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Overexpression of the NF-κB subunit c-Rel protects against human islet cell death in vitro
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
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Manuscript (Other academic)
Identifiers
URN: urn:nbn:se:uu:diva-97306OAI: oai:DiVA.org:uu-97306DiVA: diva2:172180
Available from: 2008-05-12 Created: 2008-05-12 Last updated: 2010-01-13Bibliographically approved
In thesis
1. MEKK-1 and NF-κB Signaling in Pancreatic Islet Cell Death
Open this publication in new window or tab >>MEKK-1 and NF-κB Signaling in Pancreatic Islet Cell Death
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 1 diabetes is an autoimmune disease resulting in the selective destruction of the insulin producing β-cells in the pancreas. Pro-inflammatory cytokines and the free radical nitric oxide (NO) have been implicated in mediating the destruction of β-cells, possibly through activation of the mitogen activated protein kinases (MAPKs) JNK, ERK and p38. In addition to MAPKs, cytokine signaling also results in activation of the transcription factor nuclear factor-kappaB (NF-κB). The upstream signaling events leading to MAPK and NF-κB activation in β-cells are not well known. The work presented in this thesis therefore aims at characterizing the regulation of MAPKs and NF-κB in human islets, with emphasis on the role of the MAPK activator MAP/ERK kinase kinase-1 (MEKK-1) in islet cell death.

It was found that MEKK-1 was phosphorylated in response to the nitric oxide donor DETA/NONOate (DETA/NO), the β-cell toxin streptozotocin (STZ) and pro-inflammatory cytokines and that MEKK-1 downstream signaling in response to the same treatments involved activation of JNK but not ERK and p38. MEKK-1 was also found to be essential for cytokine-induced NF-κB activation. MEKK-1 downregulation protected human islet cells from DETA/NO-, STZ, and cytokine-induced cell death. Furthermore, overexpression of the NF-κB subunit c-Rel protected human islet cells from STZ and hydrogen peroxide-induced cell death indicating that NF-κB activity protects against cell death in human islets. In summary, these results support an essential role for MEKK-1 in the activation of JNK and NF-κB, with important consequences for human islet cell death and that strategies preventing human islets death by inhibition of the JNK pathway instead of NF-κB might be suitable.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 43 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 360
Keyword
Cell biology, MEKK-1, JNK, human islets, β-cells, siRNA, apoptosis, cell death, MAPK, nitric oxide, cytokines, streptozotocin, c-Rel, NF-κB, Cellbiologi
Identifiers
urn:nbn:se:uu:diva-8896 (URN)978-91-554-7222-1 (ISBN)
Public defence
2008-06-03, C2:301, BMC, Husargatan 3, Uppsala, 13:15 (English)
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Available from: 2008-05-12 Created: 2008-05-12 Last updated: 2009-09-04Bibliographically approved

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