BAX translocation is a critical event in neuronal apoptosis: Regulation by neuroprotectants, BCL-2, and caspases
BAX translocation is a critical event in neuronal apoptosis: Regulation by neuroprotectants, BCL-2, and caspases
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DOI：
10.1523/jneurosci.19-17-07476.1999
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发表时间：
1999-09-01
影响因子：
5.3
通讯作者：
Johnson, EM
中科院分区：
文献类型：
--
作者：
Putcha, GV;Deshmukh, M;Johnson, EM
BCL-2蛋白家族的成员可以促进或抑制细胞程序性死亡。在这里，我们报道了在神经生长因子(NGF)剥夺后经历细胞凋亡的新生交感神经元表现出依赖于蛋白质合成的、不依赖于caspase的Bax从胞浆到线粒体的亚细胞重新分布，随后是线粒体细胞色素c的丢失和细胞死亡。在剥夺时增加神经保护剂KCl或cAMP的浓度可以阻止bax移位和细胞色素c的释放。然而，在NGF停用12小时后给予KCl或cAMP可显著阻止线粒体细胞色素c的丢失，但不能阻止Bax的重新分布；NGF抢救可显著阻止这两种情况的发生。Bcl2的过表达既没有改变Bax的正常亚细胞定位，也没有阻止其在剥夺后的重新分布，但确实抑制了随后的细胞色素c的释放、caspase的激活和细胞死亡。Bcl2的过表达不能阻止细胞色素c胞浆微量注射到NGF剥夺的死亡能力神经元所致的细胞死亡。这些观察结果表明，Bax的亚细胞重新分布是营养因子剥夺诱导神经细胞凋亡的关键事件。BCL-2主要在线粒体水平起作用，阻止Bax介导的细胞色素c释放，而NGF、KCl或cAMP可能在多个检查点终止细胞凋亡程序。
Members of the BCL-2 family of proteins either promote or repress programmed cell death. Here we report that neonatal sympathetic neurons undergoing apoptosis after nerve growth factor (NGF) deprivation exhibited a protein synthesis-dependent, caspase-independent subcellular redistribution of BAX from cytosol to mitochondria, followed by a loss of mitochondrial cytochrome c and cell death. Treatment with elevated concentrations of the neuroprotectants KCl or cAMP at the time of deprivation prevented BAX translocation and cytochrome c release. However, administration of KCl or cAMP 12 hr after NGF withdrawal acutely prevented loss of mitochondrial cytochrome c, but not redistribution of BAX; rescue with NGF acutely prevented both events. Overexpression of Bcl-2 neither altered the normal subcellular localization of BAX nor prevented its redistribution with deprivation but did inhibit the subsequent release of cytochrome c, caspase activation, and cell death. Bcl-2 overexpression did not prevent cell death induced by cytoplasmic microinjection of cytochrome c into NGF-deprived competent-to-die neurons. These observations suggest that the subcellular redistribution of BAX is a critical event in neuronal apoptosis induced by trophic factor deprivation. BCL-2 acts primarily, if not exclusively, at the level of mitochondria to prevent BAX-mediated cytochrome c release, whereas NGF, KCl, or cAMP may abort the apoptotic program at multiple checkpoints.