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Gene Review

FOXM1  -  forkhead box M1

Homo sapiens

Synonyms: FKHL16, FOXM1B, Forkhead box protein M1, Forkhead-related protein FKHL16, HFH-11, ...
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Disease relevance of FOXM1


High impact information on FOXM1

  • The forkhead box m1 (Foxm1) transcription factor is essential for initiation of carcinogen-induced liver tumors; however, whether FoxM1 constitutes a therapeutic target for liver cancer treatment remains unknown [5].
  • In the current study, we show that IL-1beta induces destruction of INS-1 insulinoma cells, while having no effect on a second insulinoma cell line RIN1046-38 and its engineered derivatives, and that this difference is correlated with a higher level of expression of manganese superoxide dismutase (MnSOD) in the latter cells [6].
  • The well-characterized synaptotagmin isoforms I and II are present in pancreatic beta-cell lines RINm5F, INS-1 and HIT-T15 as shown by Northern and Western blots [7].
  • The topology of the LexA DNA binding domain is found to be the same as for the DNA binding domains of the catabolic activator protein, human histone 5, the HNF-3/fork head protein and the Kluyveromyces lactis heat shock transcription factor [8].
  • Mammalian hepatocyte nuclear factor-3 (HNF-3) and the Drosophila homeotic gene fork head proteins are prototypes of an extensive family of cell-specific transcription factors that share homology in the winged helix DNA-binding domain [9].

Chemical compound and disease context of FOXM1

  • To further investigate the molecular mechanisms implicated in these adaptation processes to hyperglycemia, we have studied the regulation of genes encoding key glycolytic enzymes in the glucose-responsive beta-cell line INS-1 [10].
  • We investigated the involvement of apoptotic events in INS-1 insulinoma cells overexpressing wild-type HNF-1 alpha (WT-HNF-1 alpha) or a dominant-negative mutant (DN-HNF-1 alpha) under control of a doxycycline-dependent transcriptional activator [11].
  • We recently isolated and characterized a novel member of the winged helix (formerly HNF-3/Forkhead) transcriptional regulatory family, termed Genesis. Genesis was found to be a transcriptional repressor expressed almost exclusively in embryonic stem cells or embryonal carcinoma cells [12].
  • We also compared results, including observations of osteolysis, of the Trident study group with those of the predecessor alumina bearing couple design to determine clinical improvement and radiographic stability [13].
  • These results suggest that insulin secretion from the rat insulinoma cell line, INS-1, is modulated by troglitazone, acting somewhere in the ATP-sensitive K(+) channel pathway, possibly through PPAR gamma [14].

Biological context of FOXM1

  • Given the role of FOXM1 in cell proliferation, the up-regulation of FOXM1 in BCCs may be one of the mechanisms whereby Shh signaling exerts its mitogenic effect on basal keratinocytes, leading to the development of this common human cancer [1].
  • The FOXM1 forkhead proteins, originally identified as M-phase phosphoproteins, are proliferation-associated transcriptional regulators involved in cell cycle progression, genetic stability and tumorigenesis [15].
  • We suggest that the very high potential of the transactivation domain has to be tightly controlled by these two inhibitory domains because FOXM1 stimulates proliferation by promoting G1/S transition, as well as G2/M transition, and because deregulation of such potent activators of proliferation can result in tumorigenesis [16].
  • Consequently, the G1-phase proliferation signal cyclin D1/Cdk4 converts FOXM1c from an almost inactive form into a strong transactivator in G1-phase, i.e., just at the time point at which the transcriptional activity of FOXM1 is required for stimulation of the G1/S-transition [17].
  • The deduced MPP1 and MPP2 amino acid sequences are not closely related to any previously described proteins [18].

Anatomical context of FOXM1

  • All three known FOXM1 isoforms (a, b, and c) were detected in human skin and cultured keratinocytes, and the transcriptionally active FOXM1b isoform was found to be up-regulated in BCCs [1].
  • In the present study, the role of SOCS-3 in GH signaling was investigated in the pancreatic beta-cell lines RIN-5AH and INS-1 by means of inducible expression systems [19].
  • We report here one such novel interaction between STAT-3 and hepatocyte nuclear factor 3 (HNF-3) in the absence of DNA [20].
  • Analysis of the promoter in synchronized Rat-1 fibroblasts revealed a fragment of 300 bases responsible for the cell cycle-specific expression of the TRIDENT gene [21].
  • Consistent with a role in transcription, small interfering RNA-mediated knockdown of PDX-1 led to decreased mafA mRNA production in INS-1-derived beta-cell lines (832/13 and 832/3), while MafA expression was undetected in the pancreatic epithelium of Nkx2.2 null animals [22].

Associations of FOXM1 with chemical compounds

  • Finally, 5-bromodeoxyuridine incorporation followed by fluorescence-activated cell sorting analysis showed that SOCS-3 inhibits GH-induced proliferation of INS-1 cells [19].
  • Antibodies or Fab-fragments directed against the Ca2+-dependent phospholipid binding site of the first C2 domain of synaptotagmin I or II inhibited Ca2+-stimulated, but not GTPgammaS-induced exocytosis from streptolysin-O-permeabilized INS-1 and HIT-T15 cells [7].
  • The mei4+ open reading frame encodes a 57-kDa serine-rich protein comprised of 517 amino acids with a forkhead/HNF3 DNA-binding domain in the amino-terminal region [23].
  • Such control is likely mediated via the expression of immediate-early response genes since several of these genes including c-fos are strongly induced by glucose in the beta-cell line INS-1, provided costimulation with cAMP-raising glucoincretin hormones [24].
  • Furthermore, expression of this truncated HNF3 protein results in a proportionate reduction of glucocorticoid-stimulated glucose production from lactate and pyruvate in these cells [25].

Physical interactions of FOXM1

  • In particular we show that the hamster CYP7A1 insulin response sequence is part of a complex unit involved in specific interactions with multiple transcription factors such as members of the HNF-3 family; this region does not bind very strongly to HNF-3 and as a consequence partly contributes to the transactivation of the gene [26].
  • Eight of these were novel, including a gross gene deletion, three missense mutations, two micro-deletions, a splicing mutation and a single base-pair substitution in the HNF-3 binding site in the PROC gene promoter [27].
  • The effects of GH and PRL on [Ca2+]i, JAK2 phosphorylation and DNA binding of the STATs were virtually identical in INS-1 cells [28].
  • Sequences were inserted at position -21, separating both HNF-3 binding sites from the HNF-1-HNF-6 binding site, and position -5, separating the HNF-3-HNF-1-HNF-6 complex from the transcription start site [29].
  • Results of gel mobility shift assays and DNase I and exonuclease III in vitro protection assays indicate that factors with DNA-binding properties similar to those of the HNF-3/fork head family of transcription factors are present in adipocytes and interact with LP-alpha and LP-beta [30].

Regulatory relationships of FOXM1


Other interactions of FOXM1

  • GLI family transcription factors then activate transcription of Hedgehog target genes, such as FOXE1 and FOXM1 encoding Forkhead-box transcription factors [36].
  • PTCH1, FOXM1 and CCND2 are direct transcriptional targets of Hedgehog signaling [37].
  • Partial-length cDNAs encoding two MPM2-reactive proteins termed MPM2-reactive phosphoproteins 1 and 2 (MPP1 and MPP2) were isolated [18].
  • Transcription is stimulated and repressed by several transcription factors, including B-MYB, E2F, FOXM1, and NF-Y [38].
  • Expression of GLI1 and FOXM1 mRNA increased with exogenous exposure to SHh [2].

Analytical, diagnostic and therapeutic context of FOXM1


  1. FOXM1 is a downstream target of Gli1 in basal cell carcinomas. Teh, M.T., Wong, S.T., Neill, G.W., Ghali, L.R., Philpott, M.P., Quinn, A.G. Cancer Res. (2002) [Pubmed]
  2. Sonic Hedgehog-dependent proliferation in a series of patients with colorectal cancer. Douard, R., Moutereau, S., Pernet, P., Chimingqi, M., Allory, Y., Manivet, P., Conti, M., Vaubourdolle, M., Cugnenc, P.H., Loric, S. Surgery (2006) [Pubmed]
  3. Human FOX gene family (Review). Katoh, M., Katoh, M. Int. J. Oncol. (2004) [Pubmed]
  4. Increased levels of the FoxM1 transcription factor accelerate development and progression of prostate carcinomas in both TRAMP and LADY transgenic mice. Kalin, T.V., Wang, I.C., Ackerson, T.J., Major, M.L., Detrisac, C.J., Kalinichenko, V.V., Lyubimov, A., Costa, R.H. Cancer Res. (2006) [Pubmed]
  5. A cell-penetrating ARF peptide inhibitor of FoxM1 in mouse hepatocellular carcinoma treatment. Gusarova, G.A., Wang, I.C., Major, M.L., Kalinichenko, V.V., Ackerson, T., Petrovic, V., Costa, R.H. J. Clin. Invest. (2007) [Pubmed]
  6. Stable expression of manganese superoxide dismutase (MnSOD) in insulinoma cells prevents IL-1beta- induced cytotoxicity and reduces nitric oxide production. Hohmeier, H.E., Thigpen, A., Tran, V.V., Davis, R., Newgard, C.B. J. Clin. Invest. (1998) [Pubmed]
  7. The first C2 domain of synaptotagmin is required for exocytosis of insulin from pancreatic beta-cells: action of synaptotagmin at low micromolar calcium. Lang, J., Fukuda, M., Zhang, H., Mikoshiba, K., Wollheim, C.B. EMBO J. (1997) [Pubmed]
  8. Solution structure of the LexA repressor DNA binding domain determined by 1H NMR spectroscopy. Fogh, R.H., Ottleben, G., Rüterjans, H., Schnarr, M., Boelens, R., Kaptein, R. EMBO J. (1994) [Pubmed]
  9. The winged helix transcription factor HFH-4 is expressed during choroid plexus epithelial development in the mouse embryo. Lim, L., Zhou, H., Costa, R.H. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  10. Induction by glucose of genes coding for glycolytic enzymes in a pancreatic beta-cell line (INS-1). Roche, E., Assimacopoulos-Jeannet, F., Witters, L.A., Perruchoud, B., Yaney, G., Corkey, B., Asfari, M., Prentki, M. J. Biol. Chem. (1997) [Pubmed]
  11. Dominant-negative suppression of HNF-1 alpha results in mitochondrial dysfunction, INS-1 cell apoptosis, and increased sensitivity to ceramide-, but not to high glucose-induced cell death. Wobser, H., Düssmann, H., Kögel, D., Wang, H., Reimertz, C., Wollheim, C.B., Byrne, M.M., Prehn, J.H. J. Biol. Chem. (2002) [Pubmed]
  12. Forced expression of Genesis, a winged helix transcriptional repressor isolated from embryonic stem cells, blocks granulocytic differentiation of 32D myeloid cells. Xu, D., Yoder, M., Sutton, J., Hromas, R. Leukemia (1998) [Pubmed]
  13. A titanium-encased alumina ceramic bearing for total hip arthroplasty: 3- to 5-year results. D'Antonio, J.A., Capello, W.N., Manley, M.T., Naughton, M., Sutton, K. Clin. Orthop. Relat. Res. (2005) [Pubmed]
  14. Troglitazone ameliorates lipotoxicity in the beta cell line INS-1 expressing PPAR gamma. Kawai, T., Hirose, H., Seto, Y., Fujita, H., Fujita, H., Ukeda, K., Saruta, T. Diabetes Res. Clin. Pract. (2002) [Pubmed]
  15. Regulation of the transcription factor FOXM1c by Cyclin E/CDK2. Lüscher-Firzlaff, J.M., Lilischkis, R., Lüscher, B. FEBS Lett. (2006) [Pubmed]
  16. Despite its strong transactivation domain, transcription factor FOXM1c is kept almost inactive by two different inhibitory domains. Wierstra, I., Alves, J. Biol. Chem. (2006) [Pubmed]
  17. Transcription factor FOXM1c is repressed by RB and activated by cyclin D1/Cdk4. Wierstra, I., Alves, J. Biol. Chem. (2006) [Pubmed]
  18. Cloning of cDNAs for M-phase phosphoproteins recognized by the MPM2 monoclonal antibody and determination of the phosphorylated epitope. Westendorf, J.M., Rao, P.N., Gerace, L. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  19. The effect of suppressor of cytokine signaling 3 on GH signaling in beta-cells. Rønn, S.G., Hansen, J.A., Lindberg, K., Karlsen, A.E., Billestrup, N. Mol. Endocrinol. (2002) [Pubmed]
  20. Interaction between STAT-3 and HNF-3 leads to the activation of liver-specific hepatitis B virus enhancer 1 function. Waris, G., Siddiqui, A. J. Virol. (2002) [Pubmed]
  21. The human TRIDENT/HFH-11/FKHL16 gene: structure, localization, and promoter characterization. Korver, W., Roose, J., Heinen, K., Weghuis, D.O., de Bruijn, D., van Kessel, A.G., Clevers, H. Genomics (1997) [Pubmed]
  22. FoxA2, Nkx2.2, and PDX-1 regulate islet beta-cell-specific mafA expression through conserved sequences located between base pairs -8118 and -7750 upstream from the transcription start site. Raum, J.C., Gerrish, K., Artner, I., Henderson, E., Guo, M., Sussel, L., Schisler, J.C., Newgard, C.B., Stein, R. Mol. Cell. Biol. (2006) [Pubmed]
  23. The Schizosaccharomyces pombe mei4+ gene encodes a meiosis-specific transcription factor containing a forkhead DNA-binding domain. Horie, S., Watanabe, Y., Tanaka, K., Nishiwaki, S., Fujioka, H., Abe, H., Yamamoto, M., Shimoda, C. Mol. Cell. Biol. (1998) [Pubmed]
  24. Essentiality of intron control in the induction of c-fos by glucose and glucoincretin peptides in INS-1 beta-cells. Susini, S., Van Haasteren, G., Li, S., Prentki, M., Schlegel, W. FASEB J. (2000) [Pubmed]
  25. The molecular physiology of hepatic nuclear factor 3 in the regulation of gluconeogenesis. Wang, J.C., Stafford, J.M., Scott, D.K., Sutherland, C., Granner, D.K. J. Biol. Chem. (2000) [Pubmed]
  26. Identification and characterization of cis-acting elements conferring insulin responsiveness on hamster cholesterol 7alpha-hydroxylase gene promoter. De Fabiani, E., Crestani, M., Marrapodi, M., Pinelli, A., Golfieri, V., Galli, G. Biochem. J. (2000) [Pubmed]
  27. Molecular genetic analysis of severe protein C deficiency. Millar, D.S., Johansen, B., Berntorp, E., Minford, A., Bolton-Maggs, P., Wensley, R., Kakkar, V., Schulman, S., Torres, A., Bosch, N., Cooper, D.N. Hum. Genet. (2000) [Pubmed]
  28. GH signalling in pancreatic beta-cells. Sekine, N., Wollheim, C.B., Fujita, T. Endocr. J. (1998) [Pubmed]
  29. Unique distance- and DNA-turn-dependent interactions in the human protein C gene promoter confer submaximal transcriptional activity. Spek, C.A., Bertina, R.M., Reitsma, P.H. Biochem. J. (1999) [Pubmed]
  30. Characterization of the human lipoprotein lipase (LPL) promoter: evidence of two cis-regulatory regions, LP-alpha and LP-beta, of importance for the differentiation-linked induction of the LPL gene during adipogenesis. Enerbäck, S., Ohlsson, B.G., Samuelsson, L., Bjursell, G. Mol. Cell. Biol. (1992) [Pubmed]
  31. Transcriptional regulation of human CYP3A4 basal expression by CCAAT enhancer-binding protein alpha and hepatocyte nuclear factor-3 gamma. Rodríguez-Antona, C., Bort, R., Jover, R., Tindberg, N., Ingelman-Sundberg, M., Gómez-Lechón, M.J., Castell, J.V. Mol. Pharmacol. (2003) [Pubmed]
  32. The Forkhead box M1 protein regulates the transcription of the estrogen receptor alpha in breast cancer cells. Madureira, P.A., Varshochi, R., Constantinidou, D., Francis, R.E., Coombes, R.C., Yao, K.M., Lam, E.W. J. Biol. Chem. (2006) [Pubmed]
  33. Expression of the transcription factor STAT-1 alpha in insulinoma cells protects against cytotoxic effects of multiple cytokines. Chen, G., Hohmeier, H.E., Newgard, C.B. J. Biol. Chem. (2001) [Pubmed]
  34. TRPM4 controls insulin secretion in pancreatic beta-cells. Cheng, H., Beck, A., Launay, P., Gross, S.A., Stokes, A.J., Kinet, J.P., Fleig, A., Penner, R. Cell Calcium (2007) [Pubmed]
  35. Ghrelin is expressed in a novel endocrine cell type in developing rat islets and inhibits insulin secretion from INS-1 (832/13) cells. Wierup, N., Yang, S., McEvilly, R.J., Mulder, H., Sundler, F. J. Histochem. Cytochem. (2004) [Pubmed]
  36. Identification and characterization of rat Desert hedgehog and Indian hedgehog genes in silico. Katoh, Y., Katoh, M. Int. J. Oncol. (2005) [Pubmed]
  37. Hedgehog signaling pathway and gastric cancer. Katoh, Y., Katoh, M. Cancer Biol. Ther. (2005) [Pubmed]
  38. A roller coaster ride with the mitotic cyclins. Fung, T.K., Poon, R.Y. Semin. Cell Dev. Biol. (2005) [Pubmed]
  39. Cloning of a cellular factor, interleukin binding factor, that binds to NFAT-like motifs in the human immunodeficiency virus long terminal repeat. Li, C., Lai, C.F., Sigman, D.S., Gaynor, R.B. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  40. Hepatocyte nuclear factor 3 activates transcription of thyroid transcription factor 1 in respiratory epithelial cells. Ikeda, K., Shaw-White, J.R., Wert, S.E., Whitsett, J.A. Mol. Cell. Biol. (1996) [Pubmed]
  41. Discrete and complementary mechanisms of protection of beta-cells against cytokine-induced and oxidative damage achieved by bcl-2 overexpression and a cytokine selection strategy. Tran, V.V., Chen, G., Newgard, C.B., Hohmeier, H.E. Diabetes (2003) [Pubmed]
  42. Hepatic nuclear factor 3 and nuclear factor 1 regulate 5-aminolevulinate synthase gene expression and are involved in insulin repression. Scassa, M.E., Guberman, A.S., Ceruti, J.M., Cánepa, E.T. J. Biol. Chem. (2004) [Pubmed]
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