Presenilin 1 (PS1) is linked with Alzheimer's disease but exhibits function
al roles regulating growth and development. For instance, PS1 binds to beta
-catenin and modulates beta -catenin signaling. In the current study, we o
bserved that knockout of PSI inhibited beta -catenin-mediated transcription
by 35%, as shown by a luciferase reporter driven by the hTcf-4 promoter. O
verexpressing 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 glyc
ogen synthase kinase 3 beta (GSK 3 beta), we examined whether inhibiting GS
K 3 beta activity overcomes the inhibition of beta -catenin transcription i
nduced by mutant PS1 constructs. Cells expressing wild-type or mutant PS1 w
ere 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, sug
gesting that regulation of beta -catenin by PS1 was not affected by the act
ivity of GSK 3 beta. To investigate how PS1 might regulate beta -catenin si
gnaling, we determined whether PSI interacts with other elements of the bet
a -catenin signaling cascade, such as the Tcf-4 transcription factor. Coimm
unoprecipitation studies showed binding of PS1 and hTcf-4, and examining nu
clear isolates indicated that nuclear hTcf-4 was decreased in cells express
ing 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.