title: Protein phosphatase 2A (B55α) prevents premature activation of forkhead transcription factor FoxM1 by antagonizing cyclin A/cyclin-dependent kinase-mediated phosphorylation.
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.
authors.affiliation: Department of Medical Oncology and Cancer Genomics Centre, UMC Utrecht, Universiteitsweg 100, Stratenum 2.118, Utrecht 3584 CG, The Netherlands.
authors.forename: Mónica
authors.initials: M
authors.lastname: Alvarez-Fernández
authors.forename: Vincentius A
authors.initials: VA
authors.lastname: Halim
authors.forename: Melinda
authors.initials: M
authors.lastname: Aprelia
authors.forename: Jamila
authors.initials: J
authors.lastname: Laoukili
authors.forename: Shabaz
authors.initials: S
authors.lastname: Mohammed
authors.forename: René H
authors.initials: RH
authors.lastname: Medema
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D019925:Cyclin A / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D011485:Protein Binding; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D019925:Cyclin A; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C512974:PPP2R2A protein, human; D010455:Peptides; D018844:Cyclin-Dependent Kinases; D054648:Protein Phosphatase 2