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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 (PS1Δcat) or by two different familial Alzheimer's disease mutants. In contrast, PS1Δcat 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 γ-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. presenilin β-catenin Notch-1 β-amyloid precursor protein cyclin D1 Footnotes 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. Submitted: 1 November 2000 Revision requested 26 December 2000 Accepted: 5 January 2001
The Journal of Cell Biology – Rockefeller University Press
Published: Feb 19, 2001
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