IRES-mediated translation of delta160p53 regulates p53 functions and fine-tunes cancer homeostasis

Mutations in the p53 gene and its 12 isoforms can impact its functions. N-terminally truncated variants, such as delta40p53, delta133p53, and delta160p53, are crucial regulators of cancer fate because they form tetramers. Although the mechanisms behind delta40p53- and delta133p53-mediated regulation of cancer are well understood, the mechanism behind delta160p53 remains unclear.

This research explored the production and function of delta160p53, as well as its regulation through internal ribosomal entry site (IRES)-mediated translation.

The researchers observed differential synthesis of delta160p53 under various stress conditions and confirmed its IRES-mediated translation using bicistronic luciferase constructs. No cryptic promoters or splicing sites were detected within the IRES sequence. Interestingly, delta160p53 induced cell death and late apoptosis while promoting proliferation and increasing the number of cells in the S phase.

Additionally, it enhanced drug resistance in cancer cells. Unlike other truncated p53 isoforms, delta160p53 did not activate p53-responsive promoters. RNA sequencing analysis of delta160p53 overexpression revealed similar findings, along with the inhibition of other tumor suppressor genes.

The findings of this study offer insights into the IRES-mediated translation of delta160p53, suggesting that it could serve as a novel target for cancer treatment strategies.