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F Mascarelli, C Hecquet, G Lefevre, M Valtink, K Engelmann; Activation and Role of MAP Kinase-dependent Pathways in Retinal Pigment Epithelial Cells . Invest. Ophthalmol. Vis. Sci. 2002;43(13):4582.
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Purpose: Retinal pigment epithelial (RPE) cell proliferation and death are important steps in the pathogenesis of ocular diseases such as proliferative retinopathy and age-related macular degeneration. Mitogen-activated protein kinases (MAPKs) play key roles relaying signals leading to cell proliferation and death. We therefore investigated the involvement of the three MAPKs, ERK2, JNK1 and P38, in RPE cell proliferation and death. Methods: Human RPE cells were grown in 10% FCS. The activation of ERK2, JNK1 and P38 cascades and their potential targets was detected by western blotting. Pharmacological inhibitors and activators, and antisense (AS) oligonucleotide (ODN) directed against MAPK genes and their targets were used to analyze the signaling involved in RPE cell proliferation and cell death. Results: ERK2, JNK1 and P38, and their respective upstream activating kinases, MEK1/2, MKK4 and MKK3/6, were all activated in FCS-stimulated cells. ERK2 inhibition, reduced cell proliferation, whereas inhibition of JNK1 and P38 did not affect cell proliferation. In contrast, the overactivation of both JNK1 and P38 induced cell death. Analysis of cyclin D1 and c-myc production in ERK-inhibited and JNK1/P38 activated RPE cells showed that cell proliferation, but not cell death, was mediated by cyclin D1 and c-myc. Conclusion: These data suggest that the regulation of MAPKs signaling controlling RPE cell proliferation and death is complex but specific. This may have important implications for the development of more selective methods for retinal anti-proliferative and anti-degenerative therapy
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