Mitochondrial reactive oxygen species perturb AKT/cyclin D1 cell cycle signaling via oxidative inactivation of PP2A in low-dose irradiated human fibroblasts

2016 Fiscal Year Final Research Report

• Project/Area Number: 15K12220
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Environmental impact assessment
• Research Institution: National Institute of Public Health
• Principal Investigator: Shimura Tsutomu 国立保健医療科学院, その他部局等, 上席主任研究官 (40463799)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Keywords: ミトコンドリア / 活性酸素 / 低線量放射線 / サイクリンD1 / AKT

Outline of Final Research Achievements

We investigated the effect of repeated exposure to low-dose radiation in normal human fibroblasts. Long-term low dose fractionated radiation (FR) with 0.01 Gy/fraction or 0.05 Gy/fraction for 31 days 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. The antioxidants provided protection against the harmful cell cycle perturbations induced by low-dose long-term FR.
Our study highlights a specific role of mitochondrial ROS in perturbation of AKT/cyclin D1 cell cycle signaling after low-dose long-term FR.

Free Research Field

放射線生物学