The Energy Sensor AMP-activated Protein Kinase Directly Regulates the Mammalian FOXO3 Transcription Factor*
By E. L. Greer, Philip R. Oskoui, Max R. Banko, Jay M. Maniar, Melanie P. Gygi, Steven P. Gygi, A. Brunet. Journal of Biological Chemistry, 2007
859 citations recorded by the source corpus.
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.
Subfields: Aging, Geriatrics and Gerontology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/d158d24ad5f74fbe4f2e2fb4f55b98bd2a5613ac
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Aging
In Geriatrics and Gerontology
In Molecular Biology
Citations in the corpus
- FoxO transcription factors; Regulation by AKT and 14-3-3 proteins. (2011, background): “S413/588/626 are targeted by AMPK in response to nutrient deprivation and this phosphorylation positively regulates FoxO transcriptional activity, without affecting localization or DNA binding directly [112].”
- Metabolic regulation of hematopoietic stem cells in the hypoxic niche. (2011, background): “Metabolic profiling showed that cells expressing mutant IDH1 or IDH2 generated high levels of 2-hydroxyglutarate (2-HG), a metabolite also detected in leukemic cells (Ward et al., 2010; Gross et al., 2010).”
- AMPK - a nutrient and energy sensor that maintains energy homeostasis (2012, positive): “elegans and mammalian cells, AMPK upregulates genes involved in oxidative metabolism and oxidative stress resistance by regulating transcription factors of the abnormal dauer formation 16 (DAF-16)/forkhead box O (FOXO) famil”
- Redox regulation of FoxO transcription factors (2015, background): “FoxO3 transcription was induced by glucocorticoid receptor (GR)-binding steroids and further augmented by activation of AMP-activated protein kinase (AMPK).”
- Long live FOXO: unraveling the role of FOXO proteins in aging and longevity (2015, background): “Germ line loss stimulates nuclear accumulation of DAF-16/FoxO and the expression of the transcription elongation/splicing factor homolog TCER-1 in intestinal cells.”
- New insights into activation and function of the AMPK (2022, background): “AMPK also induces the expression of autophagy-related genes by modulating transcription factors such as FOXO3 (refs.(74,75)) and BRD4 (ref.”
- The AMP-activated protein kinase (AMPK) signaling pathway coordinates cell growth, autophagy, & metabolism (2011, positive): “It is worth noting that although AMPK activation inhibits expression of FOXO gluconeogenic targets in the liver, in other cell types AMPK is reported to stimulate a set of FOXO-dependent target genes in stress resistance through direct phosphorylation of novel sites in FOXO3 and FOXO4 (although not ”