Genotoxic exposure: novel cause of selection for a functional [Delta]N-p53 isoform

• Published in: Oncogene Vol. 30; no. 15; p. 1764
• Main Authors: Melis, J P M, Hoogervorst, E M, Van Oostrom, C T M, Zwart, E, Breit, T M, Pennings, J L A, De Vries, A, Van Steeg, H
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group 14-04-2011
• Subjects: Genes; Genotype & phenotype; Homeostasis; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2010.552

The p53 gene is frequently mutated in cancers and it is vital for cell cycle control, homeostasis and carcinogen-esis. 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-acetylaminouorene (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 DN-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 DN-p53 accounts, at least in mice, for a cancer phenotype. We also show that gene expression proles of embryonic stem (ES) cells carrying the DN-p53 isoform in a p53-null background are divergent from p53 knockout ES cells, and therefore postulate that DN-p53 itself has functional transcriptional properties.