title: Activation of caspases in p53-induced transactivation-independent apoptosis.
abstract: Though p53-induced apoptosis plays an important role in tumor suppression, the mechanism(s) by which p53 induces apoptosis is still unclear. To elucidate the p53-induced apoptotic pathway, we examined the role of p53 transactivation activity and caspase in J138V5C cells carrying a human temperature-sensitive (ts) p53 mutant (138Ala-->Val). The results showed that p53-induced apoptosis was not blocked by cycloheximide, which effectively prevented the expression of p53 target genes, indicating that transactivation was not essential for p53-induced apoptosis in this system. Western blot analysis showed that PARP, CPP32 and ICH-1 precursors were cleaved during apoptosis. The CPP32-preferential tetrapeptide inhibitor Ac-DEVD-CHO blocked the cleavage of ICH-1 and PARP precursors, suggesting that CPP32 or some other DEVD-sensitive caspase(s) is the upstream activator of ICH-1. We also examined the role of the Fas pathway by using Fas and Fas ligand-neutralizing antibodies. Both antibodies failed to block p53-induced apoptosis, suggesting that the Fas pathway was not essential for p53-induced apoptosis in this system. Taken together, our results indicate that p53-induced, transactivation-independent apoptosis in Jurkat cells involves sequential activation of CPP32 or some other DEVD-sensitive caspase(s) and ICH-1, via a Fas-independent pathway.
authors: Department of Molecular Cellular Oncology, Tokyo Medical and Dental University.
authors: C
authors: C
authors: Gao
authors: N
authors: N
authors: Tsuchida
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000502:physiology*; D003513:Cycloheximide / Q000494:pharmacology; D004789:Enzyme Activation; D006801:Humans; D019169:Jurkat Cells; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D019014:fas Receptor / Q000502:physiology
chemical_list: D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D003513:Cycloheximide; D020169:Caspases