Presenilin 1 negatively regulates beta-catenin/T cell factor/lymphoid enhancer factor-1 signaling independently of beta-amyloid precursor protein and notch processing.
In addition to its documented role in the proteolytic processing of Notch-1 and the beta-amyloid precursor protein, presenilin 1 (PS1) associates with beta-catenin. In this study, we show that this interaction plays a critical role in regulating beta-catenin/T Cell Factor/Lymphoid Enhancer Factor-1 (LEF) signaling. PS1 deficiency results in accumulation of cytosolic beta-catenin, leading to a beta-catenin/LEF-dependent increase in cyclin D1 transcription and accelerated entry into the S phase of the cell cycle. Conversely, PS1 specifically represses LEF-dependent transcription in a dose-dependent manner. The hyperproliferative response can be reversed by reintroducing PS1 expression or overexpressing axin, but not a PS1 mutant that does not bind beta-catenin (PS1Deltacat) or by two different familial Alzheimer's disease mutants. In contrast, PS1Deltacat restores Notch-1 proteolytic cleavage and Abeta generation in PS1-deficient cells, indicating that PS1 function in modulating beta-catenin levels can be separated from its roles in facilitating gamma-secretase cleavage of beta-amyloid precursor protein and in Notch-1 signaling. Finally, we show an altered response to Wnt signaling and impaired ubiquitination of beta-catenin in the absence of PS1, a phenotype that may account for the increased stability in PS1-deficient cells. Thus, PS1 adds to the molecules that are known to regulate the rapid turnover of beta-catenin.
Soriano
S
S
Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, USA.
Kang
D E
DE
Fu
M
M
Pestell
R
R
Chevallier
N
N
Zheng
H
H
Koo
E H
EH
D000544:Alzheimer Disease; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D060466:Axin Protein; D019938:Cyclin D1; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D003600:Cytosol; D004268:DNA-Binding Proteins / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology; D005786:Gene Expression Regulation; D051821:Lymphoid Enhancer-Binding Factor 1; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D053764:Presenilin-1; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000378:metabolism; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D016196:S Phase; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism; D051153:Wnt Proteins; D060508:Wnt3 Protein; D051176:beta Catenin
D016564:Amyloid beta-Protein Precursor; D060466:Axin Protein; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D053764:Presenilin-1; D011506:Proteins; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D014452:Ubiquitins; D051153:Wnt Proteins; D060508:Wnt3 Protein; D051176:beta Catenin; D019938:Cyclin D1; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse