In the previous studies, we have demonstrated that the tumor suppressor gene p53 is required for DNA strand break-induced neuronal apoptosis in organotypic slice cultures of cerebellum as well as in dissociated cerebellar neuron cultures. In this study, we further investigated the role of p53 in neuronal apoptosis, by examining whether caspases and c-Jun N-terminal kinase (JNK) are involved in the DNA strand break-induced apoptosis. The protein level of phospho-JNK increased in p53 wild-type mouse cerebellar granule neurons after exposure to bleomycin. On the other hand, the response was nor observed in cerebellar granule neurons of p53-deficient mice. Caspase-3-like protease was activated and poly(ADP-ribose) polymerase (PARP) was cleaved in the bleomycin-induced apoptosis. Caspase-3-like protease inhibitor decreased the number of TUNEL-positive but not p53- or c-Jun-positive neurons in bleomycin-induced death. These results suggest that JNK and caspase-3-like protease are involved in the signaling cascade of DNA strand break-induced, p53-dependent apoptosis. (C) 2001 Elsevier Science B.V. All rights reserved.