Activator protein-1 mediates shear stress-induced prostaglandin d synthase gene expression in vascular endothelial cells.
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.[1]References
- Activator protein-1 mediates shear stress-induced prostaglandin d synthase gene expression in vascular endothelial cells. Miyagi, M., Miwa, Y., Takahashi-Yanaga, F., Morimoto, S., Sasaguri, T. Arterioscler. Thromb. Vasc. Biol. (2005) [Pubmed]
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