Presenilin 1 negatively regulates β-catenin/T cell factor/lymphoid enhancer factor-1 signaling independently of β-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 (PS1 Delta cat) or by two different familial Alzheimer's disease mutants. In contrast, PS1 Delta cat restores Notch-1 proteolytic cleavage and A beta 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.