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

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.

[1]  G. Evan,et al.  A modified oestrogen receptor ligand-binding domain as an improved switch for the regulation of heterologous proteins. , 1995, Nucleic acids research.

[2]  S. R. Datta,et al.  DNA Repair Pathway Stimulated by the Forkhead Transcription Factor FOXO3a Through the Gadd45 Protein , 2002, Science.

[3]  E. Lam,et al.  Control of Cell Cycle Exit and Entry by Protein Kinase B-Regulated Forkhead Transcription Factors , 2002, Molecular and Cellular Biology.

[4]  Stephen S. Taylor,et al.  Bub1 is required for kinetochore localization of BubR1, Cenp-E, Cenp-F and Mad2, and chromosome congression , 2004, Journal of Cell Science.

[5]  R. Costa,et al.  Premature Expression of the Winged Helix Transcription Factor HFH-11B in Regenerating Mouse Liver Accelerates Hepatocyte Entry into S Phase , 1999, Molecular and Cellular Biology.

[6]  K. Yao,et al.  Molecular Analysis of a Novel Winged Helix Protein, WIN , 1997, The Journal of Biological Chemistry.

[7]  A. V. van Rossum,et al.  Ablation of the retinoblastoma gene family deregulates G(1) control causing immortalization and increased cell turnover under growth-restricting conditions. , 2000, Genes & development.

[8]  A. Shevchenko,et al.  Forkhead transcription factors, Fkh1p and Fkh2p, collaborate with Mcm1p to control transcription required for M-phase , 2000, Current Biology.

[9]  K. Yoda,et al.  Human CENP-I specifies localization of CENP-F, MAD1 and MAD2 to kinetochores and is essential for mitosis , 2003, Nature Cell Biology.

[10]  N. Motoyama,et al.  FOXO Forkhead Transcription Factors Induce G2-M Checkpoint in Response to Oxidative Stress* , 2002, The Journal of Biological Chemistry.

[11]  Mike Tyers,et al.  The fork'ed path to mitosis , 2000, Genome Biology.

[12]  H. Clevers,et al.  The winged-helix transcription factor Trident is expressed in cycling cells. , 1997, Nucleic acids research.

[13]  Ronald W. Davis,et al.  Transcriptional regulation and function during the human cell cycle , 2001, Nature Genetics.

[14]  C. Sardet,et al.  Retinoblastoma Protein Transcriptional Repression through Histone Deacetylation of a Single Nucleosome , 2002, Molecular and Cellular Biology.

[15]  T. Nakazawa,et al.  Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues. , 2000, The Biochemical journal.

[16]  Mike Tyers,et al.  Mechanisms that help the yeast cell cycle clock tick: G2 cyclins transcriptionally activate G2 cyclins and repress G1 cyclins , 1993, Cell.

[17]  L. Johnston,et al.  The forkhead protein Fkh2 is a component of the yeast cell cycle transcription factor SFF , 2000, The EMBO journal.

[18]  E. Lam,et al.  Cell Cycle Inhibition by FoxO Forkhead Transcription Factors Involves Downregulation of Cyclin D , 2002, Molecular and Cellular Biology.

[19]  H. Clevers,et al.  Uncoupling of S phase and mitosis in cardiomyocytes and hepatocytes lacking the winged-helix transcription factor Trident , 1998, Current Biology.

[20]  W. Earnshaw,et al.  The hBUB1 and hBUBR1 kinases sequentially assemble onto kinetochores during prophase with hBUBR1 concentrating at the kinetochore plates in mitosis , 1998, Chromosoma.

[21]  C. Martínez-A,et al.  Forkhead transcription factors contribute to execution of the mitotic programme in mammals , 2001, Nature.

[22]  D. Botstein,et al.  Two yeast forkhead genes regulate the cell cycle and pseudohyphal growth , 2000, Nature.

[23]  L. Lim,et al.  Hepatocyte Nuclear Factor 3 / fork head Homolog 11 Is Expressed in Proliferating Epithelial and Mesenchymal Cells of Embryonic and Adult Tissues , 1996 .

[24]  R. Medema,et al.  Polo-like kinase-1 is a target of the DNA damage checkpoint , 2000, Nature Cell Biology.

[25]  Lukas Endler,et al.  Forkhead-like transcription factors recruit Ndd1 to the chromatin of G2/M-specific promoters , 2000, Nature.

[26]  B. Futcher Transcriptional regulatory networks and the yeast cell cycle. , 2002, Current opinion in cell biology.

[27]  R. Agami,et al.  Survivin is required for a sustained spindle checkpoint arrest in response to lack of tension , 2003, The EMBO journal.

[28]  D. Lockhart,et al.  Mitotic misregulation and human aging. , 2000, Science.

[29]  R. Medema,et al.  Decisions on life and death: FOXO Forkhead transcription factors are in command when PKB/Akt is off duty , 2003, Journal of leukocyte biology.

[30]  R. Bernards,et al.  A System for Stable Expression of Short Interfering RNAs in Mammalian Cells , 2002, Science.

[31]  Stephen S. Taylor,et al.  Farnesylation of Cenp-F is required for G2/M progression and degradation after mitosis. , 2002, Journal of cell science.

[32]  M. Greenberg,et al.  Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor , 1999, Cell.

[33]  B. Schaar,et al.  Characterization of the Kinetochore Binding Domain of CENP-E Reveals Interactions with the Kinetochore Proteins CENP-F and hBUBR1 , 1998, The Journal of cell biology.

[34]  J. McIntosh,et al.  Unstable kinetochore-microtubule capture and chromosomal instability following deletion of CENP-E. , 2002, Developmental cell.

[35]  H. Clevers,et al.  The winged-helix transcription factor Trident is expressed in actively dividing lymphocytes. , 1997, Immunobiology.

[36]  C. Ball,et al.  Identification of genes periodically expressed in the human cell cycle and their expression in tumors. , 2002, Molecular biology of the cell.