Presenilin 1 regulates beta-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 PS1 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 3beta (GSK 3beta), we examined whether inhibiting GSK 3beta 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 3beta, or transfected with beta-catenin constructs that lack the GSK 3beta 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 3beta. To investigate how PS1 might regulate beta-catenin signaling, we determined whether PS1 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 3beta activity.
Mesh Terms:
Alzheimer Disease, Animals, Calcium-Calmodulin-Dependent Protein Kinases, Cell Line, Cell Nucleus, Cytoskeletal Proteins, Glycogen Synthase Kinase 3, Glycogen Synthase Kinases, Humans, Immunoblotting, Immunohistochemistry, Lithium Chloride, Luciferases, Membrane Proteins, Mice, Mice, Knockout, Mutation, Plasmids, Precipitin Tests, Presenilin-1, Promoter Regions, Genetic, Protein Binding, Signal Transduction, TCF Transcription Factors, Trans-Activators, Transcription Factors, Transcription, Genetic, beta Catenin
Alzheimer Disease, Animals, Calcium-Calmodulin-Dependent Protein Kinases, Cell Line, Cell Nucleus, Cytoskeletal Proteins, Glycogen Synthase Kinase 3, Glycogen Synthase Kinases, Humans, Immunoblotting, Immunohistochemistry, Lithium Chloride, Luciferases, Membrane Proteins, Mice, Mice, Knockout, Mutation, Plasmids, Precipitin Tests, Presenilin-1, Promoter Regions, Genetic, Protein Binding, Signal Transduction, TCF Transcription Factors, Trans-Activators, Transcription Factors, Transcription, Genetic, beta Catenin
J. Biol. Chem.
Date: Oct. 19, 2001
PubMed ID: 11504726
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