Redox regulation of cAMP-responsive element-binding protein and induction of manganous superoxide dismutase in nerve growth factor-dependent cell survival
Redox regulation of cAMP-responsive element-binding protein and induction of manganous superoxide dismutase in nerve growth factor-dependent cell survival
复制标题
DOI：
10.1074/jbc.m301089200
复制
发表时间：
2003-05-09
影响因子：
4.8
通讯作者：
Galeotti, T
中科院分区：
文献类型：
--
作者：
Bedogni, B;Pani, G;Galeotti, T
活性氧（ROS）在神经系统中既是信号分子又是细胞损伤的介导因子，并且与神经退行性疾病的发病机制有关。神经营养因子，如神经生长因子（NGF），在发育过程中支持神经元存活，并通过激活细胞内信号促进神经元损伤后的再生，其分子效应物和下游靶点在很大程度上仍然未知。在此我们提供证据表明，在PC12细胞（一种对NGF有反应的细胞系）中由NGF引发的早期氧化信号在防止血清剥夺诱导的细胞凋亡中起关键作用。这种氧化还原信号级联涉及磷脂酰肌醇3 - 激酶、小GTP酶Rac - 1和转录因子cAMP反应元件结合蛋白（CREB），CREB是促进NGF依赖性存活的关键分子。我们发现ROS对于CREB的NGF依赖性磷酸化是必需的，这一事件与CREB活性直接相关，而过氧化氢可诱导强烈的CREB磷酸化。与未处理的细胞相比，暴露于NGF的细胞显示细胞内ROS含量后期下降，并且线粒体抗氧化酶锰超氧化物歧化酶（一种细胞死亡的普遍抑制剂）的表达增加。相应地，低浓度的线粒体靶向抗氧化剂Mito Q（米托喹醇/米托醌）可选择性地抑制血清剥夺诱导的细胞凋亡。综上所述，这些数据表明CREB的氧化依赖激活是PC12细胞中NGF存活信号的一个组成部分，并勾勒出一个有趣的回路，通过该回路，细胞质氧化还原级联至少部分通过增加线粒体对氧化应激的抗性来促进细胞存活。
Reactive oxygen species (ROS) act as both signaling molecules and mediators of cell damage in the nervous system and are implicated in the pathogenesis of neurodegenerative diseases. Neurotrophic factors such as the nerve-derived growth factor (NGF) support neuronal survival during development and promote regeneration after neuronal injury through the activation of intracellular signals whose molecular effectors and downstream targets are still largely unknown. Here we present evidence that early oxidative signals initiated by NGF in PC12 cells, an NGF-responsive cell line, play a critical role in preventing apoptosis induced by serum deprivation. This redox-signaling cascade involves phosphatidylinositol 3-kinase, the small GTPase Rac-1, and the transcription factor cAMP-responsive element-binding protein ( CREB), a molecule essential to promote NGF-dependent survival. We found that ROS are necessary for NGF-dependent phosphorylation of CREB, an event directly correlated with CREB activity, whereas hydrogen peroxide induces a robust CREB phosphorylation. Cells exposed to NGF show a late decrease in the intracellular content of ROS when compared with untreated cells and increased expression of the mitochondrial antioxidant enzyme manganese superoxide dismutase, a general inhibitor of cell death. Accordingly, serum deprivatio-induced apoptosis was selectively inhibited by low concentrations of the mitochondrially targeted antioxidant Mito Q (mitoquinol/mitoquinone). Taken together, these data demonstrate that the oxidant-dependent activation of CREB is a component of NGF survival signaling in PC12 cells and outline an intriguing circuitry by which a cytosolic redox cascade promotes cell survival at least in part by increasing mitochondrial resistance to oxidative stress.