Mitochondrial translocation of p53 underlies the selective death of hippocampal CA1 neurons after global cerebral ischaemia
Mitochondrial translocation of p53 underlies the selective death of hippocampal CA1 neurons after global cerebral ischaemia
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DOI：
10.1042/bst0341283
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发表时间：
2006-12-01
影响因子：
3.9
通讯作者：
Chan, P. H.
中科院分区：
文献类型：
--
作者：
Endo, H.;Saito, A.;Chan, P. H.
p53是一种肿瘤抑制因子，参与DNA修复和细胞死亡过程，并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。在后一过程中，p53通过与保护性Bcl-2家族蛋白形成抑制性复合物而诱导线粒体外膜的透化，导致在几种细胞系系统中细胞色素c的释放。然而，目前还不清楚线粒体p53通路如何介导脑缺血后神经元凋亡。我们研究线粒体p53通路和脆弱的海马CA 1神经元之间的相互作用，使用tGCl（短暂性全脑缺血）大鼠模型。我们发现p53的线粒体易位及其与Bcl-X-L的结合。p53特异性抑制剂pifithrin-alpha阻止了线粒体p53易位、p53与Bcl-X-L之间的相互作用、线粒体释放细胞色素c以及随后的CA 1神经元死亡。这些结果表明，线粒体p53通路在tGCl后迟发性CA 1神经元死亡中起作用。
p53, a tumour suppressor, is involved in DNA repair and cell death processes and mediates apoptosis in response to death stimuli by transcriptional activation of pro-apoptotic genes and by transcription-independent mechanisms. in the latter process, p53 induces permeabilization of the outer mitochondrial membrane by forming an inhibitory complex with a protective Bcl-2 family protein, resulting in cytochrome c release in several cell line systems. However, it is unclear how the mitochondrial p53 pathway mediates neuronal apoptosis after cerebral ischaemia. We examined interaction between the mitochondrial p53 pathway and vulnerable hippocampal CA1 neurons using a tGCl (transient global cerebral ischaemia) rat model. We showed mitochondrial translocation of p53 and its binding to Bcl-X-L. Mitochondrial p53 translocation, interaction between p53 and Bcl-X-L, and cytochrome c release from mitochondria and subsequent CA1 neuronal death were prevented by pifithrin-alpha, a p53-specific inhibitor. These results suggest that the mitochondrial p53 pathway plays a role in delayed CA1 neuronal death after tGCl.