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The tumor suppressor p53 acquires oncogenic functions due to a translational switch during integrated stress response

2020-11-20Conference object Restricted access
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dc.contributor.authorLacerda, Rafaela
dc.contributor.authorFonseca Costa, Inês
dc.contributor.authorLópez-Iniesta, M.
dc.contributor.authorRomão, Luísa
dc.contributor.authorCandeias, Marco M.
dc.date.accessioned2021-03-13T11:20:27Z
dc.date.embargo2025-12-31
dc.date.issued2020-11-20
dc.description.abstractTo cope with the stress stimuli to which they are often exposed, eukaryotic cells have developed adaptive pathways that restore cellular homeostasis. Under stress conditions there is an overall decrease of protein synthesis, and a concomitant induction of alternative mechanisms of mRNA translation initiation. The tumour suppressor protein p53 has been considered the guardian of the genome and a master regulator of many cellular functions. However, apart from the full-length p53 (FLp53), several p53 isoforms have been described so far. Some functions of shorter p53 isoforms have already been elucidated and they are different from and complement FLp53 activity, the most mutated gene in cancer. Here we show that the integrated stress response (ISR) leads to the specific induction of Δ160p53 isoform. Using bicistronic constructs we confirmed the presence of an Internal Ribosome Entry Site (IRES) in p53 mRNA that controls Δ160p53 isoform translation. Subjecting cells to endoplasmic reticulum stress showed that eIF2α phosphorylation is a key event leading to cap-independent expression of Δ160p53 during ISR. Additionally, cancer-specific mutations in p53 also enhanced cap-independent translation of Δ160p53 via Δ160p53IRES. An antisense morpholino oligo targeting Δ160IRES efficiently reduced Δ160p53 protein levels and significantly impaired oncogenic functions of Δ160p53. Our data support a model in which an IRES structure in the coding region of p53 is activated under stress conditions, leading to the expression of the oncogenic shorter Δ160p53 isoform, whose structure is affected by cancer-specific mutations in the p53 gene. A better understanding of Δ160p53IRES structure and function may be advantageous for a more efficient therapeutic targeting of p53.pt_PT
dc.description.sponsorshipFCT PTDC/MED-ONC/32048/2017pt_PT
dc.description.versionN/Apt_PT
dc.identifier.urihttp://hdl.handle.net/10400.18/7438
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.relationStudying and targeting the non-coding functions of p53 mRNA in carcinogenesis
dc.subjectTumorpt_PT
dc.subjectCancer Cellpt_PT
dc.subjectmRNA Translationpt_PT
dc.subjectDoenças Genéticaspt_PT
dc.subjectGenómica Funcional e Estruturalpt_PT
dc.titleThe tumor suppressor p53 acquires oncogenic functions due to a translational switch during integrated stress responsept_PT
dc.typeconference object
dspace.entity.typePublication
oaire.awardTitleStudying and targeting the non-coding functions of p53 mRNA in carcinogenesis
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FMED-ONC%2F32048%2F2017/PT
oaire.citation.conferencePlaceLisboa, Portugal (online)pt_PT
oaire.citation.title24ª Reunião Científica da Sociedade Portuguesa de Genética Humana, 20 novembro 2020pt_PT
oaire.fundingStream3599-PPCDT
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsembargoedAccesspt_PT
rcaap.typeconferenceObjectpt_PT
relation.isProjectOfPublication6a8083d6-0c9b-4c73-a81b-fd723a022f17
relation.isProjectOfPublication.latestForDiscovery6a8083d6-0c9b-4c73-a81b-fd723a022f17

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