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)

Exposure of pig epidermal sheets to the protein kinase C (PKC) activator, phorbol 12-myristate, 13-acetate (PMA) resulted in an increase in forskolin-induced cyclic AMP accumulation in the epidermis. Cholera toxin-induced cyclic AMP accumulation was moderately increased by PMA treatment, but this was not statistically significant. On the other hand, receptor-mediated adenylate cyclase responses (beta-adrenergic-, prostaglandin E-, adenosine-, and histamine (H2)-adenylate cyclase responses) were significantly decreased. These PMA-induced effects on the epidermal adenylate cyclase system were mimicked by 1-oleoyl-2-acetyl-glycerol, a membrane-permeable synthetic diacylglycerol, and by the non-phorbol PKC activator, mezerein. 4-O-methyl PMA, a very weak PKC activator, had no effect on adenylate cyclase responses of the epidermis. The addition of the PKC inhibitor, H-7 (1-(5-isoquinoline-sulfonyl)-2-methyl piperazine dihydrochloride), to the incubation medium significantly inhibited the effect of PMA on forskolin-induced cyclic AMP accumulation. Furthermore, following H-7 treatment, the epidermal receptor-adenylate cyclase responses were significantly increased. These results indicate that PKC modulates epidermal adenylate cyclase responses resulting in an increase in forskolin-induced cyclic AMP accumulation and a decrease in receptor-adenylate cyclase responses of the epidermis.
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PMID:Effects of the tumor promoter, phorbol 12-myristate, 13-acetate, on the epidermal adenylate cyclase system: evidence for adenylate cyclase-regulation by protein kinase C. 254 24

The addition of 1-oleoyl-2-acetylglycerol (OAG), or phorbol-12-myristate-13-acetate (PMA) to platelets induced the phosphorylation of a 47,000 dalton protein (47 Kd), fusion of granule membranes with membranes of the surface connected canalicular system, the formation of large vesicles and the secretion of serotonin. 1-(5-isoquinolinesulfonyl)-2-methyl-piperazine (H7), and sphingosine, inhibitors of protein kinase C, significantly inhibited the ultrastructural changes and the phosphorylation of 47 Kd. N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA1004), structurally similar to H7, but a weaker inhibitor of protein kinase C, did not attenuate these responses to OAG or to PMA. H7, but not HA1004, also markedly inhibited secretion induced by the synergistic combination of OAG and the calcium ionophore A23187. Amiloride and 5-(N,N dimethyl)-amiloride, inhibitors of the Na+/H+ transporter, did not inhibit the ultrastructural response and the protein phosphorylation induced by OAG, or the secretion induced by the combination of A23187 and OAG. The results link the activation of protein kinase C by diglycerides to the labilization and fusion of granule membranes important for secretion.
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PMID:A role for protein kinase C in the membrane fusion necessary for platelet granule secretion. 255 64

Neutrophils treated with 1,2-dioctanoyl-sn-glycerol (DiC8) are known to release large quantities of superoxide (O2-) and to exhibit an intense phosphorylation of two proteins with molecular masses of approximately 47 and 49 kDa. In this paper, we report that O2- release from guinea pig cells stimulated with a near optimal amount of DiC8 (2.0 microM) is markedly inhibited (greater than or equal to 70%) by antagonists of protein kinase C (i.e. 150 nM staurosporine; 200 microM 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (H-7], whereas that from cells stimulated with an optimal amount of DiC8 (7.8 microM) is not (approximately 25% inhibition). However, staurosporine (150 nM) effectively reduced the level of phosphorylation of the 47- and the 49-kDa proteins to that observed in unstimulated cells when either amount of DiC8 (i.e. 2.0 or 7.8 microM) was utilized. Thus, neutrophils stimulated with 7.8 microM DiC8 in the presence of staurosporine release large quantities of O2- without an enhanced phosphorylation of the 47- and the 49-kDa proteins. In contrast, these antagonists of protein kinase C effectively blocked O2- release from neutrophils stimulated with an optimal amount of phorbol 12-myristate 13-acetate (PMA), and the percentage of inhibition was not affected by increasing the concentration of PMA 160-fold. These data show that DiC8 and PMA, both activators of protein kinase C, can have distinct effects on O2- release by neutrophils. Moreover, they suggest that DiC8 (or a metabolite) under certain circumstances may function in a stimulatory pathway for O2- release that is independent of protein kinase C. Differences in the morphology of neutrophils stimulated with PMA and DiC8 are presented. Ancillary data on human neutrophils are also provided.
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PMID:1,2-dioctanoyl-sn-glycerol can stimulate neutrophils by different mechanisms. Evidence for a pathway that does not involve phosphorylation of the 47-kDa protein. 255 67

The human erythroid myeloid leukaemia cell line K562 was used as target for human neutrophil cytotoxicity. Neutrophils demonstrated cytotoxicity against K562 only in the presence of a second stimulus, tetradecanoyl phorbol acetate (TPA), a result consistent with previous observations. We now demonstrate that antibody-coated K562 (using OKT9 and 345 monoclonal antibodies) are similarly only sensitive to neutrophils when TPA is added. The presence of both antibody and TPA in the cytotoxic assay resulted in significantly higher levels of cytotoxicity than in the absence of antibody; the result being consistent with a synergistic action between protein kinase C activation and Fc receptor perturbation in the neutrophil. The cytotoxicity against non-coated and antibody-coated targets was markedly inhibited, particularly against the former, by the protein kinase C inhibitor, 1-(5-isoquinoline-sulfonyl)-2-methyl piperazine (H-7). There were marked differences in the extracellular calcium dependency of the two types of cytotoxicity reactions. TPA-activated respiratory burst was unaffected by the presence of non-coated and OKT9-coated targets, whereas TPA-induced lysosomal enzyme release was significantly increased by non-coated targets and a further increase occurred in the presence of OKT9-coated K562.
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PMID:Triggering of neutrophil cytotoxicity against an antibody-coated tumour target by TPA. 256 Apr 63

T cell surface proteins involved in transmembrane signalling resulting in the activation of T cells were investigated utilizing as probes monoclonal antibodies directed at T cell surface antigens. Here we report that mAbs that react with a framework determinant of alpha/beta heterodimer of T cell receptor for antigen, anti-TCR-1, and those with the SRBC-binding epitope of the CD2 antigen, OKT11, are synergistic in promoting T cell proliferation. The proliferative response is dependent upon crosslinking of anti-TCR-1 and OKT11, and is associated with a significant increase in the concentration of intracellular free calcium in T cells. Moreover, EGTA and a direct (staurosporine) or a competitive (1-[5-isoquinolinylsulfonyl]-2-methyl piperazine) inhibitor of protein kinase C prevents T cell proliferation accomplished with crosslinked anti-TCR-1 and OKT11. Our findings, in addition to demonstrating the synergism between the signals initiated via the T cell receptor for antigen and the CD2 antigen, suggest a role for calcium and protein kinase C in the transduction of signals generated with crosslinked anti-TCR-1 and OKT11.
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PMID:Transmembrane signalling via the T cell antigen receptor heterodimer and the CD2 antigen. A synergistic pathway for activation of T cells. 256 20

A phorbol ester, 12-O-tetradecanoylphorbol 13-acetate (TPA), induced the cleavage of nuclear DNA at linker regions in cultured mouse thymocytes. Similar DNA fragmentation was induced by 1-oleoyl-2-acetyl-glycerol, a synthetic diacylglycerol, but not by 4 alpha-phorbol-12,13 didecanoate. The DNA fragmentation was inhibited by 1-(5-isoquinoline-sulfonyl)-2-methyl-piperazine dihydrochloride, an inhibitor of protein kinase C, as well as actinomycin D and cycloheximide. It appears that TPA induces DNA cleavage through activation of protein kinase C and synthesis of yet unidentified protein(s). That the inhibition of DNA fragmentation was accompanied by a reduction in cell lysis suggests a causal relationship between DNA fragmentation and cell death.
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PMID:12-O-tetradecanoylphorbol 13-acetate induces DNA cleavage at linker regions in mouse thymocytes. 278 91

The addition of low concentrations of the chemotactic factor fMet-Leu-Phe to rabbit neutrophils in the absence of cytochalasin B produces very little superoxide. This level of superoxide can be greatly increased in neutrophils pretreated for 30 min with 10 microM of the diacyl-glycerol kinase inhibitor R59022. This potentiation occurs also in the presence of cytochalasin B. In addition, while the small level of superoxide generated by fMet-Leu-Phe is not inhibited by the protein kinase C inhibitor 1-(5-isoquinoline-sulfonyl)-2-methyl piperazine (H-7), the increase by R59022 is completely abolished by this compound. In addition, this increase can be potentiated further by leupeptin. Unlike superoxide generation, the release of lysozyme or N-acetyl-beta-glucosaminidase produced by fMet-Leu-Phe is not stimulated by R59022. The results presented here suggest that stimulation of the oxidative burst requires the generation and the maintenance of a sufficient amount of diacylglycerol and/or the rearrangement of the cytoskeleton such as the inhibition of actin polymerization. Furthermore, the membrane-associated form of protein kinase C is the one responsible for the activation of the oxidative burst. The relationship between protein kinase C activation and the stimulated oxidative burst and the physiological role of chemotactic factors in the functions of the neutrophils are discussed.
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PMID:The diacylglycerol kinase inhibitor R59022 potentiates superoxide production but not secretion induced by fMet-Leu-Phe: effects of leupeptin and the protein kinase C inhibitor H-7. 282 10

The effects of 1-(5-isoquinoline sulphonyl)-2-methyl piperazine (H-7), a recently described inhibitor of Ca2+/phospholipid-dependent protein kinase (protein kinase C), were studied during under-agarose migration of human polymorphonuclear neutrophils (PMN) stimulated by various chemoattractants, in order to determine whether protein kinase C is involved in PMN locomotion. The effect of H-7 on the oxidative burst induced by phorbol 12-myristate 13-acetate or N-formyl-methionyl-leucyl-phenylalanine (FMLP) was also measured. Pre-incubation of PMN with H-7 concentrations ranging from 50 to 400 microM inhibited: (i) spontaneous PMN migration under agarose; (ii) the directed migration induced by activated serum, leukotriene B4 or FMLP; and (iii) the speed of the migration induced by FMLP. The inhibition by H-7 of FMLP-induced directed migration was less when FMLP was used at high concentrations which, in the absence of H-7, inhibit locomotion. H-7 depressed the oxidative burst induced by phorbol myristate acetate (PMA) but not that induced by FMLP. All the effects of H-7 on the oxidative burst and migration were reversed by washing PMN after H-7 treatment. These findings indicate that protein kinase C, inhibitable by H-7, is involved in a mechanism controlling the speed of PMN locomotion.
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PMID:Negative effect of a protein kinase C inhibitor (H-7) on human polymorphonuclear neutrophil locomotion. 283 13

Rat adrenocortical carcinoma cells possess a high density of atrial natriuretic factor (ANF) receptors which are coupled with membrane guanylate cyclase and corticosterone production. Herein we show that pretreatment of these cells with phorbol 12-myristate 13-acetate (PMA), a known activator of protein kinase C, attenuates the ANF-stimulated cyclic GMP accumulation in a dose-dependent manner. The half maximum inhibitory concentration of PMA was 10(-10) M. When these cells were incubated with PMA in the presence of 1-(5-isoquinolinyl-sulfonyl)-2-methyl piperazine, a protein kinase C inhibitor, the PMA-mediated attenuation of ANF-stimulated cyclic GMP formation is blocked. These results suggest that protein kinase C negatively regulates the ANF-receptor coupled membrane guanylate cyclase system in these cells.
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PMID:Negative regulation of atrial natriuretic factor receptor coupled membrane guanylate cyclase by phorbol ester. Potential protein kinase C regulation of cyclic GMP signal in isolated adrenocortical carcinoma cells of rat. 289 95

alpha 2-adrenergic receptor-mediated signal transduction in rat adrenocortical carcinoma cells occurs through the opposing regulation of two second messengers, cyclic GMP and cyclic AMP, in which guanylate cyclase is coupled positively and adenylate cyclase negatively to the receptor signal. We now show that in these cells phorbol 12-myristate 13-acetate (PMA), a known activator of protein kinase C, inhibits the alpha 2-agonist (p-aminoclodine)-dependent production of cyclic GMP in a dose-dependent and time-dependent fashion. The half-maximal inhibitory concentration of PMA was 10(-10) M. A protein kinase C inhibitor, 1-(5-isoquinolinyl-sulfonyl)-2-methyl piperazine (H-7), caused the release of the PMA-dependent attenuation of p-aminoclodine-stimulated cyclic GMP formation. These results suggest that protein kinase C negatively regulates the alpha 2-receptor coupled cyclic GMP system in these cells, a feature apparently shared with the other cyclic GMP-coupled receptors such as those of muscarine, histamine, and atrial natriuretic factor.
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PMID:Inhibition of alpha 2-adrenergic receptor-mediated cyclic GMP formation by a phorbol ester, a protein kinase C activator. 290 36


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