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

• Published in: Science (American Association for the Advancement of Science) Vol. 324; no. 5932; pp. 1289 - 1293
• Main Authors: Dioum, Elhadji M, Chen, Rui, Alexander, Matthew S, Zhang, Quiyang, Hogg, Richard T, Gerard, Robert D, Garcia, Joseph A
• Format: Journal Article
• Language: English
• Published: Washington The American Association for the Advancement of Science 05.06.2009
• Subjects: Cellular biology; Hypoxia; Proteins; Signal transduction
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1169956

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]