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Activation of mitogen-activated protein kinases is essential for hydrogen peroxide -induced apoptosis in retinal pigment epithelial cells

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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.

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Authors and Affiliations

  1. Department of Ophthalmology, The Mackay Memorial Hospital, Taipei, Taiwan

    T.-C. Ho, H.-C. Cheng, A.-C. Wu, H.-K. Chen & Y.-P. Tsao

  2. Mackay Medicine, Nursing and Management College, Taipei, Taiwan

    Y.-C. Yang

  3. School of Medicine, Taipei Medical University, Taipei, Taiwan

    Y.-C. Yang

  4. Department of Microbiology and Immunology, The National Defense Medical Center, Taipei, Taiwan

    S.-L. Chen & Y.-P. Tsao

  5. Department of Microbiology, The School of Medicine, National Taiwan University, Taipei, Taiwan

    S.-L. Chen

Authors
  1. T.-C. Ho
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  2. Y.-C. Yang
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  3. H.-C. Cheng
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  4. A.-C. Wu
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  5. S.-L. Chen
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  6. H.-K. Chen
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  7. Y.-P. Tsao
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Corresponding author

Correspondence to Y.-P. Tsao.

Additional information

Y.-C. Yang and T.-C. Ho contributed equally to the work described herein.

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Ho, TC., Yang, YC., Cheng, HC. et al. Activation of mitogen-activated protein kinases is essential for hydrogen peroxide -induced apoptosis in retinal pigment epithelial cells. Apoptosis 11, 1899–1908 (2006). https://doi.org/10.1007/s10495-006-9403-6

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  • DOI: https://doi.org/10.1007/s10495-006-9403-6

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