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The proapoptotic BH3-only proteins Bim and Puma are downstream of endoplasmic reticulum and mitochondrial oxidative stress in pancreatic islets in response to glucotoxicity.
- Source :
-
Cell death & disease [Cell Death Dis] 2014 Mar 13; Vol. 5, pp. e1124. Date of Electronic Publication: 2014 Mar 13. - Publication Year :
- 2014
-
Abstract
- Apoptosis of pancreatic beta cells is a feature of type 2 diabetes and its prevention may have therapeutic benefit. High glucose concentrations induce apoptosis of islet cells, and this requires the proapoptotic Bcl-2 homology domain 3 (BH3)-only proteins Bim and Puma. We studied the stress pathways induced by glucotoxicity in beta cells that result in apoptosis. High concentrations of glucose or ribose increased expression of the transcription factor CHOP (C/EBP homologous protein) but not endoplasmic reticulum (ER) chaperones, indicating activation of proapoptotic ER stress signaling. Inhibition of ER stress prevented ribose-induced upregulation of Chop and Puma mRNA, and partially protected islets from glucotoxicity. Loss of Bim or Puma partially protected islets from the canonical ER stressor thapsigargin. The antioxidant N-acetyl-cysteine also partially protected islets from glucotoxicity. Islets deficient in both Bim and Puma, but not Bim or Puma alone, were significantly protected from killing induced by the mitochondrial reactive oxygen species donor rotenone. Our data demonstrate that high concentrations of glucose induce ER and oxidative stress, which causes cell death mediated by Bim and Puma. We observed significantly higher Bim and Puma mRNA in islets of human donors with type 2 diabetes. This indicates that inhibition of Bim and Puma, or their inducers, may prevent beta-cell destruction in type 2 diabetes.
- Subjects :
- Animals
Antioxidants pharmacology
Apoptosis Regulatory Proteins deficiency
Apoptosis Regulatory Proteins genetics
Bcl-2-Like Protein 11
Cell Line
Diabetes Mellitus, Type 2 metabolism
Diabetes Mellitus, Type 2 pathology
Endoplasmic Reticulum drug effects
Endoplasmic Reticulum pathology
Humans
Insulin-Secreting Cells metabolism
Insulin-Secreting Cells pathology
Islets of Langerhans drug effects
Islets of Langerhans pathology
Membrane Proteins deficiency
Membrane Proteins genetics
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Mitochondria drug effects
Mitochondria pathology
Oxidants pharmacology
Proto-Oncogene Proteins deficiency
Proto-Oncogene Proteins genetics
RNA, Messenger metabolism
Ribose metabolism
Tissue Culture Techniques
Transcription Factor CHOP deficiency
Transcription Factor CHOP genetics
Tumor Suppressor Proteins deficiency
Tumor Suppressor Proteins genetics
Apoptosis drug effects
Apoptosis Regulatory Proteins metabolism
Endoplasmic Reticulum metabolism
Endoplasmic Reticulum Stress drug effects
Glucose metabolism
Islets of Langerhans metabolism
Membrane Proteins metabolism
Mitochondria metabolism
Oxidative Stress drug effects
Proto-Oncogene Proteins metabolism
Tumor Suppressor Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 5
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 24625983
- Full Text :
- https://doi.org/10.1038/cddis.2014.88