Abstract
Simple SummaryThe tumor suppressor p53 is a complex cell signaling hub encompassing multiple transcription programs and governs a vast repertoire of biological responses. However, despite several decades of research, how p53 selects one program over another is still elusive. Recent attempts have used meta-analyses of p53 ChIP-seq data to determine the core p53 transcriptional program, conserved across different models and stimuli. This review highlights the complexity of the multiple layers of p53 regulation and the context specificity of p53 target genes. More specifically, we discuss the controversy over the mechanisms of p53-dependent transcriptional repression and its potential role in the flexibility of p53 response.p53 is a major tumor suppressor that integrates diverse types of signaling in mammalian cells. In response to a broad range of intra- or extra-cellular stimuli, p53 controls the expression of multiple target genes and elicits a vast repertoire of biological responses. The exact code by which p53 integrates the various stresses and translates them into an appropriate transcriptional response is still obscure. p53 is tightly regulated at multiple levels, leading to a wide diversity in p53 complexes on its target promoters and providing adaptability to its transcriptional program. As p53-targeted therapies are making their way into clinics, we need to understand how to direct p53 towards the desired outcome (i.e., cell death, senescence or other) selectively in cancer cells without affecting normal tissues or the immune system. While the core p53 transcriptional program has been proposed, the mechanisms conferring a cell type- and stimuli-dependent transcriptional outcome by p53 require further investigations. The mechanism by which p53 localizes to repressed promoters and manages its co-repressor interactions is controversial and remains an important gap in our understanding of the p53 cistrome. We hope that our review of the recent literature will help to stimulate the appreciation and investigation of largely unexplored p53-mediated repression.
Highlights
The transcription factor p53 is the most frequently mutated gene in cancer and arguably the most critical barrier against tumorigenesis
We suggest that the low occupancy of p53 at repressed promoters most probably reflects a fewer number of cells in which p53 is bound to these promoters at a given moment
To identify genes involved in the diversification of the p53 transcriptional response in a signal- and lineage-dependent manner, we need to consider lower affinity/lower occupancy p53 binding sites, including those in p53-repressed genes
Summary
The transcription factor p53 is the most frequently mutated gene in cancer and arguably the most critical barrier against tumorigenesis. Several studies tried to simplify the complexity of the p53 response toward its core target genes by performing a meta-analysis of p53 cistrome and transcriptome in multiple cell lines upon different stimuli. ∆133p53 isoforms change the promoter selectivity of p53, thereby modifying the p53 transcriptional response and cellular outcome [34,35] Another level of regulation is the persistence of p53 on the promoter. Time-course ChIP-seq experiments have demonstrated a similar pulsatile dynamic of p53 binding on its target promoters [38] Converting these p53 pulses into a sustained signal, for instance upon MDM2 inhibition, changes the p53 transcription profile and affects cell fate decision [36,37].
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