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Gene Review

FOXO1  -  forkhead box O1

Homo sapiens

Synonyms: FKH1, FKHR, FOXO1A, Forkhead box protein O1, Forkhead box protein O1A, ...
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Disease relevance of FOXO1

  • In addition, FOXO1A was transcriptionally down-regulated in some prostate cancers [1].
  • Human endometrial fibroblasts (HuF) expressed FOXO1A, progesterone receptor A (PGRA), and progesterone receptor B (PGRB) proteins, whereas the endometrial adenocarcinoma cell line, HEC-1B cells, expressed only FOXO1A and no detectable PGR proteins [2].
  • Furthermore, expression of the FOXO1 protein is lost in a mouse lymphoma model, where Skp2 is overexpressed [3].
  • We determined whether expression of Pax3-FKHR in the mouse germ line would render these animals prone to the development of rhabdomyosarcomas [4].
  • Since Pax3 induced a mesenchymal to epithelial transition (MET) in human SaOS-2 osteosarcomas, we hypothesized that Pax3/FKHR would also induce a morphological change in SaOS-2 cells [5].
  • Taken together, these data provide insight into the phosphoinositide-3-kinase/Akt/FOXO pathway for the determination of progestin responsiveness and the development of alternate therapies for endometrial cancer [6].
  • The three microRNAs, miR-27a, miR-96 and miR-182, were observed to be highly expressed in MCF-7 breast cancer cells, in which the level of FOXO1 protein is very low [7].

Psychiatry related information on FOXO1

  • Analysis of hippocampi from patients with intractable epilepsy revealed that Bim levels were significantly lower than in controls and FKHR was inhibited; we were able to reproduce these results experimentally in rats by evoking multiple brief, noninjurious electroshock seizures [8].

High impact information on FOXO1

  • In C. elegans, removing the germ cells extends life span by triggering the nuclear localization and activation of the DAF-16/FOXO transcription factor in the intestine [9].
  • Thus, forkhead factor(s) play a critical role in the development of muscle atrophy, and inhibition of Foxo factors is an attractive approach to combat muscle wasting [10].
  • Here, we show that in cultured myotubes undergoing atrophy, the activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction [10].
  • These findings indicate that the t(2;13) generates a potentially tumorigenic fusion transcription factor consisting of intact PAX3 DNA binding domains, a truncated fork head DNA binding domain and C-terminal FKHR regions [11].
  • Polymerase chain reaction analysis demonstrates that a 5'PAX3-3' FKHR chimaeric transcript is expressed in all eight alveolar rhabdomyosarcomas investigated [11].

Chemical compound and disease context of FOXO1


Biological context of FOXO1


Anatomical context of FOXO1


Associations of FOXO1 with chemical compounds


Physical interactions of FOXO1


Enzymatic interactions of FOXO1

  • These experiments suggest that DYRK1A may phosphorylate FKHR at Ser(329) in vivo [28].
  • FKHR is phosphorylated by protein kinase B (PKB) at Thr24, Ser256 and Ser319 in response to growth factors, stimulating the nuclear exit and inactivation of this transcription factor [29].
  • CDK2 specifically phosphorylated FOXO1 at serine-249 (Ser(249)) in vitro and in vivo [30].
  • Expression of a constitutively active form of FKHR that cannot be phosphorylated by Akt produces the same effect as reconstitution of PTEN on PTEN-deficient tumor cells [31].
  • Furthermore, the binding affinity of HNF-4 with phosphorylated FKHR significantly decreased in comparison to that with unphosphorylated FKHR [27].

Regulatory relationships of FOXO1


Other interactions of FOXO1

  • Although PAX3-FKHR exhibits transforming activity in immortalized fibroblast cell lines, a direct role of this fusion protein in tumorigenesis in vivo has not been shown [4].
  • Insulin suppresses the hPDK4 induction by glucocorticoids through inactivation of the FOXO factors [22].
  • TIMP3 and CNR1 levels decreased even further in response to H+dbcAMP compared with FOXO1A alone [16].
  • Furthermore, in HEC-1B cells, FOXO1A increased IGFBP1 promoter activity, and coexpression of PGRA or PGRB further increased the promoter activity in a cooperative manner [2].
  • When FKHR and HOXA10 are expressed together, promoter activity is markedly up-regulated, which is indicative of cooperativity [18].

Analytical, diagnostic and therapeutic context of FOXO1


  1. FOXO1A is a candidate for the 13q14 tumor suppressor gene inhibiting androgen receptor signaling in prostate cancer. Dong, X.Y., Chen, C., Sun, X., Guo, P., Vessella, R.L., Wang, R.X., Chung, L.W., Zhou, W., Dong, J.T. Cancer Res. (2006) [Pubmed]
  2. Role of FOXO1A in the regulation of insulin-like growth factor-binding protein-1 in human endometrial cells: interaction with progesterone receptor. Kim, J.J., Buzzio, O.L., Li, S., Lu, Z. Biol. Reprod. (2005) [Pubmed]
  3. Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation. Huang, H., Regan, K.M., Wang, F., Wang, D., Smith, D.I., van Deursen, J.M., Tindall, D.J. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  4. Pax3-FKHR knock-in mice show developmental aberrations but do not develop tumors. Lagutina, I., Conway, S.J., Sublett, J., Grosveld, G.C. Mol. Cell. Biol. (2002) [Pubmed]
  5. Cell-type-specific regulation of distinct sets of gene targets by Pax3 and Pax3/FKHR. Begum, S., Emani, N., Cheung, A., Wilkins, O., Der, S., Hamel, P.A. Oncogene (2005) [Pubmed]
  6. The regulation and function of the forkhead transcription factor, Forkhead box O1, is dependent on the progesterone receptor in endometrial carcinoma. Ward, E.C., Hoekstra, A.V., Blok, L.J., Hanifi-Moghaddam, P., Lurain, J.R., Singh, D.K., Buttin, B.M., Schink, J.C., Kim, J.J. Endocrinology (2008) [Pubmed]
  7. Coordinate regulation of FOXO1 by miR-27a, miR-96, and miR-182 in breast cancer cells. Guttilla, I.K., White, B.A. J. Biol. Chem. (2009) [Pubmed]
  8. Bim regulation may determine hippocampal vulnerability after injurious seizures and in temporal lobe epilepsy. Shinoda, S., Schindler, C.K., Meller, R., So, N.K., Araki, T., Yamamoto, A., Lan, J.Q., Taki, W., Simon, R.P., Henshall, D.C. J. Clin. Invest. (2004) [Pubmed]
  9. Germ-cell loss extends C. elegans life span through regulation of DAF-16 by kri-1 and lipophilic-hormone signaling. Berman, J.R., Kenyon, C. Cell (2006) [Pubmed]
  10. 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]
  11. Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Galili, N., Davis, R.J., Fredericks, W.J., Mukhopadhyay, S., Rauscher, F.J., Emanuel, B.S., Rovera, G., Barr, F.G. Nat. Genet. (1993) [Pubmed]
  12. Oxidant-mediated Akt Activation in Human RPE Cells. Yang, P., Peairs, J.J., Tano, R., Jaffe, G.J. Invest. Ophthalmol. Vis. Sci. (2006) [Pubmed]
  13. Estrogen regulation of Pak1 and FKHR pathways in breast cancer cells. Mazumdar, A., Kumar, R. FEBS Lett. (2003) [Pubmed]
  14. Decreased akt activity is associated with activation of forkhead transcription factor after transient forebrain ischemia in gerbil hippocampus. Kawano, T., Morioka, M., Yano, S., Hamada, J., Ushio, Y., Miyamoto, E., Fukunaga, K. J. Cereb. Blood Flow Metab. (2002) [Pubmed]
  15. The progression of LNCaP human prostate cancer cells to androgen independence involves decreased FOXO3a expression and reduced p27KIP1 promoter transactivation. Lynch, R.L., Konicek, B.W., McNulty, A.M., Hanna, K.R., Lewis, J.E., Neubauer, B.L., Graff, J.R. Mol. Cancer Res. (2005) [Pubmed]
  16. FOXO1A differentially regulates genes of decidualization. Buzzio, O.L., Lu, Z., Miller, C.D., Unterman, T.G., Kim, J.J. Endocrinology (2006) [Pubmed]
  17. Analysis of FOXO1A as a candidate gene for type 2 diabetes. Karim, M.A., Craig, R.L., Wang, X., Hale, T.C., Elbein, S.C. Mol. Genet. Metab. (2006) [Pubmed]
  18. Regulation of insulin-like growth factor binding protein-1 promoter activity by FKHR and HOXA10 in primate endometrial cells. Kim, J.J., Taylor, H.S., Akbas, G.E., Foucher, I., Trembleau, A., Jaffe, R.C., Fazleabas, A.T., Unterman, T.G. Biol. Reprod. (2003) [Pubmed]
  19. PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children's oncology group. Sorensen, P.H., Lynch, J.C., Qualman, S.J., Tirabosco, R., Lim, J.F., Maurer, H.M., Bridge, J.A., Crist, W.M., Triche, T.J., Barr, F.G. J. Clin. Oncol. (2002) [Pubmed]
  20. SH2-B is a positive regulator of nerve growth factor-mediated activation of the Akt/Forkhead pathway in PC12 cells. Wang, X., Chen, L., Maures, T.J., Herrington, J., Carter-Su, C. J. Biol. Chem. (2004) [Pubmed]
  21. Ligand-dependent interaction of estrogen receptor-alpha with members of the forkhead transcription factor family. Schuur, E.R., Loktev, A.V., Sharma, M., Sun, Z., Roth, R.A., Weigel, R.J. J. Biol. Chem. (2001) [Pubmed]
  22. Protein kinase B-alpha inhibits human pyruvate dehydrogenase kinase-4 gene induction by dexamethasone through inactivation of FOXO transcription factors. Kwon, H.S., Huang, B., Unterman, T.G., Harris, R.A. Diabetes (2004) [Pubmed]
  23. Insulin-like growth factor 1/insulin signaling activates androgen signaling through direct interactions of Foxo1 with androgen receptor. Fan, W., Yanase, T., Morinaga, H., Okabe, T., Nomura, M., Daitoku, H., Fukamizu, A., Kato, S., Takayanagi, R., Nawata, H. J. Biol. Chem. (2007) [Pubmed]
  24. Induction of cyclin D2 in rat granulosa cells requires FSH-dependent relief from FOXO1 repression coupled with positive signals from Smad. Park, Y., Maizels, E.T., Feiger, Z.J., Alam, H., Peters, C.A., Woodruff, T.K., Unterman, T.G., Lee, E.J., Jameson, J.L., Hunzicker-Dunn, M. J. Biol. Chem. (2005) [Pubmed]
  25. An engineered PAX3-KRAB transcriptional repressor inhibits the malignant phenotype of alveolar rhabdomyosarcoma cells harboring the endogenous PAX3-FKHR oncogene. Fredericks, W.J., Ayyanathan, K., Herlyn, M., Friedman, J.R., Rauscher, F.J. Mol. Cell. Biol. (2000) [Pubmed]
  26. Negative regulation of the forkhead transcription factor FKHR by Akt. Tang, E.D., Nuñez, G., Barr, F.G., Guan, K.L. J. Biol. Chem. (1999) [Pubmed]
  27. Hepatocyte nuclear factor-4 is a novel downstream target of insulin via FKHR as a signal-regulated transcriptional inhibitor. Hirota, K., Daitoku, H., Matsuzaki, H., Araya, N., Yamagata, K., Asada, S., Sugaya, T., Fukamizu, A. J. Biol. Chem. (2003) [Pubmed]
  28. The kinase DYRK1A phosphorylates the transcription factor FKHR at Ser329 in vitro, a novel in vivo phosphorylation site. Woods, Y.L., Rena, G., Morrice, N., Barthel, A., Becker, W., Guo, S., Unterman, T.G., Cohen, P. Biochem. J. (2001) [Pubmed]
  29. Two novel phosphorylation sites on FKHR that are critical for its nuclear exclusion. Rena, G., Woods, Y.L., Prescott, A.R., Peggie, M., Unterman, T.G., Williams, M.R., Cohen, P. EMBO J. (2002) [Pubmed]
  30. CDK2-Dependent Phosphorylation of FOXO1 as an Apoptotic Response to DNA Damage. Huang, H., Regan, K.M., Lou, Z., Chen, J., Tindall, D.J. Science (2006) [Pubmed]
  31. Forkhead transcription factors are critical effectors of cell death and cell cycle arrest downstream of PTEN. Nakamura, N., Ramaswamy, S., Vazquez, F., Signoretti, S., Loda, M., Sellers, W.R. Mol. Cell. Biol. (2000) [Pubmed]
  32. FOXO1 functions as a master switch that regulates gene expression necessary for tumor necrosis factor-induced fibroblast apoptosis. Alikhani, M., Alikhani, Z., Graves, D.T. J. Biol. Chem. (2005) [Pubmed]
  33. Roles of the forkhead in rhabdomyosarcoma (FKHR) phosphorylation sites in regulating 14-3-3 binding, transactivation and nuclear targetting. Rena, G., Prescott, A.R., Guo, S., Cohen, P., Unterman, T.G. Biochem. J. (2001) [Pubmed]
  34. The transcription of FOXO genes is stimulated by FOXO3 and repressed by growth factors. Essaghir, A., Dif, N., Marbehant, C.Y., Coffer, P.J., Demoulin, J.B. J. Biol. Chem. (2009) [Pubmed]
  35. MDM2 acts downstream of p53 as an E3 ligase to promote FOXO ubiquitination and degradation. Fu, W., Ma, Q., Chen, L., Li, P., Zhang, M., Ramamoorthy, S., Nawaz, Z., Shimojima, T., Wang, H., Yang, Y., Shen, Z., Zhang, Y., Zhang, X., Nicosia, S.V., Zhang, Y., Pledger, J.W., Chen, J., Bai, W. J. Biol. Chem. (2009) [Pubmed]
  36. Structural characterization of the FKHR gene and its rearrangement in alveolar rhabdomyosarcoma. Davis, R.J., Bennicelli, J.L., Macina, R.A., Nycum, L.M., Biegel, J.A., Barr, F.G. Hum. Mol. Genet. (1995) [Pubmed]
  37. Use of a novel FISH assay on paraffin-embedded tissues as an adjunct to diagnosis of alveolar rhabdomyosarcoma. Nishio, J., Althof, P.A., Bailey, J.M., Zhou, M., Neff, J.R., Barr, F.G., Parham, D.M., Teot, L., Qualman, S.J., Bridge, J.A. Lab. Invest. (2006) [Pubmed]
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