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oai:repisalud.isciii.es:20.500.12105/68472024-11-29T22:25:25Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc 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 author 2017 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. 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 Modulation of telomere protection by the PI3K/AKT pathway