| Mcl-1 downregulation by pro-inflammatory cytokines and palmitate is an early event contributing to β-cell apoptosis. | |
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MedLine Citation:
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PMID: 20798690 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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F Allagnat; D Cunha; F Moore; J M Vanderwinden; D L Eizirik; A K Cardozo |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-08-27 |
Journal Detail:
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Title: Cell death and differentiation Volume: 18 ISSN: 1476-5403 ISO Abbreviation: Cell Death Differ. Publication Date: 2011 Feb |
Date Detail:
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Created Date: 2011-01-10 Completed Date: 2011-04-25 Revised Date: 2012-02-01 |
Medline Journal Info:
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Nlm Unique ID: 9437445 Medline TA: Cell Death Differ Country: England |
Other Details:
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Languages: eng Pagination: 328-37 Citation Subset: IM |
Affiliation:
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Laboratoire de Médecine Expérimentale, Université Libre de Bruxelles (ULB), Route de Lennik 808, Brussels, Belgium. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis* Caspase 3 / metabolism Cell Line, Tumor Cytochromes c / metabolism Cytokines / pharmacology* Down-Regulation Endoplasmic Reticulum / metabolism Insulin-Secreting Cells / cytology, metabolism* Palmitates / pharmacology* Proto-Oncogene Proteins c-bcl-2 / genetics, metabolism* RNA Interference RNA, Small Interfering / metabolism Rats Thapsigargin / pharmacology bcl-2-Associated X Protein / metabolism bcl-X Protein / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Cytokines; 0/Palmitates; 0/Proto-Oncogene Proteins c-bcl-2; 0/RNA, Small Interfering; 0/bcl-2-Associated X Protein; 0/bcl-X Protein; 0/myeloid cell leukemia sequence 1 protein; 67526-95-8/Thapsigargin; 9007-43-6/Cytochromes c; EC 3.4.22.-/Caspase 3 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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