Synaptic Activity-Mediated Suppression of p53 and Induction of Nuclear Calcium-Regulated Neuroprotective Genes Promote Survival through Inhibition of Mitochondrial Permeability Transition
Synaptic Activity-Mediated Suppression of p53 and Induction of Nuclear Calcium-Regulated Neuroprotective Genes Promote Survival through Inhibition of Mitochondrial Permeability Transition
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DOI：
10.1523/jneurosci.0802-09.2009
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发表时间：
2009-04-08
影响因子：
5.3
通讯作者：
Bading, Hilmar
中科院分区：
文献类型：
--
作者：
Lau, David;Bading, Hilmar
由遗传或环境因素引起的细胞应激被认为是病理条件下细胞死亡的主要诱导因素。肿瘤抑制因子p53的凋亡功能的诱导是对严重的遗传毒性和氧化应激的常见细胞反应。在神经系统中，p53的积累和p53活性增加与急性和慢性神经退行性疾病中的神经元损失相关。在这里，我们表明，调节p53基因（trp53）是突触活性控制的，钙依赖性神经保护转录程序的一个组成部分。动作电位（AP）爆发抑制trp53的表达和下调关键的促凋亡p53靶基因，apaf 1和bbc 3（美洲狮）。同时，AP爆发激活了核钙诱导的神经保护基因btg2。使用RNA干扰或表达Btg2的内源性p53水平的耗竭使神经元对兴奋性毒性诱导的线粒体通透性转换更具抗性，并促进神经元在严重细胞应激下的存活。我们建议，抑制p53功能与核钙调节的神经保护基因在一个协调和协同的方式，以促进神经元的生存，通过稳定线粒体对细胞的压力。
Cellular stress caused by genetic or environmental factors are considered to be the major inducers of cell death under pathological conditions. Induction of the apoptotic function of the tumor suppressor p53 is a common cellular response to severe genotoxic and oxidative stresses. In the nervous system, accumulation of p53 and increased p53 activity are associated with neuronal loss in acute and chronic neurodegenerative disorders. Here, we show that regulation of the p53 gene (trp53) is an integral part of a synaptic activity-controlled, calcium-dependent neuroprotective transcriptional program. Action potential (AP) bursting suppresses trp53 expression and downregulates key proapoptotic p53 target genes, apaf1 and bbc3 (puma). At the same time, AP bursting activates the nuclear calcium-induced neuroprotective gene, btg2. Depletion of endogenous p53 levels using RNA interference or expression of Btg2 renders neurons more resistant against excitotoxicity-induced mitochondrial permeability transitions and promotes neuronal survival under severe cellular stresses. We propose that suppression of p53 functions together with nuclear calcium-regulated neuroprotective genes in a coordinate and synergistic manner to promote neuronal survival through the stabilization of mitochondria against cellular stresses.