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Gene Review

Foxo1  -  forkhead box O1

Mus musculus

Synonyms: AI876417, Afxh, FKHR, Fkhr, Fkhr1, ...
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Disease relevance of Foxo1

  • In contrast, a transcriptionally inactive mutant Foxo1 partially rescues inhibition of C2C12 differentiation mediated by wortmannin, but not by rapamycin, and is able to induce aggregation-independent myogenic conversion of teratocarcinoma cells [1].
  • In the present study we mutated Leu375 to alanine in the nuclear export signal of Foxo1 (mouse FOXO1), so that it would remain in the nucleus of H4IIE rat hepatoma cells after insulin treatment, and determined whether insulin could still inhibit transcription stimulated by the Foxo1 mutant [2].
  • We propose that low expression of SIRT1 and Foxo1 leads to impaired Foxo1-C/EBPalpha complex formation, which contributes to the diminished adiponectin expression in obesity and type 2 diabetes [3].
  • Foxo transcription factors blunt cardiac hypertrophy by inhibiting calcineurin signaling [4].
  • Transgenic mice expressing a constitutively active Foxo1 allele exhibited hypertriglyceridemia [5].

Psychiatry related information on Foxo1


High impact information on Foxo1

  • Haploinsufficiency of the gene for the transcription factor Foxo1 resulted in a marked increase in the number, but not the size, of cells and resulted in the restoration of glucose homeostasis in betaPdk1(-/-) mice [7].
  • Conversely, a gain-of-function Foxo1 mutation targeted to liver and pancreatic beta-cells results in diabetes arising from a combination of increased hepatic glucose production and impaired beta-cell compensation due to decreased Pdx1 expression [8].
  • These data indicate that Foxo1 is a negative regulator of insulin sensitivity in liver, adipocytes and pancreatic beta-cells [8].
  • We show that haploinsufficiency of the Foxo1 gene, encoding a forkhead transcription factor (forkhead box transcription factor O1), restores insulin sensitivity and rescues the diabetic phenotype in insulin-resistant mice by reducing hepatic expression of glucogenetic genes and increasing adipocyte expression of insulin-sensitizing genes [8].
  • Two components known to have important physiological roles in this process are the forkhead transcription factor FOXO1 (also known as FKHR) and peroxisome proliferative activated receptor-gamma co-activator 1 (PGC-1alpha; also known as PPARGC1), a transcriptional co-activator; whether and how these factors collaborate has not been clear [9].

Chemical compound and disease context of Foxo1

  • While loss of insulin response is associated with unrestrained apoC-III production and impaired triglyceride metabolism, these data suggest that Foxo1 provides a molecular link between insulin deficiency or resistance and aberrant apoC-III production in the pathogenesis of diabetic hypertriglyceridemia [5].

Biological context of Foxo1

  • We propose that insulin/IGFs regulate beta cell proliferation by relieving Foxo1 inhibition of Pdx1 expression in a subset of cells embedded within pancreatic ducts [10].
  • Although the morphology of the endothelial cell colonies was identical in both genotypes in the absence of exogenous vascular endothelial growth factor (VEGF), Foxo1-deficient endothelial cells showed a markedly different morphological response compared with wild-type endothelial cells in the presence of exogenous VEGF [11].
  • Conversely, expression of a constitutively active Akt (Akt-Myr) in insulin receptor-deficient hepatocytes led to an overall increase in the level of Foxo1 phosphorylation, but failed to induce T(24) and S(316) phosphorylation [12].
  • We conclude that insulin can inhibit Foxo1-stimulated transcription even when nuclear export of Foxo1 is prevented, indicating that insulin inhibition can occur by direct mechanisms that do not depend on altering the subcellular distribution of the transcription factor [2].
  • The forkhead transcription factor Foxo1 has been implicated as a mediator of insulin action in regulating hepatic gluconeogenesis, and a Foxo1 mutant (Foxo1-Delta256), devoid of its carboxyl domain, has been shown to interfere with Foxo1 function and inhibit gluconeogenic gene expression in cultured cells [13].

Anatomical context of Foxo1

  • The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth [10].
  • We show that a constitutively active Foxo1 mutant inhibits differentiation of C2C12 cells and prevents myotube differentiation induced by constitutively active Akt [1].
  • A rapid entry of Foxo1 into the nucleus accompanied by a rapid exit from the cytosol and an earlier activation of caspase-8 were observed in brown adipocytes lacking IGF-IR upon serum deprivation [14].
  • These results suggest that Foxo1 is essential to the ability of endothelial cells to respond properly to a high dose of VEGF, thereby playing a critical role in normal vascular development [11].
  • The Foxo1-deficient mice died around embryonic day 11 because of defects in the branchial arches and remarkably impaired vascular development of embryos and yolk sacs [11].

Associations of Foxo1 with chemical compounds


Enzymatic interactions of Foxo1

  • In this study, we have further analyzed the ability of Akt to phosphorylate different Foxo1 sites in control and insulin receptor-deficient hepatocytes [12].

Regulatory relationships of Foxo1


Other interactions of Foxo1

  • We show that Foxo1 acts as a repressor of Foxa2-dependent (Hnf-3beta-dependent) expression from the Pdx1 promoter [10].
  • The mammalian orthologs of DAF-16, the closely-related FOXO subclass of forkhead transcription factors (FKHR/FOXO1, FKHRL1/FOXO3a, and AFX/FOXO4), also have important roles in cell cycle arrest, apoptosis and stress responses in vitro, but their in vivo physiological roles are largely unknown [24].
  • We investigated the consequences of the nutritional changes in Akt-mediated Foxo1 phosphorylation and translocation in the liver using control C57BL/6 and diabetic db/db mice [25].
  • On the other hand, both Foxo3a- and Foxo4-null mice were viable and grossly indistinguishable from their littermate controls, indicating dispensability of these two members of the Foxo transcription factor family for normal vascular development [24].
  • Thus, as a target of FSH (cAMP), E2 and IGF-I signaling in granulosa cells, FKHR likely coordinates numerous cell survival mechanisms [22].
  • Inhibition of myoblast differentiation by constitutively active Foxo1 is partly rescued by inhibition of Notch signaling while Foxo1 loss of function precludes Notch inhibition of myogenesis and increases myogenic determination gene (MyoD) expression [26].

Analytical, diagnostic and therapeutic context of Foxo1


  1. Regulation of insulin-like growth factor-dependent myoblast differentiation by Foxo forkhead transcription factors. Hribal, M.L., Nakae, J., Kitamura, T., Shutter, J.R., Accili, D. J. Cell Biol. (2003) [Pubmed]
  2. Insulin inhibition of transcription stimulated by the forkhead protein Foxo1 is not solely due to nuclear exclusion. Tsai, W.C., Bhattacharyya, N., Han, L.Y., Hanover, J.A., Rechler, M.M. Endocrinology (2003) [Pubmed]
  3. SIRT1 Regulates Adiponectin Gene Expression through Foxo1-C/Enhancer-binding Protein {alpha} Transcriptional Complex. Qiao, L., Shao, J. J. Biol. Chem. (2006) [Pubmed]
  4. Foxo transcription factors blunt cardiac hypertrophy by inhibiting calcineurin signaling. Ni, Y.G., Berenji, K., Wang, N., Oh, M., Sachan, N., Dey, A., Cheng, J., Lu, G., Morris, D.J., Castrillon, D.H., Gerard, R.D., Rothermel, B.A., Hill, J.A. Circulation (2006) [Pubmed]
  5. Foxo1 mediates insulin action on apoC-III and triglyceride metabolism. Altomonte, J., Cong, L., Harbaran, S., Richter, A., Xu, J., Meseck, M., Dong, H.H. J. Clin. Invest. (2004) [Pubmed]
  6. Forkhead transcription factor FOXO1 (FKHR)-dependent induction of PDK4 gene expression in skeletal muscle during energy deprivation. Furuyama, T., Kitayama, K., Yamashita, H., Mori, N. Biochem. J. (2003) [Pubmed]
  7. Ablation of PDK1 in pancreatic beta cells induces diabetes as a result of loss of beta cell mass. Hashimoto, N., Kido, Y., Uchida, T., Asahara, S., Shigeyama, Y., Matsuda, T., Takeda, A., Tsuchihashi, D., Nishizawa, A., Ogawa, W., Fujimoto, Y., Okamura, H., Arden, K.C., Herrera, P.L., Noda, T., Kasuga, M. Nat. Genet. (2006) [Pubmed]
  8. Regulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1. Nakae, J., Biggs, W.H., Kitamura, T., Cavenee, W.K., Wright, C.V., Arden, K.C., Accili, D. Nat. Genet. (2002) [Pubmed]
  9. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Puigserver, P., Rhee, J., Donovan, J., Walkey, C.J., Yoon, J.C., Oriente, F., Kitamura, Y., Altomonte, J., Dong, H., Accili, D., Spiegelman, B.M. Nature (2003) [Pubmed]
  10. The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth. Kitamura, T., Nakae, J., Kitamura, Y., Kido, Y., Biggs, W.H., Wright, C.V., White, M.F., Arden, K.C., Accili, D. J. Clin. Invest. (2002) [Pubmed]
  11. Abnormal angiogenesis in Foxo1 (Fkhr)-deficient mice. Furuyama, T., Kitayama, K., Shimoda, Y., Ogawa, M., Sone, K., Yoshida-Araki, K., Hisatsune, H., Nishikawa, S., Nakayama, K., Nakayama, K., Ikeda, K., Motoyama, N., Mori, N. J. Biol. Chem. (2004) [Pubmed]
  12. Insulin regulation of gene expression through the forkhead transcription factor Foxo1 (Fkhr) requires kinases distinct from Akt. Nakae, J., Kitamura, T., Ogawa, W., Kasuga, M., Accili, D. Biochemistry (2001) [Pubmed]
  13. Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice. Altomonte, J., Richter, A., Harbaran, S., Suriawinata, J., Nakae, J., Thung, S.N., Meseck, M., Accili, D., Dong, H. Am. J. Physiol. Endocrinol. Metab. (2003) [Pubmed]
  14. Susceptibility to apoptosis in insulin-like growth factor-I receptor-deficient brown adipocytes. Valverde, A.M., Mur, C., Brownlee, M., Benito, M. Mol. Biol. Cell (2004) [Pubmed]
  15. Targeting foxo1 in mice using antisense oligonucleotide improves hepatic and peripheral insulin action. Samuel, V.T., Choi, C.S., Phillips, T.G., Romanelli, A.J., Geisler, J.G., Bhanot, S., McKay, R., Monia, B., Shutter, J.R., Lindberg, R.A., Shulman, G.I., Veniant, M.M. Diabetes (2006) [Pubmed]
  16. Insulin/Foxo1 pathway regulates expression levels of adiponectin receptors and adiponectin sensitivity. Tsuchida, A., Yamauchi, T., Ito, Y., Hada, Y., Maki, T., Takekawa, S., Kamon, J., Kobayashi, M., Suzuki, R., Hara, K., Kubota, N., Terauchi, Y., Froguel, P., Nakae, J., Kasuga, M., Accili, D., Tobe, K., Ueki, K., Nagai, R., Kadowaki, T. J. Biol. Chem. (2004) [Pubmed]
  17. Enhanced expression of PDX-1 and Ngn3 by exendin-4 during beta cell regeneration in STZ-treated mice. Kodama, S., Toyonaga, T., Kondo, T., Matsumoto, K., Tsuruzoe, K., Kawashima, J., Goto, H., Kume, K., Kume, S., Sakakida, M., Araki, E. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  18. Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine 253 through a Wortmannin-sensitive pathway. Nakae, J., Park, B.C., Accili, D. J. Biol. Chem. (1999) [Pubmed]
  19. Foxo1 links insulin signaling to C/EBPalpha and regulates gluconeogenesis during liver development. Sekine, K., Chen, Y.R., Kojima, N., Ogata, K., Fukamizu, A., Miyajima, A. EMBO J. (2007) [Pubmed]
  20. Nuclear forkhead box O1 controls and integrates key signaling pathways in hepatocytes. Naïmi, M., Gautier, N., Chaussade, C., Valverde, A.M., Accili, D., Van Obberghen, E. Endocrinology (2007) [Pubmed]
  21. Orexin-A inhibits glucagon secretion and gene expression through a Foxo1-dependent pathway. Göncz, E., Strowski, M.Z., Grötzinger, C., Nowak, K.W., Kaczmarek, P., Sassek, M., Mergler, S., El-Zayat, B.F., Theodoropoulou, M., Stalla, G.K., Wiedenmann, B., Plöckinger, U. Endocrinology (2008) [Pubmed]
  22. Expression of FKHR, FKHRL1, and AFX genes in the rodent ovary: evidence for regulation by IGF-I, estrogen, and the gonadotropins. Richards, J.S., Sharma, S.C., Falender, A.E., Lo, Y.H. Mol. Endocrinol. (2002) [Pubmed]
  23. IRS-2 mediates the antiapoptotic effect of insulin in neonatal hepatocytes. Valverde, A.M., Fabregat, I., Burks, D.J., White, M.F., Benito, M. Hepatology (2004) [Pubmed]
  24. Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. Hosaka, T., Biggs, W.H., Tieu, D., Boyer, A.D., Varki, N.M., Cavenee, W.K., Arden, K.C. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  25. Nutrient control of phosphorylation and translocation of Foxo1 in C57BL/6 and db/db mice. Aoyama, H., Daitoku, H., Fukamizu, A. Int. J. Mol. Med. (2006) [Pubmed]
  26. A Foxo/Notch pathway controls myogenic differentiation and fiber type specification. Kitamura, T., Kitamura, Y.I., Funahashi, Y., Shawber, C.J., Castrillon, D.H., Kollipara, R., DePinho, R.A., Kitajewski, J., Accili, D. J. Clin. Invest. (2007) [Pubmed]
  27. Glucose-dependent insulinotropic polypeptide (GIP) stimulation of pancreatic beta-cell survival is dependent upon phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling, inactivation of the forkhead transcription factor Foxo1, and down-regulation of bax expression. Kim, S.J., Winter, K., Nian, C., Tsuneoka, M., Koda, Y., McIntosh, C.H. J. Biol. Chem. (2005) [Pubmed]
  28. Simvastatin induces activation of the serine-threonine protein kinase AKT and increases survival of isolated human pancreatic islets. Contreras, J.L., Smyth, C.A., Bilbao, G., Young, C.J., Thompson, J.A., Eckhoff, D.E. Transplantation (2002) [Pubmed]
  29. Regulation of alkaline phosphatase promoter activity by forkhead transcription factor FKHR. Hatta, M., Daitoku, H., Matsuzaki, H., Deyama, Y., Yoshimura, Y., Suzuki, K., Matsumoto, A., Fukamizu, A. Int. J. Mol. Med. (2002) [Pubmed]
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