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 Previous Article

Molecular and Cellular Biology, May 2008, p. 3076-3087, Vol. 28, No. 9
0270-7306/08/$08.00+0     doi:10.1128/MCB.01710-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Activation of FoxM1 during G2 Requires Cyclin A/Cdk-Dependent Relief of Autorepression by the FoxM1 N-Terminal Domain{triangledown} ,{dagger}

Jamila Laoukili,1,2* Monica Alvarez,1 Lars A. T. Meijer,3 Marie Stahl,1 Shabaz Mohammed,4 Livio Kleij,1 Albert J. R. Heck,4 and René H. Medema1*

Department of Medical Oncology, Laboratory of Experimental Oncology, University Medical Center Utrecht, Utrecht, The Netherlands,1 Department of Human Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands,2 Department of Physiological Chemistry and Centre for Biomedical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands,3 Biomolecular Mass Spectrometry and Proteomics Group, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands4

Received 17 September 2007/ Returned for modification 30 October 2007/ Accepted 2 February 2008

The Forkhead transcription factor FoxM1 is an important regulator of gene expression during the G2 phase. Here, we show that FoxM1 transcriptional activity is kept low during G1/S through the action of its N-terminal autoinhibitory domain. We found that cyclin A/cdk complexes are required to phosphorylate and activate FoxM1 during G2 phase. Deletion of the N-terminal autoinhibitory region of FoxM1 generates a mutant of FoxM1 ({Delta}N-FoxM1) that is active throughout the cell cycle and no longer depends on cyclin A for its activation. Mutation of two cyclin A/cdk sites in the C-terminal transactivation domain leads to inactivation of full-length FoxM1 but does not affect the transcriptional activity of the {Delta}N-FoxM1 mutant. We show that the intramolecular interaction of the N- and C-terminal domains depends on two RXL/LXL motifs in the C terminus of FoxM1. Mutation of these domains leads to a similar gain of function as deletion of the N-terminal repressor domain. Based on these observations we propose a model in which FoxM1 is kept inactive during the G1/S transition through the action of the N-terminal autorepressor domain, while phosphorylation by cyclin A/cdk complexes during G2 results in relief of inhibition by the N terminus, allowing activation of FoxM1-mediated gene transcription.

* Corresponding author. Mailing address: Laboratory of Experimental Oncology, Department of Medical Oncology, University Medical Center, Stratenum 2.118, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands. Phone: 31-88-7568066. Fax: 31-88-7568479. E-mail for J. Laoukili: j.laoukili{at}amc.uva.nl. E-mail for René H. Medema: r.h.medema{at}umcutrecht.nl

{triangledown} Published ahead of print on 19 February 2008.

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

Molecular and Cellular Biology, May 2008, p. 3076-3087, Vol. 28, No. 9
0270-7306/08/$08.00+0     doi:10.1128/MCB.01710-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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