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.
Palacino
J J
JJ
Department of Pharmacology and Neuroscience Program, Loyola University Medical Center, Maywood, Illinois 60153, USA.
Murphy
M P
MP
Murayama
O
O
Iwasaki
K
K
Fujiwara
M
M
Takashima
A
A
Golde
T E
TE
Wolozin
B
B
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D018021:Lithium Chloride / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D053764:Presenilin-1; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015398:Signal Transduction; D051820:TCF Transcription Factors; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C544895:Tcf7l2 protein, mouse; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin; D008156:Luciferases; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride