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.
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.
Mesh Terms:
Antineoplastic Agents, Apoptosis, Bungarotoxins, Carcinogens, Carcinoma, Small Cell, Cell Division, Cell Line, Tumor, Cell Nucleus, Cell Survival, Cisplatin, Enzyme Inhibitors, Flavonoids, Humans, Lung Neoplasms, Mitochondria, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, Nitrosamines, Phosphorylation, Protein Kinase C, Protein Kinase C-alpha, Proto-Oncogene Proteins c-bcl-2, Proto-Oncogene Proteins c-myc, RNA, Small Interfering, Receptors, Nicotinic, Signal Transduction, Staurosporine
Antineoplastic Agents, Apoptosis, Bungarotoxins, Carcinogens, Carcinoma, Small Cell, Cell Division, Cell Line, Tumor, Cell Nucleus, Cell Survival, Cisplatin, Enzyme Inhibitors, Flavonoids, Humans, Lung Neoplasms, Mitochondria, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, Nitrosamines, Phosphorylation, Protein Kinase C, Protein Kinase C-alpha, Proto-Oncogene Proteins c-bcl-2, Proto-Oncogene Proteins c-myc, RNA, Small Interfering, Receptors, Nicotinic, Signal Transduction, Staurosporine
J. Biol. Chem.
Date: Sep. 17, 2004
PubMed ID: 15210690
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