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Publicação
Cancer-specific mutations in p53 induce the translation of Δ160p53 promoting tumorigenesis
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Orientador(es)
Resumo(s)
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.
Descrição
Palavras-chave
Cancer GOFs Mutant p53 p53 mRNA p53 Isoforms Δ160p53 Cancro Expressão Génica Genómica Funcional e Estrutural
Contexto Educativo
Citação
EMBO Rep. 2016 Nov;17(11):1542-1551. doi:10.15252/embr.201541956. Epub 2016 Oct 4
Editora
EMBO Press