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

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...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2009-06, Vol.324 (5932), p.1289-1293
Main Authors: Dioum, Elhadji M, Chen, Rui, Alexander, Matthew S, Zhang, Quiyang, Hogg, Richard T, Gerard, Robert D, Garcia, Joseph A
Format: Article
Language:English
Subjects:
Cellular biology
Hypoxia
Proteins
Signal transduction
Online Access:Get full text
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Summary: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-2α) during hypoxia. The effect of Sirt1 on HIF-2α required direct interaction of the proteins and intact deacetylase activity of Sirt1. Select lysine residues in HIF-2α 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-2α target gene erythropoietin accordingly. Thus, Sirt1 promotes HIF-2 signaling during hypoxia and likely other environmental stresses. [PUBLICATION ABSTRACT]
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1169956