Abstract
The identification of the cellular targets of small molecules with anticancer activity is crucial to their further development as drug candidates. Here, we present the application of a large-scale RNA interference-based short hairpin RNA (shRNA) barcode screen to gain insight in the mechanism of action of nutlin-3 (1). Nutlin-3 is a small-molecule inhibitor of MDM2, which can activate the p53 pathway. Nutlin-3 shows strong antitumor effects in mice, with surprisingly few side effects on normal tissues. Aside from p53, we here identify 53BP1 as a critical mediator of nutlin-3-induced cytotoxicity. 53BP1 is part of a signaling network induced by DNA damage that is frequently activated in cancer but not in healthy tissues. Our results suggest that nutlin-3's tumor specificity may result from its ability to turn a cancer cell-specific property (activated DNA damage signaling) into a weakness that can be exploited therapeutically.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Blotting, Western
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Cell Line, Tumor
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Cells, Cultured
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DNA Damage
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Electronic Data Processing
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Fibroblasts / metabolism
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Gene Expression Regulation, Neoplastic*
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Genes, p53
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Genetic Techniques*
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Humans
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Imidazoles / chemistry
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Intracellular Signaling Peptides and Proteins / chemistry
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Mice
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Microscopy, Fluorescence
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Models, Chemical
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Neoplasms / drug therapy*
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Nuclear Proteins
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Nucleic Acid Hybridization
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Oligonucleotide Array Sequence Analysis
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Phosphoproteins / chemistry
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Piperazines / chemistry
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Plasmids / metabolism
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Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-mdm2 / metabolism*
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RNA Interference
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RNA, Small Interfering / chemistry*
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Signal Transduction
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor p53-Binding Protein 1
Substances
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Antineoplastic Agents
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Imidazoles
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Intracellular Signaling Peptides and Proteins
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Nuclear Proteins
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Phosphoproteins
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Piperazines
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RNA, Small Interfering
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TP53BP1 protein, human
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Tumor Suppressor Protein p53
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Tumor Suppressor p53-Binding Protein 1
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nutlin 3
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Proto-Oncogene Proteins c-mdm2
Associated data
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PubChem-Substance/8139831
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PubChem-Substance/8139832