Document Detail


Activator protein-1 mediates shear stress-induced prostaglandin d synthase gene expression in vascular endothelial cells.
MedLine Citation:
PMID:  15718494     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: We attempted to determine the molecular mechanism of fluid shear stress-induced lipocalin-type prostaglandin D synthase (l-PGDS) expression in vascular endothelial cells. METHODS AND RESULTS: We examined the promoter region of the l-PGDS gene by loading laminar shear stress (20 dyne/cm2), using a parallel-plate flow chamber, on endothelial cells transfected with luciferase reporter vectors containing the 5'-flanking regions of the human l-PGDS gene. A deletion mutant analysis revealed that a shear stress-responsive element resided in the region between -2607 and -2523 bp. A mutation introduced into the putative binding site for activator protein-1 (AP-1) within this region eliminated the response to shear stress. In an electrophoretic mobility shift assay, shear stress stimulated nuclear protein binding to the AP-1 binding site, which was supershifted by antibodies to c-Fos and c-Jun. Shear stress elevated the c-Jun phosphorylation level in a time-dependent manner, similar to that of l-PGDS gene expression. SP600125, a c-Jun N-terminal kinase inhibitor, decreased the c-Jun phosphorylation, DNA binding of AP-1, and l-PGDS expression induced by shear stress. Additionally, an mRNA chase experiment using actinomycin D demonstrated that shear stress did not stabilize l-PGDS mRNA. CONCLUSIONS: Shear stress induces l-PGDS expression by transcriptional activation through the AP-1 binding site.
Authors:
Megumi Miyagi; Yoshikazu Miwa; Fumi Takahashi-Yanaga; Sachio Morimoto; Toshiyuki Sasaguri
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2005-02-17
Journal Detail:
Title:  Arteriosclerosis, thrombosis, and vascular biology     Volume:  25     ISSN:  1524-4636     ISO Abbreviation:  Arterioscler. Thromb. Vasc. Biol.     Publication Date:  2005 May 
Date Detail:
Created Date:  2005-05-02     Completed Date:  2005-12-29     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9505803     Medline TA:  Arterioscler Thromb Vasc Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  970-5     Citation Subset:  IM    
Affiliation:
Department of Clinical Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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MeSH Terms
Descriptor/Qualifier:
5' Flanking Region
Animals
Arteries / cytology
Cattle
Cells, Cultured
Endothelium, Vascular / cytology,  physiology*
Gene Expression Regulation, Enzymologic / physiology*
Humans
Intramolecular Oxidoreductases / genetics*
JNK Mitogen-Activated Protein Kinases / metabolism
Lipocalins
Phosphorylation
RNA Stability / physiology
Response Elements
Stress, Mechanical
Transcription Factor AP-1 / metabolism*
Transcriptional Activation / physiology
Umbilical Veins / cytology
Chemical
Reg. No./Substance:
0/Lipocalins; 0/Transcription Factor AP-1; EC 2.7.11.24/JNK Mitogen-Activated Protein Kinases; EC 5.3.-/Intramolecular Oxidoreductases; EC 5.3.99.2/prostaglandin R2 D-isomerase

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