Kras regulatory elements and exon 4A determine mutation specificity in lung cancer

Minh D. To, Christine E. Wong, Anthony Karnezis, Reyno Del Rosario, Roberto Di Lauro, Allan Balmain

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Abstract

Kras is the most frequently mutated ras family member in lung carcinomas, whereas Hras mutations are common in tumors from stratified epithelia such as the skin. Using a Hras knock-in mouse model, we demonstrate that specificity for Kras mutations in lung and Hras mutations in skin tumors is determined by local regulatory elements in the target ras genes. Although the Kras 4A isoform is dispensable for mouse development, it is the most important isoform for lung carcinogenesis in vivo and for the inhibitory effect of wild-type (WT) Kras on the mutant allele. Kras 4A expression is detected in a subpopulation of normal lung epithelial cells, but at very low levels in lung tumors, suggesting that it may not be required for tumor progression. The two Kras isoforms undergo different post-translational modifications; therefore, these findings can have implications for the design of therapeutic strategies for inhibiting oncogenic Kras activity in human cancers.

Original languageEnglish (US)
Pages (from-to)1240-1244
Number of pages5
JournalNature Genetics
Volume40
Issue number10
DOIs
StatePublished - Oct 1 2008
Externally publishedYes

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ASJC Scopus subject areas

  • Genetics

Cite this

To, M. D., Wong, C. E., Karnezis, A., Del Rosario, R., Di Lauro, R., & Balmain, A. (2008). Kras regulatory elements and exon 4A determine mutation specificity in lung cancer. Nature Genetics, 40(10), 1240-1244. https://doi.org/10.1038/ng.211