c-Abl neutralizes the inhibitory effect of Mdm2 on p53

Upon exposure to stress signals, the p53 tumor suppressor protein is stabil ized and induces growth suppression. p53 activities are efficiently inhibit ed by the Mdm2 oncoprotein through an autoregulatory feedback loop. In addi tion, Mdm2 promotes p53 degradation, thereby terminating its growth inhibit ory signal. Hence, p53 exerts its effects during the interval between p53 a ctivation and the subsequent inhibition by Mdma. Modulation of this interva l by regulatory proteins may determine the extent and duration of p53 activ ity, Recent studies have shown that the c-Abl protein-tyrosine kinase binds p53 and enhances its transcriptional activity. Here we provide an explanat ion for the cooperation between these proteins. We demonstrate that c-Abl i ncreases the expression level of the p53 protein, The enhanced expression i s achieved by inhibiting Mdm2-mediated degradation of p53, This provides a likely mechanistic explanation for the findings that c-Abl overcomes the in hibitory effects of Mdma on p53-mediated transcriptional activation and apo ptosis. These results suggest that c-Abl modulates the time window within w hich p53 remains active. The ability of c-Abl to neutralize the inhibitory effects of Mdma on p53 may be important for its growth inhibitory function.