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The MAPK kinase kinase-1 is essential for stress-induced pancreatic islet cell death
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
2008 (English)In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 149, no 6, 3046-3053 p.Article in journal (Refereed) Published
Abstract [en]

The aim of the present investigation was to characterize the role of the MAPK kinase kinase-1 (MEKK-1) in stress-induced cell death of insulin producing cells. We observed that transient overexpression of the wild type MEKK-1 protein in the insulin-producing cell lines RIN-5AH and betaTC-6 increased c-Jun N-terminal kinase (JNK) phosphorylation and augmented cell death induced by diethylenetriamine/nitroso-1-propylhydrazino)-1-propanamine (DETA/NO), streptozotocin (STZ), and hydrogen peroxide (H2O2). Furthermore, DETA/NO or STZ induced a rapid threonine phosphorylation of MEKK-1. Silencing of MEKK-1 gene expression in betaTC-6 and human dispersed islet cells, using in vitro-generated diced small interfering RNA, resulted in protection from DETA/NO, STZ, H2O2, and tunicamycin induced cell death. Moreover, in DETA/NO-treated cells diced small interfering RNA-mediated down-regulation of MEKK-1 resulted in decreased activation of JNK but not p38 and ERK. Inhibition of JNK by treatment with SP600125 partially protected against DETA/NO- or STZ-induced cell death. In summary, our results support an essential role for MEKK-1 in JNK activation and stress-induced beta-cell death. Increased understanding of the signaling pathways that augment or diminish beta-cell MEKK-1 activity may aid in the generation of novel therapeutic strategies in the treatment of type 1 diabetes.

Place, publisher, year, edition, pages
2008. Vol. 149, no 6, 3046-3053 p.
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Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-99813DOI: 10.1210/en.2007-0438ISI: 000256053100042PubMedID: 18308848OAI: oai:DiVA.org:uu-99813DiVA: diva2:208789
Available from: 2009-03-20 Created: 2009-03-20 Last updated: 2017-12-13Bibliographically approved

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