title: Plk1 Regulates the Repressor Function of FoxM1b by inhibiting its Interaction with the Retinoblastoma Protein.
abstract: FoxM1b is a cell cycle-regulated transcription factor, whose over-expression is a marker for poor outcome in cancers. Its transcriptional activation function requires phosphorylation by Cdk1 or Cdk2 that primes FoxM1b for phosphorylation by Plk1, which triggers association with the co-activator CBP. FoxM1b also possesses transcriptional repression function. It represses the mammary differentiation gene GATA3 involving DNMT3b and Rb. We investigated what determines the two distinct functions of FoxM1b: activation and repression. We show that Rb binds to the C-terminal activation domain of FoxM1b. Analyses with phospho-defective and phospho-mimetic mutants of FoxM1b identified a critical role of the Plk1 phosphorylation sites in regulating the binding of FoxM1b to Rb and DNMT3b. That is opposite of what was seen for the interaction of FoxM1b with CBP. We show that, in addition to GATA3, FoxM1b also represses the mammary luminal differentiation marker FoxA1 by promoter-methylation, and that is regulated by the Plk1 phosphorylation sites in FoxM1b. Our results show that the Plk1 phosphorylation sites in FoxM1b serve as a regulator for its repressor function, and they provide insights into how FoxM1b inhibits differentiation genes and activates proliferation genes during cancer progression.
authors.affiliation: Department of Biochemistry and Molecular Genetics (M/C 669), University of Illinois, College of Medicine, 900 S, USA Ashland Ave., Chicago, IL-60607, USA.
authors.forename: Nishit K
authors.initials: NK
authors.lastname: Mukhopadhyay
authors.affiliation: Department of Biochemistry and Molecular Genetics (M/C 669), University of Illinois, College of Medicine, 900 S, USA Ashland Ave., Chicago, IL-60607, USA.
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Chand
authors.affiliation: Department of Biochemistry and Molecular Genetics (M/C 669), University of Illinois, College of Medicine, 900 S, USA Ashland Ave., Chicago, IL-60607, USA.
authors.forename: Akshay
authors.initials: A
authors.lastname: Pandey
authors.affiliation: Department of Biochemistry and Molecular Genetics (M/C 669), University of Illinois, College of Medicine, 900 S, USA Ashland Ave., Chicago, IL-60607, USA.
authors.forename: Dragana
authors.initials: D
authors.lastname: Kopanja
authors.affiliation: Department of Hematology/Oncology, University of California, Los Angeles, CA, USA.
authors.forename: Janai R
authors.initials: JR
authors.lastname: Carr
authors.affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Yi-Ju
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Genetics (M/C 669), University of Illinois, College of Medicine, 900 S, USA Ashland Ave., Chicago, IL-60607, USA.
authors.forename: Xiubei
authors.initials: X
authors.lastname: Liao
authors.affiliation: Department of Biochemistry and Molecular Genetics (M/C 669), University of Illinois, College of Medicine, 900 S, USA Ashland Ave., Chicago, IL-60607, USA.|Jesse Brown VA Medical Center, 820 S. Damen Ave., Chicago, IL-60612, USA.
authors.forename: Pradip
authors.initials: P
authors.lastname: Raychaudhuri
mesh_terms: D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D000072278:Forkhead Box Protein M1 / Q000737:chemistry / Q000378:metabolism*; D050990:GATA3 Transcription Factor / Q000235:genetics; D006801:Humans; D061986:MCF-7 Cells; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D000072417:Protein Domains; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000378:metabolism; D000097584:DNA Methyltransferase 3B; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D004248:DNA (Cytosine-5-)-Methyltransferases; D000072278:Forkhead Box Protein M1; D050990:GATA3 Transcription Factor; D010446:Peptide Fragments; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D012795:Sialoglycoproteins; D000097584:DNA Methyltransferase 3B; D000097869:Polo-Like Kinase 1; C107585:FOXM1 protein, human; C571744:bone sialoprotein (35-62), human