دورية أكاديمية
A mouse model for Li-Fraumeni-Like Syndrome with cardiac angiosarcomas associated to POT1 mutations.
| العنوان: | A mouse model for Li-Fraumeni-Like Syndrome with cardiac angiosarcomas associated to POT1 mutations. |
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| المؤلفون: | Martínez, Paula, Sánchez-Vázquez, Raúl, Ferrara-Romeo, Iole, Serrano, Rosa, Flores, Juana M, Blasco, MA |
| المساهمون: | Agencia Estatal de Investigación (España), Comunidad de Madrid (España), Ministerio de Ciencia e Innovación (España), Unión Europea. Comisión Europea. European Research Council (ERC), Fundación Banco Santander |
| بيانات النشر: | Public Library of Science (PLOS) |
| سنة النشر: | 2022 |
| المجموعة: | REPISALUD (REPositorio Institucional en SALUD del Instituto de Salud Carlos III - ISCIII) |
| مصطلحات موضوعية: | Hemangiosarcoma, Telomerase, Animals, Endothelial Cells, Fibroblasts, Humans, Li-Fraumeni Syndrome, Mice, Mutation, Shelterin Complex, Telomere, Telomere-Binding Proteins |
| الوصف: | The shelterin protein POT1 has been found mutated in many different familial and sporadic cancers, however, no mouse models to understand the pathobiology of these mutations have been developed so far. To address the molecular mechanisms underlying the tumorigenic effects of POT1 mutant proteins in humans, we have generated a mouse model for the human POT1R117C mutation found in Li-Fraumeni-Like families with cases of cardiac angiosarcoma by introducing this mutation in the Pot1a endogenous locus, knock-in for Pot1aR117C. We find here that both mouse embryonic fibroblasts (MEFs) and tissues from Pot1a+/ki mice show longer telomeres than wild-type controls. Longer telomeres in Pot1a+/ki MEFs are dependent on telomerase activity as they are not found in double mutant Pot1a+/ki Tert-/- telomerase-deficient MEFs. By using complementation assays we further show that POT1a pR117C exerts dominant-negative effects at telomeres. As in human Li-Fraumeni patients, heterozygous Pot1a+/ki mice spontaneously develop a high incidence of angiosarcomas, including cardiac angiosarcomas, and this is associated to the presence of abnormally long telomeres in endothelial cells as well as in the tumors. The Pot1a+/R117C mouse model constitutes a useful tool to understand human cancers initiated by POT1 mutations. ; Research in the Blasco lab is funded by Spanish Estate Research Agency, Spanish Ministry of Science and Innovation, cofunded by the European Regional Development Fund (ERDF) (SAF2017-82623-R (MAB and PM) and SAF201572455-EXP (MAB)), the Comunidad de Madrid Project (S2017/BMD-3770 (MAB)), the World Cancer Research (WCR) Project (16-1177) (MAB), the European Research Council (ERC-AvG Shelterines GA882385) (MAB) and the Fundacion Botin (Spain) (MAB). ; Sí |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1553-7404 |
| العلاقة: | https://doi.org/10.1371/journal.pgen.1010260Test.; info:eu-repo/grantAgreement/EC/H2020/882385/EU; info:eu-repo/grantAgreement/ES/SAF2017-82623-R; info:eu-repo/grantAgreement/ES/SAF201572455-EXP; PLoS Genet . 2022 ;18(6):e1010260; http://hdl.handle.net/20.500.12105/18980Test; PLoS genetics |
| DOI: | 10.1371/journal.pgen.1010260 |
| الإتاحة: | https://doi.org/20.500.12105/18980Test https://doi.org/10.1371/journal.pgen.1010260Test https://hdl.handle.net/20.500.12105/18980Test |
| حقوق: | http://creativecommons.org/licenses/by-nc-nd/4.0Test/ ; Attribution-NonCommercial-NoDerivatives 4.0 Internacional ; open access |
| رقم الانضمام: | edsbas.79B5681 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 15537404 |
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| DOI: | 10.1371/journal.pgen.1010260 |