Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.26 (GSK)
 6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Presenilin 1 regulates beta-catenin-mediated transcription in a glycogen synthase kinase-3-independent fashion. 1150 26