Minimal overexpression of the p58PITSLRE protein kinase in Chinese hamster ovary cells induces telephase delay, abnormal cytokinesis, retarded cell growth and apoptosis. Fas mediated T cell death is correlated with p58PITSLRE proteolysis and an increase in its histone H1 kinase activity. In this study, it was found that p58PITSLRE had different effects on the apoptosis induced by etoposide, cycloheximide and serum-withdrawal in human hepatocarcinoma cells. The ectopic expression of p58PITSLRE in human hepatocarcinoma cells suppressed apoptosis induced by etoposide, while enhancing the apoptosis induced by cycloheximide and serum-withdrawal respectively. Elevated expression of p58PITSLRE was found during the apoptosis induced by etoposide, whereas most of p58PITSLRE was proteolytically processed during apoptosis induced by cycloheximide and serum-withdrawal. Furthermore, transient transfection of p50PITSLRE resembling the proteolytic form of p58PITSLRE enhanced the 7,721 cells susceptibility to apoptosis induced by all the three stimuli. These findings suggest that the full-length p58PITSLRE might protect the cells from the apoptosis induced by etoposide and its proteolysis might contribute to and enhance the apoptosis induced by cycloheximide and serum-withdrawal respectively.