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Plk1-dependent phosphorylation of FoxM1 regulates a transcriptional programme required for mitotic progression

Nature Cell Biology volume 10, pages 1076–1082 (2008)Cite this article

Abstract

Proper control of entry into and progression through mitosis is essential for normal cell proliferation and the maintenance of genome stability1,2,3,4. The mammalian mitotic kinase Polo-like kinase 1 (Plk1) is involved in multiple stages of mitosis5. Here we report that Forkhead Box M1 (FoxM1), a substrate of Plk1 (refs 6, 7, 8), controls a transcriptional programme that mediates Plk1-dependent regulation of cell-cycle progression. The carboxy-terminal domain of FoxM1 binds Plk1, and phosphorylation of two key residues in this domain by Cdk1 is essential for Plk1–FoxM1 interaction. Formation of the Plk1–FoxM1 complex allows for direct phosphorylation of FoxM1 by Plk1 at G2/M and the subsequent activation of FoxM1 activity, which is required for expression of key mitotic regulators, including Plk1 itself. Thus, Plk1-dependent regulation of FoxM1 activity provides a positive-feedback loop ensuring tight regulation of transcriptional networks essential for orderly mitotic progression.

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Figure 1: Plk1 interacts with FoxM1 in vitro and in vivo.
Figure 2: Plk1 phosphorylates FoxM1 in vitro and in vivo.
Figure 3: Plk1 activates FoxM1 transcriptional activity.
Figure 4: Plk1-dependent phosphorylation of FoxM1 is required for expression of the G2/M transcriptional programme and orderly mitotic progression in vivo.

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Acknowledgements

We are grateful for extensive discussions with R.H. Medema and J. Laoukili and their input. We thank H.M. Thompson for editing the manuscript. Mass spectrometry analysis was performed by Taplin Biological Mass Spectrometry Facility at Harvard University. This work was supported in part by grants from the National Institutes of Health (NIH RO1 CA113381 to JC), Mayo SPORE P50 (CA116201 project no. 1 to J.C.) and the T.J. Martell Foundation (to D.J.T.). J.C. is a recipient of an Era of Hope Scholars award from DOD. Z.F. is a recipient of a Ruth L. Kirschstein NRSA individual Fellowship from NIH.

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Authors and Affiliations

  1. Urology and Molecular Biology, Mayo Clinic College of Medicine, Rochester, 55905, Minnesota, USA

    Zheng Fu & Donald J. Tindall

  2. Pediatrics and Molecular Biology, Mayo Clinic College of Medicine, Rochester, 55905, Minnesota, USA

    Liviu Malureanu & Jan M. van Deursen

  3. Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA,

    Zheng Fu, Liviu Malureanu & Jan M. van Deursen

  4. Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, 06520-8040, Connecticut, USA

    Jun Huang & Junjie Chen

  5. Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, 87131, New Mexico, USA

    Wei Wang & Hao Li

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Contributions

Z.F. performed most of experiments, analysed the data and wrote the paper; L.M. and J.M.V. analysed the time-lapse imaging data; J.H. performed the experiments shown in Fig. S2a and b; W.W. and H. L. synthesized ON01910; Z.F. and J.C. designed the experiments; J.C. and D.J. T. supervised the study and revised the paper.

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Correspondence to Donald J. Tindall or Junjie Chen.

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Fu, Z., Malureanu, L., Huang, J. et al. Plk1-dependent phosphorylation of FoxM1 regulates a transcriptional programme required for mitotic progression. Nat Cell Biol 10, 1076–1082 (2008). https://doi.org/10.1038/ncb1767

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