skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Effects of mutant human Ki-ras{sup G12C} gene dosage on murine lung tumorigenesis and signaling to its downstream effectors

Abstract

Studies in cell culture have suggested that the level of RAS expression can influence the transformation of cells and the signaling pathways stimulated by mutant RAS expression. However, the levels of RAS expression in vivo appear to be subject to feedback regulation, limiting the total amount of RAS protein that can be expressed. We utilized a bitransgenic mouse lung tumor model that expressed the human Ki-ras{sup G12C} allele in a tetracycline-inducible, lung-specific manner. Treatment for 12 months with 500 {mu}g/ml of doxycycline (DOX) allowed for maximal expression of the human Ki-ras{sup G12C} allele in the lung, and resulted in the development of focal hyperplasia and adenomas. We determined if different levels of mutant RAS expression would influence the phenotype of the lung lesions. Treatment with 25, 100 and 500 {mu}g/ml of DOX resulted in dose-dependent increases in transgene expression and tumor multiplicity. Microscopic analysis of the lungs of mice treated with the 25 {mu}g/ml dose of DOX revealed infrequent foci of hyperplasia, whereas mice treated with the 100 and 500 {mu}g/ml doses exhibited numerous hyperplastic foci and also adenomas. Immunohistochemical and RNA analysis of the downstream effector pathways demonstrated that different levels of mutant RAS transgene expression resulted in differencesmore » in the expression and/or phosphorylation of specific signaling molecules. Our results suggest that the molecular alterations driving tumorigenesis may differ at different levels of mutant Ki-ras{sup G12C} expression, and this should be taken into consideration when inducible transgene systems are utilized to promote tumorigenesis in mouse models.« less

Authors:
 [1];  [2];  [3]; ;  [1];  [4];  [5];  [1]
  1. Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157 (United States)
  2. Section on Comparative Medicine, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157 (United States)
  3. Department of Molecular Biomedical Sciences, North Carolina State College of Veterinary Medicine, Raleigh, NC 27606 (United States)
  4. Section on Biostatistics, Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157 (United States)
  5. Department of Medical Genetics, Wake Forest University School of Medicine, Winston-Salem, NC 27157 (United States)
Publication Date:
OSTI Identifier:
21140929
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 231; Journal Issue: 1; Other Information: DOI: 10.1016/j.taap.2008.04.014; PII: S0041-008X(08)00180-4; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ADENOMAS; CELL CULTURES; DOSES; GENES; IN VIVO; LUNGS; MICE; MUTANTS; PHENOTYPE; PHOSPHATES; PHOSPHORYLATION; POLYMERASE CHAIN REACTION; POTASSIUM IODIDES; PROTEINS; RNA; TETRACYCLINES; TRANSCRIPTION

Citation Formats

Dance-Barnes, Stephanie T, Kock, Nancy D, Floyd, Heather S, Moore, Joseph E, Mosley, Libyadda J, D'Agostino, Ralph B, Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC 27157, Pettenati, Mark J, Miller, Mark Steven, and Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC 27157. Effects of mutant human Ki-ras{sup G12C} gene dosage on murine lung tumorigenesis and signaling to its downstream effectors. United States: N. p., 2008. Web. doi:10.1016/j.taap.2008.04.014.
Dance-Barnes, Stephanie T, Kock, Nancy D, Floyd, Heather S, Moore, Joseph E, Mosley, Libyadda J, D'Agostino, Ralph B, Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC 27157, Pettenati, Mark J, Miller, Mark Steven, & Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC 27157. Effects of mutant human Ki-ras{sup G12C} gene dosage on murine lung tumorigenesis and signaling to its downstream effectors. United States. https://doi.org/10.1016/j.taap.2008.04.014
Dance-Barnes, Stephanie T, Kock, Nancy D, Floyd, Heather S, Moore, Joseph E, Mosley, Libyadda J, D'Agostino, Ralph B, Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC 27157, Pettenati, Mark J, Miller, Mark Steven, and Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC 27157. 2008. "Effects of mutant human Ki-ras{sup G12C} gene dosage on murine lung tumorigenesis and signaling to its downstream effectors". United States. https://doi.org/10.1016/j.taap.2008.04.014.
@article{osti_21140929,
title = {Effects of mutant human Ki-ras{sup G12C} gene dosage on murine lung tumorigenesis and signaling to its downstream effectors},
author = {Dance-Barnes, Stephanie T and Kock, Nancy D and Floyd, Heather S and Moore, Joseph E and Mosley, Libyadda J and D'Agostino, Ralph B and Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC 27157 and Pettenati, Mark J and Miller, Mark Steven and Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC 27157},
abstractNote = {Studies in cell culture have suggested that the level of RAS expression can influence the transformation of cells and the signaling pathways stimulated by mutant RAS expression. However, the levels of RAS expression in vivo appear to be subject to feedback regulation, limiting the total amount of RAS protein that can be expressed. We utilized a bitransgenic mouse lung tumor model that expressed the human Ki-ras{sup G12C} allele in a tetracycline-inducible, lung-specific manner. Treatment for 12 months with 500 {mu}g/ml of doxycycline (DOX) allowed for maximal expression of the human Ki-ras{sup G12C} allele in the lung, and resulted in the development of focal hyperplasia and adenomas. We determined if different levels of mutant RAS expression would influence the phenotype of the lung lesions. Treatment with 25, 100 and 500 {mu}g/ml of DOX resulted in dose-dependent increases in transgene expression and tumor multiplicity. Microscopic analysis of the lungs of mice treated with the 25 {mu}g/ml dose of DOX revealed infrequent foci of hyperplasia, whereas mice treated with the 100 and 500 {mu}g/ml doses exhibited numerous hyperplastic foci and also adenomas. Immunohistochemical and RNA analysis of the downstream effector pathways demonstrated that different levels of mutant RAS transgene expression resulted in differences in the expression and/or phosphorylation of specific signaling molecules. Our results suggest that the molecular alterations driving tumorigenesis may differ at different levels of mutant Ki-ras{sup G12C} expression, and this should be taken into consideration when inducible transgene systems are utilized to promote tumorigenesis in mouse models.},
doi = {10.1016/j.taap.2008.04.014},
url = {https://www.osti.gov/biblio/21140929}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 1,
volume = 231,
place = {United States},
year = {Fri Aug 15 00:00:00 EDT 2008},
month = {Fri Aug 15 00:00:00 EDT 2008}
}