Abstract
Since its discovery in 1979, p53 has shown multiple facets. Initially the tumor suppressor p53 protein was considered as a stress sensor able to maintain the genome integrity by regulating transcription of genes involved in cell cycle arrest, apoptosis and DNA repair. However, it rapidly came into light that p53 regulates gene expression to control a wider range of biological processes allowing rapid cell adaptation to environmental context. Among them, those related to cancer have been extensively documented. In addition to its role as transcription factor, scattered studies reported that p53 regulates miRNA processing, modulates protein activity by direct interaction or exhibits RNA-binding activity, thus suggesting a role of p53 in regulating several layers of gene expression not restricted to transcription. After 40 years of research, it appears more and more clearly that p53 is strongly implicated in translational regulation as well as in the control of the production and activity of the translational machinery. Translation control of specific mRNAs could provide yet unsuspected capabilities to this well-known guardian of the genome.
Highlights
The TP53 gene codes the canonical p53 protein, which had been discovered as a cellular protein of53 kDa co-immunoprecipitating with the large T antigen of SV40 virus in 1979 [1,2]
This protein is composed of a N-terminal transactivation domain (TAD) involved in the recruitment of transcriptional co-factors, a central DNA-binding domain (DBD) directly interacting with DNA in a sequence-dependent manner through specific p53-response elements, and a C-terminal domain of oligomerisation (OD), the p53 transcription factor being active as tetramer [4]
While only few studies have been dedicated to understanding the role of p53-mediated translational regulation in the fine modulation of gene expression driven by p53, the relationship between p53 and translation has been largely reviewed to illustrate different facets of p53 biology since: (i) an increase in p53 mRNA translation contributes to p53 activation in response to stress [23]; (ii) alteration of ribosome biogenesis corresponds to one of the stresses able to activate a p53-dependent response [24,25]; (iii) usage of alternative translation start sites allow expression of different p53 isoforms modulating p53 transcriptional activity [23,26,27]; and (iv) antibiotics targeting the translational machinery could restore wild-type p53 transcriptional activity from nonsense p53 mutant [28,29,30]
Summary
The TP53 gene codes the canonical p53 protein, which had been discovered as a cellular protein of. Recent studies performed in mice suggest that p53 tumor suppressor activity is not strictly dependent upon major p53 effector pathways, such as cell cycle arrest and apoptosis, as expected [12,13,14] It is still not clear whether its tumor suppressor activity could result from the additional biological cellular functions that have been recently linked to p53, including for example metabolism, maintenance of stem characteristics, reproduction or aging, to cite only some of them [15]. While only few studies have been dedicated to understanding the role of p53-mediated translational regulation in the fine modulation of gene expression driven by p53, the relationship between p53 and translation has been largely reviewed to illustrate different facets of p53 biology since: (i) an increase in p53 mRNA translation contributes to p53 activation in response to stress [23];. Following a brief overview of the basics of translational regulation and its involvement in cancer, we will discuss the role of p53 in translational reprogramming, either through direct or indirect intervention, to attempt discerning whether p53-dependent translation of some specific mRNAs could contribute to the p53-mediated regulation of gene expression
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