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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
4
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pubmed:dateCreated |
2006-3-20
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pubmed:databankReference |
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pubmed:abstractText |
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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Imidazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Intracellular Signaling Peptides...,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/Piperazines,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-mdm2,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Small Interfering,
http://linkedlifedata.com/resource/pubmed/chemical/TP53BP1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Suppressor Protein p53,
http://linkedlifedata.com/resource/pubmed/chemical/nutlin 3
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
1552-4450
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
2
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
202-6
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pubmed:dateRevised |
2007-1-12
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pubmed:meshHeading |
pubmed-meshheading:16474381-Animals,
pubmed-meshheading:16474381-Antineoplastic Agents,
pubmed-meshheading:16474381-Automatic Data Processing,
pubmed-meshheading:16474381-Blotting, Western,
pubmed-meshheading:16474381-Cell Line, Tumor,
pubmed-meshheading:16474381-Cells, Cultured,
pubmed-meshheading:16474381-DNA Damage,
pubmed-meshheading:16474381-Fibroblasts,
pubmed-meshheading:16474381-Gene Expression Regulation, Neoplastic,
pubmed-meshheading:16474381-Genes, p53,
pubmed-meshheading:16474381-Genetic Techniques,
pubmed-meshheading:16474381-Humans,
pubmed-meshheading:16474381-Imidazoles,
pubmed-meshheading:16474381-Intracellular Signaling Peptides and Proteins,
pubmed-meshheading:16474381-Mice,
pubmed-meshheading:16474381-Microscopy, Fluorescence,
pubmed-meshheading:16474381-Models, Chemical,
pubmed-meshheading:16474381-Neoplasms,
pubmed-meshheading:16474381-Nuclear Proteins,
pubmed-meshheading:16474381-Nucleic Acid Hybridization,
pubmed-meshheading:16474381-Oligonucleotide Array Sequence Analysis,
pubmed-meshheading:16474381-Phosphoproteins,
pubmed-meshheading:16474381-Piperazines,
pubmed-meshheading:16474381-Plasmids,
pubmed-meshheading:16474381-Proto-Oncogene Proteins c-mdm2,
pubmed-meshheading:16474381-RNA, Small Interfering,
pubmed-meshheading:16474381-RNA Interference,
pubmed-meshheading:16474381-Signal Transduction,
pubmed-meshheading:16474381-Tumor Suppressor Protein p53
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pubmed:year |
2006
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pubmed:articleTitle |
An shRNA barcode screen provides insight into cancer cell vulnerability to MDM2 inhibitors.
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pubmed:affiliation |
Division of Molecular Carcinogenesis and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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