Internal Translation of p53 Oncoproteins During ISR

Maria José López-Iniesta et al.

p53 is the most known and studied tumour suppressor gene. Yet we have recently shown that p53 is also a proto-oncogene, as it encodes the Δ160p53 oncoprotein. Integrated stress response (ISR) is a survival pathway frequently activated in cancers, marked by the phosphorylation of eukaryotic initiation factor 2alpha (eIF2a) and a defined reprogramming in mRNA translation. Here we identified ISR as a powerful trigger of p53 oncogene, leading to the induction of not only Δ160p53 but also Δ133p53, another protein variant of the p53 gene. Upon ISR the two isoforms were translated internally from p53 full-length (FL) transcript through an internal regulator of expression site (IRES) located in the vicinity of codon 160. Frameshift mutations upstream of codons 133 and 160 demonstrated that FLp53 protein synthesis is not required for making Δ133p53 and Δ160p53. Instead, targeting IRES(160) with an antisense oligo was sufficient to efficiently and specifically impair the expression of these isoforms without affecting FLp53 levels. This in turn averted ISR’s protective program culminating in cancer cell cycle arrest and death. Mechanistically, FLp53 showed 3 times more affinity to Δ160p53 than to other isoforms, Δ40p53 or Δ133p53. During ISR Δ160p53 localized to the nucleus and strongly inhibited FLp53-mediated activation of pro-apoptotic gene p53 upregulated modulator of apoptosis (PUMA). Our results uncover a new branch of the ISR network essential for cancer cell survival and growth and establish the proof of concept for a new strategy to target cancer.