title: Involvement of mutation-based inhibition of beta-catenin phosphorylation at Ser33 in the malignant progression of lung (pre)neoplastic lesions induced by N-nitrosobis(2-hydroxypropyl)amine in male Fischer 344 rats.
abstract: In this study we investigated the Ser33 phosphorylation status of beta-catenin protein in relation to genomic mutations in lung (pre)neoplastic lesions induced by N-nitrosobis(2-hydroxypropyl)amine (BHP) in male Fischer 344 rats. Six-week-old animals received 2000 ppm of BHP in the drinking water for 8 weeks and were sacrificed 12 weeks thereafter. Histopathologically, 69 of 75 rats demonstrated multiple lung (pre)neoplastic lesions, classified into 27 slight and 33 advanced hyperplasias (preneoplasms) and 61 neoplasms, including adenomas, adenocarcinomas, and adenosquamous carcinomas. Nucleotide mutation analysis of the beta-catenin gene detected a total of 33 mutations in 12 assessed lung (pre)neoplastic lesions. The mutations tended to accumulate in positions near the phosphorylation region of the gene, between codons 33 and 45. Immunohistochemical analysis showed beta-catenin protein expression to be increased and its localization changed from the cell membrane to the cytoplasm and finally the nuclei with advancing malignancy of the lung lesions. In contrast, the expression of phosphorlyated beta-catenin protein at Ser33 was weakened in lung (pre)neoplastic lesions compared to normal lung tissues. These results suggest that BHP-induced mutation of the beta-catenin gene results in amino acid conversions in its product protein, which in turn lead to inhibition of phosphorylation of the protein and escape from protein degradation. These phenomena might contribute to the malignant progression of the lung (pre)neoplastic lesions, which start from the relatively early stage in lung carcinogenesis.
authors.affiliation: Laboratory of Protection of Body Function, Department of Food and Nutritional Science, Graduate School of Agriculture, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya, Tokyo, 156-0054, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Igarashi
authors.affiliation: Low Dose Radiation Effect Project, Research Center of Radiation Safety, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage, City of Chiba, Chiba, 263-8555, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, 4-6-1 Shirokanedai, Minato, Tokyo, 108-8636, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Second Department of Biochemistry, Hirosaki University School of Medicine, 5 Zaifuchou, Hirosaki, Aomori, 036-8562, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Molecular Predictive Medicine and Sport Science, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-0004, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Sakurai
authors.affiliation: Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo, Tokyo, 113-8657, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Endo
authors.affiliation: Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo, Tokyo, 113-8657, Japan.
authors.forename: Nozomi
authors.initials: N
authors.lastname: Miyajima
authors.affiliation: Laboratory of Protection of Body Function, Department of Food and Nutritional Science, Graduate School of Agriculture, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya, Tokyo, 156-0054, Japan.|Safety Assessment Division, Chemical Management Center, National Institute of Technology and Evaluation, 2-49-10 Nishihara, Shibuya, Tokyo, 151-0066, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Maekawa
authors.affiliation: Department of Communication Disorders, School of Psychological Science, Health Sciences University of Hokkaido, 2-5 Ainosato, Kita, Sapporo, Hokkaido, 002-8072, Japan.
authors.forename: Tsuneyuki
authors.initials: T
authors.lastname: Oikawa
authors.affiliation: Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, 4-6-1 Shirokanedai, Minato, Tokyo, 108-8636, Japan.
authors.forename: Sumio
authors.initials: S
authors.lastname: Sugano
authors.affiliation: Laboratory of Protection of Body Function, Department of Food and Nutritional Science, Graduate School of Agriculture, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya, Tokyo, 156-0054, Japan. agalennde.dai@nifty.com.|Department of Environmental Health and Toxicology, Tokyo Metropolitan Institute of Public Health, 3-24-1 Hyakunincho, Shinjuku, Tokyo, 169-0073, Japan. agalennde.dai@nifty.com.
authors.forename: Dai
authors.initials: D
authors.lastname: Nakae
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009154:Mutation; D009602:Nitrosamines; D010766:Phosphorylation; D011230:Precancerous Conditions / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D012694:Serine / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: C495268:Ctnnb1 protein, rat; D009602:Nitrosamines; D051176:beta Catenin; D012694:Serine; C012457:diisopropanolnitrosamine