RESUMO
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.
Assuntos
Envelhecimento/genética , Neoplasias da Mama/genética , Dano ao DNA/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Telômero/genética , Proteína 1 de Ligação a Repetições Teloméricas/metabolismo , Animais , Classe I de Fosfatidilinositol 3-Quinases , Dano ao DNA/efeitos dos fármacos , Humanos , Camundongos , Transplante de Neoplasias , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação , Estabilidade Proteica , Telômero/efeitos dos fármacos , Proteína 1 de Ligação a Repetições Teloméricas/efeitos dos fármacos , Tiazóis/farmacologiaRESUMO
SUMMARY: The C(18) ketone (5E,7E)-6-methyl-8-(2,6,6-trimethylcyclohex-1-enyl)octa-5,7-dien-2-one (D'orenone) has been postulated to be an early cleavage product of beta-carotene en route to trisporic acids; these act as morphogenetic factors during the sexual reproduction of zygomycetes. Here we report that D'orenone blocks the highly polarized tip growth of root hairs, causing tip growth to stop completely within a few minutes. Importantly, external auxin reverses the effects of D'orenone on root hairs. Further analysis revealed that D'orenone lowers the auxin concentration in trichoblasts via PIN2-mediated auxin efflux to below the critical levels essential for root hair growth. D'orenone specifically increases PIN2 protein abundance without affecting PIN2 transcripts, and the PIN2 expression domain enlarges and shifts basipetally, resulting in more active auxin transport. The observation that D'orenone does not interfere with the root hair growth in roots of null mutant lines provides additional evidence that PIN2 is its specific target.
