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FoxM1 is required for execution of the mitotic programme and chromosome stability

Abstract

Transcriptional induction of cell-cycle regulatory proteins ensures proper timing of subsequent cell-cycle events. Here we show that the Forkhead transcription factor FoxM1 regulates expression of many G2-specific genes and is essential for chromosome stability. Loss of FoxM1 leads to pleiotropic cell-cycle defects, including a delay in G2, chromosome mis-segregation and frequent failure of cytokinesis. We show that transcriptional activation of cyclin B by FoxM1 is essential for timely mitotic entry, whereas CENP-F, another direct target of FoxM1 identified here, is essential for precise functioning of the mitotic spindle checkpoint. Thus, our data uncover a transcriptional cluster regulated by FoxM1 that is essential for proper mitotic progression.

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Figure 1: FoxM1-deficient MEFs exhibit a defect in mitotic entry and chromosomal instability.
Figure 2: Depletion of endogenous human FoxM1 protein results in accumulation of tetraploid and polyploid cells and disturbs normal cell-cycle progression.
Figure 3: Overexpression of FoxM1 results in an increase of mitotic cell population.
Figure 4: FoxM1 induces expression of a large set of G2/M genes.
Figure 5: Cyclin B overexpression is sufficient for rescuing the defective mitotic entry in FoxM1-depleted cells.
Figure 6: CENP-F is a direct transcriptional target gene of FoxM1.
Figure 7: Down-regulation of CENP-F protein causes chromosome misalignment and a spindle checkpoint defect.

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Acknowledgements

We would like to thank the other members of the laboratory for helpful discussions and daily support. We would also like to thank M. Heimerikx and A. Velds for expert technical assistance with microarray analyses, R. Beijersbergen for the retro-pSuper-CENP-F, S. Taylor for the anti-BubR1 antibody and helpful discussion, R. Herrera for help with ChIP assays, and L. Oomen and L. Brocks for support with confocal microscopy. The authors acknowledge support from the Dutch Cancer Society and from the FCT (to A.B).

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Correspondence to René H. Medema.

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Laoukili, J., Kooistra, M., Brás, A. et al. FoxM1 is required for execution of the mitotic programme and chromosome stability. Nat Cell Biol 7, 126–136 (2005). https://doi.org/10.1038/ncb1217

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