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Junko Inumaru^1,2, Osamu Nagano^1,3, Eri Takahashi^1,2, Takatsugu Ishimoto¹, Satoshi Nakamura⁴, Yoshimi Suzuki⁴, Shin-ichiro Niwa⁴, Kazuo Umezawa⁵, Hidenobu Tanihara² and Hideyuki Saya^1,3

¹ Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan
² Department of Ophthalmology and Visual Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
³ CREST, Japan Science and Technology Agency, Tokyo 102-0075, Japan
⁴ Link Genomics, Inc., Tokyo 103-0024, Japan
⁵ Faculty of Science and Technology, Keio University, Yokohama 223-0061, Japan

Oxidative stress is regarded as a causative factor in aging and various degenerative diseases. Here, we show the mechanism by which oxidative stress induces disruption of cell–cell junctions using retinal pigment epithelial cells. We demonstrated that reactive oxygen species (ROS)-mediated activation of Src kinase increases the tyrosine phosphorylation state of p120-catenin and rapidly triggers translocation of p120-catenin and internalization of N-cadherin from the cell–cell adhesion sites to an early endosomal compartment. Endosomal accumulation of p120-catenin resulted in stress fiber formation and cell–cell dissociation through the activation of Rho/Rho kinase pathway. However, these cytoskeletal remodeling and cell–cell dissociation induced by oxidative stress were transient, due to the activation of nuclear factor-B (NF-B) and the expression of manganese superoxide dismutase (Mn-SOD). Using the NF-B specific inhibitor DHMEQ, we found that NF-B is part of a negative feedback loop to control intracellular ROS levels. Finally, we demonstrated that H₂O₂ treatment alone does not induce the epithelial mesenchymal transition (EMT) in retinal pigment epithelial cells, which can be induced by TNF- treatment. These findings suggest that oxidative stress is a crucial factor to induce the cell–cell dissociation, an initial step of EMT, but does not provide sufficient signals to establish and to maintain the EMT.

Both authors contributed equally to this work.

^* Correspondence: hsaya{at}a5.keio.jp

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