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MEKK-1 and NF-κB Si...
MEKK-1 and NF-κB Signaling in Pancreatic Islet Cell Death
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- Mokhtari, Dariush, 1977- (författare)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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Welsh, Nils (preses)
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Welsh, Michael (preses)
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Tengholm, Anders (preses)
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- Persaud, Shanta, Dr (opponent)
- Div.of Reproduction and Endocrinology, King's College, London
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(creator_code:org_t)
- ISBN 9789155472221
- Uppsala : Acta Universitatis Upsaliensis, 2008
- Engelska 43 s.
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Serie: Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 ; 360
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https://uu.diva-port...
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https://urn.kb.se/re...
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Abstract
Ämnesord
Stäng
- 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.
Nyckelord
- Cell biology
- MEKK-1
- JNK
- human islets
- β-cells
- siRNA
- apoptosis
- cell death
- MAPK
- nitric oxide
- cytokines
- streptozotocin
- c-Rel
- NF-κB
- Cellbiologi
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