Letter abstract
Nature Genetics 40, 1240 - 1244 (2008)
Published online: 31 August 2008 | doi:10.1038/ng.211
Kras regulatory elements and exon 4A determine mutation specificity in lung cancer
Minh D To1, Christine E Wong1, Anthony N Karnezis1,2, Reyno Del Rosario1, Roberto Di Lauro3,4 & Allan Balmain1
Kras is the most frequently mutated ras family member in lung carcinomas1, 2, whereas Hras mutations are common in tumors from stratified epithelia such as the skin. Using a Hras knock-in mouse model3, 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 development4, 5, it is the most important isoform for lung carcinogenesis in vivo and for the inhibitory effect of wild-type (WT) Kras on the mutant allele6, 7. 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 modifications8; therefore, these findings can have implications for the design of therapeutic strategies for inhibiting oncogenic Kras activity in human cancers.
- University of California San Francisco Helen Diller Family Comprehensive Cancer Center, Cancer Research Institute, San Francisco, California 94115, USA.
- Department of Pathology, University of California San Francisco, San Francisco, California 94115, USA.
- Stazione Zoologica Anton Dohrn, 80121, Naples, Italy.
- Institute of Genetic Research "Gaetano Salvatore" (IRGS), Biogem s.c.a.r.l., 83031, Ariano Irpino, Italy.
Correspondence to: Allan Balmain1 e-mail: abalmain@cc.ucsf.edu
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