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Mol. Cell. Biol. doi:10.1128/MCB.01710-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Activation of FoxM1 during G2 requires CyclinA/Cdk-dependent relief of auto-repression by the FoxM1 N-terminal domain

Department of Medical Oncology, Laboratory of Experimental Oncology, University Medical Center Utrecht, the Netherlands; Department of Human Genetics, Academic Medical Center (AMC), University of Amsterdam, the Netherlands; Department of Physiological Chemistry and Centre for Biomedical Genetics, University Medical Center Utrecht, the Netherlands; Biomolecular Mass Spectrometry and Proteomics Group, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, the Netherlands

^* To whom correspondence should be addressed. Email: j.laoukili{at}amc.uva.nl. r.h.medema{at}umcutrecht.nl.

	Abstract

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 auto-inhibitory domain. We find that CyclinA/cdk complexes are required to phosphorylate and activate FoxM1 during G2-phase. Deletion of the N-terminal auto-inhibitory region of FoxM1 generates a mutant of FoxM1 ( N-FoxM1) that is active throughout the cell cycle and no longer depends on cyclinA for its activation. Mutation of two CyclinA/cdk sites in the C-terminal transactivation domain (TAD) 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 auto-repressor domain, while phosphorylation by cyclinA/cdk complexes during G2 results in relief of inhibition by the N-terminus allowing activation of FoxM1-mediated gene transcription.

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