An insight into the mechanistic role of p53-mediated autophagy induction in response to proteasomal inhibition-induced neurotoxicity
An insight into the mechanistic role of p53-mediated autophagy induction in response to proteasomal inhibition-induced neurotoxicity
复制标题
深入了解 p53 介导的自噬诱导对蛋白酶体抑制诱导的神经毒性的机制作用
DOI：
10.4161/auto.5.5.8377
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发表时间：
2009-07-01
期刊：
影响因子：
13.3
通讯作者：
Le, Weidong
中科院分区：
文献类型：
--
作者：
Du, Yunlan;Yang, Dehua;Le, Weidong
泛素-蛋白酶体系统（UPS）和自噬-溶酶体途径（ALP）是蛋白质降解细胞机制的两个最重要的组成部分。在本研究中，我们在体外研究了两个系统的功能关系以及 p53 的相互作用。我们的研究表明，蛋白酶体抑制剂乳胞素诱导 p53 水平和自噬活性增加，而 p53 的 pifithrin-α 或 p53 小干扰 RNA (siRNA) 抑制 p53 会减弱自噬诱导并增加蛋白质聚集。此外，我们发现自噬抑制剂3-甲基腺嘌呤或Beclin 1 siRNA预处理进一步激活p53及其下游凋亡途径，而自噬诱导剂雷帕霉素则表现出相反的作用。此外，我们证明雷帕霉素预处理增加了多巴胺（DA）神经元中的酪氨酸羟化酶（TH）蛋白水平，这与其诱导自噬降解聚集蛋白有关。我们的结果表明，p53 可以介导蛋白酶体抑制诱导的自噬增强，进而可以部分阻断 p53 或其下游线粒体依赖性细胞凋亡途径。雷帕霉素进一步诱导自噬，通过下调 p53 及其相关细胞凋亡途径以及诱导自噬降解聚集蛋白，保护 DA 神经元免受乳胞素介导的细胞死亡。因此，雷帕霉素可能是一种有前途的药物，可用于预防与帕金森病（PD）相关的神经元损伤。因此，我们的研究为这两种蛋白质降解系统之间的功能联系提供了机制上的见解。
The ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP) are the two most important components of cellular mechanisms for protein degradation. In the present study we investigated the functional relationship of the two systems and the interactional role of p53 in vitro. Our study showed that the proteasome inhibitor lactacystin induced an increase in p53 level and autophagy activity, whereas inhibition of p53 by pifithrin-α or small interference RNA (siRNA) of p53 attenuated the autophagy induction and increased protein aggregation. Furthermore, we found that the pretreatment with the autophagy inhibitor 3-methyladenine or Beclin 1 siRNA further activated p53 and its downstream apoptotic pathways, while the autophagy inducer rapamycin showed the opposite effects. Moreover, we demonstrated that rapamycin pretreatment increased tyrosine hydroxylase (TH) protein level in dopamine (DA) neurons, which was associated with its induction of autophagy to degrade aggregated proteins. Our results suggest that p53 can mediate proteasomal inhibition-induced autophagy enhancement which in turn can partially block p53 or its downstream mitochondria-dependent apoptotic pathways. Further autophagy induction with rapamycin protects DA neurons from lactacystin-mediated cell death by downregulating p53 and its related apoptotic pathways and by inducing autophagy to degrade aggregated proteins. Therefore, rapamycin may be a promising drug for protection against neuronal injury relevant to Parkinson’s disease (PD). Our studies thus provide a mechanistic insight into the functional link between the two protein degradation systems.