Bijur G N, De Sarno P, Jope R S
Department of Psychiatry and Behavioral Neurobiology, University of Alabama, Birmingham, Alabama 35294-0017, USA.
J Biol Chem. 2000 Mar 17;275(11):7583-90. doi: 10.1074/jbc.275.11.7583.
The potential role of glycogen synthase kinase-3beta in modulating apoptosis was examined in human SH-SY5Y neuroblastoma cells. Staurosporine treatment caused time- and concentration-dependent increases in the activities of caspase-3 and caspase-9 but not caspase-1, increased proteolysis of poly(ADP-ribose) polymerase, and induced morphological changes consistent with apoptosis. Overexpression of glycogen synthase kinase-3beta to levels 3.5 times that in control cells did not alter basal indices of apoptosis but potentiated staurosporine-induced activation of caspase-3, caspase-9, proteolysis of poly(ADP-ribose) polymerase, and morphological changes indicative of apoptosis. Inhibition of glycogen synthase kinase-3beta by lithium attenuated the enhanced staurosporine-induced activation of caspase-3 in cells overexpressing glycogen synthase kinase-3beta. In cells subjected to heat shock, caspase-3 activity was more than three times greater in glycogen synthase kinase-3beta-transfected than control cells, and this potentiated response was inhibited by lithium treatment. Thus, glycogen synthase kinase-3beta facilitated apoptosis induced by two experimental paradigms. These findings indicate that glycogen synthase kinase-3beta may contribute to pro-apoptotic-signaling activity, that inhibition of glycogen synthase kinase-3beta can contribute to anti-apoptotic-signaling mechanisms, and that the neuroprotective actions of lithium may be due in part to its inhibitory modulation of glycogen synthase kinase-3beta.
在人SH-SY5Y神经母细胞瘤细胞中研究了糖原合酶激酶-3β在调节细胞凋亡中的潜在作用。星形孢菌素处理导致半胱天冬酶-3和半胱天冬酶-9的活性呈时间和浓度依赖性增加，但半胱天冬酶-1的活性未增加，增加了聚（ADP-核糖）聚合酶的蛋白水解，并诱导了与细胞凋亡一致的形态学变化。将糖原合酶激酶-3β过表达至对照细胞中水平的3.5倍，并未改变细胞凋亡的基础指标，但增强了星形孢菌素诱导的半胱天冬酶-3、半胱天冬酶-9的激活、聚（ADP-核糖）聚合酶的蛋白水解以及指示细胞凋亡的形态学变化。锂对糖原合酶激酶-3β的抑制减弱了在过表达糖原合酶激酶-3β的细胞中星形孢菌素诱导的半胱天冬酶-3激活的增强。在经受热休克的细胞中，糖原合酶激酶-3β转染的细胞中半胱天冬酶-3的活性比对照细胞高3倍多，并且这种增强的反应被锂处理所抑制。因此，糖原合酶激酶-3β促进了由两种实验范式诱导的细胞凋亡。这些发现表明，糖原合酶激酶-3β可能有助于促凋亡信号活性，糖原合酶激酶-3β的抑制可能有助于抗凋亡信号机制，并且锂的神经保护作用可能部分归因于其对糖原合酶激酶-3β的抑制调节。
