Τίτλος:
Oncogene-induced reactive oxygen species fuel hyperproliferation and DNA damage response activation
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Oncogene-induced reactive oxygen species (ROS) have been proposed to be signaling molecules that mediate proliferative cues. However, ROS may also cause DNA damage and proliferative arrest. How these apparently opposite roles can be reconciled, especially in the context of oncogene-induced cellular senescence, which is associated both with aberrant mitogenic signaling and DNA damage response (DDR)-mediated arrest, is unclear. Here, we show that ROS are indeed mitogenic signaling molecules that fuel oncogene-driven aberrant cell proliferation. However, by their very same ability to mediate cell hyperproliferation, ROS eventually cause DDR activation. We also show that oncogenic Ras-induced ROS are produced in a Rac1 and NADPH oxidase (Nox4)-dependent manner. In addition, we show that Ras-induced ROS can be detected and modulated in a living transparent animal: the zebrafish. Finally, in cancer we show that Nox4 is increased in both human tumors and a mouse model of pancreatic cancer and specific Nox4 small-molecule inhibitors act synergistically with existing chemotherapic agents. © 2014 Macmillan Publishers Limited All rights reserved.
Συγγραφείς:
Ogrunc, M.
Di Micco, R.
Liontos, M.
Bombardelli, L.
Mione, M.
Fumagalli, M.
Gorgoulis, V.G.
D'Adda Di Fagagna, F.
Περιοδικό:
Cell Death and Differentiation
Εκδότης:
Nature Publishing Group
Λέξεις-κλειδιά:
Rac1 protein; reactive oxygen metabolite; reduced nicotinamide adenine dinucleotide phosphate oxidase 4; NOX4 protein, human; Rac1 protein; RAC1 protein, human; reactive oxygen metabolite; reduced nicotinamide adenine dinucleotide phosphate oxidase, animal experiment; animal tissue; article; cancer model; cell proliferation; controlled study; DNA damage; human; human cell; mitogenesis; mouse; nonhuman; oncogene; pancreas cancer; priority journal; senescence; signal transduction; transgenic zebrafish; animal; cell proliferation; DNA damage; drug effects; drug screening; genetics; metabolism; oxidation reduction reaction; oxidative stress; pancreas tumor; pathology; toxicity; tumor cell line, Animalia; Danio rerio, Animals; Cell Line, Tumor; Cell Proliferation; DNA Damage; Humans; Mice; NADPH Oxidase; Oxidation-Reduction; Oxidative Stress; Pancreatic Neoplasms; rac1 GTP-Binding Protein; Reactive Oxygen Species; Xenograft Model Antitumor Assays
