Journal
DIABETES
Volume 60, Issue 12, Pages 3279-3288Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db11-0758
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Funding
- Communaute Francaise de Belgique-Actions de Recherche Concertees, Fonds National de la Recherche Scientifique, Belgium
- Belgium Program on Interuniversity Poles of Attraction initiated by the Belgium State [IUAP P6/40]
- European Union
- Education Department of the Basque Country
- Fonds National de la Recherche Scientifique, Belgium
- EMBO
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OBJECTIVE-Genome-wide association studies allowed the identification of several associations between specific loci and type 1 diabetes (T1D). However, the mechanisms by which most candidate genes predispose to T1D remain unclear. We presently evaluated the mechanisms by which PTPN2, a candidate gene for T1D, modulates beta-cell apoptosis after exposure to type I and II interferons (IFNs), cytokines that contribute to beta-cell loss in early T1D. RESEARCH DESIGN AND METHODS-Small interfering RNAs were used to inhibit PTPN2, STAT1, Bim, and Jun NH2-terminal lcinase 1 (JNK1) expression. Cell death was assessed by Hoechst and propidium iodide staining. BAX translocation, Bim phosphorylation, cytochrome c release, and caspases 9 and 3 activation were measured by Western blot or immunofluorescence. RESULTS-PTPN2 knockdown exacerbated type I IFN-induced apoptosis in INS-1E, primary rat, and human beta-cells. PTPN2 silencing and exposure to type I and H IFNs induced BAX translocation to the mitochondria, cytochrome c release, and caspase 3 activation. There was also an increase in Bim phosphorylation that was at least in part regulated by JNK1. Of note, both Bim and JNK1 knockdown protected beta-cells against IFN-induced apoptosis in PTPN2-silenced cells. CONCLUSIONS-The present findings suggest that local IFN production may interact with a genetic factor (PTPN2) to induce aberrant proapoptotic activity of the BH3-only protein Bim, resulting in increased beta-cell apoptosis via JNK activation and the intrinsic apoptotic pathway. This is the first indication of a direct interaction between a candidate gene for T1D and the activation of a specific downstream proapoptotic pathway in beta-cells. Diabetes 60:3279-3288, 2011
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