Activation of mitogen-activated protein kinases is essential for hydrogen peroxide -induced apoptosis in retinal pigment epithelial cells |
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Authors: | T-C Ho Y-C Yang H-C Cheng A-C Wu S-L Chen H-K Chen Y-P Tsao |
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Institution: | (1) Department of Ophthalmology, The Mackay Memorial Hospital, Taipei, Taiwan;(2) Mackay Medicine, Nursing and Management College, Taipei, Taiwan;(3) School of Medicine, Taipei Medical University, Taipei, Taiwan;(4) Department of Microbiology and Immunology, The National Defense Medical Center, Taipei, Taiwan;(5) Department of Microbiology, The School of Medicine, National Taiwan University, Taipei, Taiwan |
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Abstract: | Retinal pigment epithelial (RPE) cells are constantly exposed to oxidative injury while clearing byproducts of photoreceptor
turnover, a circumstance thought to be responsible for degenerative retinal diseases. The mechanisms of hydrogen peroxide
(H2O2)-induced apoptosis in RPE cells are not fully understood. We studied signal transduction mechanisms of H2O2-induced apoptosis in the human RPE cell line ARPE-19. Activation of two stress kinases (JNK and p38) occurs during H2O2 stimulation, and H2O2-mediated cell death was significantly reduced by their specific inhibition. Exposure to a lethal dose of H2O2 elicited Bax translocation to the mitochondria and release of apoptosis-inducing factor (AIF) from the mitochondria, both
of which were abolished by either JNK- or p38-specific inhibitors. Both H2O2-induced cell death and JNK/p38 phosphorylation were partially inhibited by C. difficile toxin B, inhibitor of Rho, Rac, and cdc42. Use of pull-down assays revealed that the small GTPase activated by H2O2 is Rac1. This study is the first to demonstrate that H2O2 induces a Rac1/JNK1/p38 signaling cascade, and that JNK and p38 activation is important for H2O2-induced apoptosis as well as AIF/Bax translocation of RPE cells.
Y.-C. Yang and T.-C. Ho contributed equally to the work described herein. |
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Keywords: | JNK p38 Rac1 RPE AIF Hydrogen peroxide |
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