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Mol Biol Cell ; 29(18): 2228-2242, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29975106

RESUMO

Ionizing radiation (IR) not only activates DNA damage response (DDR) in irradiated cells but also induces bystander effects (BE) in cells not directly targeted by radiation. How DDR pathways activated in irradiated cells stimulate BE is not well understood. We show here that extracellular vesicles secreted by irradiated cells (EV-IR), but not those from unirradiated controls (EV-C), inhibit colony formation in unirradiated cells by inducing reactive oxygen species (ROS). We found that µEV-IR from Abl nuclear localization signal-mutated ( Abl-µNLS) cells could not induce ROS, but expression of wild-type Abl restored that activity. Because nuclear Abl stimulates miR-34c biogenesis, we measured miR-34c in EV and found that its levels correlated with the ROS-inducing activity of EV. We then showed that EV from miR-34c minigene-transfected, but unirradiated cells induced ROS; and transfection with miR-34c-mimic, without radiation or EV addition, also induced ROS. Furthermore, EV-IR from miR34-family triple-knockout cells could not induce ROS, whereas EV-IR from wild-type cells could cause miR-34c increase and ROS induction in the miR-34 triple-knockout cells. These results establish a novel role for extracellular vesicles in transferring nuclear Abl-dependent and radiation-induced miR-34c into unirradiated cells to cause bystander oxidative stress.


Assuntos
Efeito Espectador/efeitos da radiação , Vesículas Extracelulares/efeitos da radiação , Fibroblastos/efeitos da radiação , MicroRNAs/biossíntese , Proteínas Proto-Oncogênicas c-abl/metabolismo , Animais , Técnicas de Cultura de Células , Dano ao DNA , Reparo do DNA , Vesículas Extracelulares/metabolismo , Fibroblastos/metabolismo , Células HEK293 , Humanos , Camundongos , Estresse Oxidativo/efeitos da radiação , Radiação Ionizante , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos da radiação
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