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Human TP53 is a tumour suppressor that acquires oncogenic functions during integrated stress response (ISR) due to a translational switch

2021-05-25Conference object Restricted access
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dc.contributor.authorLacerda, Rafaela
dc.contributor.authorFonseca Costa, Inês
dc.contributor.authorLópez-Iniesta, Maria
dc.contributor.authorRomão, Luísa
dc.contributor.authorCandeias, Marco M.
dc.date.accessioned2022-07-09T15:00:25Z
dc.date.embargo2027-12-31
dc.date.issued2021-05-25
dc.description.abstractEukaryotic cells have developed different mechanisms and adaptive pathways that allow them to cope with external stress stimuli. Under stress conditions, global protein synthesis is shut down, and some alternative mechanisms of mRNA translation initiation are induced. Although the tumour suppressor protein p53 — the most mutated gene in cancer — has been considered the guardian of the genome and a master regulator of several cellular functions, the truth is it is not just one isoform, the full-length (FLp53), but also many other p53 isoforms that have been described so far. Based on our previous results, some functions of the shorter isoforms are different from and complement FLp53 activity. Here we show the specific induction of Δ160p53 isoform during integrated stress response (ISR). We confirmed the presence of an Internal Ribosome Entry Site (IRES) in p53 mRNA that controls Δ160p53 isoform translation, using a bicistronic reporter construct. When subjecting cells to endoplasmic reticulum stress, we showed that eIF2α phosphorylation is a key event leading to cap-independent expression of Δ160p53 during ISR. Also, some cancer-specific mutations in the DNA-binding domain of p53 enhance cap-independent translation of Δ160p53 via Δ160p53IRES. Using an antisense morpholino oligo targeting Δ160IRES significantly reduces Δ160p53 protein levels and impaired its oncogenic functions. Additionally, we found the 5’untranslated region of Δ160p53 inhibits the IRES activity. 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.sponsorshipFCTpt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.urihttp://hdl.handle.net/10400.18/8128
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.subjectRNA Cancerpt_PT
dc.subjectGenómica Funcionalpt_PT
dc.subjectGenómica Funcional e Estruturalpt_PT
dc.subjectDoenças Genéticaspt_PT
dc.titleHuman TP53 is a tumour suppressor that acquires oncogenic functions during integrated stress response (ISR) due to a translational switchpt_PT
dc.typeconference object
dspace.entity.typePublication
oaire.citation.conferencePlace(Online)pt_PT
oaire.citation.title26th Annual Meeting of the RNA Society (RNA 2021), 25 May-4 June 2021pt_PT
rcaap.rightsembargoedAccesspt_PT
rcaap.typeconferenceObjectpt_PT

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