Regulation of Hypoxia-Inducible Factor 2α Signaling by the Stress-Responsive Deacetylase Sirtuin 1

Elhadji M. Dioum, Rui Chen, Matthew S. Alexander, Quiyang Zhang, Richard T. Hogg, Robert D. Gerard, Joseph A. Garcia

Research output: Contribution to journalArticlepeer-review

347 Scopus citations

Abstract

To survive in hostile environments, organisms activate stress-responsive transcriptional regulators that coordinated 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.

Original languageEnglish (US)
Pages (from-to)1289-1293
Number of pages5
JournalScience
Volume324
Issue number5932
DOIs
StatePublished - 2009

ASJC Scopus subject areas

  • General

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