Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 285, Issue 26, Pages 19910-19920Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.122374
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Funding
- Communaute Francaise de Belgique
- Actions de Recherche Concertees
- National de la Recherche Scientifique Belgium
- Fonds National de la Recherche Scientifique Belgium
- Belgium Program on Interuniversity Poles of Attraction initiated by the Belgium State [IUAP P6/40]
- Juvenile Diabetes Research Foundation [17-2009-106]
- European Union
- European Community
- Naimit
- Belgian Federal Science Policy Office
- European Molecular Biology Organization (EMBO)
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Type 1 diabetes is an autoimmune disorder characterized by chronic inflammation and pancreatic beta-cell loss. Here, we demonstrate that the proinflammatory cytokine interleukin-1 beta, combined with interferon-gamma, induces the expression of the Bcl-2 homology 3 ( BH3)-only activator PUMA (p53 up-regulated modulator of apoptosis) in beta-cells. Transcriptional activation of PUMA is regulated by nuclear factor-kappa B and endoplasmic reticulum stress but is independent of p53. PUMA activation leads to mitochondrial Bax translocation, cytochrome c release, and caspase-3 cleavage resulting in beta-cell demise. The antiapoptotic Bcl-XL protein is localized mainly at the mitochondria of the beta-cells and antagonizes PUMA action, but Bcl-XL is inactivated by the BH3-only sensitizer DP5/Hrk in cytokine-exposed beta-cells. Moreover, a pharmacological mimic of the BH3-only sensitizer Bad, which inhibits Bcl-XL and Bcl-2, induces PUMA-dependent beta-cell death and potentiates cytokine-induced apoptosis. Our data support a hierarchical activation of BH3-only proteins controlling the intrinsic pathway of beta-cell apoptosis in the context of inflammation and type 1 diabetes.
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