Etude de L'implication de la voie RAF/MEK/ERK dans la tumorigenese du mélanome choroïdien humain

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Sustained versus transient ERK1/2 signaling underlies the anti- and proapoptotic effects of oxidative stress

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 ␣␤ MAPKs and ERK1/2 and their potential targets was detected by Western blot analysis and immunochemistry with specific antiphospho 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-stressinduced RPE cell death. In contrast, neither JNKs nor p38 ␣␤ 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. (Invest Ophthalmol Vis Sci. 2006;47:4614 -4623

Mechanisms of resistance to imatinib mesylate in KIT-positive metastatic uveal melanoma

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