Fas-associated Death Receptor Signalling Evoked by Human Amylin in Islet B-cells

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dc.contributor.author Zhang, Shaoping en
dc.contributor.author Liu, Hong en
dc.contributor.author Yu, H en
dc.contributor.author Cooper, Garth en
dc.date.accessioned 2012-03-11T23:03:54Z en
dc.date.issued 2008 en
dc.identifier.citation Diabetes 57(2):348-356 Feb 2008 en
dc.identifier.issn 0012-1797 en
dc.identifier.uri http://hdl.handle.net/2292/13752 en
dc.description.abstract OBJECTIVE--Aggregation of human amylin (hA) into [beta]-sheet-containing oligomers is linked to islet [beta]-cell dysfunction and the pathogenesis of type 2 diabetes. Here, we investigated possible contributions of Fas-associated death-receptor signaling to the mechanism of hA-evoked [beta]-cell apoptosis. RESEARCH DESIGN AND METHODS--We measured responses to hA in isolated mouse islets and two insulinoma cell lines, wherein we measured Fas/Fas ligand (FasL) and Fas-associated death domain (FADD) expression by quantitative RT-PCR, Western blotting, and immunofluorescence staining. We used two anti-Fas/FasL blocking antibodies and the Fas/FasL antagonist Kp7-6 to probe roles of Fas interactions in the regulation of apoptosis in hA-treated [beta]-cells and measured Kp7-6-mediated effects on [beta]-sheet formation and aggregation using circular dichroism and thioflavin-T binding. RESULTS--hA treatment stimulated Fas and FADD expression in [beta]-cells. Both blocking antibodies suppressed hA-evoked apoptosis but did not modify its aggregation. Therefore, Fas receptor interactions played a critical role in induction of this pathway. Interestingly, hA-evoked [beta]-cell apoptosis was suppressed and rescued by Kp7-6, which also impaired hA [beta]-sheet formation. CONCLUSIONS--This is the first report linking hA-evoked induction and activation of Fas and FADD to [beta]-cell apoptosis. We have identified a Fas/FasL antagonist, Kp7-6, as a potent inhibitor of hA aggregation and related [beta]-cell death. These results also support an interaction between hA and Fas on the surface of apoptotic [beta]-cells. Increased expression and activation of Fas in [beta]-cells could constitute a molecular event common to the pathogenesis of both type 1 and type 2 diabetes, although the mode of pathway activation may differ between these common forms of diabetes. en
dc.publisher American Diabetes Association en
dc.relation.ispartofseries Diabetes en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. Details obtained from http://www.sherpa.ac.uk/romeo/issn/0012-1797/ en
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm en
dc.title Fas-associated Death Receptor Signalling Evoked by Human Amylin in Islet B-cells en
dc.type Journal Article en
dc.identifier.doi 10.2337/db07-0849 en
pubs.begin-page 348 en
pubs.volume 57 en
dc.rights.holder Copyright: American Diabetes Association en
dc.identifier.pmid 17977957 en
pubs.end-page 356 en
dc.rights.accessrights http://purl.org/eprint/accessRights/RestrictedAccess en
pubs.subtype Article en
pubs.elements-id 92772 en
pubs.org-id Science en
pubs.org-id Biological Sciences en
pubs.org-id Science Research en
pubs.org-id Maurice Wilkins Centre (2010-2014) en
dc.identifier.eissn 1939-327X en
pubs.record-created-at-source-date 2010-09-01 en
pubs.dimensions-id 17977957 en

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