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- Title
PTPN2, a Candidate Gene for Type 1 Diabetes, Modulates Pancreatic β-Cell Apoptosis via Regulation of the BH3-Only Protein Bim.
- Authors
Santin, Izortze; Moore, Fabrice; Colli, Maikel L.; Gurzov, Esteban N.; Marselli, Lorella; Marchetti, Piero; Eizirik, Decio L.
- Abstract
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 β-cell apoptosis after exposure to type I and II interferons (IFNs), cytokines that contribute to β-cell loss in early T1D. RESEARCH DESIGN ANDMETHODS--Small interfering RNAs were used to inhibit PTPN2, STAT1, Bim, and Jun NH2-terminal kinase 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 β-cells. PTPN2 silencing and exposure to type I and II 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 β-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 β-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 β-cells.
- Subjects
TREATMENT of diabetes; ANTIVIRAL agents; CARBOHYDRATE intolerance; APOPTOSIS; CYTOCHROME c
- Publication
Diabetes, 2011, Vol 60, Issue 12, p3279
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db11-0758