PMID- 17679932
OWN - NLM
STAT- MEDLINE
DCOM- 20070918
LR  - 20091119
IS  - 1090-0535 (Electronic)
IS  - 1090-0535 (Linking)
VI  - 13
DP  - 2007 Jul 24
TI  - Mechanism of Src kinase induction of cortical cataract following exposure to 
      stress: destabilization of cell-cell junctions.
PG  - 1298-310
AB  - PURPOSE: Activation of stress pathways is a primary cause of age-related 
      cataracts. Our laboratory previously developed a lens cataract model in which 
      activation of the p38 kinase/Src family kinase (SFK) stress-signaling pathway is 
      responsible for the induction of cortical opacities. Here, we use this model to 
      investigate further the mechanism of stress-induced cataract. METHODS: Cortical 
      cataracts were induced by mechanical stress and prevented by exposure to the SFK 
      inhibitor PP1. Organization of the actin cytoskeleton, cadherin junctions and 
      membrane structure was determined by fluorescence imaging. Apoptosis was examined 
      by both terminal dUTP nick-end labeling (TUNEL) and DEVDase assays. N-cadherin 
      cleavage was examined by western blot analysis. RESULTS: In this cortical 
      cataract model, activation of SFKs in the lens epithelium caused increased 
      cleavage of N-cadherin, the loss of cadherin cell-cell junctions, and the 
      disorganization of the actin cytoskeleton. As the function of cadherin junctions 
      and the cytoskeleton are required for assembling a polarized epithelium and 
      protecting it against apoptotic cell death, the SFK-dependent disassembly of 
      these structures was likely responsible for the observed loss of integrity and 
      apoptosis of the lens epithelium. Apoptotic death of lens epithelial cells 
      preceded the appearance of cortical opacities, suggesting that the lens 
      epithelium provided an important line of defense for the lens fiber cells. 
      Opacification was related to defects in the membrane structure of cortical fiber 
      cells. Linearity of fiber cell membranes was lost. Extensive undulations and 
      interdigitations of these membranes occurred as well as large separations between 
      fiber cells as is common to many types of cataract. CONCLUSIONS: Src kinase 
      activation-induced loss of cadherin junctions and apoptosis of the lens 
      epithelium leads to altered fiber cell organization and lens opacification.
FAU - Zhou, Jian
AU  - Zhou J
AD  - Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 
      Philadelphia, PA 19107, USA.
FAU - Leonard, Michelle
AU  - Leonard M
FAU - Van Bockstaele, Elisabeth
AU  - Van Bockstaele E
FAU - Menko, A Sue
AU  - Menko AS
LA  - eng
GR  - ES007282/ES/NIEHS NIH HHS/United States
GR  - EY014258/EY/NEI NIH HHS/United States
GR  - EY014798/EY/NEI NIH HHS/United States
GR  - EY10577/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20070724
PL  - United States
TA  - Mol Vis
JT  - Molecular vision
JID - 9605351
RN  - 0 (4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine)
RN  - 0 (Cadherins)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyrimidines)
RN  - EC 2.7.10.2 (src-Family Kinases)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Cadherins/metabolism
MH  - Cataract/*enzymology/pathology
MH  - Cell Membrane/drug effects
MH  - Cells, Cultured
MH  - Chick Embryo
MH  - Enzyme Activation/drug effects
MH  - Enzyme Induction/drug effects
MH  - Epithelial Cells/drug effects/enzymology/pathology
MH  - Epithelium/enzymology/pathology
MH  - Intercellular Junctions/*drug effects
MH  - Lens, Crystalline/drug effects/enzymology/pathology/ultrastructure
MH  - Pyrazoles/*pharmacology
MH  - Pyrimidines/*pharmacology
MH  - Stress, Mechanical
MH  - src-Family Kinases/*biosynthesis
EDAT- 2007/08/08 09:00
MHDA- 2007/09/19 09:00
CRDT- 2007/08/08 09:00
PHST- 2007/08/08 09:00 [pubmed]
PHST- 2007/09/19 09:00 [medline]
PHST- 2007/08/08 09:00 [entrez]
AID - v13/a142 [pii]
PST - epublish
SO  - Mol Vis. 2007 Jul 24;13:1298-310.