Genotoxic exposure: novel cause of selection for a functional ΔN-p53 isoform

Abstract

The p53 gene is frequently mutated in cancers and it is vital for cell cycle control, homeostasis and carcinogenesis. We describe a novel p53 mutational spectrum, different to those generally observed in human and murine tumors. Our study shows a high prevalence of nonsense mutations in the p53 N terminus of 2-acetylaminofluorene (2-AAF)-induced urinary bladder tumors. These nonsense mutations forced downstream translation initiation at codon 41 of Trp53, resulting in the aberrant expression of the p53 isoform ΔN-p53 (or p44). We propose a novel mechanism for the origination and the selection for this isoform. We show that chemical exposure can act as a novel cause of selection for this truncated protein. In addition, our data suggest that the occurrence of ΔN-p53 accounts, at least in mice, for a cancer phenotype. We also show that gene expression profiles of embryonic stem (ES) cells carrying the ΔN-p53 isoform in a p53-null background are divergent from p53 knockout ES cells, and therefore postulate that ΔN-p53 itself has functional transcriptional properties.

DOI: 10.1038/onc.2010.552

Cite this paper

@article{Melis2011GenotoxicEN, title={Genotoxic exposure: novel cause of selection for a functional ΔN-p53 isoform}, author={Joost P. M. Melis and Esther M Hoogervorst and Conny Th. M. van Oostrom and Erik W. Zwart and T M Breit and Jeroen L. A. Pennings and Annemieke de Vries and Harry van Steeg}, journal={Oncogene}, year={2011}, volume={30}, pages={1764-1772} }