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Molecular and Cellular Biology, January 2009, p. 570-581, Vol. 29, No. 2
0270-7306/09/$08.00+0     doi:10.1128/MCB.01275-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

CUX1 and E2F1 Regulate Coordinated Expression of the Mitotic Complex Genes Ect2, MgcRacGAP, and MKLP1 in S Phase {triangledown} ,{dagger}

Laetitia Seguin,1 Caroline Liot,1 Rym Mzali,1 Ryoko Harada,2 Aurelie Siret,1 Alain Nepveu,2 and Jacques Bertoglio1*

INSERM U749, Faculté de Pharmacie Paris XI, 92296 Châtenay-Malabry, France,1 Molecular Oncology Group, McGill University, Montreal, Quebec H3A 1A1, Canada2

Received 12 August 2008/ Returned for modification 13 September 2008/ Accepted 3 November 2008

Rho GTPases are critical for mitosis progression and completion of cytokinesis. During mitosis, the GDP/GTP cycle of Rho GTPases is regulated by the exchange factor Ect2 and the GTPase activating protein MgcRacGAP which associates with the kinesin MKLP1 in the centralspindlin complex. We report here that expression of Ect2, MgcRacGAP, and MKLP1 is tightly regulated during cell cycle progression. These three genes share similar cell cycle-related signatures within their promoter regions: (i) cell cycle gene homology region (CHR) sites located at –20 to +40 nucleotides of their transcription start sites that are required for repression in G1, (ii) E2F binding elements, and (iii) tandem repeats of target sequences for the CUX1 transcription factor. CUX1 and E2F1 bind these three promoters upon S-phase entry, as demonstrated by chromatin immunoprecipitation, and regulate transcription of these genes, as established using promoter-luciferase reporter constructs and expression of activated or dominant negative transcription factors. Overexpression of either E2F1 or CUX1 increased the levels of the endogenous proteins whereas small interfering RNA knockdown of E2F1 or use of a dominant negative E2F1 reduced their expression levels. Thus, CUX1, E2F, and CHR elements provide the transcriptional controls that coordinate induction of Ect2, MgcRacGAP, and MKLP1 in S phase, leading to peak expression of these interacting proteins in G2/M, at the time they are required to regulate cytokinesis.

* Corresponding author. Mailing address: INSERM U749, Faculté de Pharmacie, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France. Phone: 33 146835508. Fax: 33 146835496. E-mail: jacques.bertoglio{at}u-psud.fr

{triangledown} Published ahead of print on 17 November 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, January 2009, p. 570-581, Vol. 29, No. 2
0270-7306/09/$08.00+0     doi:10.1128/MCB.01275-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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