Alternative titles; symbols
HGNC Approved Gene Symbol: FOXM1
Cytogenetic location: 12p13.33 Genomic coordinates (GRCh38): 12:2,857,680-2,877,174 (from NCBI)
The 'forkhead' gene family, originally identified in Drosophila, comprises transcription factors with a conserved 100-amino acid DNA-binding motif. One group of factors with the forkhead, or winged-helix, domain is the hepatocyte nuclear factor-3 family of proteins, which appears to regulate cell-specific transcription in hepatocytes and in respiratory and intestinal epithelia. In an attempt to identify forkhead domain transcription factors involved in intestinal cell differentiation, Ye et al. (1997) isolated FKHL16, which they designated HNF3/forkhead homolog-11 (HFH11), from a human colon carcinoma cell line. On Northern blots, FKHL16 was expressed primarily in thymus, testis, small intestine, and colon, moderately in ovary, and at reduced levels in other tissues. Ye et al. (1997) found 2 alternatively spliced FKHL16 mRNAs, yielding predicted proteins of 801 (HFH11A) and 748 (HFH11B) amino acids. Both isoforms contain 2 PEST regions, associated with rapid protein degradation. Expression studies in mouse revealed that Fkhl16 is transcribed broadly in embryos, but is expressed only in adult organs containing proliferating cells involved in replenishing differentiated cell populations or in response to growth factors released during injury or repair.
A partial FKHL16 cDNA, called MPP2 (MPM2 reactive phosphoprotein-2) was isolated by Westendorf et al. (1994), who found it to be one of the proteins phosphorylated by M-phase kinases.
Independently, Yao et al. (1997) isolated human and rat FKHL16, or WIN, cDNAs. The predicted rat and human FKHL16 proteins share 81% sequence identity. Yao et al. (1997) reported that human and rat FKHL16 mRNAs are differentially spliced within the coding sequence of the winged-helix DNA-binding domain at sites encoding regions that are important for directing DNA binding specificity. RNase protection studies indicated that the alternatively spliced transcripts have different relative abundances in various tissues, suggesting that the splicing events may be regulated. Using a PCR-based strategy, the authors determined the DNA sequences to which rat FKHL16 binds in vitro.
By analyzing the promoter region of human FKHL16, or TRIDENT, Korver et al. (1997) found that the 300 bp upstream of the transcription start site are essential for the cell cycle-specific expression of FKHL16. They stated that the promoter data in combination with the expression of FKHL16 in cycling, but not resting, cells indicate that this protein is likely to play a role in the control of cell proliferation.
By analysis of cDNA microarrays, Ly et al. (2000) showed that diminished proliferation exhibited by fibroblasts from either elderly patients or patients with Hutchinson-Gilford progeria (176670) was associated with reduced expression of cell cycle genes as well as a decline in FOXM1B (HFH11B) levels. Wang et al. (2001) showed that increased levels of Foxm1b in regenerating liver of old transgenic mice restored the sharp peaks in hepatocyte DNA replication and mitosis that are the hallmarks of young regenerating mouse liver. Restoration of the young regenerating liver phenotype was associated with increased expression of numerous cell cycle regulatory genes. Cotransfection assays in the human hepatoma HepG2 cell line demonstrated that FOXM1B protein stimulated expression of both the cyclin B1 (123836) and cyclin D1 (168461) promoters, suggesting that these cyclin genes are a direct FOXM1B transcription target. The results suggested that FOXM1B controls the transcription network of genes that are essential for cell division and exit from mitosis. The results indicated that reduced expression of the FOXM1B transcription factor contributes to the decline in cellular proliferation observed in the aging process.
Wang et al. (2002) showed that the FOXM1B transcription factor regulates expression of cell cycle proteins essential for hepatocyte entry into DNA replication and mitosis.
Kalinichenko et al. (2004) found that conditionally deleted Foxm1b mouse hepatocytes failed to proliferate and were highly resistant to developing chemically induced hepatocellular carcinoma (114550). This resistance was associated with sustained nuclear levels of the Cdk inhibitor p27(Kip1) (CDKN1B; 600778) and diminished expression of M-phase-promoting Cdc25b phosphatase (116949). Overexpression of Foxm1b in an osteosarcoma cell line enhanced anchorage-independent growth on soft agar. Kalinichenko et al. (2004) presented evidence that p27(Kip1) and p19(Arf) (CDKN2A; 600160) interact with Foxm1b and inhibit Foxm1b transcriptional activity. Furthermore, exposure to a membrane-transducing synthetic peptide based on N-terminal sequences of p19(Arf) reduced Foxm1b transcriptional activity and diminished Foxm1b-induced growth on soft agar.
Laoukili et al. (2005) found that Foxm1-null mouse embryonic fibroblasts and human osteosarcoma cells treated with FOXM1 interfering RNA were delayed in G2. There was an increase in cells with 4n or polyploid DNA content, but no increase in the mitotic index. FOXM1 depletion led to pleiotropic G2/M defects, including chromosome misalignment, spindle checkpoint dysfunction, and defects in cytokinesis. Laoukili et al. (2005) reported that the C terminus of FOXM1 contains a transcriptional activation domain, and FOXM1 proteins lacking the C terminus behaved in a dominant-negative manner, causing cell-cycle defects similar to those observed with FOXM1 RNA interference. Overexpression of FOXM1 caused increased entry into mitosis. Using high-density human cDNA microarrays, Laoukili et al. (2005) found that FOXM1 regulated the expression of a large number of G2/M-specific genes, most importantly cyclin B and CENPF (600236). Transcriptional activation of cyclin B was essential for timely mitotic entry, whereas activation of CENPF was required for sustained activation of the mitotic spindle checkpoint. Laoukili et al. (2005) concluded that FOXM1 regulates a transcriptional cluster that is essential for proper mitotic progression.
Saldivar et al. (2018) demonstrated that cells transactivate the mitotic gene network as they exit the S phase through a CDK1 (116940)-directed FOXM1 phosphorylation switch. During normal DNA replication, the checkpoint kinase ATR (601215) is activated by ETAA1 (613196) to block this switch until the S phase ends. ATR inhibition prematurely activates FOXM1, deregulating the S/G2 transition and leading to early mitosis, underreplicated DNA, and DNA damage. Thus, ATR couples DNA replication with mitosis and preserves genome integrity by enforcing an S/G2 checkpoint.
Korver et al. (1997) found that the FKHL16 gene contains 10 exons, which span approximately 25 kb.
By somatic cell hybrid analysis, radiation hybrid mapping, and fluorescence in situ hybridization, Korver et al. (1997) localized the FKHL16 gene to chromosome 12p13, telomeric to the FGF6 gene (134921).
Using targeted deletion of the Foxm1 gene in mice, Kim et al. (2005) found that Foxm1 knockout led to embryonic lethality due to severe abnormalities in the development of the liver and heart. Foxm1 -/- lungs displayed severe abnormalities in the development of pulmonary microvasculature that was associated with diminished pulmonary levels of Pecam1 (173445), Tgfbr2 (190182), Adam17 (603639), Flk1 (KDR; 191306), Flt1 (165070), Plk1 (602098), Aurora B kinase (604970), Lama4 (600133), and Foxf1 (601089). Foxm1 was essential for proliferation of lung mesenchyme and vascular smooth muscle cells during embryonic lung development. Cotransfection experiments demonstrated that the Lama4 gene was a direct transcriptional target for Foxm1. Kim et al. (2005) concluded that FOXM1 regulates pulmonary genes essential for mesenchyme proliferation, extracellular matrix remodeling, and vasculogenesis during lung development.
Cai et al. (2013) generated 2 transgenic mouse models, 1 exhibiting Foxm1 gain of function and 1 exhibiting Foxm1 loss of function, both under control of the prostate epithelial-specific probasin promoter. In the transgenic adenocarcinoma mouse prostate (TRAMP) model that uses SV40 large T antigen to induce prostate cancer, mice lacking Foxm1 had decreased tumor growth and metastasis. Decreased prostate tumorigenesis was associated with decreased tumor cell proliferation and downregulation of Cdc25b, cyclin B1, Plk1, Lox (153455), and versican (VCAN; 118661). There was also a decrease in angiogenesis and reduced Vegfa (192240) expression. Foxm1-deficient prostate tumors and cell lines had downregulated mRNA and protein expression of Hsd11b2 (614232), an enzyme important in tumor cell proliferation. ChIP analysis identified Hsd11b2 as a direct transcriptional target of Foxm1. Without induction of prostate tumorigenesis, overexpression of Foxm1 alone or in combination with inhibition of the p19(Arf) tumor suppressor resulted in epithelial hyperplasia, but not progression to prostate cancer. Cai et al. (2013) concluded that FOXM1 expression in prostate epithelial cells is critical for prostate carcinogenesis. They proposed that inhibition of FOXM1 may be a therapeutic approach for prostate cancer chemotherapy.
Cai, Y., Balli, D., Ustiyan, V., Fulford, L., Hiller, A., Misetic, V., Zhang, Y., Paluch, A. M., Waltz, S. E., Kasper, S., Kalin, T. V. Foxm1 expression in prostate epithelial cells is essential for prostate carcinogenesis. J. Biol. Chem. 288: 22527-22541, 2013. [PubMed: 23775078] [Full Text: https://doi.org/10.1074/jbc.M113.455089]
Kalinichenko, V. V., Major, M. L., Wang, X., Petrovic, V., Kuechle, J., Yoder, H. M., Dennewitz, M. B., Shin, B., Datta, A., Raychaudhuri, P., Costa, R. H. Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19(ARF) tumor suppressor. Genes Dev. 18: 830-850, 2004. [PubMed: 15082532] [Full Text: https://doi.org/10.1101/gad.1200704]
Kim, I.-M., Ramakrishna, S., Gusarova, G. A., Yoder, H. M., Costa, R. H., Kalinichenko, V. V. The forkhead box M1 transcription factor is essential for embryonic development of pulmonary vasculature. J. Biol. Chem. 280: 22278-22286, 2005. [PubMed: 15817462] [Full Text: https://doi.org/10.1074/jbc.M500936200]
Korver, W., Roose, J., Heinen, K., Weghuis, D. O., de Bruijn, D., Geurts van Kessel, A., Clevers, H. The human TRIDENT/HFH-11/FKHL16 gene: structure, localization, and promoter characterization. Genomics 46: 435-442, 1997. [PubMed: 9441747] [Full Text: https://doi.org/10.1006/geno.1997.5065]
Laoukili, J., Kooistra, M. R. H., Bras, A., Kauw, J., Kerkhoven, R. M., Morrison, A., Clevers, H., Medema, R. H. FoxM1 is required for execution of the mitotic programme and chromosome stability. Nature Cell Biol. 7: 126-136, 2005. [PubMed: 15654331] [Full Text: https://doi.org/10.1038/ncb1217]
Ly, D. H., Lockhart, D. J., Lerner, R. A., Schultz, P. G. Mitotic misregulation and human aging. Science 287: 2486-2492, 2000. [PubMed: 10741968] [Full Text: https://doi.org/10.1126/science.287.5462.2486]
Saldivar, J. C., Hamperl, S., Bocek, M. J., Chung, M., Bass, T. E., Cisneros-Soberanis, F., Samejima, K., Xie, L., Paulson, J. R., Earnshaw, W. C., Cortez, D., Meyer, T., Cimprich, K. A. An intrinsic S/G2 checkpoint enforced by ATR. Science 361: 806-810, 2018. [PubMed: 30139873] [Full Text: https://doi.org/10.1126/science.aap9346]
Wang, X., Kiyokawa, H., Dennewitz, M. B., Costa, R. H. The Forkhead box m1b transcription factor is essential for hepatocyte DNA replication and mitosis during mouse liver regeneration. Proc. Nat. Acad. Sci. 99: 16881-16886, 2002. [PubMed: 12482952] [Full Text: https://doi.org/10.1073/pnas.252570299]
Wang, X., Quail, E., Hung, N.-J., Tan, Y., Ye, H., Costa, R. H. Increased levels of forkhead box M1B transcription factor in transgenic mouse hepatocytes prevent age-related proliferation defects in regenerating liver. Proc. Nat. Acad. Sci. 98: 11468-11473, 2001. [PubMed: 11572993] [Full Text: https://doi.org/10.1073/pnas.201360898]
Westendorf, J. M., Rao, P. N., Gerace, L. Cloning of cDNAs for M-phase phosphoproteins recognized by the MPM2 monoclonal antibody and determination of the phosphorylated epitope. Proc. Nat. Acad. Sci. 91: 714-718, 1994. [PubMed: 8290587] [Full Text: https://doi.org/10.1073/pnas.91.2.714]
Yao, K.-M., Sha, M., Lu, Z., Wong, G. G. Molecular analysis of a novel winged helix protein, WIN: expression pattern, DNA binding property, and alternative splicing within the DNA binding domain. J. Biol. Chem. 272: 19827-19836, 1997. [PubMed: 9242644] [Full Text: https://doi.org/10.1074/jbc.272.32.19827]
Ye, H., Kelly, T. F., Samadani, U., Lim, L., Rubio, S., Overdier, D. G., Roebuck, K. A., Costa, R. H. Hepatic nuclear factor 3/fork head homolog 11 is expressed in proliferating epithelial and mesenchymal cells of embryonic and adult tissues. Molec. Cell. Biol. 17: 1626-1641, 1997. [PubMed: 9032290] [Full Text: https://doi.org/10.1128/MCB.17.3.1626]