title: Conditional expression of the mutant Ki-rasG12C allele results in formation of benign lung adenomas: development of a novel mouse lung tumor model.
abstract: To determine the effects of expression of mutant Ki-ras on lung tumorigenesis, we developed a bitransgenic mouse model that expresses the human Ki-ras(G12C) allele in alveolar type II and/or Clara cells in a tetracycline-inducible, lung-specific manner. Expression of Ki-ras(G12C) caused multiple, small lung tumors over a 12-month time period. Although tumor multiplicity increased upon continued Ki-ras expression, most lung lesions were hyperplasias or well-differentiated adenomas. This is in contrast to the more severe phenotypes observed in other transgenic mouse models in which different mutant Ki-ras alleles were expressed in the lung. Expression of Ki-ras(G12C) was associated with a 2-fold increase in the activation of the Ras and Ral signaling pathways and increased phosphorylation of Ras downstream effectors, including Erk, p90 ribosomal S6 kinase, ribosomal S6 protein, p38 and MAPKAPK-2. In contrast, expression of the transgene had no effect on the activation of the JNK and Akt signaling pathways. Withdrawal of doxycycline for 1 month resulted in almost a complete absence of proliferative pulmonary lesions, suggesting tumor regression in the absence of Ki-ras expression. Mutant Ki-ras(G12C) expression was sufficient for initial lung tumor transformation, required for maintenance of tumor phenotype, and induced transformation of lung epithelial cells by the activation of multiple effector pathways. These results describe a novel mouse lung tumor model demonstrating benign tumor development in the absence of tumor progression, which will provide a new tool for understanding the early stages of lung tumor pathogenesis.
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Heather S
authors.initials: HS
authors.lastname: Floyd
authors.forename: Charles L
authors.initials: CL
authors.lastname: Farnsworth
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Kock
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Mizesko
authors.forename: Joy L
authors.initials: JL
authors.lastname: Little
authors.forename: Stephanie T
authors.initials: ST
authors.lastname: Dance
authors.forename: Jeff
authors.initials: J
authors.lastname: Everitt
authors.forename: Jay
authors.initials: J
authors.lastname: Tichelaar
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Whitsett
authors.forename: Mark Steven
authors.initials: MS
authors.lastname: Miller
mesh_terms: D000236:Adenoma / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D000483:Alleles; D000818:Animals; D001980:Bronchi; D002471:Cell Transformation, Neoplastic; D004318:Doxycycline / Q000494:pharmacology; D011905:Genes, ras / Q000235:genetics / Q000502:physiology*; D006801:Humans; D006965:Hyperplasia / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D008175:Lung Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020725:ral GTP-Binding Proteins; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D004318:Doxycycline; D047908:Intracellular Signaling Peptides and Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D017346:Protein Serine-Threonine Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D048051:p38 Mitogen-Activated Protein Kinases; D020725:ral GTP-Binding Proteins; D000099190:MAP-Kinase-Activated Kinase 2; C069329:RPS6KA1 protein, human; C512964:Rps6ka1 protein, mouse