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

Laboratory of Experimental Oncology, Department of Medical Oncology, University Medical Center, Stratenum 2.118, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
Molecular and Cellular Biology (Impact Factor: 4.78). 06/2008; 28(9):3076-87. DOI: 10.1128/MCB.01710-07
Source: PubMed


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 (ΔN-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
ΔN-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.

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    • "While it is known that cyclin B/Cdk1 can indirectly influence its own transcription, for example, through the activation of Bora, Plk1, and FoxM1, it is difficult to see how it could accomplish significant effect prior to appreciable cyclin B/Cdk1 activity, without invoking non-catalytic activity. Further, FoxM1 has been shown to require the phosphorylation of an autoinhibitory domain by cyclin A/Cdk before the transcription of cyclin B and other G2 phase targets [88]. Similarly, B-Myb also requires activation by cyclin A/Cdk [74], [89], [90]. "
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    • "CDK phosphorylates both Fkh2 and Ndd1 and is required for their interaction and recruitment to target gene promoters (Reynolds, 2003; Pic-Taylor et al, 2004). In mammals, the related forkhead protein FoxM1 regulates expression of a similar group of mitotic genes (Laoukili et al, 2005), and phosphorylation of the FoxM1 C-terminal transactivation domain by Cdk2 is required for its activity (Major et al, 2004; Lüscher-Firzlaff et al, 2006; Wierstra & Alves, 2006; Laoukili et al, 2008). Thus, the general principles of CDK-regulated transcription are conserved between yeast and mammals throughout the cell cycle. "
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    • "inhibition is relieved through Cdk2/cyclin A-dependent hyperphosphorylation of the TAD, which displaces the RD and enhances the recruitment of a transcriptional co-activator, the histone deacetylase p300/CREB binding protein (Ep300/Crebbp). This complex promotes the expression of genes responsible for driving mitotic entry (Chen et al., 2009; Laoukili et al., 2008; Major et al., 2004; Park et al., 2008). As a precautionary measure against premature activation, phosphorylation of FoxM1 can be reversed by protein phosphatase 2A (PP2A) and its regulatory subunit B55α (Alvarez-Fernández et al., 2011). "
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