Inhibition of glycogen synthase kinase 3β suppresses coxsackievirus-induced cytopathic effect and apoptosis via stabilization of β-catenin

被引:53
作者
Yuan, J [1 ]
Zhang, J [1 ]
Wong, BW [1 ]
Si, X [1 ]
Wong, J [1 ]
Yang, D [1 ]
Luo, H [1 ]
机构
[1] Univ British Columbia, James Hogg iCAPTURE Ctr Cardiovasc & Pulm Res, St Pauls Hosp, Dept Pathol & Lab Med, Vancouver, BC V6Z 1Y6, Canada
基金
加拿大健康研究院;
关键词
coxsackievirus; apoptosis; cytopathic effect; GSK3; beta; beta-catenin;
D O I
10.1038/sj.cdd.4401652
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Coxsackievirus B3 (CVB3), a common human pathogen for viral myocarditis, induces a direct cytopathic effect (CPE) and apoptosis on infected cells. To elucidate the mechanisms that contribute to these processes, we studied the role of glycogen synthase kinase 3 beta (GSK3 beta). GSK3 beta activity was significantly increased after CVB3 infection and addition of tyrosine kinase inhibitors blocked CVB3-triggered GSK3 beta activation. Inhibition of caspase activity had no inhibitory effect on CVB3-induced CPE; however, blockage of GSK3 beta activation attenuated both CVB3-induced CPE and apoptosis. We further showed that CVB3 infection resulted in reduced beta-catenin protein expression, and GSK3 beta inhibition led to the accumulation and nuclear translocation of beta-catenin. Finally, we found that CVB3-induced CPE and apoptosis were significantly reduced in cells stably overexpressing beta-catenin. Taken together, our results demonstrate that CVB3 infection stimulates GSK3 beta activity via a tyrosine kinase-dependent mechanism, which contributes to CVB3-induced CPE and apoptosis through dysregulation of beta-catenin.
引用
收藏
页码:1097 / 1106
页数:10
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