Document Detail


Mcl-1 downregulation by pro-inflammatory cytokines and palmitate is an early event contributing to β-cell apoptosis.
MedLine Citation:
PMID:  20798690     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
F Allagnat; D Cunha; F Moore; J M Vanderwinden; D L Eizirik; A K Cardozo
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-08-27
Journal Detail:
Title:  Cell death and differentiation     Volume:  18     ISSN:  1476-5403     ISO Abbreviation:  Cell Death Differ.     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-01-10     Completed Date:  2011-04-25     Revised Date:  2013-05-28    
Medline Journal Info:
Nlm Unique ID:  9437445     Medline TA:  Cell Death Differ     Country:  England    
Other Details:
Languages:  eng     Pagination:  328-37     Citation Subset:  IM    
Affiliation:
Laboratoire de Médecine Expérimentale, Université Libre de Bruxelles (ULB), Route de Lennik 808, Brussels, Belgium.
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MeSH Terms
Descriptor/Qualifier:
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:
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
Comments/Corrections

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