2026-06-14T06:44:40Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/68472024-11-29T22:25:25Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Méndez-Pertuz, Marinela
author
Martinez Rodriguez, Paula
author
Blanco-Aparicio, Carmen
author
Gomez Casero, Elena
author
Belen García, Ana
author
Martinez Torrecuadrada, Jorge Luis
author
Palafox, Marta
author
Cortés, Javier
author
Serra, Violeta
author
Pastor Fernandez, Joaquin
author
Blasco , MA
funder
Ministerio de Ciencia e Innovación (España)
funder
Botín Foundation
funder
Banco Santander
funder
Worldwide Cancer Research
2018-12-13T12:00:35Z
2018-12-13T12:00:35Z
2017
Nat Commun. 2017; 8:1278.
10.1038/s41467-017-01329-2
2041-1723
2041-1723
Nature communications
29097657
http://hdl.handle.net/20.500.12105/6847
Telomeres and the insulin/PI3K pathway are considered hallmarks of aging and cancer. Here, we describe a role for PI3K/AKT in the regulation of TRF1, an essential component of the shelterin complex. PI3K and AKT chemical inhibitors reduce TRF1 telomeric foci and lead to increased telomeric DNA damage and fragility. We identify the PI3Kα isoform as responsible for this TRF1 inhibition. TRF1 is phosphorylated at different residues by AKT and these modifications regulate TRF1 protein stability and TRF1 binding to telomeric DNA in vitro and are important for in vivo TRF1 telomere location and cell viability. Patient-derived breast cancer PDX mouse models that effectively respond to a PI3Kα specific inhibitor, BYL719, show decreased TRF1 levels and increased DNA damage. These findings functionally connect two of the major pathways for cancer and aging, telomeres and the PI3K pathway, and pinpoint PI3K and AKT as novel targets for chemical modulation of telomere protection.
eng
Modulation of telomere protection by the PI3K/AKT pathway
journal article
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Modulationoftelomereprotection_2017.pdf
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Modulation of telomere protection_2017_MOESM1_ESM.pdf
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Modulationoftelomereprotection_2017_MOESM2_ESM.pdf
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