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Reduction of p66Shc suppresses oxidative damage in retinal pigmented epithelial cells and retina
- Source :
- Journal of Cellular Physiology. 209:996-1005
- Publication Year :
- 2006
- Publisher :
- Wiley, 2006.
-
Abstract
- The largest isoform of the Shc adapter protein, p66Shc, has been implicated in oxidative damage-induced apoptosis in vital organs, because mice deficient in p66Shc have a 30% increase in life span and are resistant to the lethal effects of systemically administered paraquat, a source of severe oxidative damage. In this study, we utilized siRNA directed against the CH2 domain of Shc, to reduce p66Shc, but not p52Shc nor p46Shc in retinal pigmented epithelial (RPE) cells. RPE cells deficient in p66Shc had reduced susceptibility to oxidative stress-induced apoptosis. Compared to control cells, those with reduced p66Shc had increased basal and oxidative stress-induced NF-κB transcriptional activity, increased levels of antioxidant enzymes, and less generation of reactive oxygen species when challenged with H2O2. The increase in oxidative stress-induced NF-κB activity was mediated by activation of ERK. Compared to eyes injected with GFP siRNA, those injected with p66Shc siRNA showed less loss of retinal function as assessed by electroretinograms from paraquat-induced oxidative stress. These data suggest that p66Shc and molecular signals involved in its regulation provide therapeutic targets for retinal degenerations in which oxidative-damage plays a major role, including age-related macular degeneration and cone cell death in retinitis pigmentosa. J. Cell. Physiol. 209: 996–1005, 2006. © 2006 Wiley-Liss, Inc.
- Subjects :
- Paraquat
Src Homology 2 Domain-Containing, Transforming Protein 1
Physiology
Clinical Biochemistry
Cell
Apoptosis
Oxidative phosphorylation
Biology
medicine.disease_cause
Antioxidants
Retina
Mice
chemistry.chemical_compound
Retinitis pigmentosa
Electroretinography
medicine
Animals
Humans
Enzyme Inhibitors
RNA, Small Interfering
Extracellular Signal-Regulated MAP Kinases
Pigment Epithelium of Eye
Adaptor Proteins, Signal Transducing
chemistry.chemical_classification
Mice, Inbred BALB C
Reactive oxygen species
Herbicides
NF-kappa B
Epithelial Cells
Retinal
Hydrogen Peroxide
Cell Biology
Oxidants
medicine.disease
Cell biology
Oxidative Stress
medicine.anatomical_structure
Shc Signaling Adaptor Proteins
Biochemistry
chemistry
Female
Reactive Oxygen Species
Oxidative stress
Subjects
Details
- ISSN :
- 10974652 and 00219541
- Volume :
- 209
- Database :
- OpenAIRE
- Journal :
- Journal of Cellular Physiology
- Accession number :
- edsair.doi.dedup.....596831c9c3900f5c3512f0825aed5901