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- W2275681414 abstract "C17 Activating Kras mutations occur in 15-30% of human lung adenocarcinomas, and in the majority of carcinogen induced lung tumors in the mouse, highlighting the importance of Kras in lung carcinogenesis. Kras deficiency is embryonically lethal, but mice (HrasKI) with the Hras coding sequence placed into the Kras locus on chromosome 6 are viable. We show that urethane treated HrasKI mice develop ~10-fold more lung tumors than wild-type (WT) mice in spite of lacking Kras expression. The Kras protein is therefore not essential for lung carcinogenesis. However, while most lung tumors in this model exhibit activating mutations at codon 61 in the inserted HrasKI allele, no mutations are found at the corresponding position in the endogenous Hras locus on chromosome 7. These results demonstrate that the mechanism of Kras mutation selectivity during lung carcinogenesis involves specific regulatory elements within or near the Kras gene. Two alternative splicing isoforms of Kras, designated 4A and 4B, are present in the lung. Kras-4B is the major isoform and is thought to be the major mediator of Kras function. However, KrasKI mice with the Kras-4B coding sequence placed back into the endogenous Kras locus are highly resistant to lung tumor development. Moreover, mutations always occur in the native Kras gene and not in the KrasKI allele in lung tumors from KrasKI heterozygous animals. These results are consistent with Kras-4B having a minimal role in lung carcinogenesis and suggest that the major effect of Kras in lung tumor development is mediated through Kras-4A. Since Kras-4A and Kras-4B proteins undergo distinctive post-translational modifications, these findings can have important implications in the design of therapeutic strategies for inhibiting oncogenic Kras activity for the treatment of cancer." @default.
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- W2275681414 date "2007-11-01" @default.
- W2275681414 modified "2023-09-28" @default.
- W2275681414 title "Kras mutation selectivity and isoform specificity in lung cancer" @default.
- W2275681414 hasPublicationYear "2007" @default.
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