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Sustained versus transient ERK1/2 signaling underlies the anti- and proapoptotic effects of oxidative stress in human RPE cells.
Invest Ophthalmol Vis Sci. 2006 Oct; 47(10):4614-23.IO

Abstract

PURPOSE

Oxidative stress is thought to contribute to the pathogenesis of age-related macular degeneration (AMD), which involves retinal pigmented epithelial (RPE) cell death. However, signaling pathways involved in the oxidative-stress-induced RPE cell death are poorly understood. This study was conducted to investigate the involvement of the MAP kinase pathways during the induction of RPE cell death by oxidative stress.

METHODS

ARPE-19 cells were exposed to the oxidant tert-butyl hydroperoxide (t-BHP). Cell viability was assessed by cell counting and MTT-staining, and apoptosis was quantified by TUNEL and flow cytometry. Activation of JNK1/3, p38 alphabeta MAPKs and ERK1/2 and their potential targets was detected by Western blot analysis and immunochemistry with specific anti-phospho protein antibodies. Specific pharmacologic inhibitors directed against the MAPKs were used to analyze the signaling involved in cell death of RPE cells exposed to t-BHP.

RESULTS

Exposure of RPE cells to t-BHP, associated with increase in reactive oxygen species and intracellular glutathione depletion, induced time- and concentration-dependent apoptosis, which was associated with the accumulation of inactive ERK1/2 in cell nuclei and a transient and weak ERK1/2 activation. This activation was accompanied by a deactivation of P90(RSK), the major target of ERK1/2 and consequently by the delayed activation of its transcription factor CREB. MEK1/2 inhibition completely suppressed the transient activation of ERK1/2 and completely blocked apoptosis, demonstrating the role of the MEK-ERK module in mediating oxidative-stress-induced RPE cell death. In contrast, neither JNKs nor p38 alphabeta MAPKs were involved in mediating t-BHP-induced apoptotic signaling in RPE cells.

CONCLUSIONS

The results suggest that inhibiting the MEK-ERK module may allow the development of selective methods for treating oxidative-stress-induced RPE degeneration, such as AMD.

Authors+Show Affiliations

Institut Biomédical des Cordeliers, INSERM (Institut National de la Santé et de la Recherche Médicale) Unité 598, Paris, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17003459

Citation

Glotin, Anne-Lise, et al. "Sustained Versus Transient ERK1/2 Signaling Underlies the Anti- and Proapoptotic Effects of Oxidative Stress in Human RPE Cells." Investigative Ophthalmology & Visual Science, vol. 47, no. 10, 2006, pp. 4614-23.
Glotin AL, Calipel A, Brossas JY, et al. Sustained versus transient ERK1/2 signaling underlies the anti- and proapoptotic effects of oxidative stress in human RPE cells. Invest Ophthalmol Vis Sci. 2006;47(10):4614-23.
Glotin, A. L., Calipel, A., Brossas, J. Y., Faussat, A. M., Tréton, J., & Mascarelli, F. (2006). Sustained versus transient ERK1/2 signaling underlies the anti- and proapoptotic effects of oxidative stress in human RPE cells. Investigative Ophthalmology & Visual Science, 47(10), 4614-23.
Glotin AL, et al. Sustained Versus Transient ERK1/2 Signaling Underlies the Anti- and Proapoptotic Effects of Oxidative Stress in Human RPE Cells. Invest Ophthalmol Vis Sci. 2006;47(10):4614-23. PubMed PMID: 17003459.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sustained versus transient ERK1/2 signaling underlies the anti- and proapoptotic effects of oxidative stress in human RPE cells. AU - Glotin,Anne-Lise, AU - Calipel,Armelle, AU - Brossas,Jean-Yves, AU - Faussat,Anne-Marie, AU - Tréton,Jacques, AU - Mascarelli,Frédéric, PY - 2006/9/28/pubmed PY - 2006/10/25/medline PY - 2006/9/28/entrez SP - 4614 EP - 23 JF - Investigative ophthalmology & visual science JO - Invest Ophthalmol Vis Sci VL - 47 IS - 10 N2 - PURPOSE: Oxidative stress is thought to contribute to the pathogenesis of age-related macular degeneration (AMD), which involves retinal pigmented epithelial (RPE) cell death. However, signaling pathways involved in the oxidative-stress-induced RPE cell death are poorly understood. This study was conducted to investigate the involvement of the MAP kinase pathways during the induction of RPE cell death by oxidative stress. METHODS: ARPE-19 cells were exposed to the oxidant tert-butyl hydroperoxide (t-BHP). Cell viability was assessed by cell counting and MTT-staining, and apoptosis was quantified by TUNEL and flow cytometry. Activation of JNK1/3, p38 alphabeta MAPKs and ERK1/2 and their potential targets was detected by Western blot analysis and immunochemistry with specific anti-phospho protein antibodies. Specific pharmacologic inhibitors directed against the MAPKs were used to analyze the signaling involved in cell death of RPE cells exposed to t-BHP. RESULTS: Exposure of RPE cells to t-BHP, associated with increase in reactive oxygen species and intracellular glutathione depletion, induced time- and concentration-dependent apoptosis, which was associated with the accumulation of inactive ERK1/2 in cell nuclei and a transient and weak ERK1/2 activation. This activation was accompanied by a deactivation of P90(RSK), the major target of ERK1/2 and consequently by the delayed activation of its transcription factor CREB. MEK1/2 inhibition completely suppressed the transient activation of ERK1/2 and completely blocked apoptosis, demonstrating the role of the MEK-ERK module in mediating oxidative-stress-induced RPE cell death. In contrast, neither JNKs nor p38 alphabeta MAPKs were involved in mediating t-BHP-induced apoptotic signaling in RPE cells. CONCLUSIONS: The results suggest that inhibiting the MEK-ERK module may allow the development of selective methods for treating oxidative-stress-induced RPE degeneration, such as AMD. SN - 0146-0404 UR - https://www.unboundmedicine.com/medline/citation/17003459/Sustained_versus_transient_ERK1/2_signaling_underlies_the_anti__and_proapoptotic_effects_of_oxidative_stress_in_human_RPE_cells_ L2 - https://iovs.arvojournals.org/article.aspx?doi=10.1167/iovs.06-0297 DB - PRIME DP - Unbound Medicine ER -