Title |
Increased Cytokine-Induced Cytotoxicity of Pancreatic Islet Cells from Transgenic Mice Expressing the Src-like Tyrosine Kinase GTK
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Published in |
Molecular Medicine, May 2001
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DOI | 10.1007/bf03402213 |
Pubmed ID | |
Authors |
Cecilia Annerén, Michael Welsh |
Abstract |
The loss of beta cells in type 1 diabetes may involve protein kinases because they control cell growth, differentiation, and survival. Previous studies have revealed that GTK, a Src-like protein tyrosine kinase expressed in beta cells (also named Bsk/Iyk), regulates multiple responses including growth and survival of rat insulinoma cells (RINm5F) and differentiation of neuronal PC12 cells. In the present study, we have generated a transgenic mouse expressing a kinase active GTK mutant (GTK-Y504F) under the control of the rat insulin I promoter to establish a role of GTK in beta cells. Control and GTK-transgenic CBA mice were used for determination of in vivo glucose tolerance and the relative insulin-positive area. Isolated islets from both groups were cultured in the absence and presence of cytokines and insulin secretion, viability and protein expression were assessed. The beta-cell mass of GTK-transgenic mice was increased as a consequence of a larger pancreas and an increased relative beta-cell area. Islets isolated from the transgenic animals exhibited an enhanced glucose-induced insulin release and reduced viability in response to cytokines that could not be explained by higher levels of nitric oxide (NO) compared with control islets. Extracellular signal-regulated kinase (ERK) 1/2, p38 mitogen-activated protein kinase (MAPK), c-Jun NH2-terminal kinase (JNK), and Akt were all activated by cytokines, but GTK-transgenic islets contained higher basal levels of phosphorylated ERK1/2 and lower basal levels of phosphorylated p38 compared with the control islets. The total amount of activated MAPKs was, however, higher in the cytokine-stimulated transgenic islets compared with the control islets due to increased levels of phospho-ERK1/2. Moreover, the proline-rich tyrosine kinase (PYK) 2 (also named RAFTK/CAK beta/CADTK) levels were elevated in response to a 24-hr exposure to cytokines in control islets but not in the GTK-transgenic islets. These results suggest that although GTK increases the beta-cell mass, it also enhances islet cell death in response to cytokines and may thus be involved in the beta-cell damage in type 1 diabetes. |
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Researcher | 2 | 25% |
Professor | 1 | 13% |
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Professor > Associate Professor | 1 | 13% |
Other | 0 | 0% |
Unknown | 1 | 13% |
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Other | 0 | 0% |
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