The transforming oncoproteins determine the mechanism by which p53 suppresses cell transformation: pRb-mediated growth arrest or apoptosis.

To investigate the mechanisms by which p53 suppresses cell transformation, we used the simian virus 40 (SV40) large T antigen (LTag), the adenovirus E1a proteins, and an activated ras protein (EJ-ras), to examine different pathways of transformation for their susceptibility to suppression by p53: While p53 can suppress transformation by various oncoproteins, we have shown that it is unable to suppress the transformation of rat embryo fibroblasts (REFs) by LTag. Interestingly, the function of LTag which enables it to overcome the antiproliferative effects of p53 is not the binding and inactivation of p53, but the binding and inactivation of the pRb family of proteins. This observation indicates that pRb mediates a suppressive effect of p53 on cell transformation. We have also observed that in contrast to LTag, both E1a and EJ-ras cause transformation-related events which are susceptible to suppression by p53. Further studies have revealed that cells expressing E1a are susceptible to p53-mediated apoptosis, while cells expressing EJ-ras are susceptible to p53-induced growth inhibition. We therefore propose that p53 suppresses transformation either by arresting cell growth (mediated by pRb in late G1) or by inducing apoptosis, with the mechanism being determined by the transforming oncoprotein(s).