A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations.
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.
Mesh Terms:
Amyloid Precursor Protein Secretases, Animals, Aspartic Acid Endopeptidases, Blotting, Western, Cadherins, Carrier Proteins, Cell Line, Cell Membrane, Cells, Cultured, Cysteine Endopeptidases, Cytoplasm, Dose-Response Relationship, Drug, Down-Regulation, Endopeptidases, Genes, Dominant, Genetic Vectors, Humans, Immunoblotting, Membrane Proteins, Mice, Microscopy, Fluorescence, Multienzyme Complexes, Mutation, Neurons, Peptides, Precipitin Tests, Presenilin-1, Proteasome Endopeptidase Complex, Protein Binding, Protein Structure, Tertiary, Reverse Transcriptase Polymerase Chain Reaction, Subcellular Fractions, Synapses, Time Factors, Transcription, Genetic, Transcriptional Activation, Tubulin
Amyloid Precursor Protein Secretases, Animals, Aspartic Acid Endopeptidases, Blotting, Western, Cadherins, Carrier Proteins, Cell Line, Cell Membrane, Cells, Cultured, Cysteine Endopeptidases, Cytoplasm, Dose-Response Relationship, Drug, Down-Regulation, Endopeptidases, Genes, Dominant, Genetic Vectors, Humans, Immunoblotting, Membrane Proteins, Mice, Microscopy, Fluorescence, Multienzyme Complexes, Mutation, Neurons, Peptides, Precipitin Tests, Presenilin-1, Proteasome Endopeptidase Complex, Protein Binding, Protein Structure, Tertiary, Reverse Transcriptase Polymerase Chain Reaction, Subcellular Fractions, Synapses, Time Factors, Transcription, Genetic, Transcriptional Activation, Tubulin
Cell
Date: Sep. 05, 2003
PubMed ID: 13678586
View in: Pubmed Google Scholar
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