Presenilin 1 regulates β-catenin-mediated transcription in a glycogen synthase kinase-3-independent fashion

Presenilin 1 (PS1) is linked with Alzheimer's disease but exhibits functional roles regulating growth and development. For instance, PS1 binds to beta -catenin and modulates beta -catenin signaling. In the current study, we observed that knockout of PSI inhibited beta -catenin-mediated transcription by 35%, as shown by a luciferase reporter driven by the hTcf-4 promoter. Overexpressing wild-type PS1 increased beta -catenin-mediated transcription by 37.5%, and overexpressing PS1 with mutations associated with Alzheimer's disease decreased beta -catenin-mediated transcription by 66%. To examine whether regulation of beta -catenin by PS1 requires phosphorylation by glycogen synthase kinase 3 beta (GSK 3 beta), we examined whether inhibiting GSK 3 beta activity overcomes the inhibition of beta -catenin transcription induced by mutant PS1 constructs. Cells expressing wild-type or mutant PS1 were treated with LiCl, which inhibits GSK 3 beta, or transfected with beta -catenin constructs that lack the GSK 3 beta phosphorylation sites. Neither treatment overcame PS1-mediated inhibition of beta -catenin signaling, suggesting that regulation of beta -catenin by PS1 was not affected by the activity of GSK 3 beta. To investigate how PS1 might regulate beta -catenin signaling, we determined whether PSI interacts with other elements of the beta -catenin signaling cascade, such as the Tcf-4 transcription factor. Coimmunoprecipitation studies showed binding of PS1 and hTcf-4, and examining nuclear isolates indicated that nuclear hTcf-4 was decreased in cells expressing mutant PS1. These data show that PS1 interacts with multiple components of the beta -catenin signaling cascade and suggest that PS1 regulates beta -catenin in a manner independent of GSK 3 beta activity.