Abstract
The Notch1 receptor is a crucial controller of cell fate decisions, and is also a key regulator of cell growth and differentiation in a variety of contexts. In this study, we have demonstrated that the APP intracellular domain (AICD) attenuates Notch1 signaling by accelerated degradation of the Notch1 intracellular domain (Notch1-IC) and RBP-Jk, through different degradation pathways. AICD suppresses Notch1 transcriptional activity by the dissociation of the Notch1-IC-RBP-Jk complex after processing by γ-secretase. Notch1-IC is capable of forming a trimeric complex with Fbw7 and AICD, and AICD enhances the protein degradation of Notch1-IC through an Fbw7-dependent proteasomal pathway. AICD downregulates the levels of RBP-Jk protein through the lysosomal pathway. AICD-mediated degradation is involved in the preferential degradation of non-phosphorylated RBP-Jk. Collectively, our results demonstrate that AICD functions as a negative regulator in Notch1 signaling through the promotion of Notch1-IC and RBP-Jk protein degradation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Ammonium Chloride / pharmacology
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Amyloid beta-Protein Precursor / metabolism*
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Animals
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Cell Cycle Proteins / metabolism
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Cell Differentiation / genetics
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Cell Line
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Down-Regulation / genetics
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F-Box Proteins / metabolism
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F-Box-WD Repeat-Containing Protein 7
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Genes, Reporter
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Humans
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Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism*
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Leupeptins / pharmacology
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Luciferases / genetics
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Luciferases / metabolism
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Lysosomes / drug effects
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Lysosomes / metabolism
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Mice
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Mitogen-Activated Protein Kinase 10 / metabolism
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Phosphorylation
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Proteasome Endopeptidase Complex / metabolism
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Proteasome Inhibitors
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Protein Multimerization
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Protein Stability
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Protein Structure, Tertiary
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Receptor, Notch1 / antagonists & inhibitors
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Receptor, Notch1 / metabolism*
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Signal Transduction / drug effects*
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Transcriptional Activation
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Ubiquitin-Protein Ligases / metabolism
Substances
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APP protein, human
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Amyloid beta-Protein Precursor
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Cell Cycle Proteins
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F-Box Proteins
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F-Box-WD Repeat-Containing Protein 7
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FBXW7 protein, human
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Immunoglobulin J Recombination Signal Sequence-Binding Protein
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Leupeptins
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NOTCH1 protein, human
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Proteasome Inhibitors
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RBPJ protein, human
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Receptor, Notch1
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Ammonium Chloride
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Luciferases
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Ubiquitin-Protein Ligases
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Mitogen-Activated Protein Kinase 10
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Glycogen Synthase Kinase 3 beta
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Glycogen Synthase Kinase 3
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Proteasome Endopeptidase Complex
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde