PTPN2, a candidate gene for type 1 diabetes, modulates pancreatic ?-cell apoptosis via regulation of the BH3-only protein Bim.

ABSTRACT: 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 ?-cell apoptosis after exposure to type I and II interferons (IFNs), cytokines that contribute to ?-cell loss in early T1D.Small interfering RNAs were used to inhibit PTPN2, STAT1, Bim, and Jun NH(2)-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.PTPN2 knockdown exacerbated type I IFN-induced apoptosis in INS-1E, primary rat, and human ?-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 ?-cells against IFN-induced apoptosis in PTPN2-silenced cells.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 ?-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 ?-cells.

SUBMITTER: Santin I 

PROVIDER: S-EPMC3219938 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature