FOXO Transcription Factors: Key Regulators of Cellular Quality Control

Overview

Journal Trends Biochem Sci

Specialty Biochemistry

Date 2014 Mar 18

PMID 24630600

Citations 293

Authors

Ashley E Webb

Anne Brunet

Affiliations

Soon will be listed here.

Abstract

FOXO transcription factors are conserved regulators of longevity downstream of insulin signaling. These transcription factors integrate signals emanating from nutrient deprivation and stress stimuli to coordinate programs of genes involved in cellular metabolism and resistance to oxidative stress. Here, we discuss emerging evidence for a pivotal role of FOXO factors in promoting the expression of genes involved in autophagy and the ubiquitin-proteasome system--two cell clearance processes that are essential for maintaining organelle and protein homeostasis (proteostasis). The ability of FOXO to maintain cellular quality control appears to be critical in processes and pathologies where damaged proteins and organelles accumulate, including aging and neurodegenerative diseases.

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References

Gumucio J, Mendias C . Atrogin-1, MuRF-1, and sarcopenia. Endocrine. 2012; 43(1):12-21. PMC: 3586538. DOI: 10.1007/s12020-012-9751-7. View

Husom A, Peters E, Kolling E, Fugere N, Thompson L, Ferrington D . Altered proteasome function and subunit composition in aged muscle. Arch Biochem Biophys. 2003; 421(1):67-76. DOI: 10.1016/j.abb.2003.10.010. View

Kenyon C . The genetics of ageing. Nature. 2010; 464(7288):504-12. DOI: 10.1038/nature08980. View

Xu P, Das M, Reilly J, Davis R . JNK regulates FoxO-dependent autophagy in neurons. Genes Dev. 2011; 25(4):310-22. PMC: 3042155. DOI: 10.1101/gad.1984311. View

Kaeberlein M, Powers 3rd R, Steffen K, Westman E, Hu D, Dang N . Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science. 2005; 310(5751):1193-6. DOI: 10.1126/science.1115535. View

Demontis F, Perrimon N . FOXO/4E-BP signaling in Drosophila muscles regulates organism-wide proteostasis during aging. Cell. 2010; 143(5):813-25. PMC: 3066043. DOI: 10.1016/j.cell.2010.10.007. View

Mammucari C, Schiaffino S, Sandri M . Downstream of Akt: FoxO3 and mTOR in the regulation of autophagy in skeletal muscle. Autophagy. 2008; 4(4):524-6. DOI: 10.4161/auto.5905. View

Yeo H, Lyssiotis C, Zhang Y, Ying H, Asara J, Cantley L . FoxO3 coordinates metabolic pathways to maintain redox balance in neural stem cells. EMBO J. 2013; 32(19):2589-602. PMC: 3791369. DOI: 10.1038/emboj.2013.186. View

Melendez A, Talloczy Z, Seaman M, Eskelinen E, Hall D, Levine B . Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science. 2003; 301(5638):1387-91. DOI: 10.1126/science.1087782. View

10.

Jia K, Thomas C, Akbar M, Sun Q, Adams-Huet B, Gilpin C . Autophagy genes protect against Salmonella typhimurium infection and mediate insulin signaling-regulated pathogen resistance. Proc Natl Acad Sci U S A. 2009; 106(34):14564-9. PMC: 2731839. DOI: 10.1073/pnas.0813319106. View

11.

van der Horst A, Tertoolen L, de Vries-Smits L, Frye R, Medema R, Burgering B . FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). J Biol Chem. 2004; 279(28):28873-9. DOI: 10.1074/jbc.M401138200. View

12.

Laplante M, Sabatini D . mTOR signaling in growth control and disease. Cell. 2012; 149(2):274-93. PMC: 3331679. DOI: 10.1016/j.cell.2012.03.017. View

13.

Calnan D, Webb A, White J, Stowe T, Goswami T, Shi X . Methylation by Set9 modulates FoxO3 stability and transcriptional activity. Aging (Albany NY). 2012; 4(7):462-79. PMC: 3433933. DOI: 10.18632/aging.100471. View

14.

Morley J, Brignull H, Weyers J, Morimoto R . The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 2002; 99(16):10417-22. PMC: 124929. DOI: 10.1073/pnas.152161099. View

15.

Hu M, Lee D, Xia W, Golfman L, Ou-Yang F, Yang J . IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell. 2004; 117(2):225-37. DOI: 10.1016/s0092-8674(04)00302-2. View

16.

Kamei Y, Mizukami J, Miura S, Suzuki M, Takahashi N, Kawada T . A forkhead transcription factor FKHR up-regulates lipoprotein lipase expression in skeletal muscle. FEBS Lett. 2003; 536(1-3):232-6. DOI: 10.1016/s0014-5793(03)00062-0. View

17.

Dobrowolny G, Aucello M, Rizzuto E, Beccafico S, Mammucari C, Boncompagni S . Skeletal muscle is a primary target of SOD1G93A-mediated toxicity. Cell Metab. 2008; 8(5):425-36. DOI: 10.1016/j.cmet.2008.09.002. View

18.

Lin Y, Jhunjhunwala S, Benner C, Heinz S, Welinder E, Mansson R . A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates B cell fate. Nat Immunol. 2010; 11(7):635-43. PMC: 2896911. DOI: 10.1038/ni.1891. View

19.

Lokireddy S, Wijesoma I, Teng S, Bonala S, Gluckman P, McFarlane C . The ubiquitin ligase Mul1 induces mitophagy in skeletal muscle in response to muscle-wasting stimuli. Cell Metab. 2012; 16(5):613-24. DOI: 10.1016/j.cmet.2012.10.005. View

20.

Lopez-Otin C, Blasco M, Partridge L, Serrano M, Kroemer G . The hallmarks of aging. Cell. 2013; 153(6):1194-217. PMC: 3836174. DOI: 10.1016/j.cell.2013.05.039. View