Inhibition of v-Abl transformation by p53 and p19ARF

Tumorigenesis is a multistep process that involves the activation of oncoge nes and the inactivation of tumor suppressor genes. The transforming activi ty of the v-Abl oncogene of Abelson murine leukemia virus (A-MuLV) in immor tal cell lines has been well studied, while the effects of v-Abl in primary fibroblasts are less clear. Here we show that v-Abl causes cell cycle arre st in primary mouse embryonic fibroblasts (MEFs) and elevated levels of bot h p53 and the cyclin-dependent kinase inhibitor p21(Cip). p53(-/-) or p19AR F(-/-) MEFs were resistant to v-Abl-induced cell cycle arrest. Although wil d-type MEFs were resistant to v-Abl transforming activity, p53(-/-) or p19A RF(-/-) MEFs were susceptible. The results indicate that loss of p19ARF and p53 function plays an important role during the transformation of primary cells by v-Abl. We suggest that although v-Abl is a potent oncogene, its fu ll potential transforming activity cannot be realized until the ARF-, and p 53-dependent growth inhibitory pathway is disabled. We also show that p53 i s not the mediator of v-Abl toxicity in immortal fibroblasts and does not d etermine the susceptibility of immortal fibroblasts to v-Abl transformation .