Publication
The p53 short isoforms are activated by the integrated stress response to enhance survival in wild-type p53 cancer cell lines
| dc.contributor.author | Ramalho, Ana Catarina | |
| dc.contributor.author | López-Iniesta, Maria José | |
| dc.contributor.author | Lacerda, Rafaela | |
| dc.contributor.author | Parker, Shrutee N. | |
| dc.contributor.author | Romão, Luísa | |
| dc.contributor.author | Candeias, Marco M. | |
| dc.date.accessioned | 2024-01-16T15:29:50Z | |
| dc.date.embargo | 2028-12-31 | |
| dc.date.issued | 2023-06-12 | |
| dc.description.abstract | Introduction: The full-length p53 (FLp53) protein is a transcriptional factor that mediates cellular stress responses. The appropriate response is modulated according to the nature and extent of the damage, which means that p53 may promote cell cycle arrest and DNA repair or apoptosis in different situations. In all cases, p53 manages the response by modulating the expression of a wide range of target genes, as it contains two N-terminal transactivation domains. However, this gene also encodes for shorter isoforms that lack the N-terminal region and display oncogenic functions: Δ133p53 and Δ160p53. In contrast to the protective nature of the full-length protein, these two isoforms promote cell survival, proliferation and invasion. Both are typically overexpressed in tumours, while in normal tissues their levels are low or undetectable. Data from this study indicate that the elevated levels of these isoforms may be owed to the Integrated Stress Response (ISR), which is typically a pro-survival programme, and it is commonly activated in cancer cells. The ISR is initiated by a group of kinases in response to different stress stimuli, converging in the phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α). This blocks global translation, while promoting the expression of activating transcription factor 4 (ATF4), the main effector of ISR. Materials and Methods: In this work, cancer cell lines with endogenous p53 were used to verify the expression of its isoforms during ISR, which was induced by treatment with thapsigargin and tunicamycin. To investigate if they were translated internally, bicistronic construct systems were employed. The interaction of the isoforms with FLp53 was verified by co-immunoprecipitation and their effect on the mRNA levels of p53 target genes was evaluated. Results and discussions: The translation of Δ160p53 and Δ133p53 was promoted by ISR induction in the cell lines tested via internal translation from FLp53 mRNA. Interaction of both isoforms with FLp53 was also confirmed, and it was demonstrated that Δ160p53 selectively acts as a regulator of p53 transcriptional activity on some genes. Conclusion: These results hint at a physiological role for p53 short isoforms in the modulation of p53 target gene expression during ISR. On the other hand, their activation by abnormal ISR induction in cancer cells supports oncogenicity. The uncovering of an intersection between p53 isoforms and ISR could open a new path for future cancer therapies. | pt_PT |
| dc.description.sponsorship | This research was funded by grants 18K07229 (KAKENHI) from Japan Society for the Promotion of Science (JSPS) and PTDC/MED-ONC/32048/2017 from Fundação para a Ciência e a Tecnologia of Portugal (FCT). This work was supported by FCT through the individual research grant 2020.06982.BD | pt_PT |
| dc.description.version | N/A | pt_PT |
| dc.identifier.uri | http://hdl.handle.net/10400.18/8908 | |
| dc.language.iso | eng | pt_PT |
| dc.peerreviewed | yes | pt_PT |
| dc.relation | Unraveling the oncogenic functions and regulation of the most conserved p53 isoform, 160p53: a study in cancer cells and transgenic mice | |
| dc.subject | Cancer | pt_PT |
| dc.subject | Expressão Génica | pt_PT |
| dc.subject | p53 | pt_PT |
| dc.subject | Genómica Funcional | pt_PT |
| dc.subject | Genómica Funcional e Estrutural | pt_PT |
| dc.title | The p53 short isoforms are activated by the integrated stress response to enhance survival in wild-type p53 cancer cell lines | pt_PT |
| dc.type | conference object | |
| dspace.entity.type | Publication | |
| oaire.awardTitle | Unraveling the oncogenic functions and regulation of the most conserved p53 isoform, 160p53: a study in cancer cells and transgenic mice | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT/Concurso para Financiamento de Projetos de Investigação Científica e Desenvolvimento Tecnológico em Todos os Domínios Científicos - 2017/PTDC%2FMED-ONC%2F32048%2F2017/PT | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT/OE/2020.06982.BD/PT | |
| oaire.citation.conferencePlace | Torino, Piemonte, Itália | pt_PT |
| oaire.citation.title | Annual Congress of the European Association for Cancer Research (EACR 2023), 12-15 jun 2023 | pt_PT |
| oaire.fundingStream | Concurso para Financiamento de Projetos de Investigação Científica e Desenvolvimento Tecnológico em Todos os Domínios Científicos - 2017 | |
| oaire.fundingStream | OE | |
| project.funder.identifier | http://doi.org/10.13039/501100001871 | |
| project.funder.identifier | http://doi.org/10.13039/501100001871 | |
| project.funder.name | Fundação para a Ciência e a Tecnologia | |
| project.funder.name | Fundação para a Ciência e a Tecnologia | |
| rcaap.rights | embargoedAccess | pt_PT |
| rcaap.type | conferenceObject | pt_PT |
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| relation.isProjectOfPublication | 7c8c598f-a68b-4678-bc56-389d21d3aa8a | |
| relation.isProjectOfPublication.latestForDiscovery | 7c8c598f-a68b-4678-bc56-389d21d3aa8a |