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MBC in Press, published online ahead of print October 17, 2007
Mol. Biol. Cell 10.1091/mbc.E07-06-0612

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Submitted on June 27, 2007
Revised on September 18, 2007
Accepted on October 10, 2007

Hypoxia-inducible Factor-1{alpha} Stabilization in Nonhypoxic Conditions: Role of Oxidation and Intracellular Ascorbate Depletion

Elisabeth L. Pagé,* Denise A. Chan,{dagger} Amato J. Giaccia,{dagger} Mark Levine,{ddagger} and Darren E. Richard*

*Centre de recherche de L’Hôtel-Dieu de Québec, Department of Medicine, Université Laval, Québec, QC, G1R 2J6, Canada; {dagger}Center for Clinical Science Research, Department of Radiation Oncology, Stanford University, Stanford, CA 94305; {ddagger}Molecular and Clinical Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892

Monitoring Editor: J. Silvio Gutkind

Hypoxia-inducible factor-1 (HIF-1) is a decisive element for the transcriptional regulation of many genes induced under low oxygen conditions. Under normal oxygen conditions, HIF-1{alpha}, the active subunit of HIF-1, is hydroxylated on proline residues by specific prolyl-hydroxylases (PHD) leading to ubiquitination and degradation by the proteasome. In hypoxia, hydroxylation and ubiquitination are blocked and HIF-1{alpha} accumulates in cells. Recent studies have shown that in normal oxygen conditions G-protein-coupled receptor agonists, including Ang II and thrombin, potently induce and activate HIF-1 in vascular smooth muscle cells. The current study identifies HIF-1{alpha} protein stabilization as a key mechanism for HIF-1 induction by Ang II. We show that hydroxylation on proline 402 is altered by Ang II, decreasing pVHL binding to HIF-1{alpha} and allowing HIF-1{alpha} protein to escape subsequent ubiquitination and degradation mechanisms. We show that HIF-1{alpha} stability is mediated through the Ang II-mediated generation of hydrogen peroxide and a subsequent decrease in ascorbate levels leading to decreased HIF prolyl-hydroxylase activity and HIF-1{alpha} stabilization. These findings identify novel and intricate signaling mechanisms involved in HIF-1 complex activation and will lead to the elucidation of the importance of HIF-1 in different Ang II-related cell responses.

Address correspondence to: Darren E. Richard (darren.richard{at}crhdq.ulaval.ca)






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