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Translational switch during integrated stress response: the examples of p53 and UPF1

2020-05-26Conference object Restricted access
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dc.contributor.authorLacerda, Rafaela
dc.contributor.authorPereira, Bruna
dc.contributor.authorMenezes, Juliane
dc.contributor.authorRamos, Ana
dc.contributor.authorNeves, Ana Rita
dc.contributor.authorCandeias, Marco M
dc.contributor.authorRomão, Luísa
dc.date.accessioned2021-03-13T17:10:09Z
dc.date.embargo2025-12-31
dc.date.issued2020-05-26
dc.description.abstractThe scanning model for eukaryotic mRNA translation initiation states that the small ribosomal subunit, along with initiation factors, binds to the cap structure at the 5’ end of the mRNA and scans the 5’ untranslated region (5’UTR) until an initiation codon is found. However, when cells are exposed to stress stimuli, cap-dependent translation is inhibited, while the synthesis of some proteins is maintained by alternative mechanisms of translation initiation, which are vital for cell survival and stress recovery. Here we show two examples in which a translational switch occurs during integrated stress response (ISR). In the first case, tumor suppressor p53, we show that the ISR leads to the specific induction of a shorter p53 isoform (Δ160p53 isoform). This induction is dependent on translation elongation but does not require the eIF4E-eIF4G interaction. Studies using bicistronic constructs with wild-type Δ160p53 or reporter genes confirmed the presence of an Internal Ribosome Entry Site (IRES) in p53 mRNA, being eIF2α phosphorylation a key event leading to cap-independent expression of Δ160p53 during ISR. Interestingly, cancer-specific mutations in p53 also enhance cap-independent translation of Δ160p53 via Δ160p53IRES. Our data support a model in which an IRES structure in the coding region of p53, and the cancer-specific mutations that affect this structure, control p53 oncogenic functions by regulating Δ160p53 protein expression. A better understanding of Δ160p53IRES structure and function may be advantageous for a more efficient therapeutic targeting of p53. Human up-frameshift 1 (UPF1) is a key-protein involved in nonsense-mediated mRNA decay, telomere replication and homeostasis, and cell cycle progression. These crucial UPF1 functions suggest its tight gene expression regulation. Indeed, our results show that UPF1 5’UTR is able to mediate cap-independent translation in a bicistronic luciferase vector expressed in cervical and colorectal cancer cell lines. Such activity is maintained under endoplasmic reticulum stress. Interestingly, we found that the UPF1 5’UTR IRES function is inhibited when the first 100 nucleotides, or the last 125, are absent or altered. Understanding these IRESs mechanism of function and their biological relevance might provide tools for developing new therapies for human diseases such as cancer.pt_PT
dc.description.sponsorshipThis work was supported by grants PTDC/MED-ONC/32048/2017 and PTDC/BIM-ONC/4890/2014 from the Fundação para a Ciência e a Tecnologia (FCT), by Grants-in-Aid 16K21111 and 18K07229 from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, by Takeda Foundation and Astellas Grant, by Instituto Nacional de Saúde Doutor Ricardo Jorge, and by UIDB/04046/2020 and UIDP/04046/2020 Centre grants from FCT, Portugal (to BioISI).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.urihttp://hdl.handle.net/10400.18/7468
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.relationStudying and targeting the non-coding functions of p53 mRNA in carcinogenesis
dc.subjectmRNA Translationpt_PT
dc.subjectp53pt_PT
dc.subjectUPF1pt_PT
dc.subjectDoenças Genéticaspt_PT
dc.subjectGenómica Funcional e Estruturalpt_PT
dc.titleTranslational switch during integrated stress response: the examples of p53 and UPF1pt_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.conferencePlaceVancouver, BC, Canada (online)pt_PT
oaire.citation.title25th Anual Meeting of the RNA Society, 26 May 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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