40 Years of Research Put p53 in Translation

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.

Keywords: cancer; p53; ribosome; translational control.

Figure 1

Overview of the cap-dependent translation initiation. Cap-dependent translation initiation can be divided in four main steps: (1) 43S-PIC formation, (2) 48S-PIC assembly, (3) start codon recognition and (4) formation of the 80S mature ribosome. The Met-tRNAi-bound to eIF2 and several eIFs (1, 1A, 3 and 5) are recruited to the 40S small sub-unit ribosome to form the 43S-PIC (1). The 43S-PIC is recruited to the cap of the mRNA through the interaction with the eIF4F complex in order to form the 48S-PIC (2). The eIF4F complex is composed of three proteins: the cap-binding protein eIF4E, the RNA helicase eiF4A and the scaffolding protein eiF4G that allows 43S-PIC binding to the mRNA cap through eIF3. Formation of eIF4F complex is mainly regulated by mTOR signaling pathway, mTOR phosphorylating the translation repressor 4E-BP1 that inhibits eIF4F complex formation through the binding of eIF4E. Moreover, a «closed loop» structure of the mRNA is formed through the interaction of the PABP to the mRNA poly (A) tail to increase translation initiation efficiency by favoring the binding of eIF4E to the cap. Then, the 48S-PIC scans through the mRNA 5′UTR until the start codon (3). The start codon is recognized by the Met-tRNAi that induce the hydrolysis of eIF2-GTP bound and release of eiF2-GDP and the other eIFs (1, 3, 5 and eIF4F). The large subunit 60S of the ribosome will then join the 40S ribosome to form the 80S ribosome and start translation (4). (AAAAA)_n: poly (A) tail; CDS: mRNA coding sequence; eIF: eukaryotic initiation factor; Met-tRNAi: initiator-methionyl non-coding transfer RNA; PABP: poly (A) binding protein; PIC: pre-initiation complex; 4E-BP: 4E-binding protein. Figure adapted from [32].

Figure 2

p53 interacts with the 5′UTR of some mRNAs to inhibit their translation. Direct interaction between p53 and 5′UTR of different cellular mRNAs has been identified using in vitro approaches, the p53: RNA interaction occurring in regions known to form IRES (Internal Ribosome Entry Sites). Binding of p53 on 5′UTR has been shown to inhibit translation of the related mRNAs although the molecular mechanism remains to be clarified (dotted box). It can either result from inhibition of 80S ribosome formation, presence of p53 into polysome or p53-dependent RNA:RNA annealing to favor formation of particular mRNA structures such as IRES. (AAAAA) n: poly-A tail protecting mRNA against degradation; CAP: chemical modification of 5′ mRNA end involved in binding to canonical translation factors; CDS: coding sequence of mRNA; 5′UTR: 5′-UnTranslated Region; 40S: small ribosome subunit; 60S: large ribosome subunit; blue circle: p53 protein; orange dots: amino acids of neo-synthetized proteins.