Inhibition of v-Abl transformation by p53 and p19ARF

Abstract

Tumorigenesis is a multistep process that involves the activation of oncogenes and the inactivation of tumor suppressor genes. The transforming activity of the v-Abl oncogene of Abelson murine leukemia virus (A-MuLV) in immortal cell lines has been well studied, while the eects of v-Abl in primary ®broblasts are less clear. Here we show that v-Abl causes cell cycle arrest in primary mouse embryonic ®broblasts (MEFs) and elevated levels of both p53 and the cyclin-dependent kinase inhibitor p21Cip . p537/7 or p19ARF 7/7 MEFs were resistant to v-Abl-induced cell cycle arrest. Although wild-type MEFs were resistant to v-Abl transforming activity, p53 7/7 or p19ARF 7/7 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 full potential transforming activity cannot be realized until the ARF-, and p53-dependent growth inhibitory pathway is disabled. We also show that p53 is not the mediator of v-Abl toxicity in immortal ®broblasts and does not determine the susceptibility of immortal ®broblasts to vAbl transformation.

ATM activity contributes to the tumor-suppressing functions of p14ARF

“…In primary fibroblasts, expression of oncogenic Ras activates p53 in an ARFdependent manner (Serrano et al, 1997;Palmero et al, 1998). Expression of oncogenes such as c-myc, E1A, E2F1, v-Able and b-catenin in normal cells also leads to p53 activation through ARF (de Stanchina et al, 1998;Zindy et al, 1998;Cong et al, 1999;Dimri et al, 2000;Damalas et al, 2001). Furthermore, transgenic mice heterozygous for p19 ARF engineered to express c-myc in B cells exhibit accelerated B-cell lymphomas; 80% of such tumors had lost the wild-type p19 ARF allele (Eischen et al, 1999), lending in vivo support to the notion that ARF plays an essential role in p53 activation by hyperproliferation signals.…”

Transforming pathways activated by the v-Abl tyrosine kinase

“…Arf expression (Cong et al, 1999b). This suggests that within certain cellular contexts p53 activates an apoptotic response to the expression of v-Abl tyrosine kinase.…”

“…This was demonstrated by a failure of p53 protein accumulation, inability to induce cell cycle arrest and inability to induce p21 expression following DNA damage (Huang et al, 1996). p53, however is not directly responsible for susceptibility to v-Abl-mediated transformation, since Human Papilloma Virus E6-mediated inactivation of p53 does not render resistant cells permissive (Cong et al, 1999b). In contrast to these immortalized fibroblasts, primary mouse embryo fibroblasts (MEFs) can be rendered susceptible to v-Abl transformation by loss of either p53 or p19…”

Identification of an ataxia telangiectasia-mutated protein mediated surveillance system to regulate Bcl-2 overexpression

“…Expression of oncogenic Ras, c-Myc, E1A, E2F1, v-Abl and/or bcatenin in normal cells activates p53, at least in part, via the p14/p19 ARF tumor suppressor (Serrano et al, 1997; de Stanchina et al, 1998;Palmero et al, 1998;Zindy et al, 1998;Cong et al, 1999;Dimri et al, 2000;Damalas et al, 2001). In contrast, in colorectal cancer, expression of b-catenin induces p53 stabilization independently of p14/p19 ARF (Damalas et al, 1999).…”