title: p27Kip1 and p21Cip1 collaborate in the regulation of transcription by recruiting cyclin-Cdk complexes on the promoters of target genes.
abstract: Transcriptional repressor complexes containing p130 and E2F4 regulate the expression of genes involved in DNA replication. During the G1 phase of the cell cycle, sequential phosphorylation of p130 by cyclin-dependent kinases (Cdks) disrupts these complexes allowing gene expression. The Cdk inhibitor and tumor suppressor p27(Kip1) associates with p130 and E2F4 by its carboxyl domain on the promoters of target genes but its role in the regulation of transcription remains unclear. We report here that p27(Kip1) recruits cyclin D2/D3-Cdk4 complexes on the promoters by its amino terminal domain in early and mid G1. In cells lacking p27(Kip1), cyclin D2/D3-Cdk4 did not associate to the promoters and phosphorylation of p130 and transcription of target genes was increased. In late G1, these complexes were substituted by p21(Cip1)-cyclin D1-Cdk2. In p21(Cip1) null cells cyclin D1-Cdk2 were not found on the promoters and transcription was elevated. In p21/p27 double null cells transcription was higher than in control cells and single knock out cells. Thus, our results clarify the role of p27(Kip1) and p21(Cip1) in transcriptional regulation of genes repressed by p130/E2F4 complexes in which p27(Kip1) and p21(Cip1) play a sequential role by recruiting and regulating the activity of specific cyclin-Cdk complexes on the promoters.
authors.affiliation: Department of Cell Biology, Immunology and Neurosciences, University of Barcelona, 08036-Barcelona, Spain.
authors.forename: Serena
authors.initials: S
authors.lastname: Orlando
authors.affiliation: Department of Cell Biology, Immunology and Neurosciences, University of Barcelona, 08036-Barcelona, Spain.
authors.forename: Edurne
authors.initials: E
authors.lastname: Gallastegui
authors.affiliation: INSERM UMR1037, Cancer Research Center of Toulouse, Toulouse, France Université de Toulouse, Toulouse, France CNRS ERL5294, Toulouse, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Besson
authors.affiliation: Department of Cell Biology, Immunology and Neurosciences, University of Barcelona, 08036-Barcelona, Spain.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Abril
authors.affiliation: Department of Cell Biology, Immunology and Neurosciences, University of Barcelona, 08036-Barcelona, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Aligué
authors.affiliation: Department of Cell Biology, Immunology and Neurosciences, University of Barcelona, 08036-Barcelona, Spain.
authors.forename: Maria Jesus
authors.initials: MJ
authors.lastname: Pujol
authors.affiliation: Department of Cell Biology, Immunology and Neurosciences, University of Barcelona, 08036-Barcelona, Spain obachs@ub.edu.
authors.forename: Oriol
authors.initials: O
authors.lastname: Bachs
mesh_terms: D000818:Animals; D064096:Aurora Kinase A / Q000378:metabolism; D002478:Cells, Cultured; D056741:Cyclin D / Q000378:metabolism*; D056742:Cyclin D2 / Q000378:metabolism; D056743:Cyclin D3 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D016193:G1 Phase / Q000235:genetics; D005786:Gene Expression Regulation; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D056741:Cyclin D; D056742:Cyclin D2; D056743:Cyclin D3; D050759:Cyclin-Dependent Kinase Inhibitor p21; D012097:Repressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D064096:Aurora Kinase A; D051358:Cyclin-Dependent Kinase 4