Mitochondrial translocation of p53 mediates release of cytochrome c and hippocampal CA1 neuronal death after transient global cerebral ischemia in rats
Mitochondrial translocation of p53 mediates release of cytochrome c and hippocampal CA1 neuronal death after transient global cerebral ischemia in rats
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DOI：
10.1523/jneurosci.0897-06.2006
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发表时间：
2006-07-26
影响因子：
5.3
通讯作者：
Chan, Pak H.
中科院分区：
文献类型：
--
作者：
Endo, Hidenori;Kamada, Hiroshi;Chan, Pak H.
虽然p53是细胞应激反应的关键调节因子，但p53介导的细胞凋亡的机制尚不明确。p53可以通过促凋亡基因的转录激活和转录非依赖性机制介导对死亡刺激的细胞凋亡。最近的研究表明，p53蛋白可以通过与保护性Bcl-2家族蛋白形成抑制性复合物直接诱导线粒体外膜的透化，导致细胞色素c释放。然而，线粒体p53通路如何介导脑缺血后神经元凋亡仍不清楚。我们研究了线粒体p53通路和脆弱的海马CA 1神经元之间的相互作用，在大鼠短暂性全脑缺血（tGCI）模型。Western blot分析和免疫荧光染色显示tGCI后海马CA 1区神经元线粒体p53易位。免疫共沉淀显示，易位的p53结合Bcl-X-L的线粒体组分。为了检查特异性p53抑制剂对tGCI后线粒体p53通路和凋亡性细胞死亡的影响，我们静脉内施用匹非亭-α（PFT）。用PFT处理可防止线粒体p53易位和p53与Bcl-X-L之间的相互作用。此外，细胞色素c从线粒体释放和随后的凋亡性CA 1神经元死亡与PFT治疗减少。这些结果表明，线粒体p53通路是介导tGCI后海马CA 1区脆弱神经元延迟性死亡的新机制之一。
Although p53 is a key modulator of cellular stress responses, the mechanism of p53-mediated apoptosis is ambiguous. p53 can mediate apoptosis in response to death stimuli by transcriptional activation of proapoptotic genes and transcriptional-independent mechanisms. Recent studies have shown that the p53 protein can directly induce permeabilization of the outer mitochondrial membrane by forming a inhibitory complex with a protective Bcl-2 family protein, resulting in cytochrome c release. However, how the mitochondrial p53 pathway mediates neuronal apoptosis after cerebral ischemia remains unclear. We examined the interaction between the mitochondrial p53 pathway and vulnerable hippocampal CA1 neurons in rats using a transient global cerebral ischemia (tGCI) model. Western blot analysis and immunofluorescent staining revealed mitochondrial p53 translocation after tGCI in the hippocampal CA1 neurons. Coimmunoprecipitation revealed that translocated p53 bound to Bcl-X-L in the mitochondrial fraction. To examine the effect of a specific p53 inhibitor on the mitochondrial p53 pathway and apoptotic cell death after tGCI, we intravenously administered pifithrin-alpha (PFT). Mitochondrial p53 translocation and interaction between p53 and Bcl-X-L were prevented by treatment with PFT. Moreover, cytochrome c release from mitochondria and subsequent apoptotic CA1 neuronal death were decreased with PFT treatment. These results suggest that the mitochondrial p53 pathway is one of the novel mechanisms mediating delayed death of vulnerable hippocampal CA1 neurons after tGCI.