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Gene Review

FOXO4  -  forkhead box O4

Homo sapiens

Synonyms: AFX, AFX1, Fork head domain transcription factor AFX1, Forkhead box protein O4, MLLT7
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Disease relevance of FOXO4


High impact information on FOXO4

  • The Forkhead transcription factors AFX, FKHR and FKHR-L1 are orthologues of DAF-16, a Forkhead factor that regulates longevity in Caenorhabditis elegans [5].
  • We conclude that AFX-like proteins are involved in cell-cycle regulation and that inactivation of these proteins is an important step in oncogenic transformation [5].
  • In addition, phosphorylation of AFX by protein kinase B inhibits its transcriptional activity [6].
  • The probable human orthologues of DAF-16, FKHR and AFX, may also act downstream of insulin signalling and cooperate with TGF-beta effectors in mediating metabolic regulation [7].
  • Here we show that, in contrast to insulin signalling, low levels of oxidative stress generated by treatment with H2O2 induce the activation of FOXO4 [8].

Biological context of FOXO4

  • AFX-like Forkhead transcription factors, which are controlled by phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling, are involved in regulating cell cycle progression and cell death [9].
  • The forkhead transcription factor FOXO4 induces the down-regulation of hypoxia-inducible factor 1 alpha by a von Hippel-Lindau protein-independent mechanism [1].
  • These results indicate that phosphorylation at Thr32 and Ser197 is indispensable, whereas that at Ser262 is not critical, for regulation of the nuclear localization and transcriptional activity of FOXO4 [10].
  • AFX (also called Foxo4), a member of mammalian FOXO forkhead transcription factors, is the homolog of DAF-16, which contributes longevity and oxidative stress in Caenorhabditis elegans [11].
  • Taken together, these results demonstrate that CBP-induced acetylation of AFX is a novel modification mechanism by which AFX keeps the transcriptional activity mitigating in the nucleus [11].

Anatomical context of FOXO4

  • AFX was recovered as a phosphoprotein from transfected COS-7 cells growing in the presence of FBS, and the phosphorylation was eliminated by wortmannin, a potent inhibitor of phosphatidylinositol (PI) 3-kinase [12].
  • We have generated mouse myoblastic C2C12 cell lines in which expression of a constitutively active form of AFX (AFX-TM) is inducible by Cre-mediated recombination at loxP sites [13].
  • The role of different alpha and gamma subunit subtypes in modulation of IGABA by ALP and AFX was investigated using recombinant GABAA receptor isoforms expressed in Xenopus oocytes [14].
  • SUBJECTS AND METHODS: We studied 27 patients with amaurosis fugax (AFX), branch retinal artery occlusion (BRAO), central retinal artery occlusion (CRAO) and anterior ischaemic optic neuropathy (AION) [15].

Associations of FOXO4 with chemical compounds


Physical interactions of FOXO4

  • Although AFX interacts with the KIX domain of CBP, it does not interact with SRC and does not respond to glucocorticoids or insulin [18].
  • In contrast, mammalian SIRT1 was found to bind to FOXO4, catalyze its deacetylation in an NAD-dependent manner, and thereby increase its transactivation activity [19].

Regulatory relationships of FOXO4


Other interactions of FOXO4

  • Regulation of intracellular localization and transcriptional activity of FOXO4 by protein kinase B through phosphorylation at the motif sites conserved among the FOXO family [10].
  • Compared to the coexpression of CBP wild-type, a HAT activity-deficient mutant (DeltaHAT) efficiently leads the cooperative activation of AFX transcription in HepG2 cells [11].
  • Furthermore, 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR), an AMP-activated protein kinase activator, repressed AFX zeta-dependent reporter activation [21].
  • In one such case, RT-PCR analysis of candidate partners identified a fusion of PAX3 to AFX, which is highly similar in structure and function to FKHR [22].
  • Therefore, AF6q21, AFX, and FKHR could define a new FH subfamily particularly involved in human malignancies [23].

Analytical, diagnostic and therapeutic context of FOXO4

  • Analytical gel filtration and sedimentation equilibrium experiments indicate that doubly phosphorylated FOXO4 and 14-3-3zeta form a complex with 1:2 molar stoichiometry and a K(D) of less than 30 nM [24].
  • With the exception of AFX, the use of anti-S100A6 does not appear to offer added benefit over anti-factor XIIIa in the differential diagnosis of fibrohistiocytic lesions [25].


  1. The forkhead transcription factor FOXO4 induces the down-regulation of hypoxia-inducible factor 1 alpha by a von Hippel-Lindau protein-independent mechanism. Tang, T.T., Lasky, L.A. J. Biol. Chem. (2003) [Pubmed]
  2. Human FOX gene family (Review). Katoh, M., Katoh, M. Int. J. Oncol. (2004) [Pubmed]
  3. MLL-AFX requires the transcriptional effector domains of AFX to transform myeloid progenitors and transdominantly interfere with forkhead protein function. So, C.W., Cleary, M.L. Mol. Cell. Biol. (2002) [Pubmed]
  4. Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23). Borkhardt, A., Repp, R., Haas, O.A., Leis, T., Harbott, J., Kreuder, J., Hammermann, J., Henn, T., Lampert, F. Oncogene (1997) [Pubmed]
  5. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Medema, R.H., Kops, G.J., Bos, J.L., Burgering, B.M. Nature (2000) [Pubmed]
  6. Direct control of the Forkhead transcription factor AFX by protein kinase B. Kops, G.J., de Ruiter, N.D., De Vries-Smits, A.M., Powell, D.R., Bos, J.L., Burgering, B.M. Nature (1999) [Pubmed]
  7. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Ogg, S., Paradis, S., Gottlieb, S., Patterson, G.I., Lee, L., Tissenbaum, H.A., Ruvkun, G. Nature (1997) [Pubmed]
  8. FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. Essers, M.A., Weijzen, S., de Vries-Smits, A.M., Saarloos, I., de Ruiter, N.D., Bos, J.L., Burgering, B.M. EMBO J. (2004) [Pubmed]
  9. Control of cell cycle exit and entry by protein kinase B-regulated forkhead transcription factors. Kops, G.J., Medema, R.H., Glassford, J., Essers, M.A., Dijkers, P.F., Coffer, P.J., Lam, E.W., Burgering, B.M. Mol. Cell. Biol. (2002) [Pubmed]
  10. Regulation of intracellular localization and transcriptional activity of FOXO4 by protein kinase B through phosphorylation at the motif sites conserved among the FOXO family. Matsuzaki, H., Ichino, A., Hayashi, T., Yamamoto, T., Kikkawa, U. J. Biochem. (2005) [Pubmed]
  11. Negative regulation of forkhead transcription factor AFX (Foxo4) by CBP-induced acetylation. Fukuoka, M., Daitoku, H., Hatta, M., Matsuzaki, H., Umemura, S., Fukamizu, A. Int. J. Mol. Med. (2003) [Pubmed]
  12. Regulation of nuclear translocation of forkhead transcription factor AFX by protein kinase B. Takaishi, H., Konishi, H., Matsuzaki, H., Ono, Y., Shirai, Y., Saito, N., Kitamura, T., Ogawa, W., Kasuga, M., Kikkawa, U., Nishizuka, Y. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  13. FOXO forkhead transcription factors induce G(2)-M checkpoint in response to oxidative stress. Furukawa-Hibi, Y., Yoshida-Araki, K., Ohta, T., Ikeda, K., Motoyama, N. J. Biol. Chem. (2002) [Pubmed]
  14. Subunit dependent modulation of GABAA receptor function by neuroactive steroids. Maitra, R., Reynolds, J.N. Brain Res. (1999) [Pubmed]
  15. Microemboli are not a prerequisite in retinal artery occlusive diseases. Haase, C.G., Büchner, T. Eye (London, England) (1998) [Pubmed]
  16. Constitutively active FOXO4 inhibits Akt activity, regulates p27 Kip1 stability, and suppresses HER2-mediated tumorigenicity. Yang, H., Zhao, R., Yang, H.Y., Lee, M.H. Oncogene (2005) [Pubmed]
  17. Inhibition of akt/protein kinase B signaling by naltrindole in small cell lung cancer cells. Chen, Y.L., Law, P.Y., Loh, H.H. Cancer Res. (2004) [Pubmed]
  18. DAF-16 recruits the CREB-binding protein coactivator complex to the insulin-like growth factor binding protein 1 promoter in HepG2 cells. Nasrin, N., Ogg, S., Cahill, C.M., Biggs, W., Nui, S., Dore, J., Calvo, D., Shi, Y., Ruvkun, G., Alexander-Bridges, M.C. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  19. SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress. Kobayashi, Y., Furukawa-Hibi, Y., Chen, C., Horio, Y., Isobe, K., Ikeda, K., Motoyama, N. Int. J. Mol. Med. (2005) [Pubmed]
  20. The forkhead transcription factor AFX activates apoptosis by induction of the BCL-6 transcriptional repressor. Tang, T.T., Dowbenko, D., Jackson, A., Toney, L., Lewin, D.A., Dent, A.L., Lasky, L.A. J. Biol. Chem. (2002) [Pubmed]
  21. An mRNA splice variant of the AFX gene with altered transcriptional activity. Yang, Z., Whelan, J., Babb, R., Bowen, B.R. J. Biol. Chem. (2002) [Pubmed]
  22. Genetic heterogeneity in the alveolar rhabdomyosarcoma subset without typical gene fusions. Barr, F.G., Qualman, S.J., Macris, M.H., Melnyk, N., Lawlor, E.R., Strzelecki, D.M., Triche, T.J., Bridge, J.A., Sorensen, P.H. Cancer Res. (2002) [Pubmed]
  23. AF6q21, a novel partner of the MLL gene in t(6;11)(q21;q23), defines a forkhead transcriptional factor subfamily. Hillion, J., Le Coniat, M., Jonveaux, P., Berger, R., Bernard, O.A. Blood (1997) [Pubmed]
  24. Two 14-3-3 binding motifs are required for stable association of Forkhead transcription factor FOXO4 with 14-3-3 proteins and inhibition of DNA binding. Obsil, T., Ghirlando, R., Anderson, D.E., Hickman, A.B., Dyda, F. Biochemistry (2003) [Pubmed]
  25. S100A6 expression in fibrohistiocytic lesions. Fullen, D.R., Reed, J.A., Finnerty, B., McNutt, N.S. J. Cutan. Pathol. (2001) [Pubmed]
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