title: The transcription factor p53: not a repressor, solely an activator.
abstract: The predominant function of the tumor suppressor p53 is transcriptional regulation. It is generally accepted that p53-dependent transcriptional activation occurs by binding to a specific recognition site in promoters of target genes. Additionally, several models for p53-dependent transcriptional repression have been postulated. Here, we evaluate these models based on a computational meta-analysis of genome-wide data. Surprisingly, several major models of p53-dependent gene regulation are implausible. Meta-analysis of large-scale data is unable to confirm reports on directly repressed p53 target genes and falsifies models of direct repression. This notion is supported by experimental re-analysis of representative genes reported as directly repressed by p53. Therefore, p53 is not a direct repressor of transcription, but solely activates its target genes. Moreover, models based on interference of p53 with activating transcription factors as well as models based on the function of ncRNAs are also not supported by the meta-analysis. As an alternative to models of direct repression, the meta-analysis leads to the conclusion that p53 represses transcription indirectly by activation of the p53-p21-DREAM/RB pathway.
authors.affiliation: a Molecular Oncology; Medical School ; University of Leipzig ; Leipzig , Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Fischer
authors.forename: Lydia
authors.initials: L
authors.lastname: Steiner
authors.forename: Kurt
authors.initials: K
authors.lastname: Engeland
mesh_terms: D001665:Binding Sites; D047369:Chromatin Immunoprecipitation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D050684:E2F Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D015201:Meta-Analysis as Topic; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D022661:RNA, Untranslated / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D050684:E2F Transcription Factors; D012333:RNA, Messenger; D022661:RNA, Untranslated; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53
keywords: CDE, cell cycle-dependent element; CDKN1A; CHR, cell cycle genes homology region; ChIP, chromatin immunoprecipitation; DREAM complex; DREAM, DP, RB-like, E2F4, and MuvB complex; E2F/RB complex; HPV, human papilloma virus; NF-Y, Nuclear factor Y; cdk, cyclin-dependent kinase; genome-wide meta-analysis; p53