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Science 324 (5932): 1289-1293

Copyright © 2009 by the American Association for the Advancement of Science

Regulation of Hypoxia-Inducible Factor 2{alpha} Signaling by the Stress-Responsive Deacetylase Sirtuin 1

Elhadji M. Dioum,1,2,* Rui Chen,1,2,* Matthew S. Alexander,2 Quiyang Zhang,2 Richard T. Hogg,2 Robert D. Gerard,2,3 Joseph A. Garcia1,2,{dagger}

Abstract: To survive in hostile environments, organisms activate stress-responsive transcriptional regulators that coordinately increase production of protective factors. Hypoxia changes cellular metabolism and thus activates redox-sensitive as well as oxygen-dependent signal transducers. We demonstrate that Sirtuin 1 (Sirt1), a redox-sensing deacetylase, selectively stimulates activity of the transcription factor hypoxia-inducible factor 2 alpha (HIF-2{alpha}) during hypoxia. The effect of Sirt1 on HIF-2{alpha} required direct interaction of the proteins and intact deacetylase activity of Sirt1. Select lysine residues in HIF-2{alpha} that are acetylated during hypoxia confer repression of Sirt1 augmentation by small-molecule inhibitors. In cultured cells and mice, decreasing or increasing Sirt1 activity or levels affected expression of the HIF-2{alpha} target gene erythropoietin accordingly. Thus, Sirt1 promotes HIF-2 signaling during hypoxia and likely other environmental stresses.

1 Veterans Affairs North Texas Health Care System, Department of Medicine, 4500 South Lancaster Road, Dallas, TX 75216, USA.
2 University of Texas Southwestern Medical Center at Dallas, Department of Internal Medicine, 5323 Harry Hines Boulevard, Dallas, TX 75390–8573, USA.
3 University of Texas Southwestern Medical Center at Dallas, Department of Molecular Biology, 5323 Harry Hines Boulevard, Dallas, TX 75390–8573, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: joseph.garcia{at}utsouthwestern.edu


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