A transcriptional activation function of p53 is dispensable for and inhibitory of its apoptotic function

The tumor suppressor p53 is an inducer of cell cycle arrest and programmed cell death (apoptosis), The ability of p53 to induce cell cycle arrest is l inked to its ability to induce transcription of genes such as the cyclin-de pendent kinase inhibitor p21, However, the dependence of p53-mediated apopt osis on transcriptional activation remains control versial. Ectopic express ion of a temperature-sensitive (ts) p53 allele induced expression of p53 ta rget genes and elicited both G1 and G2/M cell cycle arrest upon shift to th e permissive temperature. Ectopic expression of the same ts p53 allele with two additional point mutations (Gln22, Ser23) that abolish p53-transcripti onal activation did not induce p53 target genes and G1 nor G2/M cell cycle arrest. In HCT116 colon carcinoma cells ectopic expression of wild type p53 does not elicit apoptosis whereas p53 mutant deficient in trans-activation induces apoptosis, The ability of wild type p53 to induce apoptosis is res tored in HCT116 cells that are null for p21, However, the trans-activation deficient mutant of p53 is still more potent mediator of apoptosis than wil d type p53 in the p21 null cells. Although the ability of Gln22,Ser23 to tr ans-activate p53 target genes is diminished, it retains the ability to repr ess Bcl-2 expression. Thus, we conclude that while ectopic expression of wi ld type p53 can induce both G1 and G2/M;I arrest, in a p21 dependent manner , without apoptosis, a p53 mutant defective in transactivation elicits apop tosis without inducing cell cycle arrest. Further, the anti-apoptotic funct ion of p53 is dependent on trans-activation and is linked to cell cycle arr est. The results strongly suggest that the transactivation deficient mutant is a more potent inducer of apoptosis because it lost its anti-apoptotic f unction and retains its ability to repress pro-apoptotic genes such as Bcl- 2, Taken together, the results imply that employing a trans-activation defi cient p53 in gene therapy approaches or the use of drugs that convert mutan t p53 to a transactivation-independent mediator of apoptosis may be much mo re efficient therapeutic approaches than current approaches that employ wil d type p53.