Cancer-specific mutations in p53 induce the translation of Δ160p53 promoting tumorigenesis
Autor(a) principal: | |
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Data de Publicação: | 2016 |
Outros Autores: | , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.18/4395 |
Resumo: | 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. |
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Cancer-specific mutations in p53 induce the translation of Δ160p53 promoting tumorigenesisCancerGOFsMutant p53p53 mRNAp53 IsoformsΔ160p53CancroExpressão GénicaGenómica Funcional e EstruturalWild-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.This research was supported mainly by Grant-in-Aid for Scientific Research on the Innovative Area of “Resonance Biology” (No. 15H0594) of the Ministry of Education, Culture, Sports, Science and Technology (MEXT) attributed to M.M.; but also by JSPS KAKENHI Grant-in-Aid for Scientific Research (S) Grant Number 15H05721 attributed to M.H. and Grant PTDC/BIM-ONC/4890/2014 from the Fundação para a Ciência e a Tecnologia (FCT) attributed to M.M.C. M.M.C. was supported by grants from the Japan Society for the Promotion of Science (JSPS Postdoctoral Fellowship), AXA Research Fund and the Ichiro Kanehara Foundation.EMBO PressRepositório Científico do Instituto Nacional de SaúdeCandeias, MarcoHagiwara, MasatoshiMatsuda, Michiyuki2017-03-02T13:17:06Z2016-112016-11-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.18/4395engEMBO Rep. 2016 Nov;17(11):1542-1551. doi:10.15252/embr.201541956. Epub 2016 Oct 41469-221X10.15252/embr.201541956info:eu-repo/semantics/embargoedAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-20T15:40:14Zoai:repositorio.insa.pt:10400.18/4395Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:39:02.326842Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Cancer-specific mutations in p53 induce the translation of Δ160p53 promoting tumorigenesis |
title |
Cancer-specific mutations in p53 induce the translation of Δ160p53 promoting tumorigenesis |
spellingShingle |
Cancer-specific mutations in p53 induce the translation of Δ160p53 promoting tumorigenesis Candeias, Marco Cancer GOFs Mutant p53 p53 mRNA p53 Isoforms Δ160p53 Cancro Expressão Génica Genómica Funcional e Estrutural |
title_short |
Cancer-specific mutations in p53 induce the translation of Δ160p53 promoting tumorigenesis |
title_full |
Cancer-specific mutations in p53 induce the translation of Δ160p53 promoting tumorigenesis |
title_fullStr |
Cancer-specific mutations in p53 induce the translation of Δ160p53 promoting tumorigenesis |
title_full_unstemmed |
Cancer-specific mutations in p53 induce the translation of Δ160p53 promoting tumorigenesis |
title_sort |
Cancer-specific mutations in p53 induce the translation of Δ160p53 promoting tumorigenesis |
author |
Candeias, Marco |
author_facet |
Candeias, Marco Hagiwara, Masatoshi Matsuda, Michiyuki |
author_role |
author |
author2 |
Hagiwara, Masatoshi Matsuda, Michiyuki |
author2_role |
author author |
dc.contributor.none.fl_str_mv |
Repositório Científico do Instituto Nacional de Saúde |
dc.contributor.author.fl_str_mv |
Candeias, Marco Hagiwara, Masatoshi Matsuda, Michiyuki |
dc.subject.por.fl_str_mv |
Cancer GOFs Mutant p53 p53 mRNA p53 Isoforms Δ160p53 Cancro Expressão Génica Genómica Funcional e Estrutural |
topic |
Cancer GOFs Mutant p53 p53 mRNA p53 Isoforms Δ160p53 Cancro Expressão Génica Genómica Funcional e Estrutural |
description |
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. |
publishDate |
2016 |
dc.date.none.fl_str_mv |
2016-11 2016-11-01T00:00:00Z 2017-03-02T13:17:06Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.18/4395 |
url |
http://hdl.handle.net/10400.18/4395 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
EMBO Rep. 2016 Nov;17(11):1542-1551. doi:10.15252/embr.201541956. Epub 2016 Oct 4 1469-221X 10.15252/embr.201541956 |
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info:eu-repo/semantics/embargoedAccess |
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embargoedAccess |
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application/pdf |
dc.publisher.none.fl_str_mv |
EMBO Press |
publisher.none.fl_str_mv |
EMBO Press |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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1799132128211894272 |