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FOXO animal models reveal a variety of diverse roles for FOXO transcription factors

Abstract

The Foxo subfamily of FOX transcription factors plays a variety of roles in a broad assortment of diverse physiological processes including cellular differentiation, tumor suppression, metabolism, cell cycle arrest, cell death and protection from stress. Animal models have proved to be invaluable tools in furthering our understanding of the role of particular genes in complex organismal processes. Multiple animal models in diverse species, including Caenorhabditis elegans, Drosophila. melanogaster and the laboratory mouse, exist for the Foxo family of transcription factors. Foxo genes are highly conserved throughout the evolution and each of these model systems has provided valuable insight into the roles of Foxo factors. Many roles are conserved among the different model organisms. Several Foxo-related animal model systems are reviewed here along with the knowledge gleaned to date from each model system.

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References

  • Adachi M, Osawa Y, Uchinami H, Kitamura T, Accili D, Brenner D . (2007). The forkhead transcription factor FoxO1 regulates proliferation and transdifferentiation of hepatic stellate cells. Gastroenterology 132: 1434–1446.

    Article  CAS  Google Scholar 

  • Arden KC . (2006). Multiple roles of FOXO transcription factors in mammalian cells point to multiple roles in cancer. Exp Gerontol 41: 709–717.

    Article  CAS  Google Scholar 

  • Castrillon DH, Miao L, Kollipara R, Horner JW, DePinho RA . (2003). Suppression of ovarian follicle activation in mice by the transcription factor Foxo3a. Science 301: 215–218.

    Article  CAS  Google Scholar 

  • Furuyama T, Kitayama K, Shimoda Y, Ogawa M, Sone K, Yoshida-Araki K et al. (2004). Abnormal angiogenesis in Foxo1 (Fkhr)-deficient mice. J Biol Chem 279: 34741–34749.

    Article  CAS  Google Scholar 

  • Giannakou ME, Goss M, Jacobson J, Vinti G, Leevers SJ, Partridge L . (2007). Dynamics of the action of dFOXO on adult mortality in Drosophila. Aging Cell 6: 429–438.

    Article  CAS  Google Scholar 

  • Giannakou ME, Goss M, Jünger MA, Hafen E, Leevers SJ, Partridge L . (2004). Long-lived Drosophila with overexpressed dFOXO in adult fat body. Science 305: 361.

    Article  CAS  Google Scholar 

  • Greer EL, Brunet A . (2005). FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 24: 7410–7425.

    Article  CAS  Google Scholar 

  • Hosaka T, Biggs W III H, Tieu D, Boyer AD, Varki NM, Cavenee WK et al. (2004). Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. Proc Natl Acad Sci USA 101: 2975–2980.

    Article  CAS  Google Scholar 

  • Hwangbo DS, Gershman B, Tu MP, Palmer M, Tatar M . (2004). Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature 429: 562–566.

    Article  CAS  Google Scholar 

  • Jacobs FM, van der Heide LP, Wijchers PJ, Burbach JP, Hoekman MF, Smidt MP . (2003). FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics. J Biol Chem 278: 35959–35967.

    Article  CAS  Google Scholar 

  • Jünger MA, Rintelen F, Stocker H, Wasserman JD, Végh M, Radimerski T et al. (2003). The Drosophila forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling. J Biol 2: 20.

    Article  Google Scholar 

  • Kamei Y, Miura S, Suzuki M, Kai Y, Mizukami J, Taniguchi T et al. (2004). Skeletal muscle FOXO1 (FKHR) transgenic mice have less skeletal muscle mass, down-regulated Type I (slow twitch/red muscle) fiber genes, and impaired glycemic control. J Biol Chem 279: 41114–41123.

    Article  CAS  Google Scholar 

  • Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R . (1993). A C. elegans mutant that lives twice as long as wild type. Nature 366: 461–464.

    Article  CAS  Google Scholar 

  • Kitamura T, Nakae J, Kitamura Y, Kido Y, Biggs III WH, Wright CV et al. (2002). The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth. J Clin Invest 110: 1839–1847.

    Article  CAS  Google Scholar 

  • Kops GJ, Dansen TB, Polderman PE, Saarloos I, Wirtz KW, Coffer PJ et al. (2002). Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419: 316–321.

    Article  CAS  Google Scholar 

  • Kramer JM, Davidge JT, Lockyer JM, Staveley BE . (2003). Expression of Drosophila FOXO regulates growth and can phenocopy starvation. BMC Dev Biol 3: 5.

    Article  Google Scholar 

  • Lin K, Dorman JB, Rodan A, Kenyon C . (1997). daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science 278: 1319–1322.

    Article  CAS  Google Scholar 

  • Lin L, Hron JD, Peng SL . (2004). Regulation of NF-kappaB, Th activation, and autoinflammation by the forkhead transcription factor Foxo3a. Immunity 21: 203–213.

    Article  CAS  Google Scholar 

  • Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA et al. (1997). The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389: 994–999.

    Article  CAS  Google Scholar 

  • Mukhopadhyay A, Tissenbaum HA . (2007). Reproduction and longevity: secrets revealed by C. elegans. Trends Cell Biol 17: 65–71.

    Article  CAS  Google Scholar 

  • Murakami S, Johnson TE . (1996). A genetic pathway conferring life extension and resistance to UV stress in Caenorhabditis elegans. Genetics 143: 1207–1218.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nakae J, Biggs III WH, Kitamura T, Cavenee WK, Wright CV, Arden KC et al. (2002). Regulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1. Nat Genet 32: 245–253.

    Article  CAS  Google Scholar 

  • Nakae J, Kitamura T, Kitamura Y, Biggs III WH, Arden KC, Accili D . (2003). The forkhead transcription factor Foxo1 regulates adipocyte differentiation. Dev Cell 4: 119–129.

    Article  CAS  Google Scholar 

  • Paik J-H, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z et al. (2007). FoxOs are lineage-restricted redundant tumor suppressors and critical regulators of endothelial cell homeostasis. Cell 128: 309–323.

    Article  CAS  Google Scholar 

  • Paradis S, Ruvkun G . (1998). Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. Genes Dev 12: 2488–2498.

    Article  CAS  Google Scholar 

  • Puig O, Marr MT, Ruhf ML, Tjian R . (2003). Control of cell number by Drosophila FOXO: downstream and feedback regulation of the insulin receptor pathway. Genes Dev 17: 2006–2020.

    Article  CAS  Google Scholar 

  • Puig O, Tjian R . (2005). Transcriptional feedback control of insulin receptor by dFOXO/FOXO1. Genes Dev 19: 2435–2446.

    Article  CAS  Google Scholar 

  • Riddle DL, Swanson MM, Albert PS . (1981). Interacting genes in nematode dauer larva formation. Nature 290: 268–271.

    Article  Google Scholar 

  • Tothova Z, Kollipara R, Huntly BJ, Lee BH, Castrillon DH, Cullen DE et al. (2007). Foxo are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128: 325–339.

    Article  CAS  Google Scholar 

  • Vogel G . (2007). Nobel Prizes. A knockout award in medicine. Science 318: 178–179.

    Article  CAS  Google Scholar 

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Correspondence to K C Arden.

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Arden, K. FOXO animal models reveal a variety of diverse roles for FOXO transcription factors. Oncogene 27, 2345–2350 (2008). https://doi.org/10.1038/onc.2008.27

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