Studying and targeting the non­canonical translation of p53 isoforms during stress and carcinogenesis

Abstract

Tumor suppressor p53 is mutated in half of all human cancers and for that reason it became one of the most studied genes in the history of medical research. Its functions as a transcription factor and its posttranslational regulation were subjects of intense studies for decades. But it was not until more recently that the importance of its translational regulation became clear. p53 is involved in many cellular processes, stress response pathways, tumor suppressing signals, developmental checkpoints and even aging. In order to diversify and differentiate its action, p53 mRNA is translated into several different isoforms that harbor different functions and act independently or together as heterotetramers. The possibility of expressing each isoform one by one through different regulatory structures in its DNA and mRNA gives p53 the ability to be activated in many different ways leading to specific and adequate cellular outcomes. p53 mRNAs can be translated into four different isoforms, each with its respective splice variations, from four diferente translation initiation codons present in codons 1, 40, 133 and 160, and named full length (FL) p53, delta40p53 (deltaNp53 or p53/47), delta133p53 and delta160p53, respectively. The shorter delta133p53 and delta160p53 isoforms are the products of an alternative transcript (delta133p53 mRNA) originating from an internal promoter in intron four of the p53 gene. Most of the p53 functions and regulatory mechanisms described so far are related to FLp53, because for many years, this was the only known p53 isoform. In this study, we want to investigate the translational regulation of other p53 isoforms and its impact on the p53 pathway, stress response and carcinogenesis.