Mcl-1 downregulation by pro-inflammatory cytokines and palmitate is an early event contributing beta cell apoptosis.
Résumé
Pancreatic beta cell apoptosis is a key feature of diabetes mellitus and the mitochondrial pathway of apoptosis is a major mediator of beta cell death. We presently evaluated the role of the myeloid cell leukemia sequence 1 (Mcl-1), an anti-apoptotic protein of the Bcl-2 family, in beta cells following exposure to well defined beta cell death effectors, e.g. pro-inflammatory cytokines, palmitate and chemical ER stressors. All cytotoxic stresses rapidly and preferentially decreased Mcl-1 protein expression as compared to the late effect observed on the other anti-apoptotic proteins Bcl-2 and Bcl-XL. This was due to ER stress-mediated inhibition of translation through eIF2α phosphorylation for palmitate and ER-stressors and to the combined action of translation inhibition and JNK activation for cytokines. Knocking-down Mcl-1 using siRNAs increased apoptosis and caspase 3 cleavage induced by cytokines, palmitate or thapsigargin, while Mcl-1 overexpression partly prevented Bax translocation to the mitochondria, cytochrome c release, caspase 3 cleavage and apoptosis induced by the beta cell death effectors. Altogether, our data suggest that Mcl-1 downregulation is a crucial event leading to beta cell apoptosis and provide new insights in the mechanisms linking ER stress and the mitochondrial intrinsic pathway of apoptosis. Mcl-1 is therefore an attractive target for the design of new strategies in the treatment of diabetes.
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