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J. Biol. Chem. 280 (21): 20589-20595

© 2005 by The American Society for Biochemistry and Molecular Biology, Inc.

Nuclear Trapping of the Forkhead Transcription Factor FoxO1 via Sirt-dependent Deacetylation Promotes Expression of Glucogenetic Genes*

David Frescas{ddagger}, Luca Valenti{ddagger}, , and Domenico Accili§

Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York 10032

Abstract: Activation of NAD-dependent deacetylases, or Sirtuins, prolongs life span and mimics the effects of caloric restriction in yeast. The FoxO subfamily of forkhead transcription factors has been shown to mediate some of the effects of Sirtuins. Here we have shown that Sirtuin activation or hydrogen peroxide treatment overrides the phosphorylation-dependent nuclear exclusion of FoxO1 caused by growth factors and causes nuclear translocation of FoxO1 in hepatocytes. Kinetic measurements of nuclear fluorescence recovery after photobleaching show that FoxO1 is readily diffusible within the nucleus under normal conditions but becomes restricted within a nuclear subdomain following treatment with the prototypical Sirtuin agonist resveratrol or oxidative stress. Expression of FoxO1 target genes is accordingly increased, leading to activation of gluconeogenesis and increased glucose release from hepatocytes. Selective modulation of the FoxO/Sirtuin interaction represents a promising therapeutic modality for metabolic disorders.

Received for publication November 1, 2004. Revision received March 18, 2005.

* This work was supported by National Institutes of Health Grants DK57539 and DK63608 (Columbia Diabetes and Endocrinology Research Center). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

{ddagger} Both authors contributed equally to this work.

§ To whom correspondence should be addressed: 1150 St. Nicholas Ave., New York, NY 10032. Tel.: 212-851-5332; Fax: 212-851-5331; E-mail: da230{at}columbia.edu.

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