelium.
M. Quintero, S. L. Colombo, A. Godfrey, and S. Moncada (2006)
PNAS 103, 5379-5384
   Abstract »    Full Text »    PDF »
Calpain Mediates a von Hippel-Lindau Protein-independent Destruction of Hypoxia-inducible Factor-1{alpha}.
J. Zhou, R. Kohl, B. Herr, R. Frank, and B. Brune (2006)
Mol. Biol. Cell 17, 1549-1558
   Abstract »    Full Text »    PDF »
Randomized Phase II Trial Comparing Nitroglycerin Plus Vinorelbine and Cisplatin With Vinorelbine and Cisplatin Alone in Previously Untreated Stage IIIB/IV Non-Small-Cell Lung Cancer.
H. Yasuda, M. Yamaya, K. Nakayama, T. Sasaki, S. Ebihara, A. Kanda, M. Asada, D. Inoue, T. Suzuki, T. Okazaki, et al. (2006)
J. Clin. Oncol. 24, 688-694
   Abstract »    Full Text »    PDF »
Nitric oxide inhibition of respiration involves both competitive (heme) and noncompetitive (copper) binding to cytochrome c oxidase.
M. G. Mason, P. Nicholls, M. T. Wilson, and C. E. Cooper (2006)
PNAS 103, 708-713
   Abstract »    Full Text »    PDF »
Nitric Oxide Is a Factor in the Stabilization of Hypoxia-Inducible Factor-1{alpha} in Cancer: Role of Free Radical Formation.
M. Quintero, P. A. Brennan, G. J. Thomas, and S. Moncada (2006)
Cancer Res. 66, 770-774
   Abstract »    Full Text »    PDF »
The oxygen sensing signal cascade under the influence of reactive oxygen species.
H. Acker (2005)
Phil Trans R Soc B 360, 2201-2210
   Abstract »    Full Text »    PDF »
Discrepancies Between Nitroglycerin and NO-Releasing Drugs on Mitochondrial Oxygen Consumption, Vasoactivity, and the Release of NO.
C. Nunez, V. M. Victor, R. Tur, A. Alvarez-Barrientos, S. Moncada, J. V. Esplugues, and P. D'Ocon (2005)
Circ. Res. 97, 1063-1069
   Abstract »    Full Text »    PDF »
Selective Activation of Inflammatory Pathways by Intermittent Hypoxia in Obstructive Sleep Apnea Syndrome.
S. Ryan, C. T. Taylor, and W. T. McNicholas (2005)
Circulation 112, 2660-2667
   Abstract »    Full Text »    PDF »
Integration of Oxygen Signaling at the Consensus HRE.
R. H. Wenger, D. P. Stiehl, and G. Camenisch (2005)
Sci. STKE 2005, re12
   Abstract »    Full Text »    PDF »
Both Microtubule-Stabilizing and Microtubule-Destabilizing Drugs Inhibit Hypoxia-Inducible Factor-1{alpha} Accumulation and Activity by Disrupting Microtubule Function.
D. Escuin, E. R. Kline, and P. Giannakakou (2005)
Cancer Res. 65, 9021-9028
   Abstract »    Full Text »    PDF »
iNOS initiates and sustains metabolic arrest in hypoxic lung adenocarcinoma cells: mechanism of cell survival in solid tumor core.
S. C. Land and C. Rae (2005)
Am J Physiol Cell Physiol 289, C918-C933
   Abstract »    Full Text »    PDF »

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