Presenilin 1 (PS1) is linked with Alzheimer's disease but exhibits functional roles regulating growth and development. For instance, PS1 binds to β-catenin and modulates β-catenin signaling. In the current study, we observed that knockout of PS1 inhibited β-catenin-mediated transcription by 35%, as shown by a luciferase reporter driven by the hTcf-4 promoter. Overexpressing wild-type PS1 increased β-catenin-mediated transcription by 37.5%, and overexpressing PS1 with mutations associated with Alzheimer's disease decreased β-catenin-mediated transcription by 66%. To examine whether regulation of β-catenin by PS1 requires phosphorylation by glycogen synthase kinase 3β (GSK 3β), we examined whether inhibiting GSK 3β activity overcomes the inhibition of β-catenin transcription induced by mutant PS1 constructs. Cells expressing wild-type or mutant PS1 were treated with LiC1, which inhibits GSK 3β, or transfected with β-catenin constructs that lack the GSK 3β phosphorylation sites. Neither treatment overcame PS1-mediated inhibition of β-catenin signaling, suggesting that regulation of β-catenin by PS1 was not affected by the activity of GSK 3β. To investigate how PS1 might regulate β-catenin signaling, we determined whether PS1 interacts with other elements of the β-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 β-catenin signaling cascade and suggest that PS1 regulates β-catenin in a manner independent of GSK 3β activity.
|Number of pages||7|
|Journal||Journal of Biological Chemistry|
|State||Published - Oct 19 2001|
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology