title: Cancer-specific mutations in p53 induce the translation of Δ160p53 promoting tumorigenesis.
abstract: 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.
authors.affiliation: Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies Kyoto University, Kyoto, Japan candeias@gmail.com.|Department of Anatomy and Developmental Biology, Graduate School of Medicine Kyoto University, Kyoto, Japan.|Departamento de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa, Portugal.
authors.forename: Marco M
authors.identifier: 0000-0002-5731-0179
authors.initials: MM
authors.lastname: Candeias
authors.affiliation: Department of Anatomy and Developmental Biology, Graduate School of Medicine Kyoto University, Kyoto, Japan.|Medical Research Support Center, Graduate School of Medicine Kyoto University, Kyoto, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hagiwara
authors.affiliation: Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies Kyoto University, Kyoto, Japan.|Department of Pathology and Biology of Diseases, Graduate School of Medicine Kyoto University, Kyoto, Japan.
authors.forename: Michiyuki
authors.initials: M
authors.lastname: Matsuda
mesh_terms: D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins; D016158:Genes, p53; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D009924:Organ Culture Techniques; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: GOFs; mutant p53; p53 isoforms; p53 mRNA; Δ160p53