Mcl-1 downregulation by pro-inflammatory cytokines and palmitate is an early event contributing to β-cell apoptosis
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| Title: | Mcl-1 downregulation by pro-inflammatory cytokines and palmitate is an early event contributing to β-cell apoptosis |
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| Authors: | Allagnat, Florent, Andrade Da Cunha, Daniel, Moore, F, Vanderwinden, J M, Eizirik, Decio L., Cardozo, Alessandra K |
| Contributors: | Peer, Hal |
| Source: | Cell Death and Differentiation |
| Publisher Information: | Springer Science and Business Media LLC, 2010. |
| Publication Year: | 2010 |
| Subject Terms: | 0301 basic medicine, pancreatic β-cells, bcl-X Protein -- metabolism, Palmitates, bcl-X Protein, Down-Regulation, Apoptosis, Cytokines -- pharmacology, Endoplasmic Reticulum, Cell Line, 03 medical and health sciences, Cell Line, Tumor, Insulin-Secreting Cells, eIF2a, Animals, Insulin-Secreting Cells -- cytology -- metabolism, RNA, Small Interfering, bcl-2-Associated X Protein, 0303 health sciences, Tumor, diabetes, Cytochromes c -- metabolism, Palmitates -- pharmacology, Caspase 3, Endoplasmic Reticulum -- metabolism, apoptosis, Caspase 3 -- metabolism, Proto-Oncogene Proteins c-bcl-2 -- genetics -- metabolism, Mcl-1, Cytochromes c, Sciences bio-médicales et agricoles, bcl-2-Associated X Protein -- metabolism, Small Interfering -- metabolism, Rats, 3. Good health, Proto-Oncogene Proteins c-bcl-2, Thapsigargin -- pharmacology, pancreatic beta cell, RNA, Cytokines, Myeloid Cell Leukemia Sequence 1 Protein, Thapsigargin, RNA Interference, JNK, ER stress |
| Description: | 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. |
| Document Type: | Article Other literature type |
| File Description: | application/pdf; 1 full-text file(s): application/pdf |
| Language: | English |
| ISSN: | 1476-5403 1350-9047 |
| DOI: | 10.1038/cdd.2010.105 |
| Access URL: | https://www.nature.com/articles/cdd2010105.pdf https://pubmed.ncbi.nlm.nih.gov/20798690 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131897/ http://europepmc.org/articles/PMC3131897 https://difusion.ulb.ac.be/vufind/Record/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/136892/Details http://www.readcube.com/articles/10.1038/cdd.2010.105 https://www.nature.com/articles/cdd2010105.pdf https://www.nature.com/articles/cdd2010105 |
| Rights: | Springer TDM |
| Accession Number: | edsair.doi.dedup.....dd55fa58919b2c05611458f96b749b4a |
| Database: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstract: | 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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| ISSN: | 14765403 13509047 |
| DOI: | 10.1038/cdd.2010.105 |