title: 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.
authors.affiliation: Laboratory for Health Protection Research, National Institute of Public Health and the Environment, Bilthoven, Utrecht, The Netherlands.
authors.forename: J P M
authors.initials: JP
authors.lastname: Melis
authors.forename: E M
authors.initials: EM
authors.lastname: Hoogervorst
authors.forename: C T M
authors.initials: CT
authors.lastname: van Oostrom
authors.forename: E
authors.initials: E
authors.lastname: Zwart
authors.forename: T M
authors.initials: TM
authors.lastname: Breit
authors.forename: J L A
authors.initials: JL
authors.lastname: Pennings
authors.forename: A
authors.initials: A
authors.lastname: de Vries
authors.forename: H
authors.initials: H
authors.lastname: van Steeg
mesh_terms: D000818:Animals; D018389:Codon, Nonsense; D020869:Gene Expression Profiling; D016158:Genes, p53; D006801:Humans; D051379:Mice; D009153:Mutagens / Q000633:toxicity*; D020033:Protein Isoforms / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D009153:Mutagens; D020033:Protein Isoforms