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)

Prostaglandins are likely to play an important role in the physiologic and pathologic responses of skeletal tissue. They are potent agonists that can stimulate and inhibit bone resorption and formation. In vivo, the major effect of exogenous prostaglandins, particularly prostaglandin E2, is to stimulate resorption and formation. These effects appear to involve replication and differentiation of osteoclast and osteoblast precursors, and to be mediated at least in part by cyclic 3' 5' adenosine monophosphate. Prostaglandins can inhibit the activity of isolated osteoclasts, probably also by a cyclic 3' 5' adenosine monophosphate-mediated mechanism. Inhibition of collagen synthesis can be seen in cell and organ cultures and appears to be caused by a receptor selective for prostaglandins of the F series and to involve activation of protein kinase C. Prostaglandin production by bone cells is regulated highly by mechanical forces, cytokines, growth factors, and systemic hormones. Prostaglandins also can amplify their own production. Regulation is associated with marked changes in the newly described "inducible" prostaglandin G/H synthase with less effect on the constitutive enzyme. Prostaglandins also may play a role in postmenopausal bone loss because estrogen deficiency, which increases bone turnover, can increase prostaglandin production in bone.
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PMID:The role of prostaglandins in the regulation of bone metabolism. 764 96

High concentrations of PGF2 alpha and PGE2 are produced by the uterus during the early postpartum period in cows and may play an important role in both placental separation and uterine involution. In the present study, we have examined the hormonal and intracellular control mechanisms involved in PGF2 alpha and PGE2 secretion by caruncular and allantochorionic tissue in vitro. Tissue explants, obtained about 6 hr postpartum from cows that delivered normally (NFM, n = 10) or cows with retained fetal membranes (RFM, n = 4), were incubated for 6 hr and PGF2 alpha and PGE2 concentrations in the medium were determined by radioimmunoassay. Addition of oxytocin (100 microU/ml), platelet activating factor (PAF, 100 ng/ml) and epidermal growth factor (EGF, 100 ng/ml) had no effect on secretion of PGF2 alpha from the caruncle, but oxytocin and PAF did stimulate PGE2. There was no difference between groups of cows. All three substances stimulated PGF2 alpha from the allantochorion of NFM, but not RFM, cows and stimulated PGE2 secretion from the allantochorion of both groups of cows. Incubation of the tissues with cholera toxin (100 ng/ml), dibutyryl cyclic adenosine 3',5'-monophosphate (dibutyryl cAMP, 1 mM), calcium ionophore A23187 (5 microM) or phorbol ester 12-myristate-13 acetate (PMA, 100 nM) showed that PGF2 alpha secretion is essentially via the calcium-protein kinase C effector pathway. However, calcium-protein kinase C and cAMP second messenger systems appear to be involved in the secretion of PGE2. Prostaglandin secretion was sensitive to cycloheximide in both caruncular and allantochorionic tissues, suggesting that protein synthesis may be involved. In conclusion, these data show that in vitro PGF2 alpha secretion can be modulated by the agonists used only in allantochorion and is essentially via the calcium-protein kinase C effector pathway. PGE2 secretion can be modified in both caruncular and allantochorion tissues and involves both inositol triphosphate-diacylglycerol and cAMP second messenger systems.
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PMID:Control of in vitro prostaglandin F2 alpha and E2 synthesis by caruncular and allantochorionic tissues from cows that calved normally and those with retained fetal membranes. 804 99

To elucidate the events elicited by the skin tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), which are modulated by linoleic acid (LA) and arachidonic acid (AA), the activity of these fatty acids in cultured mouse epidermal cells was compared. Approximately 94% of either exogenous radiolabelled fatty acid was incorporated into the total phospholipid pool over 15 h. The relative distribution among the phospholipid classes differed, however, such that approximately 70% of phospholipid-associated [14C]-LA was found in phosphatidylcholine, compared to approximately 30% for [14C]AA. Phosphatidylethanolamine and phosphatidylinositol/phosphatidylserine contained 17 and 13% of the phospholipid [14C]LA, and 34 and 30% of [14C]AA, respectively. Prostaglandin (PG) E2 production was low but similar in unstimulated cultures prelabelled with either [14C]LA or [14C]AA. However, in cultures treated with TPA (1.6 microM), [14C]AA-prelabelling resulted in approximately three times the amount of [14C]PGE2 compared with cultures prelabelled with [14C]LA. Cultured cells were found to contain significant delta 6 desaturase activity, which may enable conversion of LA to AA, and thus may account for the observed PGE2 production from [14C]LA treated cells. AA-Supplemented (1.6 microM) cultures supported approximately twice the induction of ornithine decarboxylase activity by TPA compared with cultures treated with 1.8 microM LA. Activation of partially purified protein kinase C was similar for either fatty acid tested over a 10-300 microM dose range. Overall, the results suggest that LA does not have the same biological activity as AA with regard to several TPA-associated events known to be important in skin tumor promotion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of phorbol ester-associated events in epidermal cells by linoleate and arachidonate. 831 48

Prostaglandin (PG) has been reported to be one of the important protective factors in the gastric mucosa. However the mechanism of the regulation of endogenous PG production has not been well studied. We investigated the possible roles of Ca2+, cAMP, and protein kinase C (PKC) in the regulation of PGE2 release from cultured rabbit gastric mucosal cells. PGE2 was measured by radioimmunoassay. A23187 (Ca2+ ionophore) at 2 x 10(-6) M significantly increased PGE2 release. Deprivation of Ca2+ from the medium blocked the A23187-induced increase of PGE2. TMB-8 (a putative inhibitor of Ca2+ release from intracellular stores) did not have any significant effects on the increase of PGE2-induced by A23187. Thus, A23187 increased PGE2 through the influx of extracellular Ca2+. W7 or compound 48/80 (calmodulin inhibitors) did not alter the response of PGE2 caused by A23187. Exogenous administration of cAMP, forskolin (an activator of adenylate cyclase), or 2-chloroadenosine (a possible activator of adenylate cyclase through adenosine A2 receptor) had neither significant effects on PGE2 release nor an effect on A23187-induced increase of PGE2 release. 12-O-tetradecanoylphorbol 13-acetate (TPA, an activator of PKC) significantly stimulated PGE2 release in a dose-dependent fashion, whereas another phorbol ester with no biological activity did not. A23187 at 0.8 x 10(-6) M, but not cAMP, potentiated the TPA-induced increase of PGE2. Mepacrine (a phospholipase A2 inhibitor) reduced the A23187- and TPA-induced increase of PGE2. These results suggest that Ca2+ and protein kinase C may play important roles in the regulation of PGE2 release by cultured rabbit gastric cells.
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PMID:Roles of Ca2+ and protein kinase C in regulation of prostaglandin E2 release by cultured rabbit gastric epithelial cells. 839 56

Prostaglandin H synthase (PGHS) is the rate-limiting enzyme responsible for the formation of the prostaglandins from arachidonic acid. Prostaglandins (and other metabolites) elicit signals for inflammation, which is thought to be required for tumor promotion in the mouse skin carcinogenesis model. This study was designed to examine the effect of protein kinase C (PKC)-activating tumor promoters (4 beta-12-O-tetradecanoylphorbol-13-acetate (TPA)), non-PKC-type promoters (anthralin, benzoyl peroxide, okadaic acid), and mitogens (epidermal growth factor (EGF)) on the levels of the constitutive (PGHS-1) and inducible (PGHS-2) forms of PGHS in murine keratinocytes. Northern analysis of mRNA isolated from cultures treated with TPA (1 microgram/mL) showed that a single treatment of TPA produced a sevenfold increase in PGHS-2 mRNA by 1 h that decreased by 6 h after treatment. PGHS-2 protein levels were elevated threefold by 3 h and remained elevated through 9 h. Downregulation of PKC with a second TPA treatment 15 h after the first resulted in diminished induction of PGHS-2 expression. Of the other promoters examined, anthralin (5 microM), benzoyl peroxide (10 microM), and okadaic acid (1 microM) induced PGHS-2 mRNA with different kinetics and to different extents. Additionally, the non-tumor-promoting phorbol ester analogue 4 alpha-12-O-tetradecanoylphorbol-13-acetate induced PGHS-2 mRNA significantly by 1 h, and this response remained elevated up to 6 h after treatment. Elevated PGHS-2 expression was also observed by 3 h in response to EGF (10 ng/mL) treatment. Collectively, these observations indicate that there are several different signaling pathways by which PGHS-2 can be upregulated in murine keratinocytes.
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PMID:Multifactor regulation of prostaglandin H synthase-2 in murine keratinocytes. 898 14

Prostaglandin F(2alpha) (PGF(2alpha)) exerts its biological effects by binding to and activating FP prostanoid receptors. These receptors, which include two isoforms, the FP(A) and FP(B), have been cloned from a number of species and are members of the superfamily of G-protein-coupled receptors. Previous studies have shown that the activation of FP receptors leads to phosphatidylinositol hydrolysis, intracellular calcium release, and activation of protein kinase C. Here, we demonstrate that PGF(2alpha) treatment of 293-EBNA (Epstein-Barr nuclear antigen) cells that have been stably transfected with either the FP(A) or FP(B) receptor isoforms leads to changes in cell morphology and in the cell cytoskeleton. Specifically, cells treated with PGF(2alpha) show retraction of filopodia and become rounded, and actin stress fibers are formed. Pretreatment of the cells with bisindolylmaleimide I, a protein kinase C inhibitor, has no effect on the PGF(2alpha)-induced changes in cell morphology, although it does block the effects of phorbol myristate acetate on cell morphology. On the other hand, the PGF(2alpha)-induced changes in cell morphology and formation of actin stress fibers can be blocked by pretreatment of the cells with C3 exoenzyme, a specific inhibitor of the small G-protein, Rho. Consistent with FP receptor induced formation of actin stress fibers and focal adhesions, FP(A) receptor activation also leads to rapid (within two minutes) tyrosine phosphorylation of p125 focal adhesion kinase (FAK) which can be blocked by pretreating the cells with C3 exoenzyme. Taken together, these results suggest that the FP receptor isoforms are coupled to at least two second messenger pathways, one pathway associated with protein kinase C activation, and the other with activation of Rho.
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PMID:Activation of FP prostanoid receptor isoforms leads to Rho-mediated changes in cell morphology and in the cell cytoskeleton. 1058 82

Prostaglandin F(2alpha) receptors (FP) are G protein-coupled receptors that bind prostaglandin F(2alpha) (PGF(2alpha)), resulting in the activation of an inositol phosphate (IP) second messenger pathway. Alternative mRNA splicing generates two FP receptor isoforms. These isoforms, designated FP(A) and FP(B), are otherwise identical except for their carboxyl termini. FP(B) is essentially a truncated version of FP(A) that lacks the 46 carboxyl-terminal amino acids, including four putative protein kinase C (PKC) phosphorylation sites. Until now, functional differences between these FP receptor isoforms have not been identified. We now report that pretreatment with the PKC inhibitor bisindolylmaleimide I enhanced PGF(2alpha)-stimulated IP accumulation in transfected cells stably expressing the FP(A) isoform but not in cells stably expressing the FP(B) isoform. Whole-cell phosphorylation experiments showed a strong agonist-dependent phosphorylation of the FP(A) isoform but little or no phosphorylation of the FP(B). Pretreatment of cells with bisindolylmaleimide I decreased PGF(2alpha)-stimulated phosphorylation of the FP(A) isoform consistent with a PKC-dependent phosphorylation. In vitro phosphorylation of an FP(A) carboxyl-terminal fusion protein by recombinant PKCalpha showed that the carboxyl terminus of the FP(A) is a substrate for PKC. These results suggest that PKC-dependent phosphorylation is responsible for differential regulation of second messenger signaling by FP prostanoid receptor isoforms.
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PMID:Differential regulation of prostaglandin F(2alpha) receptor isoforms by protein kinase C. 1064 45

To clarify the effects of arachidonic acid (AA) and its metabolites on desensitization of nicotinic acetylcholine (ACh) receptor channel in mouse skeletal muscle cells, we investigated the time-dependent decrease in the channel opening frequency of ACh (1 microM)-activated channel currents by the cell-attached patch clamp technique. AA (30-100 microM) applied to a patched membrane or to non-patched membrane accelerated the decrease in the channel opening frequency. A cyclooxygenase inhibitor, indomethacin (10 microM), prevented the acceleration elicited by 30 microM AA, but not by 100 microM AA. A lipoxygenase inhibitor, nordihydroguaiaretic acid (10 microM), and a cytochrome P-450 inhibitor, ketoconazole (3 microM), did not affect the acceleration by 30 microM AA. Prostaglandin (PG) D2 at 10 microM alone and at 25 nM in combination with 10 microM AA accelerated the decrease in the channel opening frequency. No acceleration was observed with PGE2 at 10 microM alone and at 25 nM in combination with 10 microM AA. Pretreatment with a protein kinase (PK) C inhibitor, staurosporine (10 nM), but not with a PKA inhibitor, H-89 (3 microM), prevented the acceleration elicited by AA + PGD2. These results suggest that AA, and PGD2 of its metabolites, cooperatively accelerate desensitization of nicotinic ACh receptor channel. The activation of PKC by AA and PGD2 may be involved in the mechanism of the cooperative acceleration of desensitization.
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PMID:Arachidonic acid and prostaglandin D2 cooperatively accelerate desensitization of nicotinic acetylcholine receptor channel in mouse skeletal muscles. 1066 20

Prostaglandin F(2alpha) (PGF(2alpha)), a mitogen for Swiss 3T3 cells, triggers cyclin D1 mRNA/protein expression prior to cellular entry into the S phase, but fails to raise cdk4 or cyclin D3 levels, while 1-oleoyl-2-diacylglycerol (OAG), a protein kinase C (PKC) and tyrosine kinase (TK) activator, induces only cyclin D1 expression with no mitogenic response. In contrast, in PKC-depleted or -inhibited cells, PGF(2alpha), but not OAG, increases cyclin D1 expression with no mitogenic response. Finally, OAG, in the presence of orthovanadate (Na(3)VO(4)) or TGF(beta1), induces DNA synthesis. Thus, it appears that PGF(2alpha) triggers cyclin D1 expression via two independent signaling events that complement with TGF(beta1)-triggered events to induce DNA synthesis.
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PMID:Prostaglandin F(2alpha) (PGF(2alpha)) induces cyclin D1 expression and DNA synthesis via early signaling mechanisms in Swiss mouse 3T3 cells. 1073 97

1. Pretreatment with ramiprilat, an angiotensin-converting enzyme (ACE) inhibitor, induced cardioprotection and its possible mechanism of action was investigated in guinea-pig Langendorff perfused heart. 2. Superoxide anion (*O2-), produced by hypoxanthine and xanthine oxidase, and the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) free radical were used for triggering free radical injury in cardiac tissue. 3. 1,1-Diphenyl-2-picryl-hydrazyl and *O2- significantly reduced left ventricular developed pressure (LVDP), +/-dP/dt(max), heart rate and coronary flow. Left ventricular end-diastolic pressure (LVEDP) was elevated and lactate dehydrogenase (LDH) leakage and the formation of thiobarbituric acid-reactive substances (TBARS) formation were significantly increased. 4. Pretreatment with ramiprilat induced cardioprotection against DPPH and *O2- free radical injury. Cardiac functions (LVDP, LVEDP and +/-dP/dt(max)) were significantly improved. Both LDH and TBARS were reduced. 5. HOE 140 (a selective bradykinin B2 receptor antagonist), calphostin C (a protein kinase C (PKC) inhibitor) and indomethacin (a cyclo-oxygenase inhibitor) all abolished the cardiac protective effect of ramiprilat. However, N(G)-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, had no effect. 6. In conclusion, ramiprilat pretreatment induces cardioprotection against either DPPH or *O2- free radical injury. The protective effect depends on activation of B2 receptors and PKC. Prostaglandin synthesis is also involved.
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PMID:Pretreatment with ramiprilat induces cardioprotection against free radical injury in guinea-pig isolated heart: involvement of bradykinin, protein kinase C and prostaglandins. 1077 22


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