EC:2.7.11.13 - FACTA Search

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

Platelet-derived growth factor (PDGF) stimulates mitogenesis and exerts other biologic activities in glomerular mesangial cells. The precise mechanism of PDGF-induced mitogenesis in these cells is not clear. The activation of a signal transducing enzyme, phosphatidylinositol 3 kinase (PI 3 kinase) is associated with mitogenesis. Activation of PI 3 kinase results from stimulation of tyrosine kinase and G-protein-coupled classes of receptors. The synthesis of D3 phosphorylated inositides, the products of this enzymatic reaction, in non-nucleated cells such as blood platelets is dependent upon protein kinase C activation and G-proteins. We studied the activation of PI 3 kinase in response to PDGF in human glomerular mesangial cells. Using a PI 3 kinase 85 kD subunit specific antibody, we detected mesangial cell PI 3 kinase protein as 110 and 85 kD heterodimer. PDGF stimulated PI 3 kinase activity in antiphosphotyrosine immunoprecipitates in a dose-dependent manner showing maximum activation at 12 ng/ml. The antiphosphotyrosine associated PI 3 kinase activity showed biphasic kinetics with a fast peak within two minutes followed by a second peak at 10 minutes. Antiphosphotyrosine and PI 3 kinase immunoprecipitation studies indicated the association of the 85 kD PI 3 kinase subunit with PDGFR. Direct immunoprecipitation with PDGFR beta antibody showed the association of PI 3 kinase activity with the PDGF-receptor. The isoquinoline sulfonyl piperazine compound H7 at concentrations that inhibit PDGF-stimulated PKC activity had no effect on PDGF-stimulated PI 3 kinase activity in antiphospotyrosine immunoprecipitates. These data indicate that PI3 kinase activation is insensitive to PKC. Treatment of mesangial cells with pertussis toxin at concentrations that partially inhibited PDGF-induced DNA synthesis in human mesangial cells did not inhibit PDGF-induced PI 3 kinase activation. These data indicate that PDGF activates PI 3 kinase in mesangial cells and that pertussis toxin-sensitive G-proteins are not involved in PI 3 kinase activation. The data further dissociate activation of PI 3 kinase from mitogenesis in human mesangial cells.
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PMID:PDGF-mediated activation of phosphatidylinositol 3 kinase in human mesangial cells. 793 47

Mouse epidermal melanoblasts preferentially proliferated from disaggregated epidermal cell suspensions derived from newborn mouse skin in a serum-free melanoblast proliferation medium containing dibutyryl adenosine 3':5'-cyclic monophosphate and basic fibroblast growth factor. After 12 days, almost all of the keratinocytes died and pure cultures of melanoblasts (approximately 80%) and melanocytes (approximately 20%) could be obtained. No further proliferation of melanoblasts was observed in the melanoblast proliferation medium. In order to clarify the role of protein kinase C, which is important for the regulation of cellular proliferation, activators or inhibitors of protein kinase C were added to the culture of the quiescent melanoblasts at 12 days. The proliferation of melanoblasts was induced by an activator of protein kinase C, N-(6-phenylhexyl)-5-chloro-1-naphthalene-sulfonamide or 1-oleoyl-2-acetyl-glycerol. It was also induced by an inhibitor of protein kinase C, staurosporine or 1-(5-isoquinolinesulfonyl)-2-methyl-piperazine. However, the melanoblasts failed to proliferate in the melanoblast proliferation medium supplemented with both the activator and the inhibitor. These results suggest that the proliferation of mouse epidermal melanoblasts in culture is regulated by activating or inhibiting the activity of protein kinase C.
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PMID:Effects of activators (SC-9 and OAG) and inhibitors (staurosporine and H-7) of protein kinase C on the proliferation of mouse epidermal melanoblasts in serum-free culture. 796 8

Pyroglutamyl peptidase II (PPII) is a thyrotropin-releasing hormone (TRH) hydrolyzing ectoenzyme with a narrow specificity. In the adenohypophysis, it is present on lactotropes. This study was undertaken in order to determine whether TRH itself regulates PPII activity in the adenohypophysis. After 5 days in culture, dispersed cells from female pituitaries expressed detectable levels of PPII activity when 10(-8) M 3,3',5'-triiodo-L-thyronine was present throughout the culture. 10(-6) M TRH decreased PPII activity with a maximal effect (down to 46% of initial values) at 16 h and an ED50 of 10(-9) M. [3Me-His2]TRH, a potent agonist of the TRH receptor was effective at lower concentrations (ED50: 1.6 x 10(-10) M). Phorbol-12-myristate-13-acetate (PMA; 10(-6) M), a protein kinase C (PKC) activator, diminished PPII activity to 61% or initial values with an ED50 of 2.2 x 10(-8) M. Maximal effects of PMA and TRH were not additive. Neither PMA nor TRH effects were reversed by inhibitors of protein kinases (1-(5-isoquinolinesulfonyl)-2-methyl-piperazine or sphingosine or staurosporine); TRH-induced downregulation of the enzyme was not modified by PMA pretreatment. TRH had no effect on two other ectopeptidases, endopeptidase 24.11 and dipeptidyl aminopeptidase IV. These data demonstrate that TRH specifically downregulates PPII activity in adenohypophyseal cells through TRH receptor activation and suggest that the activation of a presumably calcium-independent PKC mimics the TRH effect. TRH regulation of PPII activity may contribute to adjust lactotrope responsiveness to TRH.
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PMID:Thyrotropin-releasing hormone downregulates pyroglutamyl peptidase II activity in adenohypophyseal cells. 796 91

The effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on H+ secretion were studied in frog gastric mucosa and rabbit parietal cells (PC). In frog gastric mucosa, aspirin (10(-5) M) and ibuprofen (10(-4) M), but not indomethacin, naproxen and carprofen (10(-4) M each), enhanced histamine- and dibutyryl adenosine 3',5'-cyclic monophosphate-stimulated H+ secretion by 20 to 34%. Similarly, a protein kinase C (PKC) inhibitor, 1-(5-isoquinolinesulfonyl)- 2-methyl piperazine (H7, 5 x 10(-5) M), and a calcium ionophore, A23187 (10(-6) M) augmented basal and the aforementioned secretagogue-stimulated H+ secretion by approximately 50% and 20%, respectively, but a PKC activator, phorbol ester (12-O-tetradecanoyl phorbol 13-acetate, 10(-7)-10(-6) M), had no effect. The augmentation of H+ secretion by these agents was blocked by a calcium antagonist, lanthanum chloride (5 x 10(-4) M). In rabbit PC, H7 augmented secretagogue-stimulated H+ secretion by 60 to 150%, whereas 12-O-tetradecanoyl phorbol 13-acetate (10(-7) M) inhibited carbachol- and histamine-stimulated H+ secretion, respectively, by 65% and 52% without affecting dibutyryl adenosine 3',5'-cyclic monophosphate-stimulated H+ secretion. Furthermore, NSAIDs and H7-induced augmentation of dibutyryl cyclic adenosine monophosphate-stimulated H+ secretion was prevented by 12-O-tetradecanoyl phorbol 13-acetate (10(-7)-10(-6) M) in frog gastric mucosa and rabbit PC. Unlike H7, NSAIDs had no direct inhibiting action on PC membrane or cytosolic fractions of PKC, but they inhibited Sn-1,2-diacylglycerol level in PC by 20 to 30%.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A possible role of protein kinase C in augmenting H+ secretion by nonsteroidal anti-inflammatory drugs. 801 80

We examined effects of phorbol 12,13-dibutyrate (PDB), which activates protein kinase C (PKC), on prostaglandin and leukotriene production in piglet cultured glia derived from cerebral cortex and white matter. Levels of prostaglandins were determined using enzyme immunoassay. Baseline levels in media for prostaglandin F2 alpha (PGF2 alpha) were 730 +/- 116 pg/ml and increased to 1,551 +/- 196 pg/ml at 10(-8) M PDB (P < 0.05) and to 2,182 +/- 190 pg/ml at 10(-6) M PDB (P < 0.05) (n = 16). Little or no 6-keto-prostaglandin F1 alpha, prostaglandin E2, or leukotrienes C4/D4 were produced. PGF2 alpha levels in media did not increase in the presence of the vehicle for PDB (dimethyl sulfoxide) or 4 alpha-phorbol 12,13-didecanoate (PDD; a phorbol ester that does not activate protein kinase C) or when indomethacin (10 micrograms/ml), quinacrine (10(-6) M), or isoquinolinylsulfonylmethyl piperazine (10(-4) M) (an inhibitor of PKC activation) was coadministered with PDB. We conclude that glia can be important contributors of prostaglandins to extracellular-cerebrospinal fluids where they could influence cerebrovascular tone, and that PDB probably increases prostaglandin production via liberation of arachidonic acid by PKC-induced activation of phospholipase A2.
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PMID:Phorbol ester-induced prostaglandin production in piglet cortical astroglia. 804 41

Intercellular adhesion molecule 1 (ICAM-1) is a major adhesion receptor of the immune system. Its cell surface expression on a wide variety of cells including cancer cells regulated by various proinflammatory cytokines. Incubation of the human glioma cell line HS 683 and the neuroblastoma cell line SK-N-SH with 12-phorbol 13-myristic acid (PMA), retinoic acid, or gamma-interferon (IFN-gamma) strongly stimulates ICAM-1 expression. In the present study, we investigated the role of the protein kinase C (PKC)-mediated signal transduction pathway in this process. We found that IFN-gamma, but not retinoic acid, was able to induce activation and translocation of PKC after 60 min in a dose-dependent fashion, contrasting with the very rapid activation and translocation induced by PMA which occurred at 15 min. The PKC inhibitors 1-(5-isoquinolinesulfonyl)-2-methyl-piperazine dihydrochloride and staurosporine, as well as depletion of PKC by a 24-h treatment with 100 nM PMA, decreased the PMA-mediated stimulation but not the retinoic acid- or the IFN-gamma-mediated stimulation of ICAM-1 expression. On the contrary, they rather stimulated ICAM-1 expression. Furthermore, this stimulation was additive with retinoic acid and IFN-gamma. A 24-h incubation in the presence of retinoic acid or IFN-gamma strongly inhibited activation and translocation of PKC by PMA. These results suggest that although PMA-induced ICAM-1 expression is PKC dependent on HS 683 and SK-N-SH cells, the stimulation of ICAM-1 expression by retinoic acid and by IFN-gamma may be due to PKC inactivation at longer time points (24 h), as mimicked by 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride, staurosporine, or PKC depletion by high doses of PMA.
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PMID:Transduction of retinoic acid and gamma-interferon signal for intercellular adhesion molecule-1 expression on human tumor cell lines: evidence for the late-acting involvement of protein kinase C inactivation. 809 32

The endothelial cell has a unique intrinsic feature: it produces a most potent vasopressor peptide hormone, endothelin (ET-1), yet it also contains a signaling system of an equally potent hypotensive hormone, atrial natriuretic factor (ANF). This raises two related curious questions: does the endothelial cell also contain an ET-1 signaling system? If yes, how do the two systems interact with each other? The present investigation was undertaken to determine such a possibility. Bovine pulmonary artery endothelial (BPAE) cells were chosen as a model system. Identity of the ANF receptor guanylate cyclase was probed with a specific polyclonal antibody to the 180 kDa membrane guanylate cyclase (mGC) ANF receptor. A Western-blot analysis of GTP-affinity-purified endothelial cell membrane proteins recognized a 180 kDa band; the same antibody inhibited the ANF-stimulated guanylate cyclase activity; the ANF-dependent rise of cyclic GMP in the intact cells was dose-dependent. By affinity cross-linking technique, a predominant 55 kDa membrane protein band was specifically labeled with [125I]ET-1. ET-1 treatment of the cells showed a migration of the protein kinase C (PKC) activity from cytosol to the plasma membrane; ET-1 inhibited the ANF-dependent production of cyclic GMP in a dose-dependent fashion with an EC50 of 100 nM. This inhibitory effect was duplicated by phorbol 12-myristate 13-acetate (PMA), a known PKC-activator. The EC50 of PMA was 5 nM. A PKC inhibitor, 1-(5-isoquinolinyl-sulfonyl)-2-methyl piperazine (H-7), blocked the PMA-dependent attenuation of ANF-dependent cyclic GMP formation. These results demonstrate that the 180 kDa mGC-coupled ANF and ET-1 signaling systems coexist in endothelial cells and that the ET-1 signal negates the ANF-dependent guanylate cyclase activity and cyclic GMP formation. Furthermore, these results support the paracrine and/or autocrine role of ET-1.
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PMID:Interaction of atrial natriuretic factor and endothelin-1 signals through receptor guanylate cyclase in pulmonary artery endothelial cells. 809 23

1. The release of creatine kinase (CK) in the Langendorff-perfused rat heart during the Ca(2+)-paradox, was critically dependent on the duration and [Ca2+]o of the initial Ca(2+)-depletion phase. 2. When [Ca2+]i was raised by perfusion with caffeine or under N2, activation of the protein kinase C pathway (PKC) produced a small but significant release of CK. PKC stimulation is therefore able to substitute for the Cao(2+)-depletion of the Ca(2+)-paradox. 3. The PKC inhibitor, 1-(5-isoquinolinyl sulphonyl)-2-methyl piperazine, (2 x 10(-6) M) inhibited both the Ca(2+)-paradox and caffeine-induced release of CK. 4. It is concluded that the PKC pathway has a regulatory role for the damage system of the sarcolemma that is responsible for the release of cytosolic proteins.
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PMID:Does the protein kinase C pathway modulate sarcolemma damage and the release of cytosolic proteins in the rat heart? 810 Nov 61

1. The modulatory effects of carbachol, endothelin-1 and isoprenaline upon Na(+)-H+ exchange were examined in dog cardiac Purkinje fibres. Intracellular pH (pHi) and intracellular sodium activity (aiNa) were recorded using pH and Na(+)-selective microelectrodes. Acid extrusion via Na(+)-H+ exchange was estimated from the pHi recovery rate (multiplied by intrinsic buffering power (beta i) and adding mean background acid load) in response to an internal acid load induced by the removal of 20 mM NH4Cl. All experiments in this work were performed in Hepes-buffered solutions at 37 degrees C. 2. beta i was estimated at various values of pHi in the range of 7.4-6.4 and was calculated from the fall of pHi induced by the addition and removal of NH4Cl. Experiments were performed when Na(+)-H+ exchange was blocked. The values of beta i in this tissue were only slightly dependent on pHi in the range of 7.4-6.4 with an empirical relationship: beta i = -4.69 pHi + 64.59. 3. Endothelin-1 (10(-8) M) alkalinized the resting pHi by approximately 0.1 pH unit and accelerated acid extrusion, by approximately 96%, at pHi approximately 6.9. A reduction of background acid loading within the cell cannot account for the augmentation of pHi recovery, since the rate of acid extrusion was not changed either at resting pHi or at internal acidification in Na(+)-free solution (a measure of background loading) by the addition of endothelin-1. The protein kinase C inhibitors staurosporin (10(-6) M) and 1-(5-isoquinolinylsulphonyl)-2-methyl-piperazine (H-7, 50 microM) could not block the effect of endothelin-1 on the antiporter. 4. At pHi approximately 6.8, carbachol (7.5 x 10(-4) M) accelerated pHi recovery by approximately 68% and alkalinized the resting pHi by approximately 0.1 pH unit. This stimulatory effect of carbachol was completely blocked by pretreatment with atropine (10(-4) M) and staurosporine 10(-6) M. The background acid load was not reduced by adding carbachol, since the acid extrusion during pHi recovery or at the resting state was not affected by the addition of carbachol to a sodium-free solution. 5. Isoprenaline (10(-6) M) slowed pHi recovery by approximately 45% measured at pHi 6.9 with no change in resting pHi. A rise in background acid loading could not account for the reduction of acid extrusion. Pretreated with atenolol (10(-6) M), a beta 1-selective antagonist, completely blocked the effect of isoprenaline.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The modulatory effects of endothelin-1, carbachol and isoprenaline upon Na(+)-H+ exchange in dog cardiac Purkinje fibres. 812 Aug 23

The effect of norepinephrine (NE) upon human chorionic gonadotrophin (hCG) production by 6-8 week gestation placental explants has been investigated. NE (5 micrograms/ml) enhanced hCG secretion significantly from the second day of treatment. The stimulatory effect of NE on hCG secretion could be abolished by the alpha 1-receptor specific antagonist prazosin (10(-4) M) and partly diminished by the beta 1-receptor specific antagonist atenolol (10(-4) M), but was not influenced by the alpha 2-receptor specific antagonist yohimbine (10(-4) M). The involvement of the alpha-receptor in the regulation of hCG secretion was further confirmed by addition of the alpha-receptor agonist clonidine (10(-6) M) which had a similar stimulatory effect on hCG release but the effect was antagonized by both prazosin and yohimbine. Further study showed that NE induced a significant increase in cyclic adenosine monophosphate (cAMP) production by trophoblast tissue. Cyclic AMP secretion in the NE-treated group was fivefold higher than that of the control group. Both the protein kinase C (PKC) specific activator 1-deoyl-2-acetyl-sn-glycerol (OAG) and the PKC non-specific activator phorbol-12-myristate-13-acetate (PMA) had a stimulatory effect on hCG secretion, while the PKC inhibitor, 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (H7) diminished the hCG secretion stimulated by NE. The effect of NE was blocked by the voltage-dependent calcium channel blocker nifedipine but not by the voltage-independent calcium channel blocker gadolinium chloride (GdCl3). On the other hand, anti-gonadotrophin releasing hormone (GnRH) IgG and the GnRH antagonist (D-Phe2, D-Trp6)-GnRH did not influence the stimulatory effect of NE on hCG release. The results indicate that NE regulates hCG production in human first trimester trophoblast tissue. The effect of NE was mainly mediated by alpha 1 and partly by beta 1 receptors. Cyclic AMP, the PKC signal transduction pathway and the voltage-dependent calcium channels were involved in NE action.
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PMID:Norepinephrine regulates human chorionic gonadotrophin production by first trimester trophoblast tissue in vitro. 815 89

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