Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced pulmonary adenocarcinomas in Syrian golden hamsters contain beta 2-adrenergic receptor single-nucleotide polymorphisms.
Cigarette smoking contributes to the development of lung cancer throughout the world, with cases of pulmonary adenocarcinoma (PAC) the most numerous. Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which is formed from nicotine, has been demonstrated to cause mutations in genes that affect cell regulation and proliferation. Moreover, NNK has been shown to interact directly with and stimulate beta adrenergic receptor (ADRB) signal transduction pathways. Our goal was to determine whether single-nucleotide polymorphisms (SNPs) in the Adrb2 from PAC tumors were induced in golden hamsters by the injection of NNK. Here we report the cloning and sequencing of Adrb2 clones from either dissected lung tumors from NNK-injected animals or whole-lung tissue from water-injected controls. Both sets of animals contained SNPs; however, we found significantly more SNPs in the Adrb2 from NNK-injected animals than in the controls. The majority of these SNPs were novel, nonsynonymous mutations found in regions of the Adrb2 known to be involved in ligand binding, G-protein coupling, and desensitization/down-regulation. Our data verified the mutagenic effects of NNK as well as demonstrated that this animal model provides an outstanding way of identifying mutations not only in the Adrb2, but also in other genes that may play essential roles in the regulation and growth of pulmonary adenocarcinomas.
Masi
Thomas
T
Experimental Oncology Laboratory, Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37996, USA.
Cekanova
Maria
M
Walker
Kindra
K
Bernert
Heike
H
Majidi
Mourad
M
Becker
Jeffrey M
JM
Schuller
Hildegard M
HM
D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D006224:Cricetinae; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics*; D008647:Mesocricetus; D008969:Molecular Sequence Data; D009602:Nitrosamines / Q000633:toxicity*; D020641:Polymorphism, Single Nucleotide; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*
D002273:Carcinogens; D009602:Nitrosamines; D018343:Receptors, Adrenergic, beta-2; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone