Integrity of the N-terminal transcription domain of p53 is required for mutant p53 interference with drug-induced apoptosis

The present study examined whether the ability of mutant p53 to block apopt osis depended on its transcriptional activity. A core domain mutant p53 (14 3 Val to Ala), in which two N-terminal residues (22 and 23) essential for t ransactivation were also mutated (Leu to Glu and Trp to Ser, respectively), was examined. While p53 containing only the core mutation efficiently inte rfered with drug-induced apoptosis, further modification at the N-terminus abolished this blocking activity. Furthermore, expression of c-myc, a sugge sted target for core mutant p53 transactivation, was elevated in the core m utant p53-expressing cells, but was abolished in the presence of the transc ription-deficient p53 core mutant. In addition, wild-type p53, mutated in t he N-terminus (residues 22 and 23), was unable to induce apoptosis by itsel f. Nevertheless, it synergized with drugs in the induction of apoptosis. Th is suggests that the integrity of the N-terminus is essential for both the activity of wild-type p53 in apoptosis and for mutant p53-mediated block of drug-induced apoptosis. This supports the notion that core p53 mutants act via a gain of function mechanism.