The Structure of the Prostaglandin EP4 Receptor Gene and Related Pseudogenes

Foord, Steven M.; Marks, Bruno; Stolz, Martin; Bufflier, E.; Fraser, Neil; Lee, Melanie G.

doi:10.1006/geno.1996.0337

Cited by 36 publications

(29 citation statements)

References 3 publications

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“…The results showing that both PD98095 and wortmannin partially prevented Fn-stimulated EP4 promoter activity further suggested a role for PI3K and ERK kinase signaling pathways in mediating Fn up-regulation of EP4 gene expression. Several transcription factor binding sites within regions of the EP4 promoter have been characterized, including regulatory elements for AP-2, C/EBP, Sp1, and others (15,18,25). We showed that treatment of H1838 cells with Fn significantly increased protein binding activities of AP-2 in the EP4 promoter, whereas it had little effect on C/EBP and Sp1.…”

Section: Discussionmentioning

confidence: 83%

See 1 more Smart Citation

Extracellular Matrix Fibronectin Increases Prostaglandin E2 Receptor Subtype EP4 in Lung Carcinoma Cells through Multiple Signaling Pathways

Han

Ritzenthaler

Wingerd

et al. 2007

Journal of Biological Chemistry

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We have previously demonstrated that fibronectin (Fn) stimulates the proliferation of non-small cell lung carcinoma (NSCLC) cell growth through the induction of cyclooxygenase-2 (COX-2) and prostaglandin E 2 secretion. Here, we demonstrate that NSCLC cells express mRNA and protein for the prostaglandin E 2 receptor EP4 and that Fn enhances its stimulatory effect by inducing the expression of EP4, but not of EP1, EP2, and EP3 receptor subtypes. The effect of Fn on EP4 was inhibited by an antibody against ␣5␤1 integrin and by inhibitors of phosphoinositide 3-kinase (wortmannin) and extracellular signal-regulated kinase (PD98095), but not by inhibitors of protein kinase C (calphostin C), of protein kinase A (H-89), or of mammalian target of rapamycin (rapamycin). A COX-2 small interfering RNA was also inhibitory. Fn significantly increased AP-2 binding activity in the promoter of the EP4 gene, and AP-2 antisense oligonucleotides blocked Fn-induced EP4 expression. Using full-length and mutated EP4 promoter constructs, we found that Fn stimulation of EP4 gene expression was inhibited when one AP-2 site (؊1000 bp) was mutated. Fn induced nuclear AP-2␣ protein expression through multiple signaling pathways. Our results indicate that Fn-induced NSCLC cell proliferation is mediated through EP4. Furthermore, they show that Fn induces EP4 expression through the activation of ␣5␤1-dependent signals that include induction of extracellular signalregulated kinase and phosphoinositide 3-kinase pathways as well as expression of COX-2. These events lead to activation of the transcription factor AP-2␣, which interacts with specific regions in the EP4 gene promoter, leading to transcription of the EP4 gene.Extracellular matrix proteins are considered to play roles in the migration and differentiation of various cells, including carcinoma cells. Fibronectin (Fn), 2 a matrix glycoprotein highly expressed in tobacco-related lung diseases, has been shown to stimulate carcinoma cell growth, including lung carcinoma (1-3). We previously reported that Fn stimulated human lung carcinoma cell growth through induction of cyclooxygenase-2 (COX-2) signaling and subsequent production of prostaglandin E 2 (PGE 2 ) (4). High PGE 2 levels are considered important in carcinoma growth and progression, and inhibition of PGE 2 synthesis blocks growth of carcinoma cells (5). The effect of PGE 2 has been attributed to its known capacity to bind to its receptors, designated EP1, EP2, EP3, and EP4 (6). These receptors have been implicated in carcinoma cell growth and progression (5,7,8,9). PGE 2 , acting via EP4, contributes to tumor growth and progression of gallbladder and colorectal carcinoma (7,8). A recent study of EP4 knock-out mice suggested a role for EP4 receptor in colon carcinoma (7). PGE 2 and its signaling through the EP4 receptor have been shown to mediate non-small cell lung carcinoma (NSCLC) invasiveness (10). Taken together, these observations suggest that manipulation of prostaglandin metabolism downstream from COX-2 produces more profou...

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Section: Discussionmentioning

confidence: 83%

“…4A). These sites have been shown to be differentially responsive to various stimuli (15,18,25,26). We found that H1838 cells, transfected with the full-length wild-type EP4 promoter (Ϫ4200/Ϫ116 bp) luciferase reporter construct, exposed to Fn showed increased promoter activity.…”

Section: Effect Of Fn On Ep4 Gene Expression In Human Lungmentioning

confidence: 99%

Extracellular Matrix Fibronectin Increases Prostaglandin E2 Receptor Subtype EP4 in Lung Carcinoma Cells through Multiple Signaling Pathways

Han

Ritzenthaler

Wingerd

et al. 2007

Journal of Biological Chemistry

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“…Gene Structure. The human and mouse EP4 genes consist of three exons separated by two introns (Arakawa et al, 1996;Foord et al, 1996). A similar exon-intron relationship is present in the other types of prostanoid receptors, such as the DP, EP1, EP2, EP3, FP, and IP receptors (Hirata et al, 1994;Regan et al, 1994a;Batshake et al, 1995;Ogawa et al, 1995;Boie et al, 1997;Hasumoto et al, 1997;Katsuyama et al, 1998b).…”

Section: A Cloningmentioning

confidence: 94%

“…The deduced initiation site of the human EP4 does not contain a conventional TATA box, but is 70% GCrich and contains CCAAT boxes (Foord et al, 1996). The promoter region of the mouse EP4 has a TATA box (Arakawa et al, 1996).…”

Section: A Cloningmentioning

confidence: 99%

The Prostanoid EP4 Receptor and Its Signaling Pathway

Yokoyama

Iwatsubo²,

Umemura³

et al. 2013

Pharmacol Rev

227

257

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“…adrenergic alB (Ramarao et al, 1992). and the prostanoid TX (Niising et al, 1993) and EP4 (Foord et al, 1996) receptors. However, none of these introns occurs at the exact analogous position within TM6 as in the GPR26 gene.…”

Section: 7mentioning

confidence: 99%

Orphan G-protein-coupled Receptors

Marchese¹

Encyclopedia of Molecular Pharmacology

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G protein-coupled receptors (GPCRs) are integral membrane proteins that mediate signals to the interior of the cell via activation of heterotrimeric G proteins, which subsequently interact with and activate various effector proteins, ultimately resulting in a physiological response. GPCRs are involved in a number of behaviours, and have been implicated in such processes as drug addiction and neuropsychiatric diseases. To further our understanding of the molecular mechanisms involved beyond the known GPCR-endogenous ligand systems we endeavored to discover novel GPCRs, in particular opioid and opioid related receptors, potentially involved in these processes. In order to achieve this we applied two distinct homology cloning strategies to identify the DNA sequences encoding novel GPCRs. Firstly, PCR amplification of human genomic DNA and cDNA using degenerate oligonucleotides derived from the transmembrane domains (TM) of the opioid and the related somatostatin receptors, and secondly, querying publicly available sequence databases using the amino acid sequence of known GPCRs. We have discovered a novel family comprised of two receptors, named GPR7and GPR8, and a third receptor, named GPR14, that are most closely related to the opioid receptors. Our experiments also led to the cloning and successful ligand assignment of a novel P2 receptor subtype. named EY4, that selectively binds uridine nucleotides. We also report the discovery of three P2Y4 related receptors, GPRZO, GPR34, and GPR35. We also successfully identified an additional novel family comprised of three receptors, GPR3, GPR6, and GPRIZ, most closely related to the cannabinoid receptors. We also identified a novel GPCR, named GPR26, which is activated by high LPA concentrations (ECM = 0.5 pM). The other receptors we isolated. GPRI, GPR30, GPR32, GPR33 are all related to chemoatuactant receptors, and we have identified two related GPCR pseudogenes, (pGPR32 and rpGPR33. The endogenous ligands for most of these receptors have not been assigned, hence they are referred to as orphan receptors, and are useful targets for endogenous ligand discovery. Examination of the mRNA tissue expression patterns by Northern blot and in situ hybridization revealed that most are abundantly and discretely expressed in the brain, suggesting a unique role for each of these receptors in the central nervous system (CNS).

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The Structure of the Prostaglandin EP4 Receptor Gene and Related Pseudogenes

Cited by 36 publications

References 3 publications

Extracellular Matrix Fibronectin Increases Prostaglandin E2 Receptor Subtype EP4 in Lung Carcinoma Cells through Multiple Signaling Pathways

Extracellular Matrix Fibronectin Increases Prostaglandin E2 Receptor Subtype EP4 in Lung Carcinoma Cells through Multiple Signaling Pathways

The Prostanoid EP4 Receptor and Its Signaling Pathway

Orphan G-protein-coupled Receptors

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