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A Conserved Phosphorylation Site within the Forkhead Domain of FoxM1B Is Required for Its Activation by Cyclin-CDK1.

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Title: A Conserved Phosphorylation Site within the Forkhead Domain of FoxM1B Is Required for Its Activation by Cyclin-CDK1.
Authors: Yi-Ju Chen1, Dominguez-Brauer, Carmen1, Zebin Wang1, Asara, John M.2,3, Costat, Robert H.1, Tyner, Angela L.1, Lau, Lester F.1, Raychaudhuri, Pradip1 pradip@uic.edu
Source: Journal of Biological Chemistry. 10/30/2009, Vol. 284 Issue 44, p30695-30707. 13p.
Subjects: Forkhead transcription factors, Cell cycle, Phosphorylation, Cyclins, Protein kinases, Genetic transcription
Abstract: The Forkhead box M1 (FoxM1) transcription factor is critical for expression of the genes essential for G1/S transition and mitotic progression. To explore the cell cycle regulation of FoxM1, we examined the phosphorylation profile of FoxM1. Here, we show that the phosphorylated status and the activity of FoxM1 increase as cells progress from S to G2/M phases. Moreover, dephosphorylation of FoxM1 coincides with exit from mitosis. Using mass spectrometry, we have identified a new conserved phosphorylation site (Ser-251) within the forkhead domain of FoxM1. Disruption of Ser-251 inhibits phosphorylation of FoxM1 and dramatically decreases its transcriptional activity. We demonstrate that the Ser-25 1 residue is required for CDK1-dependent phosphorylation of FoxM1 as well as its inter- action with the coactivator CREB-binding protein (CBP). Interestingly, the transcriptional activity of the S251A mutant protein remains responsive to activation by overexpressed Polo-like kinase 1 (PLK1). Cells expressing the S251A mutant exhibit reduced expression of the G2/M phase genes and impaired mitotic progression. Our results demonstrate that the transcriptional activity of FoxM1 is controlled in a cell cycle-dependent fashion by temporally regulated phosphorylation and dephosphorylation events, and that the phosphorylation at Ser-251 is critical for the activation of FoxM1. [ABSTRACT FROM AUTHOR]
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Database: Engineering Source
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Abstract:The Forkhead box M1 (FoxM1) transcription factor is critical for expression of the genes essential for G1/S transition and mitotic progression. To explore the cell cycle regulation of FoxM1, we examined the phosphorylation profile of FoxM1. Here, we show that the phosphorylated status and the activity of FoxM1 increase as cells progress from S to G2/M phases. Moreover, dephosphorylation of FoxM1 coincides with exit from mitosis. Using mass spectrometry, we have identified a new conserved phosphorylation site (Ser-251) within the forkhead domain of FoxM1. Disruption of Ser-251 inhibits phosphorylation of FoxM1 and dramatically decreases its transcriptional activity. We demonstrate that the Ser-25 1 residue is required for CDK1-dependent phosphorylation of FoxM1 as well as its inter- action with the coactivator CREB-binding protein (CBP). Interestingly, the transcriptional activity of the S251A mutant protein remains responsive to activation by overexpressed Polo-like kinase 1 (PLK1). Cells expressing the S251A mutant exhibit reduced expression of the G2/M phase genes and impaired mitotic progression. Our results demonstrate that the transcriptional activity of FoxM1 is controlled in a cell cycle-dependent fashion by temporally regulated phosphorylation and dephosphorylation events, and that the phosphorylation at Ser-251 is critical for the activation of FoxM1. [ABSTRACT FROM AUTHOR]
ISSN:00219258
DOI:10.1074/jbc.M109.007997