Alternative titles; symbols
HGNC Approved Gene Symbol: FOXO4
Cytogenetic location: Xq13.1 Genomic coordinates (GRCh38): X:71,095,851-71,103,532 (from NCBI)
Parry et al. (1994) cloned and sequenced the t(X;11) breakpoint region from a cell line established from an infant with acute lymphocytic leukemia. The gene disrupted on the X chromosome, AFX1 (also symbolized MLLT7), was expressed in a variety of cell types. Sequence analysis indicated a high degree of homology between AFX1 and the forkhead family of transcription factors. The high degree of identity within the forkhead region and the lack of homology outside that region suggested to the authors that AFX1 represents a novel forkhead family member.
Borkhardt et al. (1997) cloned and characterized the entire AFX gene, which encodes a protein of 501 amino acids. The AFX protein belongs to the forkhead protein family. It is highly homologous to the FKHR protein (136533), the gene for which it is disrupted by the t(2;13) translocation characteristic of alveolar rhabdomyosarcoma.
Medema et al. (2000) demonstrated that overexpression of the forkhead transcription factors AFX, FKHRL1 (602681), or FKHR causes growth suppression in a variety of cell lines, including a Ras-transformed cell line and a cell line lacking the tumor suppressor PTEN (601728). Expression of AFX blocked cell cycle progression at phase G1, independent of functional retinoblastoma protein but dependent on the cell cycle inhibitor p27(KIP1) (600778). Medema et al. (2000) demonstrated that AFX transcriptionally activates p27(KIP1), resulting in increased protein levels, and concluded that AFX-like proteins are involved in cell cycle regulation and that inactivation of these proteins is an important step in oncogenic transformation.
Tang et al. (2002) found that HeLa cells induced to express an active form of AFX died by activating an apoptotic pathway that included a 4- to 7-fold upregulation of BLC6 (109565) expression. Examination of the BLC6 promoter identified 8 AFX binding sites, and AFX binding activated BCL6 transcription. BCL6 in turn repressed transcription of BCLX (600039), which encodes an antiapoptotic protein, 1.3- to 1.7-fold. Tang et al. (2002) concluded that AFX regulates apoptosis in part by suppressing the level of antiapoptotic BCLX through the transcriptional repressor BCL6.
Liu et al. (2005) found that Foxo4 repressed smooth muscle cell (SMC) differentiation in several rodent SMC lines by interacting with and inhibiting the activity of myocardin (MYOCD; 606127). PI3K (see 601232)/Akt (see 164730) signaling promoted SMC differentiation, at least in part, by stimulating nuclear export of Foxo4 and thereby releasing myocardin from its inhibitory influence. Accordingly, reduction of Foxo4 expression in SMCs by small interfering RNA enhanced myocardin activity and SMC differentiation. Liu et al. (2005) concluded that signal-dependent interaction of FOXO4 with myocardin couples extracellular signals with the transcriptional program of SMC differentiation.
ATXN3 (607047) functions as a deubiquitinase and as a transcriptional regulator. Expansion of a polyglutamine tract in ATXN3 causes spinocerebellar ataxia-3 (SCA3; 109150). Using immunoprecipitation analysis and protein pull-down studies, Araujo et al. (2011) found that endogenous ATXN3 interacted directly with FOXO4 in nuclear extracts of HeLa cells, rat CSM14.1 mesencephalic cells, and mouse brain. The interaction required the N-terminal Josephin domain of ATXN3. Expression of ATXN3 enhanced FOXO4-dependent expression of the antioxidant enzyme SOD2 (147460) in a manner independent of ATXN3 deubiquitinase activity. Treatment of HeLa cells with H2O2 induced nuclear translocation of FOXO4 and ATXN3, enhanced binding of FOXO4 and ATXN3 to the SOD2 promoter, and induced SOD2 expression. Coexpression of mutant ATXN3 with an expanded polyglutamine tract or knockdown of ATXN3 via short hairpin RNA reduced FOXO4 nuclear translocation and induction of SOD2. Lymphocytes from SCA3 patients exposed to oxidative stress showed reduced binding of FOXO4 to the SOD2 promoter, concomitant with impaired upregulation of SOD2 and enhanced oxidative cytotoxicity. Araujo et al. (2011) concluded that ATXN3 stabilizes FOXO4 and acts as a transcriptional coactivator with FOXO4 in the oxidative stress response.
Borkhardt et al. (1997) found that the AFX gene contains 2 exons. The single intron is 3,706 bp long.
Peters et al. (1997) found that the AFX1 gene contains 3 exons with most of exon 3 being untranslated.
The AFX1 gene maps to a YAC contig of chromosome Xq13.1 (Peters et al., 1997).
A breakpoint in 11q23 is frequently involved in translocations underlying hematologic malignancies, especially acute leukemias. The human homolog of Drosophila 'trithorax,' symbolized MLL (159555), for 'myeloid-lymphoid leukemia' or 'mixed lineage leukemia,' is located at this breakpoint. Part of the MLL gene is fused with other genes in leukemia: AF4 (159557) in t(4;11)(q21;q23); ENL (159556) in t(11;19)(q23;p13.3), AF9 (159558) in t(9;11)(p22;q23), AF6 (159559) in t(6;11)(q27;q23), and AFX in t(X;11)(q13;q23). Translocations at 11q23 result in the formation of 2 derivative chromosomes that encode chimeric transcripts. The der(11) transcript contains 5-prime MLL sequences fused to 3-prime sequences of the gene located on the partner chromosome, whereas the other derivative chromosome contains the 5-prime sequence of the partner gene potentially fused to the 3-prime sequence of MLL. However, in 25% of patients, translocations are associated with deletions of MLL sequence that is 3-prime to the breakpoint. Thus, in these cases, a fusion transcript from the other derivative chromosome cannot be formed. In addition, analysis of complex 11q23 translocations revealed that the der(11) junction is always conserved. These data indicate that the fusion transcript encoded by the der(11) must be critical to leukemogenesis. Corral et al. (1993) found from a partial sequence of a fusion between MLL and the AFX1 gene from the X chromosome that the latter is rich in ser/pro codons, like the ENL mRNA. Corral et al. (1993) concluded that heterogeneous 11q23 abnormalities may cause attachment of ser/pro-rich segments to the N terminus of MLL, lacking the zinc finger region, and that translocations occur in early hematopoietic cells, before commitment to distinct lineages.
Parry et al. (1994) predicted that a chimeric fusion protein that alters DNA binding activity results from the t(X;11) translocation.
The C. elegans transcription factor hsf1 (140580) regulates the heat-shock response and influences aging. Reducing hsf1 activity accelerates tissue aging and shortens life span; Hsu et al. (2003) showed that hsf1 overexpression extends life span. Hsu et al. (2003) found that hsf1, like the transcription factor daf16, whose human homologs include FOXO1 (136533), FOXO3 (602681), and FOXO4, is required for daf2-insulin (176730)/Igf1 receptor (147370) mutations to extend life span. Hsu et al. (2003) concluded that this is because hsf1 and daf16 together activate expression of specific genes, including genes encoding small heat-shock proteins, which in turn promote longevity. The small heat-shock proteins also delay the onset of polyglutamine-expansion protein aggregation, suggesting that these proteins couple the normal aging process to this type of age-related disease.
Paik et al. (2007) generated null and conditional alleles for Foxo1, Foxo3, and Foxo4 to assess their role in cancer in vivo. Mice with germline or somatic deletion of up to 5 Foxo alleles, including Foxo1 +/- Foxo3 -/- Foxo4 -/- mice, had only modest neoplastic phenotypes. In contrast, broad somatic deletion of Foxo1, Foxo3, and Foxo4 engendered a progressive cancer-prone condition characterized by thymic lymphomas and hemangiomas. Transcriptome and promoter analyses of differentially affected endothelium identified direct Foxo targets and revealed that Foxo regulation of these targets in vivo was highly context specific, even in the same cell type. Functional studies validated Spry2 (602466) and Pbx1 (176310), among others, as Foxo-regulated mediators of endothelial cell morphogenesis and vascular homeostasis.
Tothova et al. (2007) conditionally deleted Foxo1, Foxo3, and Foxo4 in the adult mouse hematopoietic system. Foxo-deficient mice exhibited myeloid lineage expansion, lymphoid developmental abnormalities, and a marked decrease of the lineage-negative/Sca1-positive/Kit (164920)-positive compartment containing short- and long-term hematopoietic stem cell (HSC) populations. Foxo-deficient bone marrow had defective long-term repopulating activity that correlated with increased cell cycling and apoptosis of HSCs. There was a marked context-dependent increase in reactive oxygen species (ROS) in Foxo-deficient HSCs compared with wildtype HSCs that correlated with changes in genes encoding regulators of ROS. In vivo treatment with an antioxidative agent resulted in reversion of the Foxo-deficient phenotype. Tothova et al. (2007) concluded that FOXO proteins play essential roles in the response to physiologic oxidative stress and thereby mediate quiescence and enhanced survival in the HSC compartment.
Araujo, J., Breuer, P., Dieringer, S., Krauss, S., Dorn, S., Zimmermann, K., Pfeifer, A., Klockgether, T., Wuellner, U., Evert, B. O. FOXO4-dependent upregulation of superoxide dismutase-2 in response to oxidative stress is impaired in spinocerebellar ataxia type 3. Hum. Molec. Genet. 20: 2928-2941, 2011. [PubMed: 21536589] [Full Text: https://doi.org/10.1093/hmg/ddr197]
Borkhardt, A., Repp, R., Haas, O. A., Leis, T., Harbott, J., Kreuder, J., Hammermann, J., Henn, T., Lampert, F. Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23). Oncogene 14: 195-202, 1997. [PubMed: 9010221] [Full Text: https://doi.org/10.1038/sj.onc.1200814]
Corral, J., Forster, A., Thompson, S., Lampert, F., Kaneko, Y., Slater, R., Kroes, W. G., van der Schoot, C. E., Ludwig, W.-D., Karpas, A., Pocock, C., Cotter, F., Rabbitts, T. H. Acute leukemias of different lineages have similar MLL gene fusions encoding related chimeric proteins resulting from chromosomal translocation. Proc. Nat. Acad. Sci. 90: 8538-8542, 1993. [PubMed: 8378328] [Full Text: https://doi.org/10.1073/pnas.90.18.8538]
Hsu, A.-L., Murphy, C. T., Kenyon, C. Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300: 1142-1145, 2003. Note: Erratum: Science 300: 2033 only, 2003. [PubMed: 12750521] [Full Text: https://doi.org/10.1126/science.1083701]
Liu, Z.-P., Wang, Z., Yanagisawa, H., Olson, E. N. Phenotypic modulation of smooth muscle cells through interaction of Foxo4 and myocardin. Dev. Cell 9: 261-270, 2005. [PubMed: 16054032] [Full Text: https://doi.org/10.1016/j.devcel.2005.05.017]
Medema, R. H., Kops, G. J. P. L., Bos, J. L., Burgering, B. M. T. AFX-like forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27(kip1). Nature 404: 782-787, 2000. [PubMed: 10783894] [Full Text: https://doi.org/10.1038/35008115]
Paik, J.-H., Kollipara, R., Chu, G., Ji, H., Xiao, Y., Ding, Z., Miao, L., Tothova, Z., Horner, J. W., Carrasco, D. R., Jiang, S., Gilliland, D. G., Chin, L., Wong, W. H., Castrillon, D. H., DePinho, R. A. FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 128: 309-323, 2007. [PubMed: 17254969] [Full Text: https://doi.org/10.1016/j.cell.2006.12.029]
Parry, P., Wei, Y., Evans, G. Cloning and characterization of the t(X;11) breakpoint from a leukemic cell line identify a new member of the forkhead gene family. Genes Chromosomes Cancer 11: 79-84, 1994. [PubMed: 7529552] [Full Text: https://doi.org/10.1002/gcc.2870110203]
Peters, U., Haberhausen, G., Kostrzewa, M., Nolte, D., Muller, U. AFX1 and p54(nrb): fine mapping, genomic structure, and exclusion as candidate genes of X-linked dystonia parkinsonism. Hum. Genet. 100: 569-572, 1997. [PubMed: 9341872] [Full Text: https://doi.org/10.1007/s004390050553]
Tang, T. T.-L., Dowbenko, D., Jackson, A., Toney, L., Lewin, D. A., Dent, A. L., Lasky, L. A. The forkhead transcription factor AFX activates apoptosis by induction of the BCL-6 transcriptional repressor. J. Biol. Chem. 277: 14255-14265, 2002. [PubMed: 11777915] [Full Text: https://doi.org/10.1074/jbc.M110901200]
Tothova, Z., Kollipara, R., Huntly, B. J., Lee, B. H., Castrillon, D. H., Cullen, D. E., McDowell, E. P., Lazo-Kallanian, S., Williams, I. R., Sears, C., Armstrong, S. A., Passegue, E., DePinho, R. A., Gilliland, D. G. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128: 325-339, 2007. [PubMed: 17254970] [Full Text: https://doi.org/10.1016/j.cell.2007.01.003]