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.