The intracellular domain of the amyloid precursor protein (AICD) enhances the p53-mediated apoptosis

Amyloid precursor protein (APP)-derived intracellular domain (AICD) has a cytotoxic effect on neuronal cells and also participates in the regulation of gene transactivation. However, the precise molecular mechanisms behind the AICD-mediated apoptosis remain unknown. In this study, we have demonstrated that AICD interacts with p53 and enhances its transcriptional and pro-apoptotic functions. p53 was induced to be accumulated and associated with APP in response to cisplatin. Indeed, APP-C57 was co-immunoprecipitated with the endogenous p53. Enforced expression of APP-C57 or APP-C59 in U2OS cells bearing wild-type p53 led to an increase in number of apoptotic cells, whereas they had undetectable effects on p53-deficient H1299 cells, suggesting that AICD contributes to the activation of the p53-mediated apoptotic pathway. Consistent with this notion, the p53-mediated transcriptional activation and apoptosis were significantly enhanced by co-expression with APP-C57 or APP-C59. Thus, our present results strongly suggest that AICD triggers apoptosis through the p53-dependent mechanisms. (c) 2006 Elsevier Inc. All rights reserved.