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

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 (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 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.

Published ahead of print on 19 February 2008.

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