Long-targeted expression of the c-Raf-1 kinase in transgenic mice exposes a novel oncogenic character of the wild-type protein

The c-Raf-1 kinase is a downstream effector of Ras signaling. Both proteins are highly oncogenic when they are mutationally activated, but only the Ra s GTPase is frequently mutated in naturally occurring tumors. Although the c-Raf-1 protein was found to be amplified in different lung cancer cell lin es, overexpression of the wild-type c-Raf-1 protein was shown to be insuffi cient to transform cultured cells, Here we have addressed the question of w hether overexpression of the wild-type c-Raf-1 kinase can induce lung cance r in mice, We show that lung-targeted expression of oncogenically activated or wildtype c-Raf-1 proteins induces morphologically indistinguishable lun g adenomas in transgenic mice. Compared with mice transgenic for the activa ted c-Raf-1-BxB, tumor development is delayed and occurs at a lower inciden ce in wild-type c-Raf-1 transgenic mice. Our studies show that the c-Raf-1 expression level is a critical parameter in tumor development and should be analyzed in more detail to evaluate its potential in the induction of canc er.