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)

Prostaglandin-synthesizing activities were demonstrated in cell-free extracts of rat Kupffer cells and characterized. The enzymatic properties of PGH2 synthase were found to be similar to those of synthases present in other organs or cell types. The specific activity of the enzyme was not changed by substances that stimulate prostanoid release by intact Kupffer cells; however, it was reduced by pretreatment of the cells with glucocorticoid hormones. On the other hand, the activities of PGD2 and PGE2 synthase were influenced differently by the kind of cell stimulation. While pretreatment of the intact cells with endotoxin and/or inhibition of protein kinase C led to an enhanced PGE2 formation in cell-free extracts, exposure to agents that enhance protein kinase C-dependent signalling pathways, e.g. phagocytotic stimuli or phorbol ester, suppressed PGE2 synthase activity and, therefore, led to enhanced PGD2 synthesis. It is in line with this observation that in vitro activation of protein kinase C of Kupffer cells resulted in a reduced PGE2 and an enhanced PGD2 synthase activity.
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PMID:Prostaglandin D2 and E2 syntheses in rat Kupffer cells are antagonistically regulated by lipopolysaccharide and phorbol ester. 141 80

Our current working hypothesis for the intracellular mechanism of action for LH and PGF-2 alpha is shown in Fig. 8. Luteinizing hormone appears to act primarily on the small luteal cell through the cAMP/protein kinase A effector system and thereby stimulates secretion of progesterone. Activation of the protein kinase C effector pathway is inhibitory to progesterone secretion from stimulated small luteal cells but it is not clear which hormones, if any, activate this effector system. Results from studies in whole animals suggest that LH may also stimulate differentiation of small luteal cells into large luteal cells (Donaldson & Hansel, 1965; Farin et al., 1988). Although there are LH receptors on large luteal cells, LH treatment does not stimulate progesterone secretion and does not appear to activate any of the second messenger pathways which we have examined. Prostaglandin F-2 alpha appears to act on the large luteal cell through free intracellular calcium and protein kinase C effector systems. Apparently, PGF-2 alpha-induced activation of protein kinase C results in the acute inhibition of progesterone production seen in the first 8 h after PGF-2 alpha treatment. The cytotoxic effects of PGF-2 alpha on the large luteal cell (Fitz et al., 1984; Braden et al., 1988) may be caused by a sustained elevation in free intracellular calcium concentrations. No direct effects of PGF-2 alpha on small luteal cells have been detected (no inhibition of progesterone production, no activation of protein kinase C, no increase in free intracellular calcium), which is consistent with an absence of high affinity PGF-2 alpha receptors on this cell type. The cytotoxic effects of PGF-2 alpha on small luteal cells and endothelial cells (Braden et al., 1988) may be caused by decreases in luteal blood flow (Niswender et al., 1975; Wiltbank et al., 1990b), actions of cytotoxic agents released by large luteal cells, or increases in cytotoxic white blood cells (Murdoch, 1987; Bagavandoss et al., 1988).
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PMID:Differential actions of second messenger systems in the corpus luteum. 184 52

The present article deals with the stimulation of membrane PLA2 induced by activated protein kinase C (PKC), and the effect of a deficiency in cellular PKC activity in reducing in PLA2 activity. The mode of glucocorticoid (GC) inhibition action in regulation of PLA2 activity, by enhancement of protein dephosphorylation in general, and PLA2 in particular, is hypothesized and discussed. Indirect evidence strongly suggests that activated PKC enzyme is essential for the stimulation of membrane PLA2 activity induced by the Ca2+ ionophore A23187 and other agonists. Our hypothesis suggests that membrane-associated PKC directly phosphorylates PLA2 leading to its activation. Dephosphorylation of activated PLA2, possibly by a serine/threonine protein phosphatase reduces PLA2 activity. GC could induce membrane protein phosphatases which mediate their inhibitory action on PLA2 activity. This mode of action of GC is complementary to their effect in reducting in elevated [Ca2+]i, which is essential for full expression of PLA2 activity. Thus, GC exhibits multiple actions which specifically culminate in suppression of PLA2 and other phospholipases (PI-PLC and PLD) and generally in cellular inactivation (relaxation) and reduction of allergic and inflammatory responses.
Adv Prostaglandin Thromboxane Leukot Res 1991
PMID:A novel mechanism of glucocorticosteroid (GC) action in suppression of phospholipase A2 (PLA2) activity stimulated by Ca2+ ionophore A23187: induction of protein phosphatases. 184 70

The mechanism of 12-O-tetradecanoylphorbol-13-acetate (TPA) enhanced arachidonic acid metabolism was investigated in dog urothelial cells. Primary cultures of dog urothelial cells were grown to confluency and evaluated in the presence or absence of overnight prelabeling with [3H]arachidonic acid. High-performance liquid chromatography analysis of media from TPA stimulated cells indicated that prostaglandin E2 (PGE2) was the major eicosanoid produced. Lipoxygenase products were not detected. Control cell media contained only arachidonic acid. Effects of selected inhibitors on TPA and exogenous arachidonic acid mediated increases in radioimmunoassayable PGE2 were assessed. Prostaglandin H synthase inhibitors (indomethacin and aspirin) prevented both TPA and arachidonic acid increases in PGE2. By contrast, inhibitors of phospholipases (quinacrine, W-7, and trifluoropromazine), protein synthesis (cycloheximide), and protein kinase C (staurosporine) prevented TPA but not arachidonic acid increases in PGE2. The latter agents also reduced TPA mediated increases in the release of total radioactivity from cells labeled with [3H]arachidonic acid. However, aspirin reduced the amount of 3H-prostaglandins formed with TPA. A calcium requirement was demonstrated when increases in radioimmunoassayable PGE2 elicited by TPA and the calcium ionophore A23187 were reduced with calcium depleted media. When epidermal growth factor in combination with either TPA or bradykinin was used, at least additive effects were observed with respect to release of [3H]arachidonic acid, 3H-prostaglandins, and radioimmunoassayable PGE2. These experiments suggest that separate pathways may be involved in enhanced arachidonic acid metabolism demonstrated with different agonists. For TPA, increased arachidonic acid release occurs by a calcium dependent process involving phospholipase(s), protein synthesis, and protein kinase C.
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PMID:Mechanism of 12-O-tetradecanoylphorbol-13-acetate enhanced metabolism of arachidonic acid in dog urothelial cells. 211 44

Prostaglandin (PG) F2 alpha (30 microM) stimulated both monophosphorylation and diphosphorylation of myosin light chain (MLC) in a smooth muscle cell line (SM-3). The diphosphorylation was significantly decreased by treatment with the protein kinase C inhibitor staurosporine (30 nM, 30 min) from 20.1% of total MLC to 4.5%. The protein kinase C down-regulation treatment of SM-3 cells with phorbol dibutyrate suppressed to 8.7% the MLC diphosphorylation activity in the SM-3 cells. This down-regulation treatment had little effect on the monophosphorylation. We propose that the MLC diphosphorylation in PGF2 alpha-stimulated SM-3 cells in culture may be regulated through mechanisms sensitive to protein kinase C.
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PMID:Diphosphorylation of myosin light chain in smooth muscle cells in culture. Possible involvement of protein kinase C. 226 95

The mechanism by which agonists stimulate phospholipase A2 of platelets is still much of a mystery. We have presented a discussion that suggests that neither Ca2+, protein kinase C or dissociation of the inhibitory GTP-binding protein Gi is solely responsible for activating this enzyme. We cannot exclude the possibility that there may be some contribution of each pathway for some agonists, and that the contribution may change with agonist concentration or potency. These possibilities await further clarification.
Adv Prostaglandin Thromboxane Leukot Res 1989
PMID:Relationship of inositol phospholipid metabolism to phospholipase A2. 252 38

Prostaglandin (PG) activation of the phosphoinositol transduction pathway in MDCK cells and modulation of this process by phorbol esters was studied by monitoring changes in cytosolic free Ca2+ concentration, [Cai2+], with the Ca2+-sensitive fluorescent probe, fura-2 and measurement of stimulation of inositol phosphates by anion-exchange chromatography. Cells challenged with PGE1 or PGE2 responded with a prompt and transient increase in [Cai2+] that was independent of extracellular Ca2+. The K0.5 for PGE2 for the process was 6.1 X 10(-7) M. PGE1 and PGE2 appeared to be recognized by a common receptor. PGF2 alpha was without effect. 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8) but not verapamil, a Ca2+ channel inhibitor, blocked the PGE2-evoked Ca2+ transient. Under identical conditions PGE2 increased inositol phosphate accumulation by 54 +/- 8% (inositol-1-monophosphate), 23 +/- 6% (inositol-1,4-bisphosphate), and 49 +/- 3% (total inositol trisphosphate), above control values. Brief (30-60 s) exposure of cells to phorbol-12,13-myristate (PMA) or phorbol-12,13-dibutyrate (PDB) completely blocked the PGE2-induced Ca2+ transient. The K0.5 for the process for PMA and PDB was 0.3 +/- 0.1 and 4.5 +/- 2.2 nM, respectively. Neither 4 alpha-nor 4 beta-phorbol, which lack the ability to activate protein kinase C, were effective in this regard. In contrast to complete blockade by 10(-8) PMA of the PGE2 (10(-5) M)-elicited Ca2+ transient, this concentration of PMA inhibited the Ca2+ transient evoked by 10(-9) M bradykinin (BK) by 50%. In fact 10(-4) M PMA only partially blocked the BK-elicited Ca2+ transient. In summary, in MDCK cells, the PG receptor is coupled both to the adenylate cyclase system and inositol phospholipid transduction pathway. The PG receptor appears to be regulated by protein kinase C. In addition to protein kinase C other factors regulate the BK receptor.
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PMID:Differential effects of phorbol esters on PGE2 and bradykinin-induced elevation of [Cai2+] in MDCK cells. 273 24

The shape of the time-course of cyclic AMP formation by intact human platelets in response to the stable prostaglandin I2 analogue iloprost varied with the concentration of the prostaglandin. At low concentrations of iloprost, the time-course showed a rise to a plateau with little subsequent decrease in cyclic AMP level. At high concentrations of iloprost, the initial rate of cyclic AMP formation was more rapid than at low concentrations, but the curves showed a marked time-dependent fall in cyclic AMP level to values below those observed at lower prostaglandin concentration. By contrast, PGE1 gave a rise and marked fall in cyclic AMP level at all concentrations of the prostaglandin and the curves did not cross. The time- and concentration-dependent fall in cyclic AMP level in response to iloprost was still apparent in the presence of phosphodiesterase inhibitors, indicating that inhibition of adenylate cyclase, rather than activation of cyclic AMP phosphodiesterases, was responsible for the fall in cyclic AMP level. Activators of protein kinase C, which phosphorylates platelet Ni and impairs its function, abolished the time-dependent fall in cyclic AMP level, indicating that Ni may be involved in prostaglandin-induced inhibition of adenylate cyclase. Time-courses were analyzed using an equation derived by Barber et al. (Adv. Cyc. Nuc. Res. 9, 507-516 (1978)) to yield rate constants for activation and inhibition of adenylate cyclase. Because of the difference in prostaglandin dependence of the activation and inhibition rate constants we propose that activation of adenylate cyclase in platelets is mediated by a rapid-acting stimulatory receptor, while time-dependent inhibition (desensitization) is mediated through a separate, slow-acting inhibitory receptor. The stimulatory receptor has an affinity for prostaglandin greater than the putative inhibitory receptor in the case of iloprost (as well as PGI2 and PGD2), and a lower affinity than the inhibitory receptor in the case of PGE1 (and PGE2). Prostaglandin-induced inhibition may be mediated through Ni.
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PMID:Cyclic AMP turnover in response to prostaglandins in intact platelets: evidence for separate stimulatory and inhibitory prostaglandin receptors. 284 22

A calcium-sensitive, lipid-activated protein kinase is present in ovarian granulosa cells and may modulate granulosa cell function through an effect on granulosa cells prostaglandin F2 alpha biosynthesis. Phorbol-ester activation of this protein kinase elicits a dose- and time-dependent augmentation in the synthesis of PGF2 alpha by swine granulosa cells which can be inhibited by inhibitors of prostaglandin and protein synthesis. Our studies support a linkage between protein kinase C activation and prostaglandin F2 alpha synthesis by these cells.
Adv Prostaglandin Thromboxane Leukot Res 1987
PMID:A stimulatory role for the protein kinase C pathway in ovarian prostaglandin synthesis: studies with cultured swine granulosa cells. 296 Jan 56

Prostaglandin (PG) H synthase and eicosanoid products of arachidonic acid metabolism have been implicated in several steps in the carcinogenic process. This study assessed these parameters using primary cultures of human urothelial cells. To determine the possible presence of permeability barriers to agonist stimulation, incubations were performed with adherent cells in the presence or absence of thioglycolate pretreatment or with cell suspensions. No evidence for permeability barriers was observed. With adherent cells in the absence of thioglycolate, radioimmunoassayable PGE2 was stimulated by epinephrine less than 12-O-tetradecanoylphorbol-13-acetate = thrombin less than bradykinin = A23187 much less than arachidonic acid. Tumor promoters but not non-tumor promoters stimulated PGE2 synthesis. 1-Oleoyl-2-acetylglycerol which like 12-O-tetradecanoylphorbol-13-acetate activates protein kinase C also increased PGE2 synthesis. Cells prelabeled with [14C]arachidonic acid were exposed to agonists and the profile of eicosanoids synthesized was assessed by high performance liquid chromatography. With bradykinin, the pattern of eicosanoids synthesized was 6-keto-PGE1 alpha (12% of total 14C label), thromboxane B2 (0.4%), PGF2 alpha (1.7%), PGE2 (18%), PGD2 (1%), leukotrienes (0.4 to 1%), 12-hydroxy-5,8,10-heptadecatrienoic acid (3%), 15-hydroxy-5,8,11,13-eicosatetraenoic acid (4%), 12-hydroxy-5,8,10,14-eicosatetraenoic acid (0%) and 5-hydroxy-5,8,12,14-eicosatetraenoic acid (2%). Thus, human urothelial cells contain both prostaglandin H synthase and lipoxygenase pathways with the former being more prominent. These pathways may participate in urinary bladder carcinogenesis.
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PMID:Eicosanoid synthesis by cultured human urothelial cells: potential role in bladder cancer. 309 68


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