Cisplatin-induced nitrosylation of p53 prevents its mitochondrial translocation
Cisplatin-induced nitrosylation of p53 prevents its mitochondrial translocation
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DOI：
10.1016/j.freeradbiomed.2009.03.015
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发表时间：
2009-06-15
影响因子：
7.4
通讯作者：
Shoshan, Maria
中科院分区：
文献类型：
--
作者：
Hernlund, Emma;Kutuk, Ozgur;Shoshan, Maria
据报道，对DNA损伤的细胞反应涉及p53向线粒体的快速转录非依赖性易位。我们在这里表明，DNA损伤顺铂衍生的抗癌剂奥沙利铂诱导线粒体易位和随后的Bcl-xL相互作用，而顺铂没有。差异反应是由于p53的亚硝化修饰。因此，顺铂，而不是奥沙利铂，诱导诱导型一氧化氮合酶（iNOS）的表达增加。顺铂治疗的iNOS抑制剂（1400 W）的存在下，允许p53线粒体易位。相反，奥沙利铂诱导的p53易位被所有外源性NO供体的共同治疗所阻止。在顺铂处理的细胞中，核而不是线粒体p53显示硝基酪氨酸化，这是由1400 W可重复的。我们的结论是，亚硝化蛋白修饰是更突出的顺铂比奥沙利铂和亚硝化修饰的p53是一个主要的决定因素p53亚细胞位置。(C)2009爱思唯尔公司All rights reserved.
The cellular response to DNA damage has been reported to involve rapid transcription-independent translocation of p53 to mitochondria. We show here that the DNA-damaging cisplatin-derived anticancer agent oxaliplatin induced both mitochondrial translocation and subsequent Bcl-xL interaction, whereas cisplatin did neither. The differential response was due to nitrosative modification of p53. Thus, cisplatin, but not oxaliplatin, induced increased expression of inducible nitric oxide synthase (iNOS). Cisplatin treatment in the presence of an iNOS inhibitor (1400W) allowed p53 mitochondrial translocation. Conversely, oxaliplatin-induced translocation of p53 was prevented by cotreatment with all exogenous NO donor. In cisplatin-treated cells, nuclear but not mitochondrial p53 showed nitrotyrosinylation that was inhibitable by 1400W. We conclude that nitrosative protein modification is more prominent in the response to cisplatin than oxaliplatin and that nitrosative modification of p53 is a major determinant of p53 subcellular location. (C) 2009 Elsevier Inc. All rights reserved.