Decreased tumorigenesis in mice with a Kras point mutation at C118.
KRAS, NRAS or HRAS genes are mutated to encode an active oncogenic protein in a quarter of human cancers. Redox-dependent reactions can also lead to Ras activation in a manner dependent upon the thiol residue of cysteine 118 (C118). Here, to investigate the effect of mutating this residue on tumorigenesis, we introduce a C118S mutation into the endogenous murine Kras allele and expose the resultant mice to the carcinogen urethane, which induces Kras mutation-positive lung tumours. We report that Kras(+/C118S) and Kras(C118S/C118S) mice develop fewer lung tumours. Although the Kras(C118S) allele does not appear to affect tumorigenesis when the remaining Kras allele is conditionally oncogenic, there is a moderate imbalance of oncogenic mutations favouring the native Kras allele in tumours from Kras(+/C118S) mice treated with urethane. We conclude that the Kras(C118S) allele impedes urethane-induced lung tumorigenesis.
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Lu
L
Huang
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
John
J
Carney
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Diana M
DM
Cardona
1] Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Christopher M
CM
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D000483:Alleles; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D002273:Carcinogens / Q000494:pharmacology; D005260:Female; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed / Q000379:methods; D017354:Point Mutation / Q000235:genetics* / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000502:physiology; D014520:Urethane / Q000494:pharmacology
D002273:Carcinogens; D014520:Urethane; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)