Loss of presenilin 1 is associated with enhanced beta-catenin signaling and skin tumorigenesis

Presenilin 1 (PS1) is required for the proteolytic processing of Notch and the beta -amylold precursor protein (APP), molecules that play pivotal role s in cell-fate determination during development and Alzheimer's disease pat hogenesis, respectively. In addition, PS1 interacts with beta -catenin and promotes its turnover through independent mechanisms. Consistent with this activity, we report here that PS1 is important in controlling epidermal cel l proliferation in vivo. PS1 knockout mice that are rescued through neurona l expression of human PS1 transgene develop spontaneous skin cancers. PS1-n ull keratinocytes exhibit higher cytosolic beta -catenin and beta -catenin/ lymphoid enhancer factor-1/T cell factor (beta -catenin/LEF)-mediated signa ling. This effect can be reversed by reintroducing wild-type PS1, but not a PS1 mutant active in Notch processing but defective in beta -catenin bindi ng. Nuclear beta -catenin protein can be detected in tumors. Elevated beta -catenin/LEF signaling is correlated with activation of its downstream targ et cyclin D1 and accelerated entry from G(1) into S phase of the cell cycle . This report demonstrates a function of PS1 in adult tissues, and our anal ysis suggests that deregulation of beta -catenin pathway contributes to the skin tumor phenotype.