| Small molecule-based reversible reprogramming of cellular lifespan. | |
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MedLine Citation:
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PMID: 16767085 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Most somatic cells encounter an inevitable destiny, senescence. Little progress has been made in identifying small molecules that extend the finite lifespan of normal human cells. Here we show that the intrinsic 'senescence clock' can be reset in a reversible manner by selective modulation of the ataxia telangiectasia-mutated (ATM) protein and ATM- and Rad3-related (ATR) protein with a small molecule, CGK733. This compound was identified by a high-throughput phenotypic screen with automated imaging. Employing a magnetic nanoprobe technology, magnetism-based interaction capture (MAGIC), we identified ATM as the molecular target of CGK733 from a genome-wide screen. CGK733 inhibits ATM and ATR kinase activities and blocks their checkpoint signaling pathways with great selectivity. Consistently, siRNA-mediated knockdown of ATM and ATR induced the proliferation of senescent cells, although with lesser efficiency than CGK733. These results might reflect the specific targeting of the kinase activities of ATM and ATR by CGK733 without affecting any other domains required for cell proliferation. |
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Authors:
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Jaejoon Won; Mina Kim; Nuri Kim; Jin Hee Ahn; Woo Gil Lee; Sung Soo Kim; Ki-Young Chang; Yong-Weon Yi; Tae Kook Kim |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Retracted Publication Date: 2006-06-11 |
Journal Detail:
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Title: Nature chemical biology Volume: 2 ISSN: 1552-4450 ISO Abbreviation: Nat. Chem. Biol. Publication Date: 2006 Jul |
Date Detail:
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Created Date: 2006-06-19 Completed Date: 2006-08-09 Revised Date: 2011-11-02 |
Medline Journal Info:
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Nlm Unique ID: 101231976 Medline TA: Nat Chem Biol Country: United States |
Other Details:
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Languages: eng Pagination: 369-74 Citation Subset: IM |
Affiliation:
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Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Benzeneacetamides
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chemistry,
pharmacology* Cell Aging / drug effects*, physiology* Cell Cycle / drug effects Cell Cycle Proteins / metabolism* Cell Line DNA-Binding Proteins / metabolism* Humans Molecular Structure Protein-Serine-Threonine Kinases / metabolism* Signal Transduction / drug effects Thiourea / analogs & derivatives*, chemistry, pharmacology Tumor Suppressor Proteins / metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Benzeneacetamides; 0/CGK 733; 0/Cell Cycle Proteins; 0/DNA-Binding Proteins; 0/Tumor Suppressor Proteins; 62-56-6/Thiourea; EC 2.7.1.-/ATR protein, human; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/ataxia telangiectasia mutated protein |
| Comments/Corrections | |
Erratum In:
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Nat Chem Biol. 2007 Feb;3(2):126 |
Retraction In:
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Won J, Kim M, Kim N, Ahn JH, Lee WG, Kim SS, Chang KY, Yi YW. Nat Chem Biol. 2008 Jul;4(7):431
[PMID:
18560433
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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