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      Fibrillogenic amylin evokes islet beta-cell apoptosis through linked activation of a caspase cascade and JNK1.

      The Journal of Biological Chemistry
      Amyloid, chemistry, Animals, Apoptosis, Blotting, Western, Caspase 1, metabolism, Caspase 3, Caspase 8, Caspases, Cell Line, Tumor, Enzyme Activation, Enzyme Inhibitors, pharmacology, Enzyme-Linked Immunosorbent Assay, Fibrin, Humans, Immunohistochemistry, Insulinoma, Islet Amyloid Polypeptide, Islets of Langerhans, pathology, Mitogen-Activated Protein Kinase 8, Mitogen-Activated Protein Kinases, Peptides, Protein Structure, Secondary, Protein Structure, Tertiary, Rats, Time Factors

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          Abstract

          Fibrillogenic human amylin elicits pancreatic beta-cell apoptosis that may contribute to development of type-2 diabetes. Here, we demonstrated that activation of a caspase cascade is necessary for induction of apoptosis by fibrillogenic amylin variants in two pancreatic beta-cell lines. Human amylin, as well as truncated 8-37human amylin, evoked sequential activation of caspases-8 and -3, and apoptosis, whereas non-beta-sheet forming and non-fibrillogenic homologs, such as [25,28,29triprolyl]human amylin, did not, implying that the beta-sheet conformer is required for human amylin-induced caspase activation. Significant inhibition of apoptosis was evoked by a selective caspase-1 inhibitor, indicating that caspase-1 is also essential for activation of the caspase cascade. Furthermore, we showed that specific jnk1 antisense oligonucleotides, which suppress phospho-JNK1 expression, effectively decreased human amylin-induced activation of c-Jun. Studies of the interplay between the caspase cascade and the JNK pathway showed that both apoptosis and caspase-3 activation were suppressed by treatment with a JNK inhibitor and by transfection of antisense jnk1 oligonucleotides or antisense-c-jun, whereas a selective inhibitor of caspases-1 and -3 prevented apoptosis but not c-Jun activation. Thus, the JNK1 activation preceded activation of caspases-1 and -3. However, selective JNK inhibition had no effect on caspase-8 activation, and selective caspase-8 inhibition only partially suppressed apoptosis and c-Jun activation, indicating that caspase-8 may partially act upstream of the JNK pathway. Our studies demonstrate a functional interaction of a caspase cascade and JNK1. Fibrillogenic amylin can evoke a JNK1-mediated apoptotic pathway, which is partially dependent and partially independent of caspase-8, and in which caspase-3 acts as a common downstream effector.

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