Islet beta-Cells Deficient in Bcl-xL Develop but Are Abnormally Sensitive to Apoptotic Stimuli
Details
Publication Year 2009-10, Volume 58, Issue #10, Page 2316-2323
Journal Title
DIABETES
Publication Type
Journal Article
Abstract
OBJECTIVE-Bcl-xL is an antiapoptotic member of the Bcl-2 family of proteins and a potent regulator of cell death. We investigated the importance of Bcl-xL for beta-cells by deleting the Bcl-x gene specifically in beta-cells and analyzing their survival in vivo and in culture. RESEARCH DESIGN AND METHODS-Islets with beta-cells lacking the Bcl-x gene were assessed in vivo by histology and by treatment of mice with low-dose streptozotocin (STZ). Islets were isolated by collagenase digestion and treated in culture with the apoptosis inducers staurosporine, thapsigargin, gamma-irradiation, proinflammatory cytokines, or Fas ligand. Cell death was assessed by flow cytometric analysis of subgenomic DNA. RESULTS-Bcl-xL-deficient beta-cells developed but were abnormally sensitive to apoptosis induced in vivo by low-dose STZ. Although a small proportion of beta-cells still expressed Bcl-xL, these did not have a survival advantage over their Bcl-xL-deficient neighbors. Islets appeared normal after collagenase isolation and whole-islet culture. They were, however, abnormally sensitive in culture to a number of different apoptotic stimuli including cytotoxic drugs, proinflammatory cytokines, and Fas ligand. CONCLUSIONS-Bcl-xL expression in beta-cells is dispensible during islet development in the mouse. Bcl-xL is, however, an important regulator of beta-cell death under conditions of synchronous stress. Bcl-xL expression at physiological levels may partially protect beta-cells from apoptotic stimuli, including apoptosis because of mediators implicated in type 1 diabetes and death or degeneration of transplanted islets. Diabetes 58:2316-2323, 2009
Publisher
AMER DIABETES ASSOC
Keywords
ENDOPLASMIC-RETICULUM STRESS; NONOBESE DIABETIC MICE; IMMUNOHISTOCHEMICAL ANALYSIS; CONDITIONAL DELETION; BH3-ONLY PROTEINS; TRANSGENIC MICE; IN-VIVO; DEATH; GENE; MOUSE
Publisher's Version
https://doi.org/10.2337/db08-1602
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2009-10-01 12:00:00
Last Modified: 0001-01-01 12:00:00
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