Abstract
Presenilin1 (PS1), a protein implicated in Alzheimer's disease (AD), forms complexes with N-cadherin, a transmembrane protein with important neuronal and synaptic functions. Here, we show that a PS1-dependent gamma-secretase protease activity promotes an epsilon-like cleavage of N-cadherin to produce its intracellular domain peptide, N-Cad/CTF2. NMDA receptor agonists stimulate N-Cad/CTF2 production suggesting that this receptor regulates the epsilon-cleavage of N-cadherin. N-Cad/CTF2 binds the transcription factor CBP and promotes its proteasomal degradation, inhibiting CRE-dependent transactivation. Thus, the PS1-dependent epsilon-cleavage product N-Cad/CTF2 functions as a potent repressor of CBP/CREB-mediated transcription. Importantly, PS1 mutations associated with familial AD (FAD) and a gamma-secretase dominant-negative mutation inhibit N-Cad/CTF2 production and upregulate CREB-mediated transcription indicating that FAD mutations cause a gain of transcriptional function by inhibiting production of transcriptional repressor N-Cad/CTF2. These data raise the possibility that FAD mutation-induced transcriptional abnormalities maybe causally related to the dementia associated with FAD.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amyloid Precursor Protein Secretases
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Animals
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Aspartic Acid Endopeptidases
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Blotting, Western
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Cadherins / chemistry
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Cadherins / metabolism*
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Carrier Proteins / metabolism*
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Cell Line
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Cell Membrane / metabolism
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Cells, Cultured
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Cysteine Endopeptidases / metabolism
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Cytoplasm / metabolism
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Dose-Response Relationship, Drug
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Down-Regulation
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Endopeptidases / metabolism
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Genes, Dominant
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Genetic Vectors
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Humans
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Immunoblotting
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Membrane Proteins / metabolism
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Mice
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Microscopy, Fluorescence
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Multienzyme Complexes / metabolism
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Mutation
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Neurons / metabolism
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Peptides / chemistry
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Precipitin Tests
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Presenilin-1
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Proteasome Endopeptidase Complex
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Protein Binding
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Protein Structure, Tertiary
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Reverse Transcriptase Polymerase Chain Reaction
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Subcellular Fractions / metabolism
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Synapses / metabolism
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Time Factors
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Transcription, Genetic*
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Transcriptional Activation
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Tubulin / metabolism
Substances
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Cadherins
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Carrier Proteins
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Membrane Proteins
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Multienzyme Complexes
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PSEN1 protein, human
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Peptides
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Presenilin-1
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Tubulin
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citrate-binding transport protein
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Amyloid Precursor Protein Secretases
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Endopeptidases
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Cysteine Endopeptidases
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Aspartic Acid Endopeptidases
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BACE1 protein, human
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Bace1 protein, mouse
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Proteasome Endopeptidase Complex