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4-(N-Methyl-N-nitrosamino)-1(3-pyridyl)-1-butanone(NNK) Restored the Cap-dependent Protein Translation Blocked by Rapamycin  

Kim Jun-Sung (Laboratory of Toxicology, College of Veterinary Medicine, and School of Agricultural Biotechnology, Seoul National University)
Park Jin Hong (Laboratory of Toxicology, College of Veterinary Medicine, and School of Agricultural Biotechnology, Seoul National University)
Park Sung-Jin (Laboratory of Toxicology, College of Veterinary Medicine, and School of Agricultural Biotechnology, Seoul National University)
Kim Hyun Woo (Laboratory of Toxicology, College of Veterinary Medicine, and School of Agricultural Biotechnology, Seoul National University)
Hua Jin (Laboratory of Toxicology, College of Veterinary Medicine, and School of Agricultural Biotechnology, Seoul National University)
Cho Hyun Sun (Laboratory of Toxicology, College of Veterinary Medicine, and School of Agricultural Biotechnology, Seoul National University)
Hwang Soon Kyung (Laboratory of Toxicology, College of Veterinary Medicine, and School of Agricultural Biotechnology, Seoul National University)
Chang Seung Hee (Laboratory of Toxicology, College of Veterinary Medicine, and School of Agricultural Biotechnology, Seoul National University)
Tehrani Arash Minai (Laboratory of Toxicology, College of Veterinary Medicine, and School of Agricultural Biotechnology, Seoul National University)
Cho Myung Haing (Laboratory of Toxicology, College of Veterinary Medicine, and School of Agricultural Biotechnology, Seoul National University)
Publication Information
Toxicological Research / v.21, no.4, 2005 , pp. 347-353 More about this Journal
Abstract
Eukaryotic initiation factor 4E (elF4E) is a key element for cap-dependent protein translation controlled by affinity between elF4E and 4E-binding protein 1 (4E-BP1). Rapamycin can also affect protein translation by regulating 4E-BP1 phosphorylation. Tobacco-specific nitrosamine, 4(N-methyl-N-nitrosamino )-1-(3-pyridyl)-1-butanone (NNK) is a strong lung carcinogen, but its precise lung cancer induction mechanism remains unknown. Relative roles of cap-dependent and -independent protein translation in terms of NNK-induced lung carcinogenesis were elucidated using normal human bronchial epithelial cells. NNK concentrations applied in this study did not decrease cell viability. Addition of NNK restored rapamycin-induced decrease of protein synthesis and rapamycin-induced phosphorylation of 4E-BP1, and increased expression levels of mTOR, ERK1/2, p70S6K, and Raf-1 in a concentration-dependent manner. NNK also caused perturbation of normal cell cycle progression. Taken together, NNK might cause toxicity through the combination of restoration of 4E-BP1 phosphorylation and increase of elF4E as well as mTOR protein expression, interruption of Raf1/ERK as well as the cyclin G-associated p53 network. Our data could be applied towards elucidation of the molecular basis for lung cancer treatment.
Keywords
NNK; Rapamycin; Cap-dependent protein translation;
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