Tobacco-specific nitrosamine 4-(methylnitrosamino)-1(3-pyridyl)-1-butanone promotes functional cooperation of Bcl2 and c-Myc through phosphorylation in regulating cell survival and proliferation
Tobacco-specific nitrosamine 4-(methylnitrosamino)-1(3-pyridyl)-1-butanone promotes functional cooperation of Bcl2 and c-Myc through phosphorylation in regulating cell survival and proliferation
复制标题
DOI：
10.1074/jbc.m404056200
复制
发表时间：
2004-09-17
影响因子：
4.8
通讯作者：
Deng, XM
中科院分区：
文献类型：
--
作者：
Jin, ZH;Gao, FQ;Deng, XM
亚硝胺 4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮 (NNK) 由尼古丁亚硝化形成，已被确定为香烟烟雾中最有效的致癌物质。 NNK 显着促进与吸烟相关的肺癌，但其分子机制仍然是个谜。 Bcl2和c-Myc是两种主要的致癌蛋白，共同促进肿瘤的发展。我们在此报告，NNK 通过激活 ERK1/2 和 PKCα 同时刺激 Bcl2 仅在 Ser（70）处磷酸化，以及 c-Myc 在 Thr（58）和 Ser（62）处磷酸化，这是 NNK 诱导的人肺癌细胞存活和增殖所必需的。用 staurosporine 或 PD98059 处理细胞可阻断 Bcl2 和 c-Myc 磷酸化，从而抑制 NNK 诱导的增殖。通过 RNA 干扰特异性消除 c-Myc 表达可延迟 G(1)/S 细胞周期转变并阻断 NNK 诱导的细胞增殖。 Bcl2 Ser(70) 处的磷酸化促进细胞核中和线粒体外膜上的 Bcl2 和 c-Myc 之间的直接相互作用，从而显着延长 c-Myc 蛋白的半衰期。因此，NNK 诱导的 Bcl2 和 c-Myc 在促进细胞存活和增殖方面的功能合作可能以涉及它们磷酸化的新机制发生，这可能导致人类肺癌和/或化疗耐药的发生。
Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is formed by nitrosation of nicotine and has been identified as the most potent carcinogen contained in cigarette smoke. NNK significantly contributes to smoking-related lung cancer, but the molecular mechanism remains enigmatic. Bcl2 and c-Myc are two major oncogenic proteins that cooperatively promote tumor development. We report here that NNK simultaneously stimulates Bcl2 phosphorylation exclusively at Ser(70) and c-Myc at Thr(58) and Ser(62) through activation of both ERK1/2 and PKCalpha, which is required for NNK-induced survival and proliferation of human lung cancer cells. Treatment of cells with staurosporine or PD98059 blocks both Bcl2 and c-Myc phosphorylation and results in suppression of NNK-induced proliferation. Specific depletion of c-Myc expression by RNA interference retards G(1)/S cell cycle transition and blocks NNK-induced cell proliferation. Phosphorylation of Bcl2 at Ser(70) promotes a direct interaction between Bcl2 and c-Myc in the nucleus and on the outer mitochondrial membrane that significantly enhances the half-life of the c-Myc protein. Thus, NNK-induced functional cooperation of Bcl2 and c-Myc in promoting cell survival and proliferation may occur in a novel mechanism involving their phosphorylation, which may lead to development of human lung cancer and/or chemoresistance.