Disease relevance of PTGER4

• Endothelin-1-induced prostaglandin E2-EP2, EP4 signaling regulates vascular endothelial growth factor production and ovarian carcinoma cell invasion [1].
• In this study, we investigated the signal transduction pathways mediating the role of seminal plasma and PGE(2) in the regulation of tumorigenic and angiogenic genes via the EP4 receptor in cervical adenocarcinoma (HeLa) cells [2].
• Moreover, it is suggested that EP1 and EP4 play roles in polyp formation independently [3].
• CONCLUSION: Our results show that activation of EP4 or DP receptors decreased the accumulation of OPG in supernatants of osteoblasts in culture, and suggest that these receptors could be interesting pharmacological targets in bone diseases [4].
• Gains of chromosome arm 5p are common in peritoneal carcinomatoses and several candidate genes (including PTGER4, SKP2, and ZNF622) mapping to this region were overexpressed in the tumors [5].

High impact information on PTGER4

• This suggests that the neonatal drop in prostaglandin E2 that triggers ductal closure is sensed through the EP4 receptor [6].
• In contrast, EP4 receptor mRNA is predominantly expressed in the glomerulus, where it may contribute to the regulation of glomerular hemodynamics and renin release [7].
• The major PGE2 receptors on epithelial cells, EP2 and EP4, increase cAMP production, which promotes growth and inhibits apoptosis in some cell types [8].
• The anabolic action of PGE2 in bone has been linked to an elevated level of cAMP, thereby implicating the EP2 and/or EP4 receptor subtypes in bone formation [9].
• These results suggest that activation of EP4 induces bone remodeling in vivo and that EP4-selective drugs may be beneficial in humans with osteoporosis [10].

Chemical compound and disease context of PTGER4

• In the present study, we evaluated the importance of the COX-2 product prostaglandin E2 (PGE2) and its signaling through the EP4 receptor in mediating non-small cell lung cancer (NSCLC) invasiveness [11].
• Using i.v. injected Lewis lung carcinoma (3LL), we found that tumor metastasis to lung was significantly reduced when mice were treated with a specific EP4 antagonist ONO-AE3-208 or when EP4 receptor expression was knocked down in the tumor cells using RNA interference technology [12].
• Expression of COX-2 and PGE synthase and synthesis of PGE(2)in endometrial adenocarcinoma: a possible autocrine/paracrine regulation of neoplastic cell function via EP2/EP4 receptors [13].
• Prostaglandin E2 downregulates interleukin-12 production through EP4 receptors in human monocytes stimulated with lipopolysaccharide from Actinobacillus actinomycetemcomitans and interferon-gamma [14].
• In the nephrotoxic mercury chloride (HgCl(2)) rat model of acute kidney failure systemically administered EP4 agonist reduced the serum creatinine values and increased the survival rate [15].

Biological context of PTGER4

• These studies suggest that PGE2 increases VEGF transcriptionally and involves the Sp-1 binding site via a cAMP-dependent mechanism involving EP2 and EP4 receptors [16].
• Cyclooxygenase-2 induction by bradykinin in human pulmonary artery smooth muscle cells is mediated by the cyclic AMP response element through a novel autocrine loop involving endogenous prostaglandin E2, E-prostanoid 2 (EP2), and EP4 receptors [17].
• Treatment of HeLa cells with seminal plasma or PGE(2) also rapidly induced the phosphorylation of ERK1/2 via the EP4 receptor [2].
• EP4 receptor staining increased moderately during gestation and was limited to the intima and media [18].
• EP4 receptor presumably plays a key role for active patency of the human DA in the third trimester [18].

Anatomical context of PTGER4

• HeLa cells were stably transfected with EP4 receptor in the sense orientation [2].
• Therefore, we have demonstrated that seminal plasma and PGE(2) can promote the expression of tumorigenic and angiogenic factors, in cervical adenocarcinoma cells via the EP4 receptor, EGFR, and ERK1/2 signaling pathways [2].
• We have examined the expression of three prostaglandin (PG) receptors, EP2, EP4, and FP, in a nonpigmented ciliary epithelial cell line (ODMCl-2) and in human ciliary muscle (HCM) cells [19].
• Cyclooxygenase-2-dependent prostaglandin E2 down-regulates intercellular adhesion molecule-1 expression via EP2/EP4 receptors in interleukin-1beta-stimulated human gingival fibroblasts [20].
• Detection of EP2, EP4, and FP receptors in human ciliary epithelial and ciliary muscle cells [19].

Associations of PTGER4 with chemical compounds

• EP2 and EP4 agonists, as well as PGE(2), restored the inhibitory effect of rofecoxib on mPGES expression [21].
• Changing expression of cyclooxygenases and prostaglandin receptor EP4 during development of the human ductus arteriosus [18].
• PGE2, 11-deoxy-PGE1 (a selective EP2/EP4 agonist), and Butaprost (a selective EP2 agonist) attenuated IL-1beta-elicited ICAM-1 expression, although Butaprost was less potent than PGE2 and 11-deoxy-PGE1 [20].
• We conclude that the C terminus of the EP4 receptor is involved in internalization; however, serine and threonine residues do not seem to be involved [22].
• COX2 is an enzyme that catalyzes the rate-limiting step of arachidonic acid conversion to prostaglandins, including prostaglandin E2 (PGE2) and other eicosanoids, whereas EP4 is a subtype of cell surface receptors for PGE2 [23].

Physical interactions of PTGER4

• These data indicate that PGE2 produced by COX-2 increases BMP-2 expression via binding the EP4 receptor [24].

Regulatory relationships of PTGER4

• EP1, EP2, and EP4 receptor mRNA was expressed in HGF according to reverse-transcription/polymerase chain-reaction [20].
• However, an EP4 receptor antagonist (AH23848) significantly suppressed the level of PGE(2)-induced MUC5AC gene expression and MUC5AC mucin [25].
• On the other hand, EP4R regulates tumor progression via cancer cell proliferation and MMP-2, distinct from COX-2 [26].
• PGE2 binding to EP4 stimulates osteoclastogenesis through enhancing RANKL expression [27].
• Moreover, BMP-2 expression was suppressed by an EP4 receptor antagonist [24].

Other interactions of PTGER4

• The effects of PGE(2) and selective agonists for PGE(2) receptor subtypes (EP1, EP2, EP3, and EP4) were also studied [21].
• Co-localization studies showed that the endothelial cells stained positive for EP1-EP4 and FP and that co-localization was seen for EP4 and c-kit [28].
• Butaprost, a selective EP2 agonist, and ONO-AE1-329, a selective EP4 agonist, significantly inhibited IL-1alpha-induced MMP-3 production, although butaprost was less potent than ONO-AE-1-329 [29].
• AH-23848B, an EP4 antagonist, antagonized the inhibitory effect of IL-1beta-elicited ICAM-1 expression by PGE2 [20].
• In addition, agents that increased intracellular cAMP, as is typical of EP4 receptor signaling, markedly increased CD44 expression [11].

Analytical, diagnostic and therapeutic context of PTGER4

• PGE receptor agonists EP2 (ONO-AE1 259) and EP4 (ONO-AE1 329) mimicked the effect of PGE2, and reverse transcription-PCR, Western blotting, and flow cytometry confirmed the presence of EP2 and EP4 receptors [16].
• The RT-PCR generated DNA products of predicted sizes corresponding to the EP2, EP4, and FP receptors in both ODMCl-2 and HCM cells [19].
• Northern blot analysis of human mRNA using a pseudogene probe showed hybridization only to the EP4 receptor transcript [30].
• These events correlated with sequestration of EP4, as visualized by immunofluorescence confocal microscopy and phosphorylation, as shown by [32P]orthophosphate labeling of the receptor [31].
• 0. 6. In competition radioligand bioassays, GW627368X had affinity for human prostanoid EP4 and TP receptors (pKi = 7.0 +/- 0.2 (n = 10) and 6.8 (n = 2), respectively) [32].

References