Involvement of p53 mutation and mismatch repair proteins dysregulation in NNK-induced malignant transformation of human bronchial epithelial cells.
Involvement of p53 mutation and mismatch repair proteins dysregulation in NNK-induced malignant transformation of human bronchial epithelial cells.
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p53 突变和错配修复蛋白失调参与 NNK 诱导的人支气管上皮细胞恶性转化。
DOI：
10.1155/2014/920275
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发表时间：
2014
影响因子：
--
通讯作者：
Wang Z
中科院分区：
文献类型：
--
作者：
Shen Y;Zhang S;Huang X;Chen K;Shen J;Wang Z
基因组的完整性对于正常的细胞功能和细胞存活是必不可少的。它的不稳定性可导致遗传畸变，被认为是大多数癌症的标志。为探讨烟草特异性致癌物NNK诱发人支气管上皮细胞恶性转化的过程，我们研究了NNK作用后，两个重要的基因组完整性保护因子p53和MMR系统在人支气管上皮细胞恶性转化过程中的动态变化。我们的研究结果表明，MLH 1，一个重要的MMR蛋白，表达下降的早期和维持下调在转化过程中，参与组蛋白修饰和DNA甲基化的非依赖性方式。另一种MMR蛋白PMS 2在转化后期也表现出表达下降。此外，我们进行了p53突变分析，并揭示了在密码子273处的突变，导致精氨酸被组氨酸取代。随着突变，DNA损伤诱导的p53激活显着受损。我们进一步将野生型p53重新导入转化细胞中，通过诱导细胞周期阻滞和凋亡可以消除恶性增殖。这些结果表明，p53和MMR系统在NNK诱导的转化的启动和进展中起重要作用，p53可能是烟草相关癌症的潜在治疗靶点。
Genome integrity is essential for normal cellular functions and cell survival. Its instability can cause genetic aberrations and is considered as a hallmark of most cancers. To investigate the carcinogenesis process induced by tobacco-specific carcinogen NNK, we studied the dynamic changes of two important protectors of genome integrity, p53 and MMR system, in malignant transformation of human bronchial epithelial cells after NNK exposure. Our results showed that the expression of MLH1, one of the important MMR proteins, was decreased early and maintained the downregulation during the transformation in a histone modification involved and DNA methylation-independent manner. Another MMR protein PMS2 also displayed a declined expression while being in a later stage of transformation. Moreover, we conducted p53 mutation analysis and revealed a mutation at codon 273 which led to the replacement of arginine by histidine. With the mutation, DNA damage-induced activation of p53 was significantly impaired. We further reintroduced the wild-type p53 into the transformed cells, and the malignant proliferation can be abrogated by inducing cell cycle arrest and apoptosis. These findings indicate that p53 and MMR system play an important role in the initiation and progression of NNK-induced transformation, and p53 could be a potential therapeutic target for tobacco-related cancers.
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影响因子：
5.6
作者：
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通讯作者：
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通讯作者：
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