title: K-rasG12V mediated lung tumor models identified three new quantitative trait loci modifying events post-K-ras mutation.
abstract: A high incidence of oncogenic K-ras mutations is observed in lung adenocarcinoma of human cases and carcinogen-induced animal models. The process of oncogenic K-ras-mediated lung adenocarcinogenesis can be dissected into two parts: pre- and post-K-ras mutation. Adoption of transgenic lines containing a flox-K-rasG12V transgene eliminates the use of chemical carcinogens and enables us to study directly crucial events post-K-ras mutation without considering the cellular events involved with oncogenic K-ras mutation, e.g., distribution and metabolism of chemical carcinogens, DNA repair, and somatic recombination by host factors. We generated two mouse strains C57BL/6J-Ryr2(tm1Nobs) and A/J-Ryr2(tm1Nobs) in which K-rasG12V can be transcribed from the cytomegalovirus early enhancer/chicken beta actin promoter in virtually any tissue. Upon K-rasG12V induction in lung epithelial cells by an adenovirus expressing the Cre recombinase, the number of tumors in the C57BL/6J-Ryr2(tm1Nobs/+) mouse line was 12.5 times that in the A/J-Ryr2(tm1Nobs/+) mouse line. Quantitative trait locus (QTL) analysis revealed that new three modifier loci, D3Mit19, D3Mit45 and D11Mit20, were involved in the differential susceptibility between the two lines. In addition, we found that differential expression of the wild-type K-ras gene, which was genetically turn out to be anti-oncogenic activity on K-rasG12V, could not account for the different susceptibility in our two K-rasG12V-mediated lung tumor models. Thus, we provide a genetic system that enables us to explore new downstream modifiers post-K-ras mutation.
authors.affiliation: Department of Animal Genomics, Functional Genomics Institute, Mie University Life Science Research Center, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Saito
authors.affiliation: Department of Animal Genomics, Functional Genomics Institute, Mie University Life Science Research Center, 2-174 Edobashi, Tsu, Mie 514-8507, Japan. Electronic address: nsuzuki@doc.medic.mie-u.ac.jp.
authors.forename: Noboru
authors.initials: N
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D060045:Genes, Modifier / Q000235:genetics; D011905:Genes, ras / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics*
chemical_list: D018631:ras Proteins
keywords: Genetic susceptibility; K-ras oncogenes; Lung cancer; Modifier gene; QTL