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

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 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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Available from: Shabaz Mohammed, Sep 26, 2015
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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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    ABSTRACT: Few of >150 published cell cycle modeling efforts use significant levels of data for tuning and validation. This reflects the difficultly to generate correlated quantitative data, and it points out a critical uncertainty in modeling efforts. To develop a data-driven model of cell cycle regulation, we used contiguous, dynamic measurements over two time scales (minutes and hours) calculated from static multiparametric cytometry data. The approach provided expression profiles of cyclin A2, cyclin B1, and phospho-S10-histone H3. The model was built by integrating and modifying two previously published models such that the model outputs for cyclins A and B fit cyclin expression measurements and the activation of B cyclin/Cdk1 coincided with phosphorylation of histone H3. The model depends on Cdh1-regulated cyclin degradation during G1, regulation of B cyclin/Cdk1 activity by cyclin A/Cdk via Wee1, and transcriptional control of the mitotic cyclins that reflects some of the current literature. We introduced autocatalytic transcription of E2F, E2F regulated transcription of cyclin B, Cdc20/Cdh1 mediated E2F degradation, enhanced transcription of mitotic cyclins during late S/early G2 phase, and the sustained synthesis of cyclin B during mitosis. These features produced a model with good correlation between state variable output and real measurements. Since the method of data generation is extensible, this model can be continually modified based on new correlated, quantitative data.
    PLoS ONE 05/2014; 9(5):e97130. DOI:10.1371/journal.pone.0097130 · 3.23 Impact Factor
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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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    ABSTRACT: Cyclin-dependent kinases (Cdks) are serine/threonine kinases and their catalytic activities are modulated by interactions with cyclins and Cdk inhibitors (CKIs). Close cooperation between this trio is necessary for ensuring orderly progression through the cell cycle. In addition to their well-established function in cell cycle control, it is becoming increasingly apparent that mammalian Cdks, cyclins and CKIs play indispensable roles in processes such as transcription, epigenetic regulation, metabolism, stem cell self-renewal, neuronal functions and spermatogenesis. Even more remarkably, they can accomplish some of these tasks individually, without the need for Cdk/cyclin complex formation or kinase activity. In this Review, we discuss the latest revelations about Cdks, cyclins and CKIs with the goal of showcasing their functional diversity beyond cell cycle regulation and their impact on development and disease in mammals.
    Development 08/2013; 140(15):3079-93. DOI:10.1242/dev.091744 · 6.46 Impact Factor
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    • "Its expression, both at the mRNA and protein levels, is cell cycle-regulated: it increases at the entry of S-phase, peaks during G2 and M, and is degraded during mitotic exit (Laoukili et al., 2008b; Park et al., 2008). Similarly, its transcriptional activity is tightly regulated throughout the cell cycle by multisite phosphorylation by different kinases (Fu et al., 2008; Laoukili et al., 2008a; Anders et al., 2011), and its counteracting phosphatases (Alvarez-Fernandez et al., 2011), reaching its maximum activity in the G2 phase of the cell cycle. FoxM1 is a critical cell cycle regulator. "
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    ABSTRACT: FoxM1 is a member of the forkhead family of transcription factors. Since its identification 15 year ago, numerous studies have progressively contributed to our current understanding on FoxM1 functions. Early work showed that FoxM1 regulates the transcriptional program of the G2 phase of the cell cycle, and is essential for proper mitotic progression and genomic stability. Moreover, FoxM1 was found to be overexpressed in many different types of human cancer, suggesting a role of FoxM1 in tumor proliferation. In the past years, a significant number of studies have formally demonstrated the involvement of FoxM1 in different aspects of tumorogenesis, including angiogenesis, invasion, and metastasis. In addition to this, recent studies have placed FoxM1 in DNA damage response and senescence pathways, two pathways relevant to tumor progression and the response to cancer therapies. Here, we review and discuss the molecular mechanisms through which FoxM1 executes these new roles, and the implications for the potential use of FoxM1 as a therapeutic target in cancer.
    Frontiers in Oncology 03/2013; 3:30. DOI:10.3389/fonc.2013.00030
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