p53 is multifunctional. To assess exactly what function is critical for the prevention of neoplastic transformation has proven difficult. Mutants with substitutions at positions 22 and 23 promised to address the relevance of transcription transactivation since they seemed to be defective specifically for this function. We report here that p53 mutant Q22, S23 [p53 (22,23)] is not only impaired for transactivation but for the repression of the fos promoter and SV40 early promoter. Furthermore, whereas p53 (22,23) fails to efficiently transactivate reporter genes in two p53-negative cell lines, it stimulates reporters and suppresses proliferation in two wild-type (wt) p53-positive cell lines strongly above the levels induced by the transfection procedure alone. This transactivation is refractory to inhibition by MDM-2. Finally, p53 (22,23) expressed from large plasmid quantity (1 microg) is crippled for the mediation of apoptosis in p53-negative Hep3B hepatocarcinoma cells. Nevertheless, at a quantity of only 10 ng, both mutant and wt p53 plasmids but not control plasmid, are able to induce some cell death which is not inhibitable by MDM-2. Thus, a correlation exists between p53's functions to regulate promoters and to efficiently mediate apoptosis in Hep3B cells.