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TAB1 alpha, but not TAB1 beta, mediates cytokine-induced p38 MAPK-autophosphorylation and cell death in insulin-producing cells
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-93970OAI: oai:DiVA.org:uu-93970DiVA: diva2:167635
Available from: 2006-01-27 Created: 2006-01-27 Last updated: 2010-01-13Bibliographically approved
In thesis
1. Role of MAP Kinases in the Life and Death of Beta-cells
Open this publication in new window or tab >>Role of MAP Kinases in the Life and Death of Beta-cells
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The development of diabetes mellitus depends on the balance between beta-cell proliferation and death. As mitogen-activated protein kinases (MAPK) may control this balance, the aim of this study was to investigate the events leading to MAPK activation in beta-cells and the consequences of these events. Overexpression of the SH2-domain containing adaptor protein Shb resulted in the assembly and activation of multiunit complex consisting of at least Shb, IRS-1, IRS-2, FAK and PI3K. Consequently, the phosphorylation of Akt was enhanced under basal conditions in Shb overexpression cells. This was paralleled by an attenuated activation of the MAP kinases ERK1/2. Thus, Shb-induced alterations in the IRS-1/PI3K/Akt/ERK pathway might explain the increased proliferation and apoptosis of beta-cells overexpressing Shb.

The importance of the MAP kinase p38 in nitric oxide- and cytokine-induced beta-cell death was also investigated. Knock-down of p38 expression resulted in a lowered cell death rate in response to a nitric oxide donor. In transient transfections MKK3 over-expression resulted in increased p38 phosphorylation in RIN-5AH cells. In addition, a short-term MKK3 expression resulted in increased cytokine-induced cell death. A nitric oxide synthase inhibitor abolished the MKK3-potentiating effect on cytokine-induced cell death and inhibitors of phosphatases enhanced MKK3-stimulated p38 phosphorylation. Finally, as the dominant negative mutant of MKK3 did not affect cytokine-induced p38 phosphorylation, and as wild type MKK3 did not influence p38 autophosphorylation, it may be that p38 is activated by MKK3/6-independent pathways in response to cytokines and nitric oxide.

In further support for an MKK3/6-indepedent mechanism, the adaptor protein TAB1 significantly increased the cytokine- and nitric oxide-stimulated phosphorylation of p38. The TAB1-mediated activation of p38 was paralleled by a compensatory inhibition of ERK and JNK. In summary, p38 MAPK, activated mainly by TAB1, promotes, at least in part, beta-cell death in response to cytokines or nitric oxide.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 70 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 102
Cell biology, diabetes, beta-cell, p38 MAPK, nitric oxide, apoptosis, Cellbiologi
National Category
Cell and Molecular Biology
urn:nbn:se:uu:diva-6317 (URN)91-554-6450-5 (ISBN)
Public defence
2006-02-21, Room B21, BMC, Husargatan 3, Uppsala, 13:15
Available from: 2006-01-27 Created: 2006-01-27Bibliographically approved

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