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Conditional expression of the mutant Ki-rasG12C allele results in formation of benign lung adenomas: development of a novel mouse lung tumor model.

Publication ,  Journal Article
Floyd, HS; Farnsworth, CL; Kock, ND; Mizesko, MC; Little, JL; Dance, ST; Everitt, J; Tichelaar, J; Whitsett, JA; Miller, MS
Published in: Carcinogenesis
December 2005

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.

Duke Scholars

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Published In

Carcinogenesis

DOI

ISSN

0143-3334

Publication Date

December 2005

Volume

26

Issue

12

Start / End Page

2196 / 2206

Location

England

Related Subject Headings

  • ral GTP-Binding Proteins
  • p38 Mitogen-Activated Protein Kinases
  • Tumor Cells, Cultured
  • Signal Transduction
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Pulmonary Alveoli
  • Protein Serine-Threonine Kinases
  • Phosphorylation
  • Oncology & Carcinogenesis
  • Mutation
 

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Floyd, H. S., Farnsworth, C. L., Kock, N. D., Mizesko, M. C., Little, J. L., Dance, S. T., … Miller, M. S. (2005). Conditional expression of the mutant Ki-rasG12C allele results in formation of benign lung adenomas: development of a novel mouse lung tumor model. Carcinogenesis, 26(12), 2196–2206. https://doi.org/10.1093/carcin/bgi190
Floyd, Heather S., Charles L. Farnsworth, Nancy D. Kock, Melissa C. Mizesko, Joy L. Little, Stephanie T. Dance, Jeff Everitt, Jay Tichelaar, Jeffrey A. Whitsett, and Mark Steven Miller. “Conditional expression of the mutant Ki-rasG12C allele results in formation of benign lung adenomas: development of a novel mouse lung tumor model.Carcinogenesis 26, no. 12 (December 2005): 2196–2206. https://doi.org/10.1093/carcin/bgi190.
Floyd HS, Farnsworth CL, Kock ND, Mizesko MC, Little JL, Dance ST, et al. 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.
Floyd, Heather S., et al. “Conditional expression of the mutant Ki-rasG12C allele results in formation of benign lung adenomas: development of a novel mouse lung tumor model.Carcinogenesis, vol. 26, no. 12, Dec. 2005, pp. 2196–206. Pubmed, doi:10.1093/carcin/bgi190.
Floyd HS, Farnsworth CL, Kock ND, Mizesko MC, Little JL, Dance ST, Everitt J, Tichelaar J, Whitsett JA, Miller MS. 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):2196–2206.
Journal cover image

Published In

Carcinogenesis

DOI

ISSN

0143-3334

Publication Date

December 2005

Volume

26

Issue

12

Start / End Page

2196 / 2206

Location

England

Related Subject Headings

  • ral GTP-Binding Proteins
  • p38 Mitogen-Activated Protein Kinases
  • Tumor Cells, Cultured
  • Signal Transduction
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Pulmonary Alveoli
  • Protein Serine-Threonine Kinases
  • Phosphorylation
  • Oncology & Carcinogenesis
  • Mutation