title: The p53-p21-DREAM-CDE/CHR pathway regulates G2/M cell cycle genes.
abstract: The tumor suppressor p53 functions predominantly as a transcription factor by activating and downregulating gene expression, leading to cell cycle arrest or apoptosis. p53 was shown to indirectly repress transcription of the CCNB2, KIF23 and PLK4 cell cycle genes through the recently discovered p53-p21-DREAM-CDE/CHR pathway. However, it remained unclear whether this pathway is commonly used. Here, we identify genes regulated by p53 through this pathway in a genome-wide computational approach. The bioinformatic analysis is based on genome-wide DREAM complex binding data, p53-depedent mRNA expression data and a genome-wide definition of phylogenetically conserved CHR promoter elements. We find 210 target genes that are expected to be regulated by the p53-p21-DREAM-CDE/CHR pathway. The target gene list was verified by detailed analysis of p53-dependent repression of the cell cycle genes B-MYB (MYBL2), BUB1, CCNA2, CCNB1, CHEK2, MELK, POLD1, RAD18 and RAD54L. Most of the 210 target genes are essential regulators of G2 phase and mitosis. Thus, downregulation of these genes through the p53-p21-DREAM-CDE/CHR pathway appears to be a principal mechanism for G2/M cell cycle arrest by p53.
authors.affiliation: Molecular Oncology, Medical School, University of Leipzig, Leipzig, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Fischer
authors.affiliation: Molecular Oncology, Medical School, University of Leipzig, Leipzig, Germany.
authors.forename: Marianne
authors.initials: M
authors.lastname: Quaas
authors.affiliation: Centre for Complexity & Collective Computation, Wisconsin Institute for Discovery, Madison, WI, USA Computational EvoDevo Group & Bioinformatics Group, Department of Computer Science, and Interdisciplinary Centre for Bioinformatics, University of Leipzig, Leipzig, Germany.
authors.forename: Lydia
authors.initials: L
authors.lastname: Steiner
authors.affiliation: Molecular Oncology, Medical School, University of Leipzig, Leipzig, Germany engeland@medizin.uni-leipzig.de.
authors.forename: Kurt
authors.initials: K
authors.lastname: Engeland
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D051605:Kv Channel-Interacting Proteins / Q000378:metabolism*; D051379:Mice; D008938:Mitosis / Q000235:genetics; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism*; D020218:Response Elements; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; C496749:KCNIP3 protein, human; D051605:Kv Channel-Interacting Proteins; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53