Proapoptotic stimuli induce nuclear accumulation of glycogen synthase kinase-3β
Proapoptotic stimuli induce nuclear accumulation of glycogen synthase kinase-3β
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DOI：
10.1074/jbc.m105725200
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发表时间：
2001-10-05
影响因子：
4.8
通讯作者：
Jope, RS
中科院分区：
文献类型：
--
作者：
Bijur, GN;Jope, RS
本研究的目的是确定促凋亡酶糖原合成酶激酶3 β (GSK-3 β)的细胞内分布是否受到激活凋亡信号级联反应的条件的动态调节。在未经治疗的人神经母细胞瘤SHSY5Y细胞中，GSK-3 β主要是细胞质，尽管在细胞核中也检测到低水平。细胞暴露于无血清培养基、热休克或staurosporine后，GSK-3 β的核水平迅速升高。虽然这些条件都引起GSK-3 β的丝氨酸9和/或酪氨酸磷酸化的变化，但这些修饰都与GSK-3 β的核积累无关。在caspase-9和caspase-3激活之前，热休克和staurosporine处理增加了核GSK-3 β，并且用一般的caspase抑制剂预处理后GSK-3 β的核积累没有改变。GSK-3 β抑制剂锂没有改变热休克诱导的GSK-3 β核积累，但增加了cyclin D1的核水平，表明cyclin D1是核GSK-3 β的底物。因此，GSK-3 β在细胞内的分布受到信号级联的动态调节，凋亡刺激导致GSK-3 β的核水平升高，从而促进了与核底物的相互作用。
The goal of this study was to determine whether the intracellular distribution of the proapoptotic enzyme glycogen synthase kinase-3 beta (GSK-3 beta) is dynamically regulated by conditions that activate apoptotic signaling cascades. In untreated human neuroblastoma SHSY5Y cells, GSK-3 beta was predominantly cytosolic, although a low level was also detected in the nucleus. The nuclear level of GSK-3 beta was rapidly increased after exposure of cells to serum-free media, heat shock, or staurosporine. Although each of these conditions caused changes in the serine 9 and/or tyrosine phosphorylation of GSK-3 beta, neither of these modifications was correlated with nuclear accumulation of GSK-3 beta. Heat shock and staurosporine treatments increased nuclear GSK-3 beta prior to activation of caspase-9 and caspase-3, and this nuclear accumulation of GSK-3 beta was unaltered by pretreatment with a general caspase inhibitor. The GSK-3 beta inhibitor lithium did not alter heat shock-induced nuclear accumulation of GSK-3 beta but increased the nuclear level of cyclin D1, indicating that cyclin D1 is a substrate of nuclear GSK-3 beta. Thus, the intracellular distribution of GSK-3 beta is dynamically regulated by signaling cascades, and apoptotic stimuli cause increased nuclear levels of GSK-3 beta, which facilitates interactions with nuclear substrates.