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Common p53 mutations induce IRES-mediated translation of oncogenic shorter p53 isoforms

2018-11-15Conference object Restricted access
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dc.contributor.authorPereira, Bruna
dc.contributor.authorLacerda, Rafaela
dc.contributor.authorMaria López-Iniesta, M
dc.contributor.authorRomão, Luísa
dc.contributor.authorCandeias, Marco
dc.date.accessioned2019-03-01T11:17:21Z
dc.date.embargo2025-12-31
dc.date.issued2018-11-15
dc.description.abstractAt least half of all tumors exhibit mutations in the tumor suppressor p53 gene. Indeed, the fact that p53 is frequently mutated in cancer led to its identification as an oncogene, when first described in 1979. Later, it was classified as a tumor suppressor, due to the clarification of its wild-type role in maintaining genome integrity and preventing malignant transformation. The p53 gene can encode for many p53 isoforms, by alternative splicing, alternative promoters and internal translation initiation mechanisms. While full-length p53 (FL-p53) protein works as a tumor suppressor by regulating many biological processes such as cell cycle, apoptosis, senescence and DNA repair, shorter p53 protein isoforms seem to play different roles in the cell. Recently, we have shown that the most common p53 mutations induce the expression of shorter p53 isoforms. Furthermore, we found that shorter p53 isoforms are implicated in cancer progression as they promote enhanced cell survival, proliferation, adhesion and formation of invasive cell structures. Here, with a bicistronic system containing two reporter genes (Renilla luciferase and firefly luciferase), we show that expression of shorter p53 isoforms is mediated by a non-canonical translation initiation mechanism regulated by an Internal Ribosome Entry Site (IRES) in the p53 mRNA. By investigating the effect of common p53 missense mutations on the function of this new IRES, through bioluminescence assays and Western blot analysis, we show that some p53 cancer mutations have a preponderant role in IRES-mediated translation induction of shorter p53 isoforms. With the obtained results we identified a new mechanism by which p53 cancer mutations promote tumorigenesis, which may lead to new understandings of the onset and progression of some types of tumors as well as to the development of new cancer therapies.pt_PT
dc.description.sponsorshipThis work is partially supported by Fundação para a Ciência e a Tecnologia (PTDC/BIMONC/4890/2014), by Grants-in-Aid 16K21111 and 18K07229 from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan and by Takeda Foundation.pt_PT
dc.description.versionN/Apt_PT
dc.identifier.urihttp://hdl.handle.net/10400.18/6015
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.subjectTumor Suppressor p53 Genept_PT
dc.subjectCancerpt_PT
dc.subjectDoenças Genéticaspt_PT
dc.subjectGenómica Funcional e Estruturalpt_PT
dc.titleCommon p53 mutations induce IRES-mediated translation of oncogenic shorter p53 isoformspt_PT
dc.typeconference object
dspace.entity.typePublication
oaire.citation.conferencePlacePorto, Portugalpt_PT
oaire.citation.title22ª Reunião Anual da Sociedade Portuguesa de Genética Humana - Molecular and Cytogenetics Club, 15-17 nov 2018pt_PT
rcaap.rightsembargoedAccesspt_PT
rcaap.typeconferenceObjectpt_PT

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