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J. Biol. Chem., Vol. 282, Issue 41, 30107-30119, October 12, 2007

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The Energy Sensor AMP-activated Protein Kinase Directly Regulates the Mammalian FOXO3 Transcription Factor^*

Eric L. Greer¹, Philip R. Oskoui, Max R. Banko, Jay M. Maniar, Melanie P. Gygi^¶, Steven P. Gygi^¶, and Anne Brunet²

From the Department of Genetics, the Cancer Biology Program, Stanford University, Stanford, California 94305 and the ^¶Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115

The maintenance of homeostasis throughout an organism's life span requires constant adaptation to changes in energy levels. The AMP-activated protein kinase (AMPK) plays a critical role in the cellular responses to low energy levels by switching off energy-consuming pathways and switching on energy-producing pathways. However, the transcriptional mechanisms by which AMPK acts to adjust cellular energy levels are not entirely characterized. Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites. Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. Using a genome-wide microarray analysis, we identify a set of target genes that are regulated by FOXO3 when phosphorylated at these six regulatory sites in mammalian cells. The regulation of FOXO3 by AMPK may play a crucial role in fine tuning gene expression programs that control energy balance and stress resistance in cells throughout life.

Received for publication, June 28, 2007 , and in revised form, August 17, 2007.

^* This research was supported by National Institutes of Health Grant NIA AG026648-01, a Klingenstein Fellowship Award in the Neurosciences, a Pfizer/AFAR Innovations in Aging Research grant, and an American Institute for Cancer Research grant (to A. B.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1 and Tables S1–S4.

¹ Supported by NCI, National Institutes of Health, Public Health Service Grant CA 09302 and by a National Science Foundation graduate fellowship.

² To whom correspondence should be addressed: 300 Pasteur Dr., Alway M336, Stanford, CA 94305. Fax: 650-725-1534; E-mail: anne.brunet{at}stanford.edu.

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