Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When mesenchymal precursor cells from bone marrow are cultured in the presence of dexamethasone, the existence of distinct non-adherent and adherent populations can be demonstrated. The addition of PGE2, forskolin, or dibutyryl-cAMP can induce a transition from the former to the latter and this may be an important mechanism in the bone anabolic effects of PGE2. On the other hand, phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C, and sulprostone, an agonist for the PGE2 receptor EP1/EP3 subtypes, had no effect. The phosphodiesterase inhibitor, isobutylmethylxanthine (IBMX), had a synergistic effect in combination with PGE2, whereas neomycin, an inhibitor of inositol phosphate activity, had no effect, and LiC1, an inhibitor of inositol triphosphate metabolism, had an inhibitory effect on the PGE2-induced transition. Consistent with this, the addition of PGE2 to non-adherent bone marrow cells caused a 100% increase in cAMP synthesis. These results suggest that the induction of the transition from non-adherent to adherent osteoblast precursor is mediated by the EP2-PGE2 receptor subtype via an increase in intracellular cAMP synthesis.
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PMID:PGE2 induces the transition from non-adherent to adherent bone marrow mesenchymal precursor cells via a cAMP/EP2-mediated mechanism. 748 Aug 6

Prostanoids induce expression of several immediate-early genes, but the molecular mechanisms underlying these responses remain poorly characterized. We studied induction of the proto-oncogene 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. Addition of exogenous 8-bromo-cAMP or forskolin 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 in which PGE2 induced c-fos by a cAMP-dependent mechanism. Depletion of protein kinase C blocked induction of c-fos mRNA by PGE2, whereas a protein tyrosine kinase inhibitor had no effect. We further showed that PGE2 induces the c-fos gene by increasing the transactivating capacity of the serum-response element. Transient transfections with a CAT fusion gene driven by an AP-1 cis-element demonstrated that although PGE2 markedly induced c-fos, PGE2 did not increase AP-1-driven transcriptional responses. Electrophoretic gel mobility shift assays revealed that PGE2 failed to increase binding of AP-1 complexes to a consensus AP-1 DNA sequence. Taken together, these experiments provide evidence for a cAMP-independent, protein kinase C-dependent pathway linking a PGE2 receptor on the plasma membrane to transcriptional activation in the nucleus. Regulation of gene transcription by PGE2 probably involves c-fos induction without concomitant activation of AP-1.
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PMID:PGE2 induces c-fos expression by a cAMP-independent mechanism in glomerular mesangial cells. 752 23

Inflammatory mediators such as prostaglandin E2 (PGE2) and interleukin-1 (IL-1) induce angiogenesis by yet undefined mechanisms. We demonstrate that PGE2 and IL-1 induces the expression of vascular endothelial growth factor (VEGF), a selective angiogenic factor by rheumatoid synovial fibroblast cells. Transcripts for the EP1 and EP2 subtypes of PGE receptors are expressed in synovial fibroblasts. Activators of protein kinase A pathway stimulated the expression of VEGF whereas down-regulation of protein kinase C did not influence the PGE effect, suggesting that signalling from the EP2 receptor via the protein kinase A pathway is important. The induction of VEGF expression by PGE2 and interleukin-1 alpha may be an important mechanism in inflammatory angiogenesis.
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PMID:Induction of vascular endothelial growth factor expression in synovial fibroblasts by prostaglandin E and interleukin-1: a potential mechanism for inflammatory angiogenesis. 755 49

We have documented new observations with respect to PGE2 action in the rabbit CCD. (1) PGE2 can inhibit both cAMP and vasopressin-induced water flow, depending on the sequence of PGE2 addition with respect to vasopressin or cAMP. (2) PGE2 inhibition of vasopressin or cAMP-stimulated water flow can be reversed with staurosporine. Thus, PGE2 inhibits vasopressin-stimulated water flow by activation of PKC and (3) PGE2 induces release of calcium from intracellular stores. These results strongly suggest the presence of a PGE2 receptor coupled to PIP2 hydrolysis. PGE2 mediated increases in cytosolic calcium are responsible for the inhibitory action of PGE2 on sodium transport. While stimulation of cAMP production by PGE2 may contribute to the inhibition of sodium transport, it is not required since in the presence of 8-CPTcAMP, PGE2 still decreases sodium transport. The effect of PGE2 on sodium transport is pertussis toxin insensitive and is unlikely to be mediated by an inhibitory G protein. Using PGE2 and one of its selective analogues, sulprostone, we have provided evidence for functionally distinct PGE2 receptors. Separate PGE2 receptor subtypes appear to be coupled to separate transport processes. These receptor subtypes may correspond to the EP1, EP2 and EP3 receptors described earlier in smooth muscle. Thus, an EP2 like receptor stimulates cAMP generation and water reabsorption while an EP1 like receptor increases [Ca++]i and inhibits sodium reabsorption. Finally, an EP3 receptor, equivalently activated by sulprostone and PGE2, may couple to Gi and mediate pertussis toxin sensitive inhibition of vasopressin-stimulated water flow.
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PMID:Cellular signalling of PGE2 and its selective receptor analogue sulprostone in rabbit cortical collecting duct. 782 28

Co-expression of EP2 and EP3 subtypes of prostaglandin E2 (PGE2) receptors (R) by U937 human monocytic cells permitted comparative studies of desensitization of each subtype. Specific binding of [3H]PGE2 to membranes of U937 cells showed a Kd of 2.9 +/- 0.3 nM (mean +/- SEM) and a Bmax of 40.5 +/- 1.0 fmol/mg protein, and was competitively inhibited by PGE2 > or = PGE1 > PGF2 alpha > PGD2 > PGI2. EP2 R and EP3 R mRNA were detected by reverse transcription-polymerase chain reaction and Northern blots. EP3 R expression was demonstrated by inhibition of [3H]PGE2 binding with the EP1/EP3 agonist sulprostone [50% inhibitory concentration (IC50 = 3.3 +/- 0.6 nM)] and the EP3/EP2 agonist M&B 28767 (IC50 = 2.1 +/- 0.3 nM), but not with the EP1 antagonist SC-19220. EP2 R protein was identified by Western blot analysis using specific rabbit IgG antibodies to an amino-terminal peptide of the EP2 R. EP2 R transduced PGE2 stimulation of significant increases in cellular [cAMP]i [50% effective concentration (EC50 = 20 +/- 2.5 nM)], and EP3 R mediated sulprostone inhibition of forskolin elevation of [cAMP]i (IC50 = 1.3 +/- 0.4 nM). Pretreatment of U937 cells with phorbol 12-myristate 13-acetate (PMA), which activates protein kinase C (PKC), for 1 hr reduced the total number, but not the affinity, of PGE2 R by down-regulating principally EP2 R. In contrast, a 24-hr exposure to PMA, which is known to down-regulate PKC, suppressed both the total number and affinity of PGE2 R on U937 cells with concurrent reductions in EP2 R and EP3 R. The down-regulation of EP2 R by PMA at 1 hr was blocked by staurosporine, an inhibitor of PKC, whereas the down-regulation of EP3 R by PMA at 24 hr was blocked by indomethacin. Pretreatment of U937 cells with PGE2 for 1 and 24 hr reduced both the binding affinity and the total number of PGE2 R, by co-ordinate suppression of the EP2 R and EP3 R. Desensitization of EP2 R and EP3 R for 1 hr with PGE2 suppressed subsequent PGE2-evoked chemokinetic responses to PGE2, whereas selective down-regulation of EP2 R alone by PMA for 1 hr had no effects on U937 cell migration. Thus expression of each subtype of PGE2 R is regulated independently and EP3 R, but not EP2 R, transduces PGE2 effects on migration of mononuclear phagocytes.
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PMID:Independent down-regulation of EP2 and EP3 subtypes of the prostaglandin E2 receptors on U937 human monocytic cells. 856 30

Parturition results from the establishment of phasic regular uterine contractions. Contractility in myometrial smooth muscle is stimulated by an increase in intracellular calcium ([Ca2+i]) which activates myosin light chain phosphorylation leading to increased myosin ATPase activity and enhanced rate of acto-myosin cross bridge formation. G proteins play a pivotal role in smooth muscle activation and relaxation by coupling cell membrane receptors to effector enzymes and ion channels. G alpha(s) and G alpha(i) stimulate and inhibit adenylyl cyclase, respectively and control cAMP formation. G alpha(q) stimulates phospholipase C resulting in the formation of two second messengers: inositol 1,4,5-trisphosphate (InsP3) which releases Ca2+ from the sarcoplasmic reticulum, and 1,2-diacylglycerol which activates protein kinase C. The oxytocin receptor stimulates myometrial contractility by increasing [Ca2+i] through both pertussis toxin resistant (G alpha(q)) and pertussis toxin sensitive (?G alpha (i)) pathways. beta-Adrenoceptors and prostaglandin EP2 receptors promote relaxation via G alpha(s)-adenylyl cyclase. The concentration of myometrial oxytocin receptors is five-times higher in pregnant compared to non-pregnant myometrium but decreases in samples obtained during labour. When myometrial slices are challenged with oxytocin there is a rapid increase in InsP3 levels with a time course which is similar to the rise in [Ca2+i] provoked by oxytocin in cultured myometrial cells. The formation of InsP3 in response to oxytocin in myometrial tissue at term is similar in samples obtained before and after the onset of labour. G alpha(q) and G alpha(i) are expressed at similar levels in non-pregnant and in pregnant myometrium obtained before or during labour. By contract, G alpha(s) levels are higher in pregnant compared to non-pregnant myometrium and decrease in samples obtained during labor. These changes in G alpha(s) are paralleled by prostaglandin E2-induced adenylyl cyclase activity in the same tissues. Parturition may be the consequence of downregulation of pathways that favour uterine quiescence by increasing cAMP formation, resulting in a relative dominance of stimulatory receptors that increase InsP3/Ca2+ availability.
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PMID:Parturition: activation of stimulatory pathways or loss of uterine quiescence? 871 97

In the present report, we show that prostaglandin (PG) E2 is the most potent factor which stimulates aromatase expression via cyclic AMP and promoter II. PGE2 acts via EP1 and EP2 receptor subtypes to stimulate both the PKC and PKA pathways. The combined stimulation of both of these pathways results in maximal expression of promoter II-specific CYP19 transcripts. Since PGE2 is a major secretory product both of breast tumor epithelial cells and fibroblasts, as well as of macrophages infiltrating the tumor site, then this could be the mechanism whereby estrogen biosynthesis is stimulated in breast sites adjacent to a tumor, leading in turn to increased growth and development of the tumor itself.
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PMID:Estrogen biosynthesis proximal to a breast tumor is stimulated by PGE2 via cyclic AMP, leading to activation of promoter II of the CYP19 (aromatase) gene. 894 Apr 10

Although the exact mechanism of prostaglandin E2 (PGE2)-mediated cytoprotection has not been elucidated, its ability to induce cytoprotection in cell culture suggests this action occurs at the cellular level. The present studies were conducted to determine whether PGE2 induces protection against 2,3,5-(trisglutathion-S-yl)-hydroquinone [2,3,5-(trisglutathion-S-yl)-HQ]-mediated cytotoxicity in a renal proximal tubule epithelial cell line (LLC-PK1) and to delineate the cellular and molecular mechanisms associated with this response. Pretreatment of LLC-PK1 cells with 0.01-40 microM PGE2 for 24 h fully protects against a moderately toxic concentration of 2,3,5-(trisglutathion-S-yl)-HQ. PGE2-mediated cytoprotection is observed in cells pretreated at pH 7.4 but not at pH 7.8. However, cytoprotection is observed in LLC-PK1 cells pretreated with the PGE2 analog, 11-deoxy-16,16-dimethyl PGE2 (DDM-PGE2) but not with the PGE2 receptor [E-prostanoid (EP)] agonists 17-phenyltrinor PGE2 (EP1), 11-deoxy PGE1 (EP2/EP4), sulprostone (EP1/EP3), PGE1, or PGA2. 12-O-tetradecanoylphorbol-13-acetate (TPA), a potent activator of protein kinase C (PKC), also induces cytoprotection, supporting a role for this pathway in the cytoprotective response. PGE2, DDM-PGE2, and TPA all induce the binding of nuclear proteins to a TPA responsive element (TRE), whereas analogs that did not induce cytoprotection (PGE1, 17-phenyltrinor PGE2, sulprostone) were without effect. DDM-PGE2- and TPA-mediated cytoprotection and TRE binding activity are inhibited by N-(2[[3-(4-bromophenyl)-2-propenyl]-amino]-ethyl)-5-isoquinolinesulfonam ide (H-89), a PKC inhibitor. These data suggest that cytoprotection by PGE2 and DDM-PGE2 in LLC-PK1 cells is mediated by a PKC-coupled receptor, which is pharmacologically distinct from the presently classified EP receptor subtypes.
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PMID:PGE2-mediated cytoprotection in renal epithelial cells: evidence for a pharmacologically distinct receptor. 936 28

Estrogen biosynthesis in adipose tissue increases with age and obesity, and has been implicated in the development of endometrial cancer and breast cancer. In normal human adipose tissue, expression of the CYP19 gene which encodes aromatase P450, the enzyme responsible for estrogen biosynthesis, is regulated by a distal promoter, namely promoter I.4. Stimulation of expression in adipose stromal cells by members of the type 1 cytokine family, i.e. interleukin (IL)-6, IL-11, leukemia inhibitory factor (LIF) and oncostatin M (OSM), is mediated via a Jak-STAT3 signaling pathway and a GAS element upstream of promoter I.4. In contrast, aromatase expression in breast adipose tissue proximal to tumor is increased three- to four-fold to the utilization of another promoter, namely promoter II, proximal to the translation initiation site. In the present report, we show that prostaglandin (PG) E2 is the most potent factor which stimulates aromatase expression via cyclic AMP and promoter II. PGE2 acts via EP1 and EP2 receptor subtypes to stimulate both the PKC and PKA pathways. The combined stimulation of both of these pathways results in the maximal expression of promoter II-specific CYP19 transcripts. Because PGE2 is a major secretory product both of breast tumor epithelial cells and fibroblasts, as well as of macrophages infiltrating the tumor site, then this could be the mechanism whereby estrogen biosynthesis is stimulated in breast sites adjacent to a tumor, leading in turn to increased growth and development of the tumor itself.
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PMID:Transcriptional regulation of CYP19 gene (aromatase) expression in adipose stromal cells in primary culture. 936 91

The role of cAMP in mediating prostaglandin E2 (PGE2)-stimulated aggregation of neutrophil-like HL-60 cells has been investigated. Although the EP2 receptors appear to couple to Gs-proteins, PGE2 stimulated HL-60 cell aggregation appears to be a cAMP-independent process. This response to PGE2 in independent of calcium and tyrosine kinase activity, appears to involve activation of phosphatidylinositol 3-kinase which is negatively regulated by phosphatidic acid generated from phospholipase D activity, and is partially dependent on protein kinase C activity. In contrast, although the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) produces a similar aggregation response to PGE2, FMLP uses a distinct intracellular signalling pathway. The aggregation response to FMLP involves activation of Gi-proteins, is partially dependent on extracellular calcium, is negatively regulated by protein kinase C, and is independent of phosphatidylinositol 3-kinase, phospholipase D and tyrosine kinase activity. The possibility exists that EP2 receptor activation leads to Gs-dependent, but cAMP-independent, stimulation of phosphatidylinositol 3-kinase activity in HL-60 cells.
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PMID:Cyclic AMP-independent activation of neutrophil-like HL-60 cells by prostaglandin E2. 941 17


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