期刊
BRAIN RESEARCH
卷 1190, 期 -, 页码 206-214出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.brainres.2007.11.011
关键词
glia maturation factor (GMF); Neuroblastoma (N18) cell; Glycogen synthase kinase-3 beta (GSK-3 beta); Caspase-3; Alzheimer's disease (AD)
资金
- NINDS NIH HHS [NS-47145, R01 NS047145, R01 NS047145-02, R01 NS047145-01A1, R01 NS047145-03, R01 NS047145-04] Funding Source: Medline
- BLRD VA [I01 BX002477] Funding Source: Medline
In the present study we report that a replication-defective adenovirus construct of GMF cDNA (GMF-V) induced overexpression of GMF protein in neuroblastoma (N18) cells caused cytotoxicity and loss of cell viability. A significant increase in activation of GSK-3 beta occurred after infection with GMF-V when compared with mock and lacZ controls. Overexpression of GMF also increased caspase-3 activity, an early marker of apoptosis. Depletion of GMF gene by introducing GMF-specific siRNA (GsiRNA) completely blocked both activation of GSK-3 beta and caspase-3 activation whereas a control scrambled siRNA (CsiRNA) had no effect. A cell-permeable peptide inhibitor of GSK-3 beta, and lithium completely prevented GMF-dependent activation of caspase-3. These results demonstrate that GSK-3 mediates activation of the death domain caspase by GMF overexpression. We also show that the phosphorylation of GSK-3-dependent site of Tau was a consequence of GMF-overexpression in N18 cells. Taken together our results imply that GMF is involved in the signaling leading to the activation of GSK-3 beta and caspase-3 in N18 cells and strongly suggest its involvement in neurodegeneration since GSK-3 beta is known to hyperphosphorylate tau which is associated with the neurotoxicity of neurofibrillary tangles in Alzheimer's disease. (c) 2007 Elsevier B.V. All rights reserved.
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