The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor

doi:10.1074/jbc.M705325200

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Papers In Press, published online ahead of print August 20, 2007
J. Biol. Chem, 10.1074/jbc.M705325200
Submitted on June 28, 2007
Revised on August 17, 2007
Accepted on August 17, 2007

The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor

Eric L. Greer, Philip R. Oskoui, Max R. Banko, Jay M. Maniar, Melanie P. Gygi, Steven P. Gygi, and Anne Brunet

Department of Genetics, Stanford University, Stanford, CA 94306

Corresponding Author: anne.brunet{at}stanford.edu

The maintenance of homeostasis throughout an organism’s lifespan 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 regulate energy balance and stress resistance in cells throughout life.

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