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Protein phosphatase 2A (B55α) prevents premature activation of forkhead transcription factor FoxM1 by antagonizing cyclin A/cyclin-dependent kinase-mediated phosphorylation.

Authors
  • Alvarez-Fernández, Mónica1
  • Halim, Vincentius A
  • Aprelia, Melinda
  • Laoukili, Jamila
  • Mohammed, Shabaz
  • Medema, René H
  • 1 Department of Medical Oncology and Cancer Genomics Centre, UMC Utrecht, Universiteitsweg 100, Stratenum 2.118, Utrecht 3584 CG, The Netherlands. , (Netherlands)
Type
Published Article
Journal
Journal of Biological Chemistry
Publisher
American Society for Biochemistry and Molecular Biology
Publication Date
Sep 23, 2011
Volume
286
Issue
38
Pages
33029–33036
Identifiers
DOI: 10.1074/jbc.M111.253724
PMID: 21813648
Source
Medline
License
Unknown

Abstract

The forkhead transcription factor FoxM1 controls expression of a large number of genes that are specifically expressed during the G(2) phase of the cell cycle. Throughout most of the cell cycle, FoxM1 activity is restrained by an autoinhibitory mechanism, involving a repressor domain present in the N-terminal part of the protein. Activation of FoxM1 in G(2) is achieved by Cyclin A/Cyclin-dependent kinase (Cdk)-mediated phosphorylation, which alleviates autoinhibition by the N-terminal repressor domain. Here, we show that FoxM1 interacts with B55α, a regulatory subunit of protein phosphatase 2A (PP2A). B55α binds the catalytic subunit of PP2A, and this promotes dephosphorylation and inactivation of FoxM1. Indeed, we find that overexpression of B55α results in decreased FoxM1 activity. Inversely, depletion of B55α results in premature activation of FoxM1. The activation of FoxM1 that is observed upon depletion of B55α is fully dependent on Cyclin A/Cdk-mediated phosphorylation of FoxM1. Taken together, these data demonstrate that B55α acts to antagonize Cyclin A/Cdk-dependent activation of FoxM1, to ensure that FoxM1 activity is restricted to the G(2) phase of the cell cycle.

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