Abstract
Like many signaling pathways in development, the Notch receptor pathway plays an important role in cancer pathobiology when it is dysregulated. Potential ligand-binding sites within the epidermal growth factor (EGF)-like repeats of Notch1 have been identified, but the ligand-binding domains in Notch3, which is implicated in lung cancer, are not known. In screening a library of 155 peptides representing all 34 EGF-like repeats in Notch3, we discovered two distinct ligand-binding regions involving the 7-10 and 21-22 repeats that are distinct from the putative ligand-binding domain of Notch1. In cell-based assays, peptides from these regions induced apoptosis and reduced expression of the Notch3-dependent gene Hey1. They also bound directly to the Notch ligand Jagged1, suggesting that their mechanism of action involves disrupting interactions between Notch3 and Jagged1. Recombinant Fc fusion peptides engineered for in vivo testing showed that the Notch3 peptides defined could trigger apoptosis and suppress tumor growth in tumor xenograft assays. These findings rationalize a mechanistic approach to lung cancer treatment based on Notch3 receptor-targeted therapeutic development.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Apoptosis / drug effects*
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Basic Helix-Loop-Helix Transcription Factors / biosynthesis
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Binding Sites
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Calcium-Binding Proteins / metabolism
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Cell Cycle Proteins / biosynthesis
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Cell Cycle Proteins / genetics
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Cell Growth Processes / physiology
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Drug Delivery Systems
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Epidermal Growth Factor / genetics
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Epidermal Growth Factor / metabolism
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HeLa Cells
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Humans
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Immunoglobulin Fc Fragments / genetics
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Immunoglobulin Fc Fragments / metabolism
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Intercellular Signaling Peptides and Proteins / metabolism
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Jagged-1 Protein
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Ligands
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Membrane Proteins / metabolism
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Peptide Fragments / genetics
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Peptide Fragments / metabolism
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Peptide Fragments / pharmacology*
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Peptide Library
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Protein Structure, Tertiary
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Receptor, Notch3
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Receptors, Notch / antagonists & inhibitors*
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Receptors, Notch / metabolism
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Recombinant Fusion Proteins / pharmacology*
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Serrate-Jagged Proteins
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Calcium-Binding Proteins
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Cell Cycle Proteins
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HEY1 protein, human
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Immunoglobulin Fc Fragments
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Intercellular Signaling Peptides and Proteins
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JAG1 protein, human
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Jagged-1 Protein
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Ligands
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Membrane Proteins
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NOTCH3 protein, human
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Peptide Fragments
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Peptide Library
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Receptor, Notch3
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Receptors, Notch
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Recombinant Fusion Proteins
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Serrate-Jagged Proteins
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Epidermal Growth Factor