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

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The vasoconstrictor hormone angiotensin-II (AII) raises cytosolic free calcium and stimulates protein kinase-C (PKC) activity in vascular smooth muscle cells (VSMC). Phorbol-12-myristate-13-acetate (PMA) directly activates PKC in these cells. Both of these agonists stimulate prostacyclin production. Several studies have shown that atrial natriuretic factor (ANF) does not interfere with the AII-induced early calcium response. We, therefore, examined the effects of ANF on PKC activity and prostacyclin production in cultured rat aortic VSMC. PKC activity was determined in the membranous and cytosolic fractions after anion exchange chromatography. ANF (10(-7) M) inhibited by 44 +/- 3% and 39 +/- 8% the increase in membranous PKC activity induced by AII and PMA, respectively. ANF (10(-7) M) inhibited PMA-stimulated prostacyclin production, whereas AII-induced prostacyclin production remained unaffected. Thus, our results suggest that some biological effects induced by ANF in VSMC are mediated by an inhibition of membranous PKC activity.
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PMID:Effects of atrial natriuretic factor on angiotensin-II-and phorbol ester-stimulated protein kinase-C and prostacyclin production in cultured rat aortic smooth muscle cells. 215 78

1. Neurones dissociated from Rana pipiens paravertebral sympathetic ganglia were studied by means of the whole-cell patch-clamp technique. Responses to agonists were best recorded when cyclic AMP was included in the patch pipette. 2. Two populations of cells were identified on the basis of size (input capacitance, Cin) and the presence or absence of a fast, transient outward current (A-current, IA). This current was usually present in the 'large' cells (Cin = 40.5 +/- 1.5 pF, n = 66) but absent from 'small' cells (Cin = 21.0 +/- 0.8 pF, n = 70). 3. Both cell types exhibited a slowly activating, non-inactivating K+ current (M-current, IM) which was suppressed by luteinizing hormone-releasing hormone (LHRH, 10-100 microM). Threshold for activation of IM was about -75 mV, half-maximal activation was at -50 mV and the M-conductance GM increased e-fold for at 7 mV change in membrane potential. The maximum value for IM studied in large cells by patch-clamp procedures was less than 0.2 nA. More M-channels were available per unit membrane area in the small cells (GM = 1495 microS cm-2) than in the large cells (GM = 1034 microS cm-2). Time constants for IM deactivation at -70 mV were faster in the large cells (37.2 +/- 4.6 ms, n = 16) than in the small cells (66.1 +/- 5.9 ms, n = 9). 4. Muscarine (10 microM) produced inward current in the large cells as a result of IM suppression. In 40% of the large cells, some of the M-channels were also sensitive to adrenaline (10-100 microM). In a few large cells (less than 10%) adrenaline produced outward current by increasing IM. 5. Muscarine failed to effect IM in the small cells and instead produced an inwardly rectifying K+ current which activated within 5 ms at -110 mV. The outward current produced in twenty out of thirty-seven small cells by adrenaline was occluded by that produced by muscarine, suggesting that both agonists affect the same K+ channels. 6. Inclusion of the protein kinase inhibitors, 1-(5-isoquinolinyl-sulphonyl)-2-methyl piperazine (H-7, 50 microM) or gold sodium thiomalate (GST, 50 microM) in the pipette solution failed to antagonize either muscarine-induced current. Both currents were prolonged when the 'internal solution' contained GTP-gamma-S (50 microM). 7. Phorbol-12-myristate-13-acetate (PMA, 2-5 microM) produced an inward current as a result of IM suppression in both small and large cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of muscarine and adrenaline on neurones from Rana pipiens sympathetic ganglia. 221 86

Serum-free primary cultures of neonatal (1-day-old) porcine Leydig cells were used to study the effects of phorbol-12-myristate-13-acetate and 1,2-dioctanoylglycerol on testosterone and pregnenolone production. Phorbol-12-myristate-13-acetate alone from 0.001-10 mumol/l stimulated testosterone and pregnenolone production, whereas 1,2-dioctanoylglycerol alone had no effect on steroid production, relative to control. Phorbol-12-myristate-13-acetate and 1,2-dioctanoylglycerol each inhibited pLH-stimulated testosterone and pregnenolone production. To further clarify the influence of these protein kinase C activators on steroidogenesis, cultured Leydig cells were treated with either phorbol-12-myristate-13-acetate or 1,2-dioctanoylglycerol plus forskolin (an adenylate cyclase activator). Both phorbol-12-myristate-13-acetate and 1,2-dioctanoylglycerol inhibited forskolin-stimulated testosterone production. Phorbol-12-myristate-13-acetate had no effect on forskolin-stimulated pregnenolone production and only the highest concentration of 1,2-dioctanoylglycerol (100 mumol/l) inhibited forskolin-stimulated production of pregnenolone. These data demonstrate that porcine Leydig cell steroidogenesis can be modulated by interactions of the protein kinase C and protein kinase A second messenger systems.
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PMID:In vitro modulation of porcine Leydig cell steroidogenesis by phorbol-12-myristate-13-acetate and 1,2-dioctanoylglycerol. 230 1

The possible involvement of three different second-messenger systems, namely cyclic AMP/protein kinase (PK)-A, cyclic GMP/PK-G, and diacylglycerol (DG)/PK-C systems, in the perivascular nerve terminals of guinea pig mesenteric artery was examined by intracellular microelectrode recording. Excitatory junction potentials (EJPs) were evoked by perivascular nerve stimulation. Isoproterenol (0.1 microM) enhanced the EJP amplitude without modifying the passive membrane properties of the vascular smooth muscle (VSM) cells. The facilitatory effect of isoproterenol on EJP amplitude was completely abolished by beta-adrenergic blockade (0.3 microM propranolol). Forskolin (activator of adenylate cyclase) also augmented the EJP amplitude in a concentration-dependent manner (EC50 congruent to 10 microM), without affecting the passive membrane properties of the VSM cells. In addition, forskolin (1-10 mM) markedly potentiated the isoproterenol-induced stimulation of EJP amplitude (EC50 congruent to 2 microM). A permeant analogue of cyclic AMP, 8-bromo-cyclic AMP (0.1 and 1 mM), enhanced the EJP amplitude, thus mimicking the effects of isoproterenol and forskolin. 8-Bromo-cyclic AMP had no effect on the resting potential or current-voltage relationship of the VSM cells, thus suggesting that the membrane properties of the VSM cells were not altered. 8-Bromo-cyclic GMP (1 mM) also augmented the EJP amplitude, but its facilitatory effect was weaker than that of 8-bromo-cyclic AMP. 8-Bromo-cyclic GMP hyperpolarized the VSM membrane by 4 mV and decreased the input resistance, presumably due to an increase in K+ conductance. Phorbol-12-myristate-13-acetate (PMA, 30-300 nM), a direct activator of PK-C, significantly enhanced the EJP amplitude after 40 min in a concentration-dependent manner, without affecting the resting potential of the VSM cells. From these results, we suggest that cyclic AMP/PK-A, cyclic GMP/PK-G, and DG/PK-C systems might be involved in regulation of the release of neurotransmitter in the perivascular nerve terminals. However, the possibility of some action on the postsynaptic VSM cell cannot be excluded.
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PMID:Cyclic nucleotide regulation of neurotransmission in guinea pig mesenteric artery. 248 77

Purified rat Leydig cell cytosol was found to contain a protein kinase which was dependent on the presence of both calcium and phospholipids (phosphatidylserine and diolein), i.e. calcium/phospholipid-dependent protein kinase. The peak of Ca/phospholipid-dependent protein kinase was separated from type I and type II cAMP-dependent protein kinase by DE-52 chromatography. 4 beta-Phorbol-12-myristate-13-acetate (PMA), a tumor-promoting agent, could substitute for diolein in activation of Ca/phospholipid-dependent protein kinase. PMA caused dose-dependent increments of testosterone formation by Leydig cells, whereas inactive phorbol esters had no significant effects. PMA-induced testosterone formation was dependent on extracellular calcium and could be blocked by the addition of the calcium channel-blocking agent nifedipine. Since PMA can directly activate Ca/phospholipid-dependent protein kinase and increase testosterone formation, these results suggest that Ca/phospholipid-dependent protein kinase may be involved in modulating Leydig cell steroidogenesis in addition to the classical cAMP-dependent protein kinase pathway.
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PMID:The role of calcium/phospholipid-dependent protein kinase in Leydig cell steroidogenesis. 298 10

Phorbol-12-myristate-13-acetate (PMA) in some systems causes inhibition of growth; in others, PMA exerts a mitogenic effect. We have previously reported that the PMA-induced growth arrest and differentiation in leukemic cells are associated with a rapid increase in phosphorylation-dephosphorylation of two cytosolic proteins, phosphoprotein with molecular weights of 17,000 to 20,000 (pp 17-20) and phosphoprotein with a molecular weight of 27,000 (pla approximately 5.5). The phosphorylation of these proteins was found to be catalyzed directly by cyclic adenosine 3':5'-monophosphate-dependent protein kinase. To elucidate whether these phosphorylation events are specific to certain cellular functions induced by PMA, we compared the effect of PMA on phosphorylation of proteins in several cell systems. We found that, in cells where PMA accelerates growth (NIH/3T3 mouse fibroblasts, JB-6 mouse epidermal cells, and human peripheral lymphocytes) as well as in human platelets, the phosphorylation of pp 17-20 was only slightly affected by PMA, while phosphorylation of other proteins at Mr approximately 80,000 (pl approximately 5) and Mr 20,000 (pl approximately 5.2) was markedly increased. We provide evidence to suggest that the Mr 20,000/pl 5.2 protein might be myosin light chain (Mr 20,000). In contrast to these cell systems, in the human malignant cell A431 epidermoid carcinoma, the growth of which is inhibited by PMA, the pattern of protein phosphorylation by PMA exhibited striking similarity to that of leukemic cells; phosphorylation of pp 17-20 was dramatically increased while the phosphorylation of the putative myosin light chain (Mr 20,000/pl 5.2) was not affected. The identity of pp 17-20 in A431 and HL-60 leukemic cells was demonstrated by the unique stability of its phosphoester bond to alkali treatment. These results suggest that phosphorylation of different proteins and possibly activation of different protein kinases mediate the effects of PMA on inhibition versus acceleration of growth. Specifically, phosphorylation-dephosphorylation of pp 17-20 emerges as a signal which might be preferentially involved in PMA effect in certain neoplastic cells.
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PMID:Differential phosphorylation events associated with phorbol ester effects on acceleration versus inhibition of cell growth. 659 17

We have previously reported that elicitor-induced benzophenanthridine alkaloid biosynthesis in suspension-cell cultures of Sanguinaria canadensis L. (SCP-GM) is mediated by a signal transduction system that involves calcium and possibly protein kinase(s). In this work, a number of exogenous agents were employed to further investigate the components of the signal transduction pathway involved in the induction of alkaloid biosynthesis by a fungal elicitor and abscisic acid (ABA). SCP-GM suspension-cells were treated with compounds that modify protein kinase activity, including phorbol esters, and 1-oleoyl-2-acetyl-rac-glycerol (OAG), a synthetic diacylglycerol analogue. Phorbol-12-myristate-13-acetate induced alkaloid accumulation by as much as 65-fold over control values, while the negative control, phorbol-13-monoacetate, had no effect. OAG also increased alkaloid production by approximately 25-fold as compared to controls. Likewise, pretreatment of the suspension-cell cultures with H-7 or staurosporine, significantly suppressed ABA- or fungal-induction of benzophenanthridine alkaloid biosynthesis. Modulators of GTP-binding protein activity were also active in this system. Treatment of the suspension-cells with cholera toxin (CHX) induced alkaloid accumulation by 25-fold, which increased to 34-fold when CHX was combined with a fungal elicitor derived from Penicillium expansum (PE), and 32-fold when CHX was combined with ABA. Treatment of SCP-GM cells with CHX also enhanced the activities of two N-methyltransferases in the benzophenanthridine biosynthetic pathway namely, tetrahydroberberine-N-methyltransferase and tetrahydrocoptisine-N-methyltransferase, by six and seven fold, respectively. Furthermore, benzophenanthridine alkaloid biosynthesis was induced by treating the suspension-cells with the G-protein activators, mastoparan, mas-7 or melittin, while the inactive homologue, mas-17, did not. Suppression of alkaloid accumulation occurred when the suspension-cells were treated with GDP beta S or pertussis toxin prior to treatment of the SCP-GM cells with either PE or ABA. The results support the hypothesis that one or more protein kinases, and putative G proteins are involved in the signal transduction pathway that mediates ABA and fungal-induced benzophenanthridine alkaloid biosynthesis.
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PMID:Involvement of protein kinase and G proteins in the signal transduction of benzophenanthridine alkaloid biosynthesis. 962 55

We examined the down-regulation of alpha-1B adrenoceptors in Madin-Darby canine kidney D1 (MDCK) cells with an emphasis on a possible role of protein kinase C. The alpha-1 adrenoceptor agonist phenylephrine (1-100 microM) concentration-dependently down-regulated alpha-1B adrenoceptors in MDCK cells. Down-regulation by 100 microM phenylephrine was detectable after 2 hr and maximal after 8 to 24 hr. The receptor down-regulation was accompanied by a decrease in phenylephrine-stimulated inositol phosphate formation but not by an altered expression of immunodetectable Gq/11 alpha subunits. Even though alpha-1B adrenoceptor and P2 purinergic receptor stimulation promote prostaglandin E2 formation, receptor down-regulation was not prevented by indomethacin (10 microM) treatment but was partly mimicked by treatment with the purinergic receptor agonists adenosine-5'-O-(3-thio)triphosphate and 2-methylthio-ATP (300 microM each). Phorbol-12-myristate-13-acetate (1-100 nM) concentration-dependently down-regulated MDCK alpha-1B adrenoceptors to a greater extent than did phenylephrine. Three protein kinase C inhibitors, H7 (100 microM), staurosporine (100 nM) and KT5926 (1 microM), markedly attenuated receptor down-regulation promoted by phorbol ester but did not affect that by phenylephrine. Two inhibitors of Ca++/calmodulin protein kinase pathways, KT5926 (1 microM) and W-7 (30 microM), also failed to prevent phenylephrine-induced down-regulation of alpha-1B adrenoceptors. We conclude that agonist-induced down-regulation of MDCK cell alpha-1B adrenoceptors is mimicked by a protein kinase C-activating phorbol ester but that the second messenger kinases protein kinase C and Ca++/calmodulin protein kinase do not mediate agonist-induced down-regulation of the alpha-1B adrenoceptor.
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PMID:Protein kinase C does not mediate phenylephrine-induced down-regulation of Madin-Darby canine kidney cell alpha-1B adrenoceptors. 965 39

Interleukin (IL-) 6 is closely related to gastrointestinal diseases. The question of whether gastric epithelial cell contributes to IL-6 production remains undefined. We aim to evaluate the regulatory pathway of IL-6 expression in gastric epithelial cells, by using different inflammatory cytokines, endotoxin, or protein kinase modulators. IL-6 was measured by ELISA. Phorbol-12-myristate-13-acetate (PMA), calcium ionophore A23187, TNF-alpha, IL-1beta, oncostatin M (OSM) but not lipopolysaccharide stimulated IL-6 production from gastric epithelial cell line MKN-28. Blocking protein tyrosine kinase (PTK) activation by herbimycin A or genistein, or blocking NF-kappaB activation by pyrrolidinedithiocarbamate, reduced the IL-6 expression induced by TNF-alpha, IL-1beta and OSM. Dexamethasone mimicked this effect. Protein kinase (PK) C inhibitor only reduced the PMA and OSM induced IL-6 production. Both inhibitors and activators for PKA and G-protein as well as IL-10 had no effects on IL-6 expression. These results indicate that inflammatory cytokines are crucial for IL-6 regulation in gastric epithelial cells. The IL-6 signal pathway is mediated through PTK, NF-kappaB, and also involve PKC, intracellular calcium and sensitive to dexamethasone, but is not related to PKA, G-protein and IL-10.
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PMID:Regulation of interleukin 6 production in a human gastric epithelial cell line MKN-28. 1088 Feb 63

The addition of transforming growth factor alpha (TGFalpha) to a human submandibular gland cell line (HSG) cultured on basement membrane extract Matrigel, synergistically activates the acinar cell-specific salivary amylase promoter. Signaling through beta1 integrins and increased phosphorylation of ERK1/2 are involved in the increased promoter activity. Phorbol-12-myristate-13-acetate (PMA) and thapsigargin increase amylase promoter activity, suggesting that phorbol ester and calcium-dependent protein kinase C (PKC) pathways are also involved. The combination of specific inhibitors of PKC and MEK1 inhibits the amylase promoter. Inhibitors of the calcium-dependent PKC isoforms alpha, beta, and gamma decrease the promoter activity; however, PKCbeta is not detectable in HSG cells. TGFalpha alters the cellular localization of PKCalpha but not -gamma, suggesting PKCalpha is involved in TGFalpha upregulation of the amylase promoter. Furthermore, rottlerin, a PKCdelta-specific inhibitor, increases the promoter activity, suggesting PKC isoforms differentially regulate the amylase promoter. In conclusion, beta1-integrin and TGFalpha signaling pathways regulate the amylase promoter activity in HSG cells. In response to Matrigel and TGFalpha, the activation of both PKCalpha and phosphorylation of ERK1/2 results in synergistic activation of the amylase promoter. Published 2000 Wiley-Liss, Inc.
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PMID:PKC and ERK1/2 regulate amylase promoter activity during differentiation of a salivary gland cell line. 1102 43


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