2026-04-29T12:23:07Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/189802024-11-29T20:25:12Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Martínez, Paula
author
Sánchez-Vázquez, Raúl
author
Ferrara-Romeo, Iole
author
Serrano, Rosa
author
Flores, Juana M
author
Blasco, MA
funder
Agencia Estatal de Investigación (España)
funder
Comunidad de Madrid (España)
funder
Ministerio de Ciencia e Innovación (España)
funder
Unión Europea. Comisión Europea. European Research Council (ERC)
funder
Fundación Banco Santander
2024-03-18T11:20:15Z
2024-03-18T11:20:15Z
2022-06
PLoS Genet . 2022 ;18(6):e1010260
10.1371/journal.pgen.1010260
1553-7404
PLoS genetics
35727838
http://hdl.handle.net/20.500.12105/18980
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.
eng
A mouse model for Li-Fraumeni-Like Syndrome with cardiac angiosarcomas associated to POT1 mutations.
journal article
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URL
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amousemodelfor_2023.pdf
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https://repisalud.isciii.es/bitstreams/b74eb2ea-81e7-4f46-b516-5c55c73da5b5/download
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text/plain
amousemodelfor_2023.pdf.txt