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

• Published in: Oncogene Vol. 30; no. 15; pp. 1764 - 1772
• 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: London Nature Publishing Group UK 14-04-2011; Nature Publishing Group
• Subjects: 631/208/737; 631/45/612/1244; 692/699/67/589/1336; Animals; Apoptosis; Biological and medical sciences; Bladder cancer; Carcinogenesis; Cell Biology; Cell cycle; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Codon, Nonsense; Divergence; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Profiling; Gene mutations; Genes, p53; Genetic toxicology; Genotoxicity; Health aspects; Homeostasis; Human Genetics; Humans; Internal Medicine; Medical sciences; Medicine; Medicine & Public Health; Mice; Molecular and cellular biology; Mutagens - toxicity; Mutation; Nephrology. Urinary tract diseases; Oncology; original-article; p53 Protein; Phenotypes; Physiological aspects; Protein Isoforms - genetics; Transcription; Translation initiation; Tumor suppressor genes; Tumors; Tumors of the urinary system; Urinary bladder; Urinary system involvement in other diseases. Miscellaneous; Urinary tract. Prostate gland; Netherlands; N-terminal p53 isoform (ΔN-p53, p44, p47); nonsense mutations; DNA damage; mouse urinary bladder tumor; gene expression; N-terminal p53 isoform (ΔN-p53; Molecular form; Toxicity; Nonsense mutation; Selection; Genotoxicity; Carcinogenesis; TP53 Gene; Urinary bladder; Tumor suppressor gene; Urinary system disease; Rodentia; Exposure; Urinary tract disease; Gene expression; Bladder tumor; p44; Vertebrata; p47; Mammalia; Urinary system; Mouse; DNA; nonsense mutations; mouse urinary bladder tumor; Bladder disease; Lesion
• 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 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.