A role for glycogen synthase kinase-3β in the mammalian circadian clock
A role for glycogen synthase kinase-3β in the mammalian circadian clock
复制标题
DOI：
10.1074/jbc.m503526200
复制
发表时间：
2005-08-19
影响因子：
4.8
通讯作者：
Ishida, N
中科院分区：
文献类型：
--
作者：
Iitaka, C;Miyazaki, K;Ishida, N
果蝇shaggy基因产物是哺乳动物糖原合成酶激酶-3 β（GSK-3 β）同源物，其通过TIMELESS磷酸化作用对果蝇的昼夜节律钟做出贡献，并且其调节PERIOD/TIMELESS异二聚体的核转位。我们发现，哺乳动物GSK-3 β在小鼠的视交叉上核和肝脏中表达，GSK-3 β磷酸化表现出强烈的昼夜节律振荡。在血清休克的NIH3T3细胞中也观察到节律性GSK-3 β磷酸化。将血清休克的NIH3T3细胞暴露于氯化锂（GSK-3 β的特异性抑制剂），增加GSK-3 β磷酸化并延迟节律时钟基因表达的相位。另一方面，GSK-3 β过表达使时钟基因表达的时相提前。我们还发现GSK-3 β在体外和体内与PERIOD2（PER2）相互作用。重组GSK-3 β可以在体外磷酸化PER 2。GSK-3 β促进COS1细胞中PER2的核转位。目前的数据表明GSK-3 β在哺乳动物的生物钟中起着重要的作用。
The Drosophila shaggy gene product is a mammalian glycogen synthase kinase-3 beta (GSK-3 beta) homologue that contributes to the circadian clock of the Drosophila through TIMELESS phosphorylation, and it regulates nuclear translocation of the PERIOD/TIMELESS heterodimer. We found that mammalian GSK-3 beta is expressed in the suprachiasmatic nucleus and liver of mice and that GSK-3 beta phosphorylation exhibits robust circadian oscillation. Rhythmic GSK-3 beta phosphorylation is also observed in serum-shocked NIH3T3 cells. Exposing serum-shocked NIH3T3 cells to lithium chloride, a specific inhibitor of GSK-3 beta, increases GSK-3 beta phosphorylation and delays the phase of rhythmic clock gene expression. On the other hand, GSK-3 beta overexpression advances the phase of clock gene expression. We also found that GSK-3 beta interacts with PERIOD2 (PER2) in vitro and in vivo. Recombinant GSK-3 beta can phosphorylate PER2 in vitro. GSK-3 beta promotes the nuclear translocation of PER2 in COS1 cells. The present data suggest that GSK-3 beta plays important roles in mammalian circadian clock.