Midkine Inhibits Caspase‐Dependent Apoptosis via the Activation of Mitogen‐Activated Protein Kinase and Phosphatidylinositol 3‐Kinase in Cultured Neurons
Midkine Inhibits Caspase‐Dependent Apoptosis via the Activation of Mitogen‐Activated Protein Kinase and Phosphatidylinositol 3‐Kinase in Cultured Neurons
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DOI：
10.1046/j.1471-4159.1999.02084.x
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发表时间：
1999-11
影响因子：
4.7
通讯作者：
K. Owada;N. Sanjo;Takayoshi Kobayashi;Hidehiro Mizusawa;H. Muramatsu;Takashi Muramatsu;Makoto Michikawa
中科院分区：
文献类型：
--
作者：
K. Owada;N. Sanjo;Takayoshi Kobayashi;Hidehiro Mizusawa;H. Muramatsu;Takashi Muramatsu;Makoto Michikawa
中期因子(MK)是肝素结合神经营养因子家族的新成员。MK在发育和癌变中发挥重要作用，并具有几个重要的生物学效应，包括促进轴突延伸和神经元存活。然而，到目前为止，MK对神经元发挥神经营养作用的机制尚未阐明。我们建立了小鼠大脑皮层原代培养的神经细胞去血清诱导细胞凋亡的系统。血清剥夺诱导的神经细胞凋亡伴随着caspase-3的激活。MK以剂量依赖方式抑制细胞凋亡和caspase-3的激活。去血清不能激活细胞外信号调节激酶(ERK)和Akt，而加入MK可迅速激活ERK和Akt。此外，MK抑制细胞凋亡和抑制caspase-3激活的营养作用可被丝裂原活化蛋白激酶的特异性抑制剂PD98059和磷脂酰肌醇3-激酶的特异性抑制剂麦芽甘露醇或LY294002联合处理而取消。这些PI 3-激酶抑制剂也抑制了MK对ERK的激活，证实了ERK与caspase-3通路之间的联系，而caspase-3通路受PI 3-激酶的激活所调节。这些结果表明，ERK级联信号通路通过抑制caspase-3的激活在MK介导的神经元存活中起中心作用。
Midkine (MK) is a new member of the heparin-binding neurotrophic factor family. MK plays important roles in development and carcinogenesis and has several important biological effects, including promotion of neurite extension and neuronal survival. However, the mechanism by which MK exerts its neurotrophic actions on neurons has not been elucidated to date. We have established an apoptosis induction system by serum deprivation in primary neuronal cultures isolated from mouse cerebral cortices. Neuronal apoptosis induced by serum deprivation was accompanied by the activation of caspase-3. MK, when added into the culture medium, inhibited the induction of apoptosis and activation of caspase-3 in a dose-dependent manner. Extracellular signal-regulated kinase (ERK) and Akt were not activated by serum deprivation, whereas ERK and Akt were rapidly activated by addition of MK. In addition, the trophic actions of MK of suppressing apoptosis and suppressing the activation of caspase-3 were abolished by concomitant treatment with PD98059, a specific inhibitor of mitogen-activated protein kinase kinase, and with wort-mannin or LY294002, specific inhibitors of phosphatidyl-inositol 3-kinase (PI 3-kinase). These PI 3-kinase inhibitors also inhibited the activation of ERK in response to MK, demonstrating a link between ERK and the caspase-3 pathway that is modulated by the PI 3-kinase activation. These results indicate that the ERK cascade plays a central role in MK-mediated neuronal survival via inhibition of caspase-3 activation.