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

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 en...

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Bibliographic Details
Published in:The Journal of biological chemistry 2007-10, Vol.282 (41), p.30107-30119
Main Authors: Greer, Eric L., Oskoui, Philip R., Banko, Max R., Maniar, Jay M., Gygi, Melanie P., Gygi, Steven P., Brunet, Anne
Format: Article
Language:English
Subjects:
Amino Acid Sequence
AMP-Activated Protein Kinases
Animals
Cell Line
Forkhead Box Protein O3
Forkhead Transcription Factors - metabolism
Gene Expression Regulation
Humans
Luciferases - metabolism
Mass Spectrometry
Mice
Mice, Transgenic
Models, Biological
Molecular Sequence Data
Multienzyme Complexes - metabolism
Phosphorylation
Protein-Serine-Threonine Kinases - metabolism
Transcription, Genetic
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M705325200