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MAPK kinase kinase-1 is essential for cytokine-induced c-Jun NH2-terminal kinase and nuclear factor-kappaB activation in human pancreatic islet cells
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: Diabetes, ISSN 0012-1797, Vol. 57, no 7, 1896-1904 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: The transcription factor nuclear factor-kappaB (NF-kappaB) and the mitogen-activated protein kinases (MAPKs) c-Jun NH(2)-terminal kinase (JNK) 1/2 are known to play decisive roles in cytokine-induced damage of rodent beta-cells. The upstream events by which these factors are activated in response to cytokines are, however, uncharacterized. The aim of the present investigation was to elucidate a putative role of the MAPK kinase kinase-1 (MEKK-1) in cytokine-induced signaling. RESEARCH DESIGN AND METHODS: To establish a functional role of MEKK-1, the effects of transient MEKK-1 overexpression in betaTC-6 cells, achieved by lipofection and cell sorting, and MEKK-1 downregulation in betaTC-6 cells and human islet cells, achieved by diced-small interfering RNA treatment, were studied. RESULTS: We observed that overexpression of wild-type MEKK-1, but not of a kinase dead MEKK-1 mutant, resulted in potentiation of cytokine-induced JNK activation, inhibitor of kappaB (IkappaB) degradation, and cell death. Downregulation of MEKK-1 in human islet cells provoked opposite effects, i.e., attenuation of cytokine-induced JNK and MKK4 activation, IkappaB stability, and a less pronounced NF-kappaB translocation. betaTC-6 cells with a downregulated MEKK-1 expression displayed also a weaker cytokine-induced iNOS expression and lower cell death rates. Also primary mouse islet cells with downregulated MEKK-1 expression were protected against cytokine-induced cell death. CONCLUSIONS: MEKK-1 mediates cytokine-induced JNK- and NF-kappaB activation, and this event is necessary for iNOS expression and cell death.

Place, publisher, year, edition, pages
2008. Vol. 57, no 7, 1896-1904 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-99812DOI: 10.2337/db07-1670ISI: 000257420000019PubMedID: 18420486OAI: oai:DiVA.org:uu-99812DiVA: diva2:208788
Available from: 2009-03-20 Created: 2009-03-20 Last updated: 2009-10-28Bibliographically approved

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