Submit Data |  Help |  Video Tutorials |  News |  Publications |  FTP Download |  REST API |  Citing RGD |  Contact   

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

Authors: Allagnat, F  Cunha, D  Moore, F  Vanderwinden, JM  Eizirik, DL  Cardozo, AK 
Citation: Allagnat F, etal., Cell Death Differ. 2011 Feb;18(2):328-37. doi: 10.1038/cdd.2010.105. Epub 2010 Aug 27.
Pubmed: (View Article at PubMed) PMID:20798690
DOI: Full-text: DOI:10.1038/cdd.2010.105

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 antiapoptotic protein of the Bcl-2 family, in beta-cells following exposure to well-defined beta-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 eIF2alpha 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 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 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.

Annotation

Gene Ontology Annotations
Objects Annotated

Additional Information

 
CRRD Object Information
CRRD ID: 11353801
Created: 2016-07-22
Species: All species
Last Modified: 2016-07-22
Status: ACTIVE



NHLBI Logo

RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.