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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
31
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pubmed:dateCreated |
2003-7-28
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pubmed:abstractText |
Human kininogen belongs to the plasma kallikreinkinin system. High molecular weight kininogen is the precursor for two-chain kinin-free kininogen and bradykinin. It has been shown that the two-chain kinin-free kininogen has the properties of anti-adhesion, anti-platelet aggregation, and anti-thrombosis, whereas bradykinin is a potent vasodilator and mediator of inflammation. In this study we show that the human kininogen gene is strongly up-regulated by agonists of the farnesoid X receptor (FXR), a nuclear receptor for bile acids. In primary human hepatocytes, both the endogenous FXR agonist chenodeoxycholate and synthetic FXR agonist GW4064 increased kininogen mRNA with a maximum induction of 8-10-fold. A more robust induction of kininogen expression was observed in HepG2 cells, where kininogen mRNA was increased by chenodeoxycholate or GW4064 up to 130-140-fold as shown by real time PCR. Northern blot analysis confirmed the up-regulation of kininogen expression by FXR agonists. To determine whether kininogen is a direct target of FXR, we examined the sequence of the kininogen promoter and identified a highly conserved FXR response element (inverted repeat, IR-1) in the proximity of the kininogen promoter (-66/-54). FXR/RXRalpha heterodimers specifically bind to this IR-1. A construct of a minimal promoter with the luciferase reporter containing this IR-1 was transactivated by FXR. Deletion or mutation of this IR-1 abolished FXR-mediated promoter activation, indicating that this IR-1 element is responsible for the promoter transactivation by FXR. We conclude that kininogen is a novel and direct target of FXR, and bile acids may play a role in the vasodilation and anti-coagulation processes.
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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/Chenodeoxycholic Acid,
http://linkedlifedata.com/resource/pubmed/chemical/DNA,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/GW 4064,
http://linkedlifedata.com/resource/pubmed/chemical/Isoxazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Kininogens,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Cytoplasmic and Nuclear,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Retinoic Acid,
http://linkedlifedata.com/resource/pubmed/chemical/Retinoid X Receptors,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/farnesoid X-activated receptor
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0021-9258
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pubmed:author |
pubmed-author:BlevinsRichard ARA,
pubmed-author:CuiJisongJ,
pubmed-author:HrywnaYaroslavY,
pubmed-author:HuangLiL,
pubmed-author:LewJane-LJL,
pubmed-author:PeláezFernandoF,
pubmed-author:ThompsonJohn RJR,
pubmed-author:WrightSamuel DSD,
pubmed-author:YuJinghuaJ,
pubmed-author:ZhangTheresaT,
pubmed-author:ZhaoAnnieA,
pubmed-author:de PedroNuriaN
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pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
278
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
28765-70
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pubmed:dateRevised |
2008-11-21
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pubmed:meshHeading |
pubmed-meshheading:12761213-Binding Sites,
pubmed-meshheading:12761213-Blotting, Northern,
pubmed-meshheading:12761213-Carcinoma, Hepatocellular,
pubmed-meshheading:12761213-Chenodeoxycholic Acid,
pubmed-meshheading:12761213-DNA,
pubmed-meshheading:12761213-DNA-Binding Proteins,
pubmed-meshheading:12761213-Gene Deletion,
pubmed-meshheading:12761213-Gene Expression Regulation,
pubmed-meshheading:12761213-Hepatocytes,
pubmed-meshheading:12761213-Humans,
pubmed-meshheading:12761213-Isoxazoles,
pubmed-meshheading:12761213-Kininogens,
pubmed-meshheading:12761213-Liver Neoplasms,
pubmed-meshheading:12761213-Mutagenesis, Site-Directed,
pubmed-meshheading:12761213-Polymerase Chain Reaction,
pubmed-meshheading:12761213-Promoter Regions, Genetic,
pubmed-meshheading:12761213-RNA, Messenger,
pubmed-meshheading:12761213-Receptors, Cytoplasmic and Nuclear,
pubmed-meshheading:12761213-Receptors, Retinoic Acid,
pubmed-meshheading:12761213-Repetitive Sequences, Nucleic Acid,
pubmed-meshheading:12761213-Retinoid X Receptors,
pubmed-meshheading:12761213-Transcription Factors,
pubmed-meshheading:12761213-Transcriptional Activation,
pubmed-meshheading:12761213-Transfection,
pubmed-meshheading:12761213-Tumor Cells, Cultured
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pubmed:year |
2003
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pubmed:articleTitle |
Human kininogen gene is transactivated by the farnesoid X receptor.
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pubmed:affiliation |
Department of Atherosclerosis and Endocrinology, Bioinformatics, and Molecular Profiling, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
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pubmed:publicationType |
Journal Article
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