Decreased tumorigenesis in mice with a Kras point mutation at C118

Abstract

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 KrasC118S/C118S mice develop fewer lung tumours. Although the KrasC118S 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 KrasC118S allele impedes urethane-induced lung tumorigenesis.