The CREB/CRE transcriptional pathway: protection against oxidative stress-mediated neuronal cell death.
The CREB/CRE transcriptional pathway: protection against oxidative stress-mediated neuronal cell death.
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DOI：
10.1111/j.1471-4159.2008.05864.x
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发表时间：
2009-03
影响因子：
4.7
通讯作者：
Obrietan K
中科院分区：
文献类型：
--
作者：
Lee B;Cao R;Choi YS;Cho HY;Rhee AD;Hah CK;Hoyt KR;Obrietan K
在一系列神经病理条件下，活性氧和氮物种的形成是一个沉淀事件。为了应对过量的活性氧(ROS)水平，转录依赖的机制推动ROS清除蛋白的上调，进而限制脑损伤的程度。在这里，我们采用了一种转基因方法，其中CREB介导的转录被抑制(通过A-CREB)来检查CREB/CRE通路在神经保护中的作用以及它在限制ROS毒性方面的潜在作用。利用匹罗卡品诱发的重复性癫痫模型，我们检测到A-CREB转基因小鼠的细胞死亡显著增加。与此同时，在A-CREB转基因小鼠中，酪氨酸硝化(反应物种形成的标志)显著增加。此外，在A-CREB转基因小鼠中，PGC-1α(过氧化体增殖物激活受体γ辅活化子-1α)的诱导表达降低，线粒体电子传递链复合体I的活性也降低。最后，BDNF对ROS介导的细胞死亡的神经保护作用被CREB介导的转录中断所消除。总之，这些数据既扩展了我们对CREB功能的理解，也为CREB作为对抗ROS介导的细胞死亡的神经保护信号的关键上游整合者的模型提供了体内验证。
Formation of reactive oxygen and nitrogen species is a precipitating event in an array of neuropathological conditions. In response to excessive reactive oxygen species (ROS) levels, transcriptionally-dependent mechanisms drive the upregulation of ROS scavenging proteins which, in turn, limit the extent of brain damage. Here, we employed a transgenic approach in which CREB-mediated transcription is repressed (via A-CREB) to examine the contribution of the CREB/CRE pathway to neuroprotection and its potential role in limiting ROS toxicity. Using the pilocarpine-evoked repetitive seizure model, we detected a marked enhancement of cell death in A-CREB transgenic mice. Paralleling this, there was a dramatic increase in tyrosine nitration (a marker of reactive species formation) in A-CREB transgenic mice. In addition, inducible expression of PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1α) was diminished in A-CREB transgenic mice, as was activity of complex I of the mitochondrial electron transport chain. Finally, the neuroprotective effect of BDNF against ROS-mediated cell death was abrogated by disruption of CREB-mediated transcription. Together, these data both extend our understanding of CREB functionality and provide in vivo validation for a model in which CREB functions as a pivotal upstream integrator of neuroprotective signaling against ROS-mediated cell death.
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影响因子：
4.8
作者：
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通讯作者：
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