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Possible role of β-cell NFκB activation and anti-apoptotic preconditioning in Gleevec-mediated protection against diabetes.
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
In: FASEB Journal, ISSN 1530-8660Article in journal (Refereed) In press
URN: urn:nbn:se:uu:diva-94677OAI: oai:DiVA.org:uu-94677DiVA: diva2:168622
Available from: 2006-09-05 Created: 2006-09-05 Last updated: 2010-01-14Bibliographically approved
In thesis
1. Anti-Diabetic and Beta-Cell Protective Actions of Imatinib Mesylate
Open this publication in new window or tab >>Anti-Diabetic and Beta-Cell Protective Actions of Imatinib Mesylate
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 1 diabetes is a disease resulting from the progressive immune-mediated destruction of insulin producing β-cells. In order to understand more about diabetes we need to understand the mechanisms governing β-cell death.

The leukemia drug Gleevec is a tyrosine kinase inhibitor that targets c-Abl. Surprisingly, Gleevec also counteracts Type 2 diabetes and acts as a cell death inhibiting agent, via inhibition c-Abl. Since both Type 1 and Type 2 diabetes are characterized by an increased β-cell death, and the role of c-Abl is unknown in β-cells, we wanted to investigate the following:

1.Does Gleevec act via inhibition of c-Abl in β-cells?

2.Can Gleevec treatment prevent beta-cell death and diabetes?

3.Which downstream signaling pathways are affected by Gleevec?

In paper I, in order to determine whether Gleevec acts by inhibiting c-Abl, we used RNA-interference. Interestingly, siRNA against c-Abl produced by recombinant Dicer mediate almost complete and non-toxic silencing of c-Abl mRNA in dispersed islet cells and conferred protection from streptozotocin and cytokines.

In paper II we show that Gleevec protects β-cells from nitric oxide, pro-inflammatory cytokines and streptozotocin in vitro and that Gleevec can prevent diabetes development in the NOD mouse and the streptozotocin-injected mouse. We also present the hypothesis that Gleevec induces a state resembling ischemic preconditioning.

Paper III presents an additional mechanism by which Gleevec might improve β-cell survival, i.e. via the inhibition of the downstream stress-activated protein kinase c-Jun N-terminal kinase (JNK), the activity of which has been implicated in β-cell death signaling pathways.

In paper IV we explore the interactions between the adaptor protein Shb and c-Abl. We presently show an association between Shb-c-Abl and that Shb is a substrate for the c-Abl kinase that might regulate stress-induced c-Abl activity.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 58 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 160
Cell biology, Cellbiologi, Diabetes
urn:nbn:se:uu:diva-7078 (URN)91-554-6615-X (ISBN)
Public defence
2006-09-26, B21, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2006-09-05 Created: 2006-09-05Bibliographically approved

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