Abstract
Membrane-associated prostaglandin (PG) E2 synthase (mPGES) is an inducible terminal enzyme in the biosynthetic pathway for prostaglandin E2, which participates in many biological processes. In this study, we investigated the molecular mechanism controlling the inducible expression of mPGES. The mouse mPGES gene consisted of three exons, and its 5'-proximal promoter contained consensus motifs for the binding of several transcription factors. Transgenic expression in mice of the mouse mPGES promoter flanked by a reporter gene resulted in stimulus-dependent induction of the reporter in tissues where mPGES was intrinsically induced. Deletion and site-specific mutation analyses of the 5'-flanking region demonstrated that stimulus-inducible expression of mouse and human mPGES required tandem GC boxes adjacent to the initiation site. The stimulus-induced GC box binding activity was present in nuclear extracts of cells, in which the proximal GC box was essential for binding. An 80-kDa stimulus-inducible nuclear protein that bound to this GC box was identified as the transcription factor Egr-1 (for early growth response-1). These results suggest that Egr-1 is a key transcription factor in regulating the inducible expression of mPGES.
Highlights
Membrane-associated prostaglandin (PG) E2 synthase is an inducible terminal enzyme in the biosynthetic pathway for prostaglandin E2, which participates in many biological processes
We found that the binding of Egr-1, an inducible transcription factor, to the proximal GC box is an essential event that directs the regulatory expression of Membrane-associated prostaglandin (PG) E2 synthase (mPGES)
Transgenic expression of the chimeric mouse mPGES gene (5Ј-untranslated fragment up to 1858 bp upstream of the initiating ATG) flanked by the LacZ reporter gene in mice resulted in LPS-stimulated expression of -galactosidase in tissues in which mPGES was intrinsically induced, implying that the regulatory elements for stimulus-induced mPGES expression reside within this promoter region
Summary
Membrane-associated prostaglandin (PG) E2 synthase (mPGES) is an inducible terminal enzyme in the biosynthetic pathway for prostaglandin E2, which participates in many biological processes. Transgenic expression in mice of the mouse mPGES promoter flanked by a reporter gene resulted in stimulus-dependent induction of the reporter in tissues where mPGES was intrinsically induced. An 80-kDa stimulusinducible nuclear protein that bound to this GC box was identified as the transcription factor Egr-1 (for early growth response-1). These results suggest that Egr-1 is a key transcription factor in regulating the inducible expression of mPGES. A number of studies have reported the transcriptional regulation of COX-2 expression, in which several consensus sites in the COX-2 promoter, such as NF-B, NFinterleukin 6, CRE, and E-box, have been identified as regulatory sequences for COX-2 induction in response to various stimuli (14 –18). The structure of the human mPGES gene, including a 632-bp 5Ј-flanking region, has been reported (19), transcription factors or cis elements required for gene expression of mPGES remain elusive
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
