A CBP Binding Transcriptional Repressor Produced by the PS1/ϵ-Cleavage of N-Cadherin Is Inhibited by PS1 FAD Mutations

PS1 is important for the ␥-secretase cleavages of the Philadelphia, Pennsylvania 19104 amyloid precursor protein (APP), which results in the production of the A␤ peptide of Alzheimer's disease (AD) (De Strooper et al., 1998). Recent reports, however, show that in addition to the classic ␥-secretase cleav-Summary ages of APP defined by the C terminus of various A␤ species, the PS1/␥-secretase system promotes the Presenilin1 (PS1), a protein implicated in Alzheimer's ⑀-cleavage (Weidemann et al., 2002) of several type I disease (AD), forms complexes with N-cadherin, a transmembrane proteins, including APP, Notch1, E-cadh-transmembrane protein with important neuronal and erin, and CD44. Although this cleavage is also sensitive synaptic functions. Here, we show that a PS1-depen-to ␥-secretase inhibitors, it takes place further down-dent ␥-secretase protease activity promotes an ⑀-like stream from the amyloidogenic ␥-secretase cleavages cleavage of N-cadherin to produce its intracellular do-at a site closer to the membrane/cytoplasm interface main peptide, N-Cad/CTF2. NMDA receptor agonists than the ␥-cleavages (Fortini, 2002). In certain cases, stimulate N-Cad/CTF2 production suggesting that this like E-cadherin, the ⑀-cleavage is greatly stimulated by receptor regulates the ⑀-cleavage of N-cadherin. N-Cad/ calcium imbalance or apoptosis (Marambaud et al., CTF2 binds the transcription factor CBP and promotes 2002). The ⑀-cleavage results in the release of soluble its proteasomal degradation, inhibiting CRE-depen-cytosolic peptides containing the intracellular domains dent transactivation. Thus, the PS1-dependent ⑀-cleav-(ICDs) of the cleaved substrate proteins. Some of these age product N-Cad/CTF2 functions as a potent repres-peptides have been shown to migrate to the nucleus sor of CBP/CREB-mediated transcription. Importantly, where they may act as regulators of gene expression PS1 mutations associated with familial AD (FAD) and (Fortini, 2002). PS1 forms high-molecular weight coma ␥-secretase dominant-negative mutation inhibit plexes with a number of proteins and its precise role in N-Cad/CTF2 production and upregulate CREB-medi-the ␥-and ⑀-cleavages of type I transmembrane proteins ated transcription indicating that FAD mutations cause is under intense investigation (De Strooper, 2003). a gain of transcriptional function by inhibiting produc-Transcriptional coactivator CBP (CREB binding pro-tion of transcriptional repressor N-Cad/CTF2. These tein) interacts with and regulates the activities of a multi-data raise the possibility that FAD mutation-induced tude of signal-responsive transcription factors and may transcriptional abnormalities maybe causally related thus integrate converging gene-regulatory pathways to the dementia associated with FAD. (Goodman and Smolik, 2000). CBP acts as a scaffold that facilitates recruitment of additional transcriptional Introduction modulators on the basal transcriptional complex. In addition , CBP …