Molecular mechanisms regulating dissociation of cell-cell junction of epithelial cells by oxidative stress

Genes Cells. 2009 Jun;14(6):703-16. doi: 10.1111/j.1365-2443.2009.01303.x. Epub 2009 Apr 30.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catenins
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism
  • Cell Differentiation
  • Delta Catenin
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism
  • Humans
  • Hydrogen Peroxide / pharmacology*
  • Intercellular Junctions / drug effects*
  • Mesoderm / cytology
  • Mesoderm / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Oxidative Stress*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Reactive Oxygen Species / metabolism
  • Reactive Oxygen Species / pharmacology
  • Retinal Pigment Epithelium / cytology*
  • Retinal Pigment Epithelium / drug effects
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • rho-Associated Kinases / genetics
  • rho-Associated Kinases / metabolism
  • src-Family Kinases / genetics
  • src-Family Kinases / metabolism

Substances

  • Catenins
  • Cell Adhesion Molecules
  • NF-kappa B
  • Phosphoproteins
  • Reactive Oxygen Species
  • Hydrogen Peroxide
  • Superoxide Dismutase
  • src-Family Kinases
  • rho-Associated Kinases
  • Delta Catenin
  • CTNND1 protein, human