Absence of p21WAF1 cooperates with c-myc in bypassing Ras-induced senescence and enhances oncogenic cooperation.

The absence of p21waf1 combined with an ectopic expression of c-myc prevents ras-induced senescence in mouse embryo fibroblasts. Extension of lifespan after c-myc transduction into p21-null cells was followed at later passages by apoptosis of a large fraction of c-myc-overexpressing p21-null cells. This apoptotic effect could be overridden by inactivation of the p53 tumor suppressor or oncogenic ras expression. Ras-induced inhibition of apoptosis is mediated by PI3K activation. These results suggest a functional relationship between ras and myc that may explain their oncogenic cooperation. The number of foci formed by myc+ras increased cooperatively in the absence of p21waf1. Thus, the reciprocal cooperation between myc and ras in a p21-null background during cellular immortalization lead to increased oncogenic cooperation between ras and myc.