Abstract
Truncated Notch receptors have transforming activity in vitro and in vivo. However, the role of wild-type Notch signaling in neoplastic transformation remains unclear. Ras signaling is deregulated in a large fraction of human malignancies and is a major target for the development of novel cancer treatments. We show that oncogenic Ras activates Notch signaling and that wild-type Notch-1 is necessary to maintain the neoplastic phenotype in Ras-transformed human cells in vitro and in vivo. Oncogenic Ras increases levels and activity of the intracellular form of wild-type Notch-1, and upregulates Notch ligand Delta-1 and also presenilin-1, a protein involved in Notch processing, through a p38-mediated pathway. These observations place Notch signaling among key downstream effectors of oncogenic Ras and suggest that it might be a novel therapeutic target.
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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Animals
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Cell Transformation, Neoplastic / genetics*
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Cells, Cultured
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Down-Regulation
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Female
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Gene Expression Regulation, Neoplastic / genetics
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Humans
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mice, SCID
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Mitogen-Activated Protein Kinases / metabolism
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Phenotype
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Presenilin-1
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Receptor, Notch1
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Receptors, Cell Surface*
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Signal Transduction / genetics*
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Transcription Factors*
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Up-Regulation
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Uterine Cervical Neoplasms / genetics
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Uterine Cervical Neoplasms / metabolism
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p38 Mitogen-Activated Protein Kinases
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ras Proteins / genetics
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ras Proteins / metabolism*
Substances
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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NOTCH1 protein, human
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Notch1 protein, mouse
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PSEN1 protein, human
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Presenilin-1
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Receptor, Notch1
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Receptors, Cell Surface
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Transcription Factors
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delta protein
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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ras Proteins