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

Abstract

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.

• Authors: Tsutomu Shimura, Megumi Sasatani, Kenji Kamiya, Hidehiko Kawai, Yohei Inaba, Naoki Kunugita
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 3 Pg. 3559-70 (Jan 19 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26657292 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• CCND1 protein, human
• Reactive Oxygen Species
• Cyclin D1
• Adenosine Triphosphate
• AKT1 protein, human
• Proto-Oncogene Proteins c-akt
• Protein Phosphatase 2

Topics

• Adenosine Triphosphate (metabolism)
• Antioxidants (pharmacology)
• Apoptosis (drug effects, radiation effects)
• Blotting, Western
• Cell Cycle (drug effects, radiation effects)
• Cell Proliferation (drug effects, radiation effects)
• Cells, Cultured
• Cyclin D1 (metabolism)
• DNA Damage (radiation effects)
• Fibroblasts (drug effects, metabolism, pathology, radiation effects)
• Gamma Rays
• Humans
• Lung (drug effects, metabolism, pathology, radiation effects)
• Mitochondria (drug effects, metabolism, pathology, radiation effects)
• Oxidation-Reduction
• Protein Phosphatase 2 (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Radiation Dosage
• Reactive Oxygen Species (metabolism)