| First Author | Walters JN | Year | 2012 |
| Journal | Biochem J | Volume | 443 |
| Issue | 2 | Pages | 561-71 |
| PubMed ID | 22260630 | Mgi Jnum | J:319542 |
| Mgi Id | MGI:6858249 | Doi | 10.1042/BJ20111801 |
| Citation | Walters JN, et al. (2012) Regulation of human microsomal prostaglandin E synthase-1 by IL-1beta requires a distal enhancer element with a unique role for C/EBPbeta. Biochem J 443(2):561-71 |
| abstractText | The studies of PGE2 (prostaglandin E2) biosynthesis have focused primarily on the role of cyclo-oxygenases. Efforts have shifted towards the specific PGE2 terminal synthases, particularly mPGES-1 (microsomal PGE synthase 1), which has emerged as the crucial inducible synthase with roles in pain, cancer and inflammation. mPGES-1 is induced by pro-inflammatory cytokines with studies focusing on the proximal promoter, mediated specifically through Egr-1 (early growth-response factor 1). Numerous studies demonstrate that the mPGES-1 promoter (PTGES) alone cannot account for the level of IL-1beta (interleukin 1beta) induction. We identified two DNase I-hypersensitive sites within the proximal promoter near the Egr-1 element and a novel distal site near -8.6 kb. Functional analysis of the distal site revealed two elements that co-operate with basal promoter expression and a stimulus-dependent enhancer. A specific binding site for C/EBPbeta (CCAAT/enhancer-binding protein beta) in the enhancer was directly responsible for inducible enhancer activity. ChIP (chromatin immunoprecipitation) analysis demonstrated constitutive Egr-1 binding to the promoter and induced RNA polymerase II and C/EBPbeta binding to the promoter and enhancer respectively. Knockout/knockdown studies established a functional role for C/EBPbeta in mPGES-1 gene regulation and the documented interaction between Egr-1 and C/EBPbeta highlights the proximal promoter co-operation with a novel distal enhancer element in regulating inducible mPGES-1 expression. |
