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Elevation of Ser9 phosphorylation of GSK3β is required for HERV-W env-mediated BDNF signaling in human U251 cells.

Elevation of Ser9 phosphorylation of GSK3β is required for HERV-W env-mediated BDNF signaling in human U251 cells.
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Qin C, Li S, Yan Q, Wang X, Chen Y, Zhou P, Lu M, Zhu F,


Qin C, Li S, Yan Q, Wang X, Chen Y, Zhou P, Lu M, Zhu F, (click to view)

Qin C, Li S, Yan Q, Wang X, Chen Y, Zhou P, Lu M, Zhu F,

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Neuroscience letters 2016 05 25627() 84-91 doi 10.1016/j.neulet.2016.05.036

Abstract

Human endogenous retrovirus W family (HERV-W) envelope (env) is known to be associated with neurological and psychiatric disorders, such as multiple sclerosis and schizophrenia. Previous studies showed that overexpression of HERV-W env could induce brain-derived neurotrophic factor (BDNF) gene expression. In human and rat cells, BDNF-mediated signal transduction might be modulated by glycogen synthase kinase 3β (GSK3β). Both BDNF and GSK3β are schizophrenia-related genes. In this paper, we investigated whether GSK3β was involved in the HERV-W env-induced expression of BDNF. We found that HERV-W env increased phosphorylation of GSK3β at Ser9 (p-GSK3β (Ser9)) and the ratio of p-GSK3β (Ser9) to total GSK3β (p<0.05) in U251 cells. Overexpression of HERV-W env led to a 36.2% reduction in GSK3β activity compared to control (p<0.05). The levels of β-catenin, cyclin D1 and TSC2 mRNAs were upregulated (p<0.05). These data suggested that overexpression of HERV-W env might activate the GSK3β signaling pathway in U251 cells. Further, knockdown of GSK3β reduced the expression of total GSK3β, p-GSK3β (Ser9), and the ratio of p-GSK3β (Ser9) to total GSK3β by 28.6%, 50.4%, and 30.2%, respectively (p<0.05). Levels of β-catenin, cyclin D1 and TSC2 mRNAs were also reduced (p<0.05). Interestingly, GSK3β activity increased (p<0.05). Knockdown of GSK3β also decreased mRNA and protein expression of BDNF by 49.9% and 48.5% respectively (p<0.05). These results indicated that phosphorylation of GSK3β at Ser9 might be involved in HERV-W env-induced BDNF expression, and will hopefully improve our understanding of the role of HERV-W env in neurological and psychiatric diseases (schizophrenia, etc).

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