The mouse prostaglandin E receptor EP<sub>2</sub> subtype: cloning, expression, and Northern blot analysis

Katsuyama, Masato; Nishigaki, Nobuhiro; Sugimoto, Yukihiko; Morimoto, Keizo; Negishi, Manabu; Narumiya, Shuh; Ichikawa, Atsushi

doi:10.1016/0014-5793(95)00966-d

Cited by 147 publications

(105 citation statements)

References 29 publications

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“…PGE 2 and cAMP induce angiogenesis via the PKAand PI3K/Akt-dependent signaling pathways PGE2 binds EP2 and EP4 and activates adenylate cyclase, leading to an increase in intracellular cAMP formation (Regan et al, 1994;Katsuyama et al, 1995;Breyer et al, 2001). As previously reported (Dormond et al, 2002), we found that EP2 and EP4 receptors were expressed in HUVECs and that EP4 was more abound than EP2 (data not shown), suggesting that cAMP may be involved in PGE2-mediated regulation of angiogenesis.…”

Section: Pge 2 Stimulates Cell Proliferation Migration and Tube Forsupporting

confidence: 76%

Prostaglandin E2 stimulates angiogenesis by activating the nitric oxide/cGMP pathway in human umbilical vein endothelial cells

Namkoong

Lee²,

Kim³

et al. 2005

Exp Mol Med

116

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Prostaglandin E 2 (PGE 2 ), a major product of cyclooxygenase, has been implicated in modulating angiogenesis, vascular function, and inflammatory processes, but the underlying mechanism is not clearly elucidated. We here investigated the molecular mechanism by which PGE2 regulates angiogenesis. Treatment of human umbilical vein endothelial cells (HUVEC) with PGE 2 increased angiogenesis. PGE 2 increased phosphorylation of Akt and endothelial nitric oxide synthase (eNOS), eNOS activity, and nitric oxide (NO) production by the activation of cAMP-dependent protein kinase (PKA) and phosphatidylinositol 3-kinase (PI3K). Dibutyryl cAMP (DB-cAMP) mimicked the role of PGE 2 in angiogenesis and the signaling pathway, suggesting that cAMP is a down-stream mediator of PGE2. Furthermore, PGE2 increased endothelial cell sprouting from normal murine aortic segments, but not from eNOS-deficient ones, on Matrigel. The angiogenic effects of PGE 2 were inhibited by the inhibitors of PKA, PI3K, eNOS, and soluble guanylate cyclase, but not by phospholipase C inhibitor. These results clearly show that PGE2 increased angiogenesis by activating the NO/cGMP signaling pathway through PKA/PI3K/Akt-dependent increase in eNOS activity.

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Section: Pge 2 Stimulates Cell Proliferation Migration and Tube Forsupporting

confidence: 76%

Prostaglandin E2 stimulates angiogenesis by activating the nitric oxide/cGMP pathway in human umbilical vein endothelial cells

Namkoong

Lee²,

Kim³

et al. 2005

Exp Mol Med

116

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“…Moreover, BSP transcription is mediated by EP2 and EP4 receptors (Fig. 6), through which cAMP production is stimulated (21). That transcription is suppressed by Src inhibitors to Src kinase and MAP kinase (Fig.…”

Section: Discussionmentioning

confidence: 96%

Prostaglandin E2 Stimulates Bone Sialoprotein (BSP) Expression through cAMP and Fibroblast Growth Factor 2 Response Elements in the Proximal Promoter of the Rat BSP Gene

Samoto

Shimizu

Matsuda-Honjyo

et al. 2003

Journal of Biological Chemistry

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Bone sialoprotein (BSP), an early marker of osteoblast differentiation, has been implicated in the nucleation of hydroxyapatite during de novo bone formation. Prostaglandin E 2 (PGE 2 ) has anabolic effects on proliferation and differentiation of osteoblasts via diverse signal transduction systems. Because PGE 2 increases the proportion of functional osteoblasts in fetal rat calvarial cell cultures, we investigated the regulation of BSP, as an osteoblastic marker, by PGE 2 . Treatment of rat osteosarcoma UMR 106 cells with 3 M, 300 nM, and 30 nM PGE 2 increased the steady state levels of BSP mRNA about 2.7-, 2.5-, and 2.4-fold after 12 h. From transient transfection assays, the constructs including the promoter sequence of nucleotides (nt) ؊116 to ؉60 (pLUC3) were found to enhance transcriptional activity 3.8-and 2.2-fold treated with 3 M and 30 nM PGE 2 for 12 h. 2-bp mutations were made in an inverted CCAAT box (between nt ؊50 and ؊46), a cAMP response element (CRE; between nt ؊75 and ؊68), a fibroblast growth factor 2 response element (FRE; nt ؊92 to ؊85), and a pituitaryspecific transcription factor-1 motif (between nt ؊111 and ؊105) within pLUC3 and pLUC7 constructs. Transcriptional stimulation by PGE 2 was almost completed abrogated in constructs that included 2-bp mutations in either the CRE and FRE. In gel shift analyses an increased binding of nuclear extract components to double-stranded oligonucleotide probes containing CRE and FRE was observed following treatment with PGE 2 . These studies show that PGE 2 induces BSP transcription in UMR 106 cells through juxtaposed CRE and FRE elements in the proximal promoter of the BSP gene.Prostaglandins are considered important local factors that modulate bone metabolism through their effects on osteoblastic cells and osteoclasts (1, 2). Prostaglandin E 2 (PGE 2 ), 1 a major eicosanoid produced by osteoblasts, is a potent stimulator of bone resorption (3) that can stimulate the formation of osteoclast-like multinuclear cells in mouse bone marrow cultures (4, 5). The effects of PGE 2 on osteoclastogenesis are, at least in part, mediated by osteogenic cells, which express macrophage colony-stimulating factor (6) and receptor activator of nuclear factor B ligand (RANKL) (7) that promote, and osteoprotegerin, a decoy receptor for RANKL (8), that suppresses osteoclast formation. PGE 2 has been shown to stimulate RANKL and inhibit osteoprotegerin production (7, 9) and also increases production of interleukin-6, which can further enhance osteoclastogenesis (10 -12). In contrast, studies have revealed that PGE 2 also has bone-forming activity (2, 13). Treatment of male, female, and overiectomized mice with PGE 2 increases bone mass in vivo (14), whereas PGE 2 stimulates collagen and DNA synthesis and induces bone growth in calvarial organ (15) and cell cultures in vitro (16, 17). However, PGE 2 can either stimulate or inhibit cellular growth and differentiation of osteoblastic cells depending on PGE 2 concentration (15,18,19).To explain the diverse effects of PGE 2 , th...

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“…PCR-amplified fragments were size-selected and purified from a 1% agarose gel using the QIAquick Gel Extraction kit according to the manufacturer's instructions and sequenced by the Center for Advanced DNA Technologies at the University of Texas Health Science Center, San Antonio. Northern blots were performed as described previously (45). Poly(A) ϩ RNAs were prepared using Micro Poly(A) Pure TM kit according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

Effects of Mechanical Strain on the Function of Gap Junctions in Osteocytes Are Mediated through the Prostaglandin EP2 Receptor

Cherian

Cheng

et al. 2003

Journal of Biological Chemistry

188

146

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Fluid flow conditioned medium and PGE 2 stimulated cAMP production and PKA activity suggesting that PGE 2 released by mechanically stimulated cells is responsible for the activation of cAMP and PKA. The adenylate cyclase activators, forskolin and 8-bromo-cAMP, enhanced intercellular connectivity, the number of functional gap junctions, and Cx43 protein expression, whereas the PKA inhibitor, H89, inhibited the stimulatory effect of PGE 2 on gap junctions. These studies suggest that the EP 2 receptor mediates the effects of autocrine PGE 2 on the osteocyte gap junction in response to fluid flow-induced shear stress. These data support the hypothesis that the EP 2 receptor, cAMP, and PKA are critical components of the signaling cascade between mechanical strain and gap junction-mediated communication between osteocytes.

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The mouse prostaglandin E receptor EP₂ subtype: cloning, expression, and Northern blot analysis

Cited by 147 publications

References 29 publications

Prostaglandin E2 stimulates angiogenesis by activating the nitric oxide/cGMP pathway in human umbilical vein endothelial cells

Prostaglandin E2 stimulates angiogenesis by activating the nitric oxide/cGMP pathway in human umbilical vein endothelial cells

Prostaglandin E2 Stimulates Bone Sialoprotein (BSP) Expression through cAMP and Fibroblast Growth Factor 2 Response Elements in the Proximal Promoter of the Rat BSP Gene

Effects of Mechanical Strain on the Function of Gap Junctions in Osteocytes Are Mediated through the Prostaglandin EP2 Receptor

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The mouse prostaglandin E receptor EP2 subtype: cloning, expression, and Northern blot analysis

Cited by 147 publications

References 29 publications

Prostaglandin E2 stimulates angiogenesis by activating the nitric oxide/cGMP pathway in human umbilical vein endothelial cells

Prostaglandin E2 stimulates angiogenesis by activating the nitric oxide/cGMP pathway in human umbilical vein endothelial cells

Prostaglandin E2 Stimulates Bone Sialoprotein (BSP) Expression through cAMP and Fibroblast Growth Factor 2 Response Elements in the Proximal Promoter of the Rat BSP Gene

Effects of Mechanical Strain on the Function of Gap Junctions in Osteocytes Are Mediated through the Prostaglandin EP2 Receptor

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The mouse prostaglandin E receptor EP₂ subtype: cloning, expression, and Northern blot analysis