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Transcription Factor Encyclopedia  BETA
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Forkhead box M1 (FOXM1), previously named HNF-3, HFH-11 or Trident, is a transcription factor of the Forkhead box (Fox) protein superfamily which is defined by a conserved winged helix DNA-binding domain[1]. FOXM1 is a key regulator of both G1/S and G2/M phases of the cell cycle [2][3][4][5][6][7] and mitotic spindle integrity[8]. Besides its involvement in cell cycle transitions, it also plays an important role in angiogenesis[9], metastasis[10], apoptosis[11][12][7], DNA damage repair[13] and tissue regeneration[14]. The human FOXM1 gene consists of 10 exons of which two are alternatively spliced. These splice events give rise to three different splice variants named FOXM1a, -b and -c[15][16][17]. FOXM1b and FOXM1c act as transactivators and can activate their target genes by two different mechanisms. They both activate through binding to conventional FOXM1 binding sites 5’-A(C/T)AAA(C/T)AA-3’[18] while FOXM1c can additionally activate genes by binding to the TATA-boxes[19][20][21]. The splice variant FOXM1a is transcriptionally inactive due to disruption of the transactivation domain and might also cause dominant-negative effects as it has retained a functional DNA binding domain[17]. FOXM1 is ubiquitously expressed in proliferating cells[22] and has a positive effect on cell growth by promoting G1/S as well as G2/M-transition during the cell cycle[2][3][4][5][6][7]. Its expression levels are shown to correlate with the proliferative state of a cell and are antagonistically regulated by proliferation and anti-proliferation signals. In quiescent or terminally differentiated cells FOXM1 levels are barely detectable[15]. FOXM1 deficient cells show polyploidy, aneuploidy, defects in cytokinesis, chromosome missegregation as well as an increase in the number of DNA breaks. These findings suggest an important role of FOXM1 in the maintenance of genome stability [8][23] and DNA damage repair[13]. Additionally, cells exposed to DNA damaging radiation show an increase in FOXM1 protein levels indicating its involvement in DNA repair processes[13]. Post-translational modifications play an important role in the regulation of FOXM1. The phosphorylation condition of FOXM1 determines its cellular localisation and activation state. Phosphorylation by Raf-MEK-ERK causes FOXM1 to translocate from the cytoplasm into the nucleus during late S-phase after which further phosphorylation steps take place[24][25]. Hyperphosphorylation during G2-M phase correlates with increased transcriptional activity of FOXM1 which suggests phosphorylation as an important regulation step in the activation of the protein. Conserved putative phosphorylation sites indicate the involvement of various Cyclin-Cdk complexes as well as the mitogen-activated protein kinase (MAPK) cascade[26][24][27]. Furthermore, phosphorylation by checkpoint kinase 2 in response to DNA damage was shown to increase FOXM1 stability and its transcriptional activity[13]. The important roles of FOXM1 during cell cycle progression and DNA damage repair have given this transcription factor a crucial role within the development and progression of many cancers, including colorectal [28], lung [4], prostate [29], liver [30] and breast cancer [31]. A microarray study also shows that FOXM1 expression is elevated in carcinomas of the prostate, lung, ovary, colon, pancreas, stomach, bladder, liver, kidney and breast [32]. In most human tumours FOXM1 levels are significantly higher[33] while the expression level increases with tumour grade and is inversely correlated with patient survival[34].

  1. Clark KL et al. Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5. Nature, 364(6436):412-20. (PMID 8332212)
  2. Wang IC et al. Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase. Mol. Cell. Biol., 25(24):10875-94. (PMID 16314512)
  3. Wang X et al. The Forkhead Box m1b transcription factor is essential for hepatocyte DNA replication and mitosis during mouse liver regeneration. Proc. Natl. Acad. Sci. U.S.A., 99(26):16881-6. (PMID 12482952)
  4. Kim IM et al. The Forkhead Box m1 transcription factor stimulates the proliferation of tumor cells during development of lung cancer. Cancer Res., 66(4):2153-61. (PMID 16489016)
  5. Costa RH. FoxM1 dances with mitosis. Nat. Cell Biol., 7(2):108-10. (PMID 15689977)
  6. Li SK et al. FoxM1c counteracts oxidative stress-induced senescence and stimulates Bmi-1 expression. J. Biol. Chem., 283(24):16545-53. (PMID 18408007)
  7. Chan DW et al. Over-expression of FOXM1 transcription factor is associated with cervical cancer progression and pathogenesis. J. Pathol., 215(3):245-52. (PMID 18464245)
  8. Laoukili J et al. FoxM1 is required for execution of the mitotic programme and chromosome stability. Nat. Cell Biol., 7(2):126-36. (PMID 15654331)
  9. Wang Z et al. Down-regulation of Forkhead Box M1 transcription factor leads to the inhibition of invasion and angiogenesis of pancreatic cancer cells. Cancer Res., 67(17):8293-300. (PMID 17804744)
  10. Dai B et al. Aberrant FoxM1B expression increases matrix metalloproteinase-2 transcription and enhances the invasion of glioma cells. Oncogene, 26(42):6212-9. (PMID 17404569)
  11. Madureira PA et al. The Forkhead box M1 protein regulates the transcription of the estrogen receptor alpha in breast cancer cells. J. Biol. Chem., 281(35):25167-76. (PMID 16809346)
  12. Wierstra I and Alves J. FOXM1, a typical proliferation-associated transcription factor. Biol. Chem., 388(12):1257-74. (PMID 18020943)
  13. Tan Y et al. Chk2 mediates stabilization of the FoxM1 transcription factor to stimulate expression of DNA repair genes. Mol. Cell. Biol., 27(3):1007-16. (PMID 17101782)
  14. Kalinichenko VV et al. Differential expression of forkhead box transcription factors following butylated hydroxytoluene lung injury. Am. J. Physiol. Lung Cell Mol. Physiol., 280(4):L695-704. (PMID 11238010)
  15. Korver W et al. The winged-helix transcription factor Trident is expressed in cycling cells. Nucleic Acids Res., 25(9):1715-9. (PMID 9108152)
  16. Yao KM et al. 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(32):19827-36. (PMID 9242644)
  17. Ye H et al. Hepatocyte nuclear factor 3/fork head homolog 11 is expressed in proliferating epithelial and mesenchymal cells of embryonic and adult tissues. Mol. Cell. Biol., 17(3):1626-41. (PMID 9032290)
  1. Wierstra I and Alves J. Despite its strong transactivation domain, transcription factor FOXM1c is kept almost inactive by two different inhibitory domains. Biol. Chem., 387(7):963-76. (PMID 16913846)
  2. Wierstra I and Alves J. FOXM1c transactivates the human c-myc promoter directly via the two TATA boxes P1 and P2. FEBS J., 273(20):4645-67. (PMID 16965535)
  3. Wierstra I and Alves J. FOXM1c and Sp1 transactivate the P1 and P2 promoters of human c-myc synergistically. Biochem. Biophys. Res. Commun., 352(1):61-8. (PMID 17141659)
  4. Wierstra I and Alves J. The central domain of transcription factor FOXM1c directly interacts with itself in vivo and switches from an essential to an inhibitory domain depending on the FOXM1c binding site. Biol. Chem., 388(8):805-18. (PMID 17655499)
  5. Leung TW et al. Over-expression of FoxM1 stimulates cyclin B1 expression. FEBS Lett., 507(1):59-66. (PMID 11682060)
  6. Laoukili J et al. FoxM1: at the crossroads of ageing and cancer. Biochim. Biophys. Acta, 1775(1):92-102. (PMID 17014965)
  7. Major ML et al. Forkhead box M1B transcriptional activity requires binding of Cdk-cyclin complexes for phosphorylation-dependent recruitment of p300/CBP coactivators. Mol. Cell. Biol., 24(7):2649-61. (PMID 15024056)
  8. Myatt SS and Lam EW. The emerging roles of forkhead box (Fox) proteins in cancer. Nat. Rev. Cancer, 7(11):847-59. (PMID 17943136)
  9. Lüscher-Firzlaff JM et al. Regulation of the transcription factor FOXM1c by Cyclin E/CDK2. FEBS Lett., 580(7):1716-22. (PMID 16504183)
  10. Ma RY et al. Raf/MEK/MAPK signaling stimulates the nuclear translocation and transactivating activity of FOXM1c. J. Cell. Sci., 118(Pt 4):795-806. (PMID 15671063)
  11. Yoshida Y et al. The forkhead box M1 transcription factor contributes to the development and growth of mouse colorectal cancer. Gastroenterology, 132(4):1420-31. (PMID 17408638)
  12. Kalin TV et al. Increased levels of the FoxM1 transcription factor accelerate development and progression of prostate carcinomas in both TRAMP and LADY transgenic mice. Cancer Res., 66(3):1712-20. (PMID 16452231)
  13. Kalinichenko VV et al. Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor. Genes Dev., 18(7):830-50. (PMID 15082532)
  14. Kwok JM et al. Thiostrepton selectively targets breast cancer cells through inhibition of forkhead box M1 expression. Mol. Cancer Ther., 7(7):2022-32. (PMID 18645012)
  15. Pilarsky C et al. Identification and validation of commonly overexpressed genes in solid tumors by comparison of microarray data. Neoplasia, 6(6):744-50. (PMID 15720800)
  16. Wonsey DR and Follettie MT. Loss of the forkhead transcription factor FoxM1 causes centrosome amplification and mitotic catastrophe. Cancer Res., 65(12):5181-9. (PMID 15958562)
  17. Liu M et al. FoxM1B is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells. Cancer Res., 66(7):3593-602. (PMID 16585184)
A.DNA/RNA. DNA gene containing 10 exons, 2 of which being splicing exons Va (A1) and VIIa (A2) that originates 3 different splice variants, encoding for 3 FOXM1 protein isoforms: FOXM1a, containing both alternative exons, FOXM1b, not containing any alternative exons and FOXM1c only containing exon Va.

B. Phosphorylation sites of FOXM1. Schematic figure showing confirmed phosphorylation sites in FOXM1 and the kinases involved. Phosphorylation by cyclin-cdk1/2 complexes and PlK1 increases FOXM1 activity, while cyclinA-Cdk reliefs the inhibitory function of the NRD. Chk2 increases FOXM1 stability and Raf/MEK/MAPK mediated phosphorylation stimulates nuclear translocation. The mammalian mitotic kinase Polo-like kinase 1 (Plk1) binds to and phosphorylates two residues, S715 and S724, within the carboxy-terminal domain of FOXM1.

NRD= N-terminal Repressor Domain, FKH = Forkhead DNA Binding Domain, TAD = Transactivation Domain.

This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.