Faculty Collaboration Database

Conditional expression of the mutant Ki-rasG12C allele results in formation of benign lung adenomas: development of a novel mouse lung tumor model. Carcinogenesis 2005 Dec;26(12):2196-206

Date

07/30/2005

Pubmed ID

16051643

Pubmed Central ID

PMC1351110

DOI

10.1093/carcin/bgi190

Scopus ID

2-s2.0-27944458023 (requires institutional sign-in at Scopus site)   42 Citations

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.

Author List

Floyd HS, Farnsworth CL, Kock ND, Mizesko MC, Little JL, Dance ST, Everitt J, Tichelaar J, Whitsett JA, Miller MS

MESH terms used to index this publication - Major topics in bold

Adenoma
Alleles
Animals
Bronchi
Cell Transformation, Neoplastic
Doxycycline
Genes, ras
Humans
Hyperplasia
Intracellular Signaling Peptides and Proteins
Lung Neoplasms
Mice
Mice, Transgenic
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Mutation
Phosphorylation
Pulmonary Alveoli
Ribosomal Protein S6 Kinases, 90-kDa
Signal Transduction
Tumor Cells, Cultured
p38 Mitogen-Activated Protein Kinases
ral GTP-Binding Proteins