title: PTPN2, a candidate gene for type 1 diabetes, modulates pancreatic β-cell apoptosis via regulation of the BH3-only protein Bim.
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.
  
  
  METHODS
  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.
  
  
  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.
authors: Laboratory of Experimental Medicine, Université Libre de Bruxelles, Brussels, Belgium.
authors: Izortze
authors: I
authors: Santin
authors: Fabrice
authors: F
authors: Moore
authors: Maikel L
authors: ML
authors: Colli
authors: Esteban N
authors: EN
authors: Gurzov
authors: Lorella
authors: L
authors: Marselli
authors: Piero
authors: P
authors: Marchetti
authors: Decio L
authors: DL
authors: Eizirik
mesh_terms: D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D016898:Interferon-alpha / Q000494:pharmacology; D016899:Interferon-beta / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606778:Bcl2l11 protein, rat; D016898:Interferon-alpha; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; D016899:Interferon-beta; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2