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Published online 19 February 2001. doi:10.1083/jcb.152.4.785
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© The Rockefeller University Press, 0021-9525/2001//785 $5.00
The Journal of Cell Biology, Volume 152, Number 4, , 2001 785-794

Original Article

Presenilin 1 Negatively Regulates β-Catenin/T Cell Factor/Lymphoid Enhancer Factor-1 Signaling Independently of β-Amyloid Precursor Protein and Notch Processing



Salvador Sorianoa, David E. Kanga, Maofu Fub, Richard Pestellb, Nathalie Chevalliera, Hui Zhengc, and Edward H. Kooa

a Department of Neurosciences, University of California, San Diego, La Jolla, California 92093
b The Albert Einstein Cancer Center, Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461
c Huffington Center on Aging and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093.(858) 822-1021(858) 822-1024

edkoo{at}ucsd.edu

In addition to its documented role in the proteolytic processing of Notch-1 and the β-amyloid precursor protein, presenilin 1 (PS1) associates with β-catenin. In this study, we show that this interaction plays a critical role in regulating β-catenin/T Cell Factor/Lymphoid Enhancer Factor-1 (LEF) signaling. PS1 deficiency results in accumulation of cytosolic β-catenin, leading to a β-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 β-catenin (PS1{Delta}cat) or by two different familial Alzheimer's disease mutants. In contrast, PS1{Delta}cat restores Notch-1 proteolytic cleavage and Aβ generation in PS1-deficient cells, indicating that PS1 function in modulating β-catenin levels can be separated from its roles in facilitating {gamma}-secretase cleavage of β-amyloid precursor protein and in Notch-1 signaling. Finally, we show an altered response to Wnt signaling and impaired ubiquitination of β-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 β-catenin.

Key Words: presenilin • β-catenin • Notch-1 • β-amyloid precursor protein • cyclin D1

© 2001 The Rockefeller University Press

Abbreviations used in this paper: Aβ, amyloid β-peptide; APC, adenomatous polyposis coli; APP, β-amyloid precursor protein; FAD, familial Alzheimer's disease; GSK, glycogen synthase kinase; LEF, T cell factor/lymphoid enhancer factor-1; NICD, Notch intracellular domain; PS1, presenilin 1; RT, reverse transcription.


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