PTP-S2/TC45 is a nuclear protein tyrosine phosphatase, which induces p53-dependent apoptosis. Here we show that the p53 protein level increased in MCF-7 cells in response to PTP-S2 overexpression. PTP-S2-induced p53 protein was transcriptionally active and it could activate caspase-1 gene expression from endogenous as well as ectopic promoter. Coexpression of an active site mutant of procaspase-1 strongly inhibited PTP-S2-induced apoptosis. Mutant procaspase-1 also inhibited apoptosis induced by p53 overexpression or doxorubicin treatment, which induce caspase-1 gene expression. In contrast, apoptosis induced by staurosporine or cycloheximide, which do not increase caspase-1 gene expression, was not affected by mutant procaspase-1. These results suggest that caspase-1 may be one of the mediators of p53-dependent apoptosis in human cells.