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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
10
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pubmed:dateCreated |
2002-12-20
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pubmed:abstractText |
Transforming growth factor beta (TGF-beta) is a multifunctional protein that has been shown to possess potent growth-inhibitory activity. To identify small molecular weight compounds with TGF-beta-like activities, high throughput screening was performed using mink lung epithelial cells stably transfected with a TGF-beta-responsive plasminogen activator inhibitor 1 promoter/luciferase construct. Biaryl hydroxamate compounds were identified that demonstrated TGF-beta-like activities. 7-[4-(4-cyanophenyl)phenoxy]-heptanohydroxamic acid (A-161906) demonstrated complete TGF-beta-like agonist activity in the plasminogen activator inhibitor 1/luciferase construct. A-161906 inhibited the proliferation of multiple cell lines in a concentration-dependent manner. Cells were growth arrested at the G1-S checkpoint similar to TGF-beta. Consistent with the G1-S arrest, A-161906 induced the expression of the cyclin-dependent kinase inhibitor p21waf1/cip1. A-161906 produced many cellular effects similar to that of TGF-beta but did not displace labeled TGF-beta from its receptors. Cells with mutations in either of the TGF-beta receptors I or II were growth-arrested by A-161906. Therefore, the site of action of A-161906 appears to be distal to the receptors and possibly involved with the signaling events controlled by TGF-beta. The TGF-beta mimetic effect of A-161906 can be partially, if not entirely, explained by its activity as a histone deacetylase (HDAC) inhibitor. A-161906 demonstrated potent HDAC-inhibitory activity (IC50 = 9 nM). A-161906 is a novel small molecular weight compound (< 400 MW) having TGF-beta mimetic activity as a result of its potent HDAC-inhibitory activity. These results and those of others demonstrate the importance of HDACs in regulation of the TGF-beta signaling pathway(s).
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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/Biphenyl Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/CDKN1A protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Cdkn1a protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Collagenases,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinase Inhibitor...,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclins,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Fibronectins,
http://linkedlifedata.com/resource/pubmed/chemical/Gelsolin,
http://linkedlifedata.com/resource/pubmed/chemical/Histone Deacetylase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Hydroxamic Acids,
http://linkedlifedata.com/resource/pubmed/chemical/Luciferases,
http://linkedlifedata.com/resource/pubmed/chemical/Plasminogen Activator Inhibitor 1,
http://linkedlifedata.com/resource/pubmed/chemical/Transforming Growth Factor beta
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
1535-7163
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pubmed:author |
pubmed-author:AakreMary EME,
pubmed-author:AndersonSteven NSN,
pubmed-author:GlaserKeith BKB,
pubmed-author:LeePaulP,
pubmed-author:LiJunlingJ,
pubmed-author:MorganDouglas WDW,
pubmed-author:MosesHarold LHL,
pubmed-author:MussattoDonna JDJ,
pubmed-author:O'ConnorChad ZCZ,
pubmed-author:PollockJenniferJ,
pubmed-author:SheppardGeorgeG,
pubmed-author:StewartKent DKD,
pubmed-author:WegnerCraig WCW
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pubmed:issnType |
Print
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pubmed:volume |
1
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
759-68
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:12492108-Acetylation,
pubmed-meshheading:12492108-Animals,
pubmed-meshheading:12492108-Biphenyl Compounds,
pubmed-meshheading:12492108-Blotting, Western,
pubmed-meshheading:12492108-Cell Cycle,
pubmed-meshheading:12492108-Cell Division,
pubmed-meshheading:12492108-Cell Line,
pubmed-meshheading:12492108-Collagenases,
pubmed-meshheading:12492108-Cyclin-Dependent Kinase Inhibitor p21,
pubmed-meshheading:12492108-Cyclins,
pubmed-meshheading:12492108-Dose-Response Relationship, Drug,
pubmed-meshheading:12492108-Enzyme Inhibitors,
pubmed-meshheading:12492108-Epithelial Cells,
pubmed-meshheading:12492108-Fibroblasts,
pubmed-meshheading:12492108-Fibronectins,
pubmed-meshheading:12492108-G1 Phase,
pubmed-meshheading:12492108-Gelsolin,
pubmed-meshheading:12492108-Histone Deacetylase Inhibitors,
pubmed-meshheading:12492108-Humans,
pubmed-meshheading:12492108-Hydroxamic Acids,
pubmed-meshheading:12492108-Inhibitory Concentration 50,
pubmed-meshheading:12492108-Keratinocytes,
pubmed-meshheading:12492108-Luciferases,
pubmed-meshheading:12492108-Lung,
pubmed-meshheading:12492108-Mice,
pubmed-meshheading:12492108-Mink,
pubmed-meshheading:12492108-Models, Chemical,
pubmed-meshheading:12492108-Phenotype,
pubmed-meshheading:12492108-Plasminogen Activator Inhibitor 1,
pubmed-meshheading:12492108-Promoter Regions, Genetic,
pubmed-meshheading:12492108-S Phase,
pubmed-meshheading:12492108-Time Factors,
pubmed-meshheading:12492108-Transfection,
pubmed-meshheading:12492108-Transforming Growth Factor beta
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pubmed:year |
2002
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pubmed:articleTitle |
Transforming growth factor beta mimetics: discovery of 7-[4-(4-cyanophenyl)phenoxy]-heptanohydroxamic acid, a biaryl hydroxamate inhibitor of histone deacetylase.
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pubmed:affiliation |
Global Pharmaceutical Research & Development, Abbott Laboratories, Abbott Park, Illinois 60064-6121, USA. keith.glaser@abbott.com
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pubmed:publicationType |
Journal Article
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