title: Islet beta-cells deficient in Bcl-xL develop but are abnormally sensitive to apoptotic stimuli.
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.
  
  
  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.
authors: Department of Microbiology and Immunology, University of Melbourne, Parkville, Australia.
authors: Emma M
authors: EM
authors: Carrington
authors: Mark D
authors: MD
authors: McKenzie
authors: Elisa
authors: E
authors: Jansen
authors: Michelle
authors: M
authors: Myers
authors: Stacey
authors: S
authors: Fynch
authors: Cameron
authors: C
authors: Kos
authors: Andreas
authors: A
authors: Strasser
authors: Thomas W
authors: TW
authors: Kay
authors: Clare L
authors: CL
authors: Scott
authors: Janette
authors: J
authors: Allison
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D016923:Cell Death; D003433:Crosses, Genetic; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D005260:Female; D006801:Humans; D007328:Insulin / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000502:physiology*; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics; D018345:Mice, Knockout / Q000235:genetics; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051020:bcl-X Protein / Q000172:deficiency* / Q000235:genetics
chemical_list: C494812:Bcl2l1 protein, mouse; D007328:Insulin; D053583:Interleukin-1beta; D051020:bcl-X Protein; D007371:Interferon-gamma