Mcl-1 downregulation by pro-inflammatory cytokines and palmitate is an early event contributing to β-cell apoptosis.

Détails

ID Serval
serval:BIB_D7C6851CCAAF
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Mcl-1 downregulation by pro-inflammatory cytokines and palmitate is an early event contributing to β-cell apoptosis.
Périodique
Cell death and differentiation
Auteur(s)
Allagnat F., Cunha D., Moore F., Vanderwinden J.M., Eizirik D.L., Cardozo A.K.
ISSN
1476-5403 (Electronic)
ISSN-L
1350-9047
Statut éditorial
Publié
Date de publication
02/2011
Peer-reviewed
Oui
Volume
18
Numéro
2
Pages
328-337
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
Pancreatic β-cell apoptosis is a key feature of diabetes mellitus and the mitochondrial pathway of apoptosis is a major mediator of β-cell death. We presently evaluated the role of the myeloid cell leukemia sequence 1 (Mcl-1), an antiapoptotic protein of the Bcl-2 family, in β-cells following exposure to well-defined β-cell death effectors, for example, pro-inflammatory cytokines, palmitate and chemical endoplasmic reticulum (ER) stressors. All cytotoxic stresses rapidly and preferentially decreased Mcl-1 protein expression as compared with the late effect observed on the other antiapoptotic 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 through the combined action of translation inhibition and JNK activation for cytokines. Knocking down Mcl-1 using small interference RNAs increased apoptosis and caspase-3 cleavage induced by cytokines, palmitate or thapsigargin, whereas Mcl-1 overexpression partly prevented Bax translocation to the mitochondria, cytochrome c release, caspase-3 cleavage and apoptosis induced by the β-cell death effectors. Altogether, our data suggest that Mcl-1 downregulation is a crucial event leading to β-cell apoptosis and provide new insights into 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.
Mots-clé
Animals, Apoptosis, Caspase 3/metabolism, Cell Line, Tumor, Cytochromes c/metabolism, Cytokines/pharmacology, Down-Regulation, Endoplasmic Reticulum/metabolism, Insulin-Secreting Cells/cytology, Insulin-Secreting Cells/metabolism, Myeloid Cell Leukemia Sequence 1 Protein, Palmitates/pharmacology, Proto-Oncogene Proteins c-bcl-2/genetics, Proto-Oncogene Proteins c-bcl-2/metabolism, RNA Interference, RNA, Small Interfering/metabolism, Rats, Thapsigargin/pharmacology, bcl-2-Associated X Protein/metabolism, bcl-X Protein/metabolism
Pubmed
Web of science
Open Access
Oui
Création de la notice
10/05/2019 10:06
Dernière modification de la notice
20/08/2019 16:57
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