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Original Article |
Correspondence to: Edward H. Koo, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093. Tel:(858) 822-1024 Fax:(858) 822-1021 E-mail:edkoo{at}ucsd.edu.
In addition to its documented role in the proteolytic processing of Notch-1 and the ß-amyloid precursor protein, presenilin 1 (PS1) associates with ß-catenin. In this study, we show that this interaction plays a critical role in regulating ß-catenin/T Cell Factor/Lymphoid Enhancer Factor-1 (LEF) signaling. PS1 deficiency results in accumulation of cytosolic ß-catenin, leading to a ß-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 ß-catenin (PS1
cat) or by two different familial Alzheimer's disease mutants. In contrast, PS1cat restores Notch-1 proteolytic cleavage and Aß generation in PS1-deficient cells, indicating that PS1 function in modulating ß-catenin levels can be separated from its roles in facilitating 
-secretase cleavage of ß-amyloid precursor protein and in Notch-1 signaling. Finally, we show an altered response to Wnt signaling and impaired ubiquitination of ß-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 ß-catenin.
Key Words: presenilin, ß-catenin, Notch-1, ß-amyloid precursor protein, cyclin D1
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