Induction of an immediate early gene egr-1 by zinc through extracellular signal-regulated kinase activation in cortical culture:: Its role in zinc-induced neuronal death
Induction of an immediate early gene egr-1 by zinc through extracellular signal-regulated kinase activation in cortical culture:: Its role in zinc-induced neuronal death
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DOI：
10.1046/j.1471-4159.1999.0730450.x
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发表时间：
1999-08-01
影响因子：
4.7
通讯作者：
Koh, JY
中科院分区：
文献类型：
--
作者：
Park, JA;Koh, JY
Egr-1是脑损伤后诱导的即时早期转录因子之一。然而，Egr-1诱导的机制和作用尚未确定。在本研究中，使用小鼠皮层文化，我们研究了Egr-1诱导的离子机制及其在神经元死亡中的作用。虽然锌，NMDA，或离子霉素诱导皮质培养的神经元死亡，只有锌增加Egr-1的表达，这是衰减通过阻断锌流入。有趣的是，短暂暴露于锌诱导持续的细胞外信号调节激酶（Erk）激活。PD 098059是Erk 1/2上游激酶促分裂原活化蛋白激酶激酶1（MEK 1）的抑制剂，可阻断锌引起的Erk 1/2激活、Egr-1诱导和神经元死亡。目前的研究表明，锌，而不是钙，诱导持久的Egr-1的表达在皮层文化激活Erk 1/2，这是一个级联的一部分，可能发挥积极的作用，锌的神经毒性。我们认为，内源性锌的移位可能是脑缺血中Egr-1诱导和神经元死亡的关键机制。
Egr-1 is one of the immediate early transcription factors that are induced after brain insults. However, the mechanism and the role of Egr-1 induction are not yet determined. In the present study, using mouse cortical cultures, we examined the ionic mechanism of Egr-1 induction and its role in neuronal death. Although zinc, NMDA, or ionomycin induced comparable neuronal death in cortical culture, only zinc increased Egr-1 expression, which was attenuated by blocking zinc influx. It is intriguing that brief exposure to zinc induced sustained extracellular signal-regulated kinase (Erk) activation. PD098059, an inhibitor of the Erk 1/2 upstream kinase mitogen-activated protein kinase kinase 1 (MEK1), blocked Erk 1/2 activation, Egr-1 induction, and neuronal death by zinc. The present study has demonstrated that zinc, rather than calcium, induces lasting Egr-1 expression in cortical culture by activating Erk 1/2, which is part of a cascade that may play an active role in zinc neurotoxicity. We propose that translocation of endogenous zinc may be the key mechanism of Egr-1 induction and neuronal death in brain ischemia.