Publication
The integrated stress response releases the oncoprotein in TP53
| 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 | 2024-01-22T15:13:27Z | |
| dc.date.embargo | 2028-01-31 | |
| dc.date.issued | 2023-10-26 | |
| dc.description.abstract | Introduction: The TP53 gene is surrounded by a great duality: it is a critical tumour suppressor gene, however, its protective nature is frequently lost in tumours, where it becomes a powerful oncogene. Numerous studies attribute the oncogenic profile of TP53 to the missense mutations that commonly occur in cancer. We propose that this duality is intrinsic to TP53 instead of a consequence of mere somatic mutations, which could not have been evolutionarily selected for. This gene encodes for a set of protein isoforms with distinct and complementary functions, from which the full-length p53 (FLp53) is the best characterized. FLp53 is a transcription factor that mediates stress responses by promoting cell cycle arrest, DNA repair or apoptosis. In stark contrast to FLp53, the shorter isoform Δ160p53 promotes cell survival, proliferation, and invasion, and it is commonly overexpressed in tumours. Here we identify a disruption in the normal balance of p53 isoforms upon induction of the Integrated Stress Response (ISR), with the translation of Δ160p53 being favoured. Materials and Methods: Different cell lines were used to verify the expression of endogenous p53 isoforms during ISR, and the internal translation of Δ160p53 was tested with bicistronic constructs. The interaction of Δ160p53 with FLp53 was assessed by co-immunoprecipitation followed by western blot, and its effect in the expression of target genes was measured by RT-qPCR. Cells were treated with thapsigargin and tunicamycin to induce ISR when required. Results: The induction of ISR in a group of cell lines led to increased levels of endogenous Δ160p53 protein, as well as increased luminescence signal in the bicistronic system. The FLp53-Δ160 interaction was confirmed, and the role of Δ160p53 in the selective regulation of p53 target genes was uncovered. Conclusions: These data uncover a mode of activation of the oncogenic Δ160p53 and how this isoform can work together with FLp53. In the future, we aim to explore the clinical potential of these discoveries. | 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/10400.18/8945 | |
| 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 | TP53 Gene | pt_PT |
| dc.subject | Cancer | pt_PT |
| dc.subject | Genómica Funcional | pt_PT |
| dc.subject | Expressão Génica | pt_PT |
| dc.subject | Genómica Funcional e Estrutural | pt_PT |
| dc.title | The integrated stress response releases the oncoprotein in TP53 | 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 | Porto, Portugal | pt_PT |
| oaire.citation.title | III ASPIC-ASEICA International Meeting – Cancer Immunology, Tumor Microenvironment and Metastasis, 26 -27 October, 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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