Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

An N-terminal inhibitory domain modulates activity of FoxM1 during cell cycle

Oncogene volume 27, pages 1696–1704 (2008)Cite this article

Abstract

The FoxM1 transcription factor plays critical roles in the expression of genes that are essential for cell proliferation. FoxM1 null or depleted cells fail to progress through mitosis, as expression of several mitotic genes depends upon FoxM1. The transcriptional activity of FoxM1 is stimulated by cyclin-cdk-mediated phosphorylation at a site within the transcriptional activation domain. Here, we characterize the role of an N-terminal inhibitory domain in the transcriptional activity of FoxM1. Deletion of the N-terminal 232 amino-acid residues increases the transcriptional and transforming activities of FoxM1. Moreover, while the activity of the full-length FoxM1 is stimulated by growth factors, the activity of the N-terminal deletion mutant is constitutively high in all phases of the cell cycle. The N-terminal deletion also eliminates the requirement for cyclin-cdk to activate FoxM1. We provide evidence that the N-terminal domain interacts with the C-terminal half of the transcription factor to attenuate its transcriptional activity. Moreover, the N-terminal fragment inhibits the transcriptional activity of FoxM1 in G1/S cells, but not in G2/M cells. Our results suggest that cyclin-cdk phosphorylates FoxM1 to counteract the inhibition by the N-terminal domain to fully activate FoxM1 in G2/M phase.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Gusarova GA, Wang IC, Major ML, Kalinichenko VV, Ackerson T, Petrovic V et al. (2007). A cell-penetrating ARF peptide inhibitor of FoxM1 in mouse hepatocellular carcinoma treatment. J Clin Invest 117: 99–111.

    Article  CAS  Google Scholar 

  • Kalin TV, Wang IC, Ackerson TJ, Major ML, Detrisac CJ, Kalinichenko VV et al. (2006). Increased levels of the FoxM1 transcription factor accelerate development and progression of prostate carcinomas in both TRAMP and LADY transgenic mice. Cancer Res 66: 1712–1720.

    Article  CAS  Google Scholar 

  • Kalinichenko VV, Major ML, Wang X, Petrovic V, Kuechle J, Yoder HM et al. (2004). Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor. Genes Dev 18: 830–850.

    Article  CAS  Google Scholar 

  • Kim IM, Ackerson T, Ramakrishna S, Tretiakova M, Wang IC, Kalin TV et al. (2006). The Forkhead Box m1 transcription factor stimulates the proliferation of tumor cells during development of lung cancer. Cancer Res 66: 2153–2161.

    Article  CAS  Google Scholar 

  • Korver W, Roose J, Clevers H . (1997). The winged-helix transcription factor Trident is expressed in cycling cells. Nucleic Acids Res 25: 1715–1719.

    Article  CAS  Google Scholar 

  • Korver W, Schilham MW, Moerer P, van den Hoff MJ, Dam K, Lamers WH et al. (1998). Uncoupling of S phase and mitosis in cardiomyocytes and hepatocytes lacking the winged-helix transcription factor Trident. Curr Biol 8: 1327–1330.

    Article  CAS  Google Scholar 

  • Laoukili J, Kooistra MR, Bras A, Kauw J, Kerkhoven RM, Morrison A et al. (2005). FoxM1 is required for execution of the mitotic programme and chromosome stability. Nat Cell Biol 7: 126–136.

    Article  CAS  Google Scholar 

  • Liu M, Dai B, Kang SH, Ban K, Huang FJ, Lang FF et al. (2006). FoxM1B is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells. Cancer Res 66: 3593–3602.

    Article  CAS  Google Scholar 

  • Luscher-Firzlaff JM, Westendorf JM, Zwicker J, Burkhardt H, Henriksson M, Muller R et al. (1999). Interaction of the fork head domain transcription factor MPP2 with the human papilloma virus 16 E7 protein: enhancement of transformation and transactivation. Oncogene 18: 5620–5630.

    Article  CAS  Google Scholar 

  • Major ML, Lepe R, Costa RH . (2004). Forkhead box M1B transcriptional activity requires binding of Cdk-cyclin complexes for phosphorylation-dependent recruitment of p300/CBP coactivators. Mol Cell Biol 24: 2649–2661.

    Article  CAS  Google Scholar 

  • Wang IC, Chen YJ, Hughes D, Petrovic V, Major ML, Park HJ et al. (2005). 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: 10875–10894.

    Article  CAS  Google Scholar 

  • Wang X, Hung NJ, Costa RH . (2001a). Earlier expression of the transcription factor HFH-11B diminishes induction of p21(CIP1/WAF1) levels and accelerates mouse hepatocyte entry into S-phase following carbon tetrachloride liver injury. Hepatology 33: 1404–1414.

    Article  CAS  Google Scholar 

  • Wang X, Kiyokawa H, Dennewitz MB, Costa RH . (2002). The Forkhead Box m1b transcription factor is essential for hepatocyte DNA replication and mitosis during mouse liver regeneration. Proc Natl Acad Sci USA 99: 16881–16886.

    Article  CAS  Google Scholar 

  • Wang X, Quail E, Hung NJ, Tan Y, Ye H, Costa RH . (2001b). Increased levels of forkhead box M1B transcription factor in transgenic mouse hepatocytes prevent age-related proliferation defects in regenerating liver. Proc Natl Acad Sci USA 98: 11468–11473.

    Article  CAS  Google Scholar 

  • Wierstra I, Alves J . (2006a). Despite its strong transactivation domain, transcription factor FOXM1c is kept almost inactive by two different inhibitory domains. Biol Chem 387: 963–976.

    CAS  PubMed  Google Scholar 

  • Wierstra I, Alves J . (2006b). FOXM1c is activated by cyclin E/Cdk2, cyclin A/Cdk2, and cyclin A/Cdk1, but repressed by GSK-3alpha. Biochem Biophys Res Commun 348: 99–108.

    Article  CAS  Google Scholar 

  • Wierstra I, Alves J . (2006c). Transcription factor FOXM1c is repressed by RB and activated by cyclin D1/Cdk4. Biol Chem 387: 949–962.

    CAS  PubMed  Google Scholar 

  • Wonsey DR, Follettie MT . (2005). Loss of the forkhead transcription factor FoxM1 causes centrosome amplification and mitotic catastrophe. Cancer Res 65: 5181–5189.

    Article  CAS  Google Scholar 

  • Ye H, Holterman AX, Yoo KW, Franks RR, Costa RH . (1999). Premature expression of the winged helix transcription factor HFH-11B in regenerating mouse liver accelerates hepatocyte entry into S phase. Mol Cell Biol 19: 8570–8580.

    Article  CAS  Google Scholar 

  • Ye H, Kelly TF, Samadani U, Lim L, Rubio S, Overdier DG et al. (1997). 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: 1626–1641.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

While this work was in progress, RHC died in his fight against pancreatic cancer. The authors dedicate this work to his memory. This work was supported by NIH grants to RHC. LFL is supported by NIH Grant CA46565, AT is supported by NIH Grant DK044525 and PR is supported by NIH Grants CA124488 and CA100035.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Genetics (M/C 669), College of Medicine, University of Illinois, Chicago, IL, USA

    H J Park, Z Wang, R H Costa, A Tyner, L F Lau & P Raychaudhuri

Authors
  1. H J Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Z Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R H Costa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Tyner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L F Lau
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P Raychaudhuri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P Raychaudhuri.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Park, H., Wang, Z., Costa, R. et al. An N-terminal inhibitory domain modulates activity of FoxM1 during cell cycle. Oncogene 27, 1696–1704 (2008). https://doi.org/10.1038/sj.onc.1210814

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210814

Keywords

This article is cited by

Search

Advanced search

Quick links