The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor
- PMID:17711846
- DOI: 10.1074/jbc.M705325200
The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor
Abstract
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.
Similar articles
- FOXO3 is a glucocorticoid receptor target and regulates LKB1 and its own expression based on cellular AMP levels via a positive autoregulatory loop.Lützner N, Kalbacher H, Krones-Herzig A, Rösl F.Lützner N, et al.PLoS One. 2012;7(7):e42166. doi: 10.1371/journal.pone.0042166. Epub 2012 Jul 27.PLoS One. 2012.PMID:22848740Free PMC article.
- AMPK promotes skeletal muscle autophagy through activation of forkhead FoxO3a and interaction with Ulk1.Sanchez AM, Csibi A, Raibon A, Cornille K, Gay S, Bernardi H, Candau R.Sanchez AM, et al.J Cell Biochem. 2012 Feb;113(2):695-710. doi: 10.1002/jcb.23399.J Cell Biochem. 2012.PMID:22006269
- Methylation by Set9 modulates FoxO3 stability and transcriptional activity.Calnan DR, Webb AE, White JL, Stowe TR, Goswami T, Shi X, Espejo A, Bedford MT, Gozani O, Gygi SP, Brunet A.Calnan DR, et al.Aging (Albany NY). 2012 Jul;4(7):462-79. doi: 10.18632/aging.100471.Aging (Albany NY). 2012.PMID:22820736Free PMC article.
- Regulation of fatty acid synthesis and oxidation by the AMP-activated protein kinase.Hardie DG, Pan DA.Hardie DG, et al.Biochem Soc Trans. 2002 Nov;30(Pt 6):1064-70. doi: 10.1042/bst0301064.Biochem Soc Trans. 2002.PMID:12440973Review.
- AMP-activated protein kinase regulates gene expression by direct phosphorylation of nuclear proteins.Leff T.Leff T.Biochem Soc Trans. 2003 Feb;31(Pt 1):224-7. doi: 10.1042/bst0310224.Biochem Soc Trans. 2003.PMID:12546690Review.
Cited by
- Potential role of FoxO1 and mTORC1 in the pathogenesis of Western diet-induced acne.Melnik BC, Zouboulis CC.Melnik BC, et al.Exp Dermatol. 2013 May;22(5):311-5. doi: 10.1111/exd.12142.Exp Dermatol. 2013.PMID:23614736Free PMC article.
- Anti-Aging Drugs and the Related Signal Pathways.Du N, Yang R, Jiang S, Niu Z, Zhou W, Liu C, Gao L, Sun Q.Du N, et al.Biomedicines. 2024 Jan 8;12(1):127. doi: 10.3390/biomedicines12010127.Biomedicines. 2024.PMID:38255232Free PMC article.Review.
- Vitamin D3 Exerts Beneficial Effects on C2C12 Myotubes through Activation of the Vitamin D Receptor (VDR)/Sirtuins (SIRT)1/3 Axis.Talib NF, Zhu Z, Kim KS.Talib NF, et al.Nutrients. 2023 Nov 7;15(22):4714. doi: 10.3390/nu15224714.Nutrients. 2023.PMID:38004107Free PMC article.
- AMP-activated protein kinase: a target for drugs both ancient and modern.Hardie DG, Ross FA, Hawley SA.Hardie DG, et al.Chem Biol. 2012 Oct 26;19(10):1222-36. doi: 10.1016/j.chembiol.2012.08.019.Chem Biol. 2012.PMID:23102217Free PMC article.Review.
- Cdc2-like kinase 2 is a key regulator of the cell cycle via FOXO3a/p27 in glioblastoma.Park SY, Piao Y, Thomas C, Fuller GN, de Groot JF.Park SY, et al.Oncotarget. 2016 May 3;7(18):26793-805. doi: 10.18632/oncotarget.8471.Oncotarget. 2016.PMID:27050366Free PMC article.
Publication types
MeSH terms
Substances
Related information
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Research Materials