Molecular mechanisms regulating dissociation of cell-cell junction of epithelial cells by oxidative stress.
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-kappaB (NF-kappaB) and the expression of manganese superoxide dismutase (Mn-SOD). Using the NF-kappaB specific inhibitor DHMEQ, we found that NF-kappaB is part of a negative feedback loop to control intracellular ROS levels. Finally, we demonstrated that H(2)O(2) treatment alone does not induce the epithelial mesenchymal transition (EMT) in retinal pigment epithelial cells, which can be induced by TNF-alpha 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.
Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan.
Junko
J
Inumaru
Osamu
O
Nagano
Eri
E
Takahashi
Takatsugu
T
Ishimoto
Satoshi
S
Nakamura
Yoshimi
Y
Suzuki
Shin-Ichiro
S
Niwa
Kazuo
K
Umezawa
Hidenobu
H
Tanihara
Hideyuki
H
Saya
D051177:Catenins; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007365:Intercellular Junctions / Q000187:drug effects*; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology; D055213:Retinal Pigment Epithelium / Q000166:cytology* / Q000187:drug effects; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism; D000095002:Delta Catenin
D051177:Catenins; D015815:Cell Adhesion Molecules; D016328:NF-kappa B; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D019061:src-Family Kinases; D054460:rho-Associated Kinases; D000095002:Delta Catenin; C000722347:CTNND1 protein, human