Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostanoids induce expression of several immediate-early genes but the molecular mechanisms underlying these responses remain poorly characterized. We have studied induction of the proto-oncogenc c-fos by PGE2 in mesangial cells as a model of gene regulation by prostanoids. PGE2 induced marked and transient accumulation of c-fos mRNA. Induction of c-fos by PGE2 and TxA2 did not correlate with induction of phospholipase C. Addition of exogenous cAMP failed to induce c-fos mRNA, suggesting that activation of an EP2 receptor linked to adenylate cyclase did not account for induction of c-fos by PGE2. These data contrast with previous experiments in NIH 3T3 cells where PGE2 induced c-fos by a cAMP-dependent mechanism. We further showed that PGE2 induces the c-fos gene by direct activation of the serum response element. Taken together these experiments provide evidence for a pathway linking a PGE2 receptor on the plasma membrane to transcriptional activation in the nucleus.
...
PMID:Distinct signaling pathways mediate induction of c-fos by PGE2 in glomerular mesangial cells. 954 69

We previously showed that prostaglandin E2 (PGE2) stimulates multiple intracellular signaling pathways as follows: by activation of adenylate cyclase; phosphoinositide (PI)-hydrolyzing phospholipase C and phosphatidylcholine (PC)-hydrolyzing phospholipase D; and by induction of Ca2+ influx in osteoblast-like MC3T3-E1 cells. In this study, we investigated the effect of PGE2 on the synthesis of interleukin-6 (IL-6) and its regulatory mechanism in MC3T3-E1 cells. PGE2 significantly stimulated IL-6 secretion in a dose-dependent manner in the range between 1 nmol/L and 10 micromol/L. A23187, a calcium ionophore, or dibutyryl-cAMP significantly induced IL-6 secretion. The effect of a combination of A23187 and dibutyryl-cAMP on IL-6 secretion was additive. The depletion of extracellular Ca2+ by EGTA reduced the PGE2-induced IL-6 secretion. EP1 receptor antagonist inhibited the PGE2-induced IL-6 secretion. H-89, an inhibitor of cAMP-dependent protein kinase, decreased the PGE2-induced IL-6 secretion. EP2 receptor agonist alone stimulated IL-6 secretion. However, EP4 receptor antagonist had little effect on IL-6 secretion. Calphostin C, a specific inhibitor of protein kinase C (PKC), enhanced the secretion of IL-6 induced by PGE2. The stimulative effect of PGE2 on IL-6 secretion was significantly enhanced in PKC downregulated MC3T3-E1 cells. Pertussis toxin enhanced PGE2-induced IL-6 secretion. These results strongly suggest that PGE2 stimulates IL-6 synthesis through both Ca2+ mobilization from extracellular space via EP1 receptor and cAMP production via EP2 receptor in osteoblast-like cells, and that the PKC activation by PGE2 itself regulates oversynthesis of IL-6.
...
PMID:Interleukin-6 synthesis induced by prostaglandin E2: cross-talk regulation by protein kinase C. 955 35

In a recent communication, we demonstrated that prostaglandin E2 (PGE2) lowers basal while it ablates interleukin-1beta((IL-1beta) and transforming growth factor-beta (TGFbeta) upregulated lysyl oxidase (LO) mRNA levels. Correspondingly, PGE2 increases cyclooxygenase-1 (COX1) mRNA in diploid, human embryo lung fibroblasts (IMR90) [Roy et al., 19961. We now report that these actions by PGE2 are routed through cAMP via the PGE2, EP2 receptor. Among the PGE2 receptor types, the IMR90 predominantly express the EP2 mRNA. These cells also express EP3 and EP4 mRNA at comparatively low levels. Northern blot analyses show that 11-deoxy PGE1, an EP2/EP4 agonist, emulates the action of PGE2. In a similar manner to PGE2, 11-deoxy PGE1 decreases basal and TGF-beta induced type I collagen alpha1 (COL) mRNA, basal and IL-1beta induced LO mRNA while it increases COX1 mRNA. Sulprostone, an EP3/EP1 agonist, has no effect on the expression of these three genes. Forskolin, an adenylate cyclase activator, acts in a very similar manner to PGE2 or 11-deoxy PGE1. It suppresses both basal and TGF-beta induced COL mRNA levels. Both PGE2 and 11-deoxy PGE1 increase cAMP to a level comparable with forskolin. The role of the EP2 receptor in controlling collagen production is further underscored in the immortalized Rat-1 fibroblasts, derived from Fischer rat embryos, which do not express detectable EP2 mRNA. In these cells, PGE2 has little effect on COL mRNA level, whereas forskolin increases it. Furthermore, forskolin increases cAMP level in Rat-1 cells, whereas PGE2 does not. Overall, these results illustrate that much of the PGE2 action on the expression of COL, LO, and COX1 genes is mediated through the EP2 receptor and a subsequent increase in intracellular cAMP.
...
PMID:Role of EP2 receptors and cAMP in prostaglandin E2 regulated expression of type I collagen alpha1, lysyl oxidase, and cyclooxygenase-1 genes in human embryo lung fibroblasts. 977 23

Human promyeloid HL-60 cells are differentiated by all-trans retinoic acid (RA) to granulocytes, and prostaglandin (PG) E2 potentiates the RA-induced differentiation. Here we examined which subtype of PGE receptors was involved in this potentiating activity of PGE2. Northern blot analysis demonstrated that HL-60 cells expressed three subtypes of PGE receptor, EP2, EP3, and EP4. Among various EP agonists, and EP2-selective agonist, butaprost, preferentially potentiated the RA-induced differentiation of HL-60 cells. Butaprost not only decreased the half-maximal concentration of RA but also increased the maximal level of the differentiation. Butaprost concentration-dependently stimulated the cAMP formation, and 8-Br-cAMP strongly potentiated the RA-induced differentiation. These results demonstrate that the EP2 receptor enhances the RA-induced differentiation of HL-60 cells via stimulation of adenylate cyclase.
...
PMID:Potentiation of retinoic acid-induced differentiation of HL-60 cells by prostaglandin EP2 receptor. 978 84

Prostaglandin E2 (PGE2) is an anabolic agent in vivo that stimulates bone formation by recruiting osteoblasts from bone marrow precursors. To understand which of the known PGE2 receptors (EP1-4) is involved in this process, we tested the effect of PGE2 and various EP agonists and/or antagonists on osteoblastic differentiation in cultures of bone marrow cells by counting bone nodules and measuring alkaline phosphatase activity. PGE2 increased both parameters, peaking at 100 nM, an effect that was mimicked by forskolin and was abolished by 2',3'-dideoxyadenosine (an adenylate cyclase inhibitor) and was thus cAMP dependent, pointing to the involvement of EP2 or EP4. Consistently, 17-phenyl-omega-trinor PGE2 (EP1 agonist) and sulprostone (EP3/EP1 agonist) lacked any anabolic activity. Furthermore, butaprost (EP2 agonist) was inactive, 11-deoxy-PGE1 (EP4/EP2 agonist) was as effective as PGE2, and the PGE2 effect was abolished dose dependently by the selective EP4 antagonist AH-23848B, suggesting the involvement of EP4. We also found that PGE2 increased nodule formation and AP activity when added for the initial attachment period of 24 h only. Thus this study shows that PGE2 stimulates osteoblastic differentiation in bone marrow cultures, probably by activating the EP4 receptor, and that this effect may involve recruitment of noncommitted (nonadherent) osteogenic precursors, in agreement with its suggested mode of operation in vivo.
...
PMID:The anabolic effect of PGE2 in rat bone marrow cultures is mediated via the EP4 receptor subtype. 995 Jul 99

To identify the E-prostanoid (EP) receptors that mediate the hemodynamic actions of PGE2, we studied acute vascular responses to infusions of PGE2 using lines of mice in which each of four EP receptors (EP1 through EP4) have been disrupted by gene targeting. In mixed groups of males and females, vasodepressor responses after infusions of PGE2 were significantly diminished in the EP2 -/- and EP4 -/- lines but not in the EP1 -/- or EP3 -/- lines. Because the actions of other hormonal systems that regulate blood pressure differ between sexes, we compared the roles of individual EP receptors in males and females. We found that the relative contribution of each EP-receptor subclass was strikingly different in males from that in females. In females, the EP2 and EP4 receptors, which signal by stimulating adenylate cyclase, mediate the major portion of the vasodepressor response to PGE2. In males, the EP2 receptor has a modest effect, but most of the vasodepressor effect is mediated by the phospholipase C-coupled EP1 receptor. Finally, in male mice, the EP3 receptor actively opposes the vasodepressor actions of PGE2. Thus the hemodynamic actions of PGE2 are mediated through complex interactions of several EP-receptor subtypes, and the role of individual EP receptors differs dramatically in males from that in females. These differences may contribute to sexual dimorphism of blood pressure regulation.
...
PMID:Identification of specific EP receptors responsible for the hemodynamic effects of PGE2. 1048 12

Prostaglandin (PG) E receptors are divided into four subtypes (EP1-EP4). We investigated the EP receptor subtype involved in PGE2-stimulated mucus secretion by rabbit gastric epithelial cells. Northern blot analysis revealed that epithelial cells express EP3 and EP4 receptor mRNAs, but neither EP1 nor EP2 receptor mRNAs were detected. PGE2, 11-deoxy-PGE1 (an EP3/EP4/EP2 agonist) and 16,16-dimethyl-PGE2 (an EP3/EP2/EP4 agonist) concentration-dependently promoted mucus secretion. In contrast, 17-phenyl-PGE2 (an EP3/EP1 agonist), sulprostone (an EP3/EP1 agonist), and butaprost (an EP2 agonist) failed to stimulate secretion. The effective concentrations of PGE2, 11-deoxy-PGE1, and 16,16-dimethyl-PGE2 were associated with their affinities for the EP4 receptor. In addition, PGE2, 11-deoxy-PGE1, and 16,16-dimethyl-PGE2 increased cyclic AMP (cAMP) production, but the other prostanoids had no effect. SQ22536 [9-(tetrahydro-2'-furyl)adenine; an adenylate cyclase inhibitor] inhibited both the increased cAMP production and mucus secretion induced by PGE2, 11-deoxy-PGE1, and 16,16-dimethyl-PGE2. H-89 (N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinoline sulfonamide; a protein kinase A inhibitor) also abolished the stimulatory effects of the prostanoids on mucus secretion, but calphostin C (a protein kinase C inhibitor) did not. These results indicate that PGE2 promotes mucus secretion by rabbit gastric epithelial cells, mediated through EP4 receptor stimulation and the subsequent activation of protein kinase A.
...
PMID:EP4 receptor mediation of prostaglandin E2-stimulated mucus secretion by rabbit gastric epithelial cells. 1059 Nov 56

Blastocyst implantation in the baboon usually occurs between 8 and 10 days post ovulation. Changes that occur within this window of receptivity and immediately following implantation can be divided into three distinct phases. The first phase, regulated by estrogen and progesterone, is characterized primarily by changes in both the luminal and glandular epithelial cells in preparation for blastocyst apposition and attachment. The second phase is the further modulation of these steroid induced changes in both epithelial and stromal cells by embryonic signals. The final phase is associated with trophoblast invasion and the remodeling of the endometrial stromal compartment. During the initial phase, the actions of estrogen and progesterone are dependent on the presence of specific receptors. Estrogen up-regulates both its own receptor (ER) and the progesterone receptor (PR), while progesterone down-regulates this expression pattern. However, the pattern of progesterone-induced down-regulation of ER and PR is confined to the epithelial cells and demonstrates a gradient effect from the functionalis to the basalis. What is most intriguing is that the loss of epithelial PR is closely correlated with the establishment of uterine receptivity. Coincident with the changes in ER and PR expression, epithelial cells undergo alterations in their cytoskeletal architecture and secretory profile. These changes can be counteracted by PR antagonist treatment during the luteal phase. Although estrogen and progesterone play a critical role in establishing the initial phase of uterine receptivity, it is becoming increasingly evident that the embryo induces functional receptivity in ruminants and rodents. In our studies in the primate, we demonstrate that chorionic gonadotrophin when infused in a manner that mimics blastocyst transit, has physiological effects on the three major cell types in the uterine endometrium. The luminal epithelium undergoes endoreplication and distinct epithelial plaques are evident. The glandular epithelium responds by inducing transcriptional and post-translational modifications in the major secretory product, glycodelin. The stromal fibroblasts initiate their differentiation process into a decidual phenotype and are characterized by the expression of actin filaments. In phase three, blastocyst attachment to the surface epithelium and subsequent implantation is associated with local remodeling of the maternal stroma, smooth muscle, and endothelium of the blood vessels by the trophoblast. In addition, there is a gradual diminution of the epithelial plaques on the luminal surface although the glandular epithelium remains highly secretory. The most dramatic effect is on the stromal fibroblasts, which in response to embryonic stimuli, differentiate into decidual cells, the major cell type of the gestational endometrium. This differentiation is characterized by the expression of insulin-like growth factor binding protein-1 (IGFBP-1) in these cells. The cytokine IL-1 beta is one possible embryonic signal. COX-2 is the rate-limiting enzyme for prostaglandin biosynthesis and transcription of this enzyme in response to the embryonic stimulus (IL-1 beta) results in an increase in prostaglandin biosynthesis in stromal fibroblasts at the site of implantation. Prostaglandins and PGE2 in particular, binds to its specific receptor (EP2 or EP4) and activates adenyl cyclase. The resulting increase in intracellular levels of cAMP can now activate IGFBP-1 gene transcription at the site of implantation. In summary, our studies have demonstrated that chorionic gonadotrophin, when infused into non-pregnant baboons during the window of uterine receptivity can induce epithelial responses that are similar to those observed in a fertile cycle. Stromal differentiation is initiated; however, decidualization requires a signal from the conceptus.
...
PMID:Implantation in the baboon: endometrial responses. 1079 44

Prostaglandin E2 (PGE2) markedly reduces intraocular pressure (IOP) when applied topically and induces strong relaxation of pre-contracted isolated ciliary muscle through PGE2 receptor. Because the ciliary muscle relaxation reduces IOP by enhancing uveoscleral aqueous outflow, the ciliary muscle where the existence of PGE2 receptors has been demonstrated is thought to be one of the target tissues for PGE2-induced IOP reduction. To investigate the subtypes of PGE2 receptors in the ciliary muscle, the regional distribution of four PGE2 receptor subtypes (EP1, EP2, EP3 and EP4) in the mouse ciliary body was investigated by in situ hybridization using specific probes. Consistent messenger RNA signals for EP1 and EP4 receptors were expressed in the ciliary muscle, although signal levels for these subtypes were less potent as compared with the kidney, which was used as a reference organ. EP2 and EP3 signals were not detected. Stimulation of the EP4 receptor activates adenylate cyclase, which should induce ciliary muscle relaxation. Therefore, the IOP reduction induced by PGE2 analogs may be mediated by the EP4 receptor. In contrast, stimulation of the EP1 receptor is believed to promote intracellular Ca2+ mobilization, and hence should cause ciliary muscle contraction. Thus, the coexistence of EP1 and EP4 receptors in the ciliary muscle suggests that the regulation of ciliary muscle tone by PGE2 is based on a complex mechanism involving multiple receptor subtypes.
...
PMID:Localization of prostaglandin E receptor subtypes in the ciliary body of mouse eye. 1087 May 20

Prostaglandins (PGs) are well known to be important local factors in regulating bone formation and resorption. PGE2 is a potent stimulator of bone resorption because of enhancing osteoclast formation by its indirect action through stromal cells. However, the direct action of PGE2 on functionally mature osteoclasts is still controversial. In this study using highly purified rabbit mature osteoclasts, we examined the direct effect of PGE2 on osteoclastic bone-resorbing activity and its mechanism. PGE2 inhibited resorption pit formation on a dentine slice by the purified osteoclasts in a dose- and time-dependent manner. The inhibitory effect appeared as early as 4 hours after the PGE2 addition. Forskolin and 12-0-tetradecanoyl phorbol-13-acetate (TPA), respective activators of adenylate cyclase and protein kinase C, also decreased the osteoclastic bone-resorbing activity. PGE2 increased the content of intracellular cAMP in a dose range effective for the inhibition of bone resorption, whereas the prostanoid did not alter the intracellular level of inositol triphosphate. The inhibition of osteoclastic bone resorption by PGE2 was amplified and diminished by a cAMP phosphodiesterase inhibitor (isobutyl methylxanthine) and a protein kinase A inhibitor (Rp-cAMP), respectively. Of four different subtypes of PGE2 receptors (EPs), EP4 mRNA was predominantly expressed in isolated osteoclasts, whereas the other types of EP mRNA were detected in only small amounts. These results suggest that the PGE2 inhibitory effect was mediated by an adenylate cyclase system coupled with EP4. This possible association of PGE2 with EP4 in mature osteoclasts was supported by the finding that a specific agonist of EP4 (AE-604) inhibited the bone-resorbing activity and elevated the intracellular cAMP content. However, butaprost, a selective EP2 agonist, also mimicked the PGE2 effects on isolated osteoclasts although EP2 mRNA expression was minimal. In conclusion, PGE2 directly inhibits bone-resorbing activity of functionally mature osteoclasts by activation of the adenylate cyclase system, perhaps mainly through EP4.
...
PMID:Prostaglandin E2 directly inhibits bone-resorbing activity of isolated mature osteoclasts mainly through the EP4 receptor. 1090 19


<< Previous 1 2 3 4 5 6 7 Next >>

---