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Human Kininogen Gene Is Transactivated by the Farnesoid X Receptor
- Source :
- Journal of Biological Chemistry. 278:28765-28770
- Publication Year :
- 2003
- Publisher :
- Elsevier BV, 2003.
-
Abstract
- 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.
- Subjects :
- Transcriptional Activation
Carcinoma, Hepatocellular
Receptors, Retinoic Acid
High-molecular-weight kininogen
Response element
Receptors, Cytoplasmic and Nuclear
Bradykinin
Biology
Chenodeoxycholic Acid
Transfection
Polymerase Chain Reaction
Biochemistry
chemistry.chemical_compound
Transactivation
Tumor Cells, Cultured
Humans
RNA, Messenger
Promoter Regions, Genetic
Chenodeoxycholate
Molecular Biology
Repetitive Sequences, Nucleic Acid
Kininogen
Binding Sites
Kininogens
Liver Neoplasms
DNA
Isoxazoles
Cell Biology
Blotting, Northern
Molecular biology
DNA-Binding Proteins
Retinoid X Receptors
Gene Expression Regulation
chemistry
Nuclear receptor
Hepatocytes
Mutagenesis, Site-Directed
Farnesoid X receptor
Gene Deletion
Transcription Factors
circulatory and respiratory physiology
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 278
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....69f0fbe5d6b2a857d4f1fa2d4fb6760f