Lithium blocks the c-Jun stress response and protects neurons via its action on glycogen synthase kinase 3
Lithium blocks the c-Jun stress response and protects neurons via its action on glycogen synthase kinase 3
复制标题
DOI：
10.1128/mcb.23.17.6027-6036.2003
复制
发表时间：
2003-09-01
影响因子：
5.3
通讯作者：
Coffey, ET
中科院分区：
文献类型：
--
作者：
Hongisto, V;Smeds, N;Coffey, ET
50年来，锂一直被用作治疗躁狂发作和抑郁症的有效稳定情绪的药物。最近，锂被发现可以保护神经元免受一系列神经毒性侮辱导致的死亡。然而，锂的预防作用的分子基础仍然不清楚。锂的靶标，糖原合成酶激酶3(GSK-3)，与营养剥夺后神经元的死亡有关。GSK-3发挥神经毒性作用的机制也不清楚。在这里，我们表明，锂阻断了典型的c-jun凋亡通路在失去营养支持的小脑颗粒神经元。这种作用被结构独立的GSK-3、FRAT1和靛玉红抑制剂所模拟。和锂一样，它们可以防止应激诱导的c-jun蛋白增加和随后的细胞凋亡。这些事件位于c-jun反式激活的下游，因为GSK-3抑制剂阻断了c-jun(丝氨酸/苏氨酸-->；天冬氨酸)诱导的神经元死亡，而FRAT1的表达抑制了AP1报告分子的活性。与此一致的是，AP1依赖的促凋亡Bim的表达需要GSK-3样活性。这些数据表明，GSK-3样激酶与c-jun氨基末端激酶协同作用，以协调c-jun应激反应的全面执行和神经元对营养剥夺的反应。
Lithium has been used as an effective mood-stabilizing drug for the treatment of manic episodes and depression for 50 years. More recently, lithium has been found to protect neurons from death induced by a wide array of neurotoxic insults. However, the molecular basis for the prophylactic effects of lithium have remained obscure. A target of lithium, glycogen synthase kinase 3 (GSK-3), is implicated in neuronal death after trophic deprivation. The mechanism whereby GSK-3 exerts its neurotoxic effects is also unknown. Here we show that lithium blocks the canonical c-Jun apoptotic pathway in cerebellar granule neurons deprived of trophic support. This effect is mimicked by the structurally independent inhibitors of GSK-3, FRAT1, and indirubin. Like lithium, these prevent the stress induced c-Jun protein increase and subsequent apoptosis. These events are downstream of c-Jun transactivation, since GSK-3 inhibitors block neuronal death induced by constitutively active c-Jun (Ser/Thr-->Asp) and FRAT1 expression inhibits AP1 reporter activity. Consistent with this, AP1-dependent expression of proapoptotic Bim requires GSK-3-like activity. These data suggest that a GSK-3-like kinase acts in tandem with c-Jun N-terminal kinase to coordinate the full execution of the c-Jun stress response and neuronal death in response to trophic deprivation.