Journal
CELL CYCLE
Volume 13, Issue 19, Pages 3037-3058Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/15384101.2014.949083
Keywords
CDKN1A; DREAM complex; E2F; RB complex; genome-wide meta-analysis; p53; CDE; cell cycle-dependent element; CHR; cell cycle genes homology region; DREAM; DP; RB-like; E2F4; and MuvB complex; ChIP; chromatin immunoprecipitation; NF-Y; Nuclear factor Y; cdk; cyclin-dependent kinase; HPV; human papilloma virus
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Funding
- Fritz Thyssen Foundation
- grant Origins and Evolution of Regulation in Biological Systems [24332]
- John Templeton Foundation
- Bundesministerium fur Bildung und Forschung (BMBF) through Interdisciplinary Center for Clinical Research (IZKF) at the University of Leipzig
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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.
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