Abstract
Notch receptors and their ligands have crucial roles in development and tumorigenesis. We present evidence demonstrating the existence of an antagonistic relationship between Notch 4 and Trp53, which is controlled by the Mdm2-dependent ubiquitylation and degradation of the Notch receptor. We show that this signal-controlling mechanism is mediated by physical interactions between Mdm2 and Notch 4 and suggest the existence of a trimeric complex between Trp53, Notch 4 and Mdm2, which ultimately regulates Notch activity. Functional studies indicate that Trp53 can suppress NICD4-induced anchorage-independent growth in mammary epithelial cells and present evidence showing that Trp53 has a pivotal role in the suppression of Notch-associated tumorigenesis in the mammary gland.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Cell Line
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Epithelial Cells / chemistry
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Epithelial Cells / metabolism
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Humans
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Mice
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Protein Binding
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Protein Structure, Tertiary
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Proto-Oncogene Proteins / chemistry
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-mdm2 / genetics
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Proto-Oncogene Proteins c-mdm2 / metabolism*
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Receptor, Notch4
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Receptors, Notch / chemistry
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Receptors, Notch / genetics
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Receptors, Notch / metabolism*
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Signal Transduction*
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
Substances
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NOTCH4 protein, human
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Proto-Oncogene Proteins
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Receptor, Notch4
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Receptors, Notch
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Tumor Suppressor Protein p53
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Mdm2 protein, mouse
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Proto-Oncogene Proteins c-mdm2