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

Journal Article · Fri Aug 15 04:00:00 EDT 2008 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2008.04.014· OSTI ID:21140929

Dance-Barnes, Stephanie T ^[1]; Kock, Nancy D ^[2]; Floyd, Heather S ^[3]; Moore, Joseph E; Mosley, Libyadda J ^[1]; D'Agostino, Ralph B ^[4]; Pettenati, Mark J ^[5]; Miller, Mark Steven ^[1]

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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)

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.

• OSTI ID: 21140929
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 1 Vol. 231; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

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