Proapoptotic BH3-only protein bid is essential for death receptor-induced apoptosis of pancreatic beta-cells
Details
Publication Year 2008-05, Volume 57, Issue #5, Page 1284-1292
Journal Title
DIABETES
Publication Type
Journal Article
Abstract
OBJECTIVE-Apoptosis of pancreatic P-cells is critical in both diabetes development and failure of islet transplantation. The role in these processes of pro- and antiapoptotic Bcl-2 family proteins, which regulate apoptosis by controlling mitochondrial integrity, remains poorly understood. We investigated the role of the BH3-only protein Bid and the multi-BH domain proapoptotic Bax and Bak, as well as prosurvival Bcl-2, in beta-cell apoptosis. RESEARCH DESIGN AND METHODS-We isolated islets from mice lacking Bid, Bax, or Bak and those overexpressing Bcl-2 and exposed them to Fas ligand, tumor necrosis factor (TNF)-alpha, and proinflammatory cytokines or cytotoxic stimuli that activate the mitochondrial apoptotic pathway (staurosporine, etoposide, gamma-radiation, tunicamycin, and thapsigargin). Nuclear fragmentation was measured by flow cytometry. RESULTS-Development and function of islets were not affected by loss of Bid, and Bid-deficient islets were as susceptible as wild-type islets to cytotoxic stimuli that cause apoptosis via the mitochondrial pathway. In contrast, Bid-deficient islets and those overexpressing antiapoptotic Bcl-2 were protected from Fas ligand-induced apoptosis. Bid-deficient islets were also resistant to apoptosis induced by TNF-alpha plus cycloheximide and were partially resistant to proinflammatory cytokine-induced death. Loss of the multi-BH domain proapoptotic Bax or Bak protected islets partially from death receptor-induced apoptosis. CONCLUSIONS-These results demonstrate that Bid is essential for death receptor-induced apoptosis of islets, similar to its demonstrated role in hepatocytes. This indicates that blocking Bid activity may be useful for protection of islets from immune-mediated attack and possibly also in other pathological states in which beta-cells are destroyed.
Publisher
AMER DIABETES ASSOC
Keywords
CYTOCHROME-C RELEASE; DNA-DAMAGE RESPONSE; NONOBESE DIABETIC MICE; ANTI-FAS ANTIBODY; IMMUNE-SYSTEM; CASPASE ACTIVATION; DEFICIENT MICE; BCL-2 FAMILY; STRESS; BAX
Publisher's Version
https://doi.org/10.2337/db07-1692
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2008-05-01 12:00:00
Last Modified: 0001-01-01 12:00:00
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