We have targeted a K-ras allele in mouse embryonic stem (ES) cells to express a K-Ras(V12) oncoprotein along with a marker protein (beta-geo) from a single bicistronic transcript. Expression of this oncogenic allele requires removal of a knocked in STOP transcriptional cassette by Cre recombinase. Primary mouse embryonic fibroblasts expressing this K-ras(V12) allele do not undergo proliferative senescence and proliferate as immortal cells. In mice, expression of K-ras(V12) throughout the body fails to induce unscheduled proliferation or other growth abnormalities for up to eight months. Only a percentage of K-ras(V12)-expressing lung bronchiolo-alveolar cells undergo malignant transformation leading to the formation of multiple adenomas and adenocarcinomas. These results indicate that neoplastic growth induced by an endogenous K-ras oncogene depends upon cellular context

This work was supported by grants from the V Framework Programme of the EU (to M.B. and M.S.), Ministerio de Ciencia y Tecnologı́a (to M.B.), Ministerio de Sanidad y Consumo and Comunidad Autónoma de Madrid (to C.G.), and Ligue contre le Cancer (Comité de Dordogne) and INSERM (to P.D.). N.M. was supported by a Beca de Formación para la Investigación (BEFI, Fondo de Investigación Sanitaria) and A.D. by a fellowship from the Programa de Formación de Personal Investigador (FPI, Ministerio de Ciencia y Tecnología)