Formation of novel p53 nuclear complexes during apoptosis

Columbia University Health Sciences, New York NY

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Abstract

In melanoma, the DNA damaging agent cisplatin induces apoptosis, the complex process where cell signaling pathways program cell death. One of these pathways involves the incompletely understood response of the tumor suppressor protein p53. P53 transactivates the transcription of Bas, whose expression favors apoptosis. In order for p53 to be functional in the apoptotic pathway, not only must the primary sequence of the amino acids in p53 be conserved but the mechanisms responsible for the implementation of a p53 response must also be intact in wild type form. We show that cisplatin induces the formation of previously unreported nuclear complexes between wild type p53 and Bax in two human cisplatin sensitive melanoma cell lines. These nuclear p53/Bax complexes temporally form when caspase 3 is activated and are localized near fragmented DNA. Additionally, preliminary evidence suggests that this complex has DNA nuclease activity. These complexes are not formed in other wild type p53 and mutant p53 melanoma cells lines resistant to cisplatin treatment. This novel finding suggests that in melanoma cells sensitive to chemotherapy, nuclear p53/Bax complexes may play a role in apoptosis.