Mitochondrial reactive oxygen species perturb AKT/cyclin D1 cell cycle signaling via oxidative inactivation of PP2A in lowdose irradiated human fibroblasts
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Tsutomu Shimura1, Megumi Sasatani2, Kenji Kamiya2, Hidehiko Kawai3, Yohei Inaba1, Naoki Kunugita1
1Department of Environmental Health, National Institute of Public Health, Saitama, Japan
2Department of Experimental Oncology, Research Institute for Radiation Biology and Medicine (RIRBM), Hiroshima University, Hiroshima, Japan
3Department of Molecular Radiobiology, Research Center for Radiation Genome Medicine, Research Institute for Radiation Biology and Medicine (RIRBM), Hiroshima University, Hiroshima, Japan
Tsutomu Shimura, e-mail: firstname.lastname@example.org
Keywords: mitochondria, ROS, cyclin D1, low-dose radiation, AKT
Received: August 20, 2015 Accepted: November 21, 2015 Published: December 09, 2015
Here we investigated the cellular response of normal human fibroblasts to repeated exposure to low-dose radiation. In contrast to acute single radiation, low-dose fractionated radiation (FR) with 0.01 Gy/fraction or 0.05 Gy/fraction for 31 days increased in mitochondrial mass, decreased cellular levels of the antioxidant glutathione and caused persistent accumulation of mitochondrial reactive oxygen species (ROS). Excess ROS promoted oxidative inactivation of protein phosphatase PP2A which in turn led to disruption of normal negative feed-back control of AKT/cyclin D1 signaling in cells treated with long-term FR. The resulting abnormal nuclear accumulation of cyclin D1 causes growth retardation, cellular senescence and genome instability in low-dose irradiated cells. Thus, loss of redox control and subsequently elevated levels of ROS perturb signal transduction as a result of oxidative stress. Our study highlights a specific role of mitochondrial ROS in perturbation of AKT/cyclin D1 cell cycle signaling after low-dose long-term FR. The antioxidants N-acetyl-L-cysteine, TEMPO and mitochondrial-targeted antioxidant Mito-TEMPO provided protection against the harmful cell cycle perturbations induced by low-dose long-term FR.
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