Modulation of telomere protection by the PI3K/AKT pathway

被引：58

作者：

Mendez-Pertuz, Marinela ^{[1
]}

Martinez, Paula ^{[1
]}

Blanco-Aparicio, Carmen ^{[2
]}

Gomez-Casero, Elena ^{[2
]}

Belen Garcia, Ana ^{[2
]}

Martinez-Torrecuadrada, Jorge ^{[3
]}

Palafox, Marta ^{[4
]}

Cortes, Javier ^{[4
]}

Serra, Violeta ^{[4
]}

Pastor, Joaquin ^{[2
]}

Blasco, Maria A. ^{[1
]}

机构：

[1] Spanish Natl Canc Ctr CNIO, Telomeres & Telomerase Grp, Mol Oncol Program, Melchor Fernandez Almagro 3, E-28029 Madrid, Spain

[2] Spanish Natl Canc Ctr CNIO, Expt Therapeut Program, Melchor Fernandez Almagro 3, E-28029 Madrid, Spain

[3] Spanish Natl Canc Ctr CNIO, Biotechnol Program, Melchor Fernandez Almagro 3, E-28029 Madrid, Spain

[4] VHIO, Expt Therapeut Grp, Natzaret 115-117, E-08035 Barcelona, Spain

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

关键词：

POLY(ADP-RIBOSE) POLYMERASE; LIFE-SPAN; INHIBITOR IMETELSTAT; DNA-DAMAGE; TRF1; KINASE; IDENTIFICATION; LENGTH; CANCER; BINDING;

D O I：

10.1038/s41467-017-01329-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 PI3Ka 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 PI3Ka 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.

引用

页数：17

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