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Translational activation of Δ160p53 is triggered during the Integrated Stress Response to promote survival
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Resumo(s)
The p53 gene was discovered 45 years ago, but to this day some aspects of its regulation and function remain a mystery. This gene encodes for a group of protein isoforms that display different functions, acting cooperatively in stress response. Full-length p53 (FLp53), the best studied isoform, is a transcription factor with targets across several pathways, promoting cellular adaption during stress. Classical roles of FLp53 are the induction of cell cycle arrest and, a as a last resort, apoptosis. The short isoform Δ160p53 is an oncoprotein commonly overexpressed in tumours that can be translated from the same mRNA as FLp531. The exact mechanisms and factors that regulate Δ160p53 translation and how it exerts its pro-survival functions remain unexplored.
In this work, it was demonstrated that the translation of Δ160p53 is mediated by an Internal Ribosome Entry Site (IRES) and its expression is induced by the Integrated Stress Response (ISR). Additionally, a mass spectrometry analysis uncovered potential new RNA-binding proteins involved in the translation of Δ160p53, and it was verified that translation factors specifically associated with alternative modes of initiation during the ISR promoted the translation of Δ160p53.
In parallel, Δ160p53 was found to interact with FLp53 and modulate its transcriptional activity to favour a pro-survival response to stress. While suppressing genes involved in cell cycle arrest (CDKN1A) and apoptosis (PUMA), Δ160p53 enhances the expression of genes involved in cellular metabolism and protection against ferroptosis: SESN1, SESN2 and SLC7A11. Furthermore, Δ160p53 was shown to suppress ferroptosis and to interact with the SLC7A11 promoter.
This study has uncovered new modes of p53 regulation and hints at a physiological role for Δ160p53 in the context of the ISR. However, abnormal levels of Δ160p53 may contribute to an exacerbated pro-survival p53 target signature, demonstrating the importance of p53 isoform balance.
Descrição
Palavras-chave
Integrated Stress Response (ISR) Stress Δ160p53 Genómica Funcional Genómica Funcional e Estrutural