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J. Biol. Chem., Vol. 278, Issue 52, 52810-52819, December 26, 2003

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Fibrillogenic Amylin Evokes Islet -Cell Apoptosis through Linked Activation of a Caspase Cascade and JNK1^*

Shaoping Zhang, Junxi Liu, Michael Dragunow, and Garth J. S. Cooper¶

From the School of Biological Sciences, Faculty of Science and Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, 3 Symonds St., Level 4.1, Private Bag 92019, Auckland, New Zealand

Fibrillogenic human amylin elicits pancreatic -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 -cell lines. Human amylin, as well as truncated ^8–37human amylin, evoked sequential activation of caspases-8 and -3, and apoptosis, whereas non--sheet forming and non-fibrillogenic homologs, such as [^25,28,29triprolyl]human amylin, did not, implying that the -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.

Received for publication, July 29, 2003 , and in revised form, October 1, 2003.

^* This work was supported by the Endocore Research Trust, the Maurice & Phyllis Paykel Trust, and the New Zealand Lottery Grants Board, and by a New Zealand Health Research Council grant (to M. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Tel.: 64-9-373-7599 (ext. 87239); Fax: 64-9-373-7045; E-mail: g.cooper{at}auckland.ac.nz.

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