IDENTIFICATION OF A NOVEL P53 FUNCTIONAL DOMAIN THAT IS NECESSARY FORMEDIATING APOPTOSIS

The ability of p53 to induce apoptosis requires its sequence-specific DNA binding activity; however, the transactivation-deficient p53(Gln(2 2)-Ser(23)) can still induce apoptosis, Previously, we have shown that the region between residues 23 and 97 in p53 is necessary for such ac tivity, In an effort to more precisely map a domain necessary for apop tosis within the N terminus, we found that deletion of the N-terminal 23 amino acids compromises, but does not abolish, p53 induction of apo ptosis, Surprisingly, p53(Delta 1-42), which lacks the N-terminal 42 a mino acids and the previously defined activation domain, retains the a bility to induce apoptosis to an even higher level than wild-type p53, A more extensive deletion, which eliminates the N-terminal 63 amino a cids, renders p53 completely inert in mediating apoptosis. In addition , we found that both p53(Delta 1-42) and p53(Gln(22)-Ser(23)) can acti vate a subset of cellular p53 targets. Furthermore, we showed that res idues 53 and 54 are critical for the apoptotic and transcriptional act ivities of both p53(Delta 1-42) and p53(Gln(22)-Ser(23)). Taken togeth er, these data suggest that within residues 43-63 lie an apoptotic dom ain as web as another transcriptional activation domain. We therefore postulate that the apoptotic activity in p53(Gln(22)-Ser(23)) and p53( Delta 1-42) is still transcription-dependent.