Wild‐type p53 functions as a tumour suppressor while mutant p53 possesses oncogenic potential. Until now it remains unclear how a single mutation can transform p53 into a functionally distinct gene harbouring a new set of original cellular roles. Here we show that the most common p53 cancer mutants express a larger number and higher levels of shorter p53 protein isoforms that are translated from the mutated full‐length p53 mRNA. Cells expressing mutant p53 exhibit “gain‐of‐function” cancer phenotypes, such as enhanced cell survival, proliferation, invasion and adhesion, altered mammary tissue architecture and invasive cell structures. Interestingly, Δ160p53‐overexpressing cells behave in a similar manner. In contrast, an exogenous or endogenous mutant p53 that fails to express Δ160p53 due to specific mutations or antisense knock‐down loses pro‐oncogenic potential. Our data support a model in which “gain‐of‐function” phenotypes induced by p53 mutations depend on the shorter p53 isoforms. As a conserved wild‐type isoform, Δ160p53 has evolved during millions of years. We thus provide a rational explanation for the origin of the tumour‐promoting functions of p53 mutations.
Wild‐type p53 functions as a tumour suppressor while mutant p53 functions as an oncogene. This study suggests that this switch depends on Δ160p53, the most conserved isoform of p53, which is overexpressed in p53 mutant cells and thereby promotes oncogenesis.
Cells carrying p53 mutations overexpress shorter p53 isoforms.
The Δ160p53 isoform possesses pro‐oncogenic potential similar to mutant p53.
“Gain‐of‐function” cancer phenotypes induced by mutant p53 depend on the expression of short p53 isoforms.
- Received December 21, 2015.
- Revision received August 21, 2016.
- Accepted September 6, 2016.
- © 2016 The Authors