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Gene Review

Foxo3  -  forkhead box O3

Mus musculus

Synonyms: 1110048B16Rik, 2010203A17Rik, C76856, FKHRL1, Fkhr2, ...
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Disease relevance of Foxo3a

  • Here we show that such inflammation requires the forkhead transcription factor Foxo3a: Foxo3a-deficient mice are resistant to two models of neutrophilic inflammation, immune complex-mediated inflammatory arthritis and thioglycollate-induced peritonitis [1].
  • Foxo3a-null females showed age-dependent infertility and had abnormal ovarian follicular development [2].
  • We find in a mouse model that Pml loss markedly accelerates tumour onset, incidence and progression in Pten-heterozygous mutants, and leads to female sterility with features that recapitulate the phenotype of Foxo3a knockout mice [3].
  • However, the cell lines derived from SCID mice that are defective in the catalytic subunit of DNA-dependent protein kinase retain elevated levels of p27 and Foxo3a proteins despite reactivation of v-Abl [4].
  • We demonstrate here that MLL-FKHRL1 enhances the self-renewal of murine myeloid progenitors in vitro and induces acute myeloid leukemias in syngeneic mice [5].

High impact information on Foxo3a


Biological context of Foxo3a

  • Here, we show that Foxo3a-/- female mice exhibit a distinctive ovarian phenotype of global follicular activation leading to oocyte death, early depletion of functional ovarian follicles, and secondary infertility [8].
  • As a consequence, the progressive reduction in Pml dose leads to inactivation of Foxo3a-mediated transcription of proapoptotic Bim and the cell cycle inhibitor p27(kip1) [3].
  • As a result, phosphorylation of Akt and its downstream targets, including FKHRL1 and GSK3alpha/beta, were reduced accordingly [9].
  • Thus, it comes as a surprise in this issue of Immunity that lymphoproliferative disease in Foxo3a-deficient mice may be due to T cell hyperactivity instead of cell death defects [10].
  • Apoptosis protection conferred by CD152 correlated with the up-regulation of Bcl-2 and was mediated by phosphatidylinositol 3 kinase, which prevented FasL expression through the inhibitory phosphorylation of Forkhead transcription factor FKHRL1 [11].

Anatomical context of Foxo3a

  • Thus, Foxo3a regulates helper T cell activation and tolerance by inhibiting NF-kappaB activity, reinforcing a generalized role for the forkhead proteins in the maintenance of T cell tolerance through the inhibition of inflammatory transcriptional activities [7].
  • Suppression of ovarian follicle activation in mice by the transcription factor Foxo3a [8].
  • Activation of Akt (PKB) and suppression of FKHRL1 in mouse and rat oocytes by stem cell factor during follicular activation and development [12].
  • In the embryos, expressions of AFX, FKHR and FKHRL1 mRNAs were complementary to each other and were highest in muscle, adipose tissue and embryonic liver [13].
  • Interestingly, FKHRL1 co-immunoprecipitated with Akt in PC12 cells, indicating that these two proteins can associate in these cells [14].

Associations of Foxo3a with chemical compounds


Enzymatic interactions of Foxo3a

  • Constitutive activation of Akt phosphorylated and inhibited the transcription factor Foxo3a [18].
  • Sgk is known to phosphorylate and negatively regulate pro-apoptotic forkhead transcription factor FKHRL1 [16].

Regulatory relationships of Foxo3a


Other interactions of Foxo3a

  • 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 [2].
  • Restored Foxo3a activity reversed Flt3-ITD-mediated growth properties and dominant-negative Akt prevented Flt3-ITD-mediated cytokine independence [18].
  • Regulation of NF-kappaB, Th activation, and autoinflammation by the forkhead transcription factor Foxo3a [7].
  • The negative regulators Foxj1 and Foxo3a are up-regulated by a peptide that inhibits systemic lupus erythematosus-associated T cell responses [22].
  • In turn, v-Abl reactivation reduces p27 and Foxo3a levels, thus permitting G1-arrested cells to reenter the cell cycle [4].


  1. Inflammatory arthritis requires Foxo3a to prevent Fas ligand-induced neutrophil apoptosis. Jonsson, H., Allen, P., Peng, S.L. Nat. Med. (2005) [Pubmed]
  2. 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]
  3. Identification of a tumour suppressor network opposing nuclear Akt function. Trotman, L.C., Alimonti, A., Scaglioni, P.P., Koutcher, J.A., Cordon-Cardo, C., Pandolfi, P.P. Nature (2006) [Pubmed]
  4. Growth, differentiation, and malignant transformation of pre-B cells mediated by inducible activation of v-Abl oncogene. Jacobsen, E.A., Ananieva, O., Brown, M.L., Chang, Y. J. Immunol. (2006) [Pubmed]
  5. Common mechanism for oncogenic activation of MLL by forkhead family proteins. So, C.W., Cleary, M.L. Blood (2003) [Pubmed]
  6. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Sandri, M., Sandri, C., Gilbert, A., Skurk, C., Calabria, E., Picard, A., Walsh, K., Schiaffino, S., Lecker, S.H., Goldberg, A.L. Cell (2004) [Pubmed]
  7. Regulation of NF-kappaB, Th activation, and autoinflammation by the forkhead transcription factor Foxo3a. Lin, L., Hron, J.D., Peng, S.L. Immunity (2004) [Pubmed]
  8. Suppression of ovarian follicle activation in mice by the transcription factor Foxo3a. Castrillon, D.H., Miao, L., Kollipara, R., Horner, J.W., DePinho, R.A. Science (2003) [Pubmed]
  9. Quantitative Analysis of Anti-apoptotic Function of Akt in Akt1 and Akt2 Double Knock-out Mouse Embryonic Fibroblast Cells under Normal and Stressed Conditions. Liu, X., Shi, Y., Birnbaum, M.J., Ye, K., De Jong, R., Oltersdorf, T., Giranda, V.L., Luo, Y. J. Biol. Chem. (2006) [Pubmed]
  10. Another fork in the road: Foxo3a regulates NF-kappaB activation. Su, H., Bidere, N., Lenardo, M. Immunity (2004) [Pubmed]
  11. CD152 (CTLA-4) determines the unequal resistance of Th1 and Th2 cells against activation-induced cell death by a mechanism requiring PI3 kinase function. Pandiyan, P., Gärtner, D., Soezeri, O., Radbruch, A., Schulze-Osthoff, K., Brunner-Weinzierl, M.C. J. Exp. Med. (2004) [Pubmed]
  12. Activation of Akt (PKB) and suppression of FKHRL1 in mouse and rat oocytes by stem cell factor during follicular activation and development. Reddy, P., Shen, L., Ren, C., Boman, K., Lundin, E., Ottander, U., Lindgren, P., Liu, Y.X., Sun, Q.Y., Liu, K. Dev. Biol. (2005) [Pubmed]
  13. Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues. Furuyama, T., Nakazawa, T., Nakano, I., Mori, N. Biochem. J. (2000) [Pubmed]
  14. Insulin-like growth factor-1-induced phosphorylation of the forkhead family transcription factor FKHRL1 is mediated by Akt kinase in PC12 cells. Zheng, W.H., Kar, S., Quirion, R. J. Biol. Chem. (2000) [Pubmed]
  15. GDNF rescues hyperglycemia-induced diabetic enteric neuropathy through activation of the PI3K/Akt pathway. Anitha, M., Gondha, C., Sutliff, R., Parsadanian, A., Mwangi, S., Sitaraman, S.V., Srinivasan, S. J. Clin. Invest. (2006) [Pubmed]
  16. Expression of the serum- and glucocorticoid-inducible protein kinase, Sgk, is a cell survival response to multiple types of environmental stress stimuli in mammary epithelial cells. Leong, M.L., Maiyar, A.C., Kim, B., O'Keeffe, B.A., Firestone, G.L. J. Biol. Chem. (2003) [Pubmed]
  17. Transforming growth factor beta enhances epithelial cell survival via Akt-dependent regulation of FKHRL1. Shin, I., Bakin, A.V., Rodeck, U., Brunet, A., Arteaga, C.L. Mol. Biol. Cell (2001) [Pubmed]
  18. Constitutive activation of Akt by Flt3 internal tandem duplications is necessary for increased survival, proliferation, and myeloid transformation. Brandts, C.H., Sargin, B., Rode, M., Biermann, C., Lindtner, B., Schwäble, J., Buerger, H., Müller-Tidow, C., Choudhary, C., McMahon, M., Berdel, W.E., Serve, H. Cancer Res. (2005) [Pubmed]
  19. Foxo3a induces motoneuron death through the Fas pathway in cooperation with JNK. Barthélémy, C., Henderson, C.E., Pettmann, B. BMC neuroscience [electronic resource]. (2004) [Pubmed]
  20. Accelerated ovarian failure induced by 4-vinyl cyclohexene diepoxide in Nrf2 null mice. Hu, X., Roberts, J.R., Apopa, P.L., Kan, Y.W., Ma, Q. Mol. Cell. Biol. (2006) [Pubmed]
  21. Differential regulation of Foxo3a target genes in erythropoiesis. Bakker, W.J., van Dijk, T.B., Parren-van Amelsvoort, M., Kolbus, A., Yamamoto, K., Steinlein, P., Verhaak, R.G., Mak, T.W., Beug, H., Löwenberg, B., von Lindern, M. Mol. Cell. Biol. (2007) [Pubmed]
  22. The negative regulators Foxj1 and Foxo3a are up-regulated by a peptide that inhibits systemic lupus erythematosus-associated T cell responses. Sela, U., Dayan, M., Hershkoviz, R., Cahalon, L., Lider, O., Mozes, E. Eur. J. Immunol. (2006) [Pubmed]
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