Activation of FoxM1 during G2 requires cyclin A/Cdk-dependent relief of autorepression by the FoxM1 N-terminal domain.
The Forkhead transcription factor FoxM1 is an important regulator of gene expression during the G(2) phase. Here, we show that FoxM1 transcriptional activity is kept low during G(1)/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 G(2) phase. Deletion of the N-terminal autoinhibitory region of FoxM1 generates a mutant of FoxM1 (DeltaN-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 DeltaN-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 G(1)/S transition through the action of the N-terminal autorepressor domain, while phosphorylation by cyclin A/cdk complexes during G(2) results in relief of inhibition by the N terminus, allowing activation of FoxM1-mediated gene transcription.
Laoukili
Jamila
J
Laboratory of Experimental Oncology, Department of Medical Oncology, University Medical Center, Stratenum 2.118, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands. j.laoukili@amc.uva.nl
Alvarez
Monica
M
Meijer
Lars A T
LA
Stahl
Marie
M
Mohammed
Shabaz
S
Kleij
Livio
L
Heck
Albert J R
AJ
Medema
René H
RH
D002478:Cells, Cultured; D019925:Cyclin A / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000502:physiology*; D016195:G2 Phase / Q000502:physiology*; D006801:Humans; D009154:Mutation; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D015533:Transcriptional Activation
D019925:Cyclin A; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D018844:Cyclin-Dependent Kinases