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)

Protein kinase C activators of the teleocidin family are claimed to be able to replace interleukin 2 for inducing short-term proliferation of the interleukin 2 dependent murine cytotoxic T cell line. While teleocidin B4 was found to be much more active than 12-O-tetradecanoyl-phorbol-13-acetate, a related molecule showing a substitution of a single OH by OCH3, olivoretin A, lacked detectable activity in this assay. However, the maximal proliferation achievable by protein kinase C activators did not exceed one third of the one given by recombinant interleukin 2.
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PMID:Proliferation of interleukin 2 dependent cytotoxic T cell line cells. Different protein kinase C activators achieve the same maximal promotion, but with distinct dose-response profiles. 278 67

Activation of T-lymphocytes by antigen, mitogenic lectins, or antibodies against the T-cell receptor complex, particularly in the presence of IL1, induces the secretion of the T-cell growth factor IL2. IL2 then has a major role in regulating the duration and magnitude of the immune response. Interaction of antigen, antibodies against the T-cell receptor complex, or mitogenic lectins with T-lymphocytes also induces hydrolysis of membrane phospholipids, leading to the production of diacylglycerol, an activator of the Ca2+- and phospholipid-dependent phosphotransferase, protein kinase C (PKC). Phorbol esters, potent activators of PKC, augment secretion of the T-cell growth factor, interleukin 2 (IL2). Activation of PKC may therefore serve as an important early event in the production and secretion of IL2. We have determined whether IL2 secretion can be induced in the murine cell T-lymphocyte line LBRM 331A5, where PKC is inhibited by staurosporine or sphingosine or in cells where PKC is depleted by prolonged incubation with high concentrations of phorbol esters. In cells in which PKC was either inhibited or depleted, antibodies against the T3 portion of the T-cell receptor complex and the mitogenic lectin phytohemagglutinin (PHA) still triggered IL2 secretion. In addition, the monokine IL1 augmented this IL2 secretion irrespective of whether PKC was inhibited or depleted. These data indicate that activation of PKC is not an obligatory step for IL2 secretion in LBRM 331A5 murine T-lymphocytes.
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PMID:Role of protein kinase C in interleukin 1, anti-T3, and mitogenic lectin-induced interleukin 2 secretion. 280 40

To investigate whether guanosine triphosphate-binding proteins (G proteins) are involved in T cell activation, tests were made of the effect of pertussis toxin, cholera toxin, guanosine 5'-(3-O-thio)-triphosphate, and fluoride ions on interleukin 2 (IL-2) synthesis in Jurkat cells. It was found: 1) that pertussis toxin interferes with the first pathway of T cell activation insofar as it can substitute for phytohemagglutinin or monoclonal antibodies directed against the CD3 surface proteins, suggesting that a G protein serves as transducer for signals via the T cell receptor-CD3 complex; and 2) that fluoride ions induce the release of diacylglycerol (DAG) from [3H] arachidonic acid or [3H]oleic acid-prelabeled cells. In [3H]inositol or 32P-prelabeled cells, the increase in DAG production was also found to be accompanied by a 280% increase of intracellular inositol phosphate (IP), without significant modification of IP2 and IP3. These results suggest that a G protein controls the activity of a phospholipase C in Jurkat cells that upon stimulation releases DAG but not IP3. Inasmuch as DAG, like the phorbol ester tetradecanoyl phorbol acetate, activates protein kinase C, it suggests that a G protein is also involved in the transduction of the second signal for lymphocyte activation. Fluoride ions were found to be as effective as tetradecanoyl phorbol acetate to stimulate IL-2 synthesis in Jurkat cells when used in combination with phytohemagglutinin. Finally, cholera toxin and guanosine 5'-(3-O-thio)-triphosphate were found to increase intracellular cyclic adenosine triphosphate and to inhibit IL-2 synthesis. All together these results suggest that several G proteins are involved in the transduction of the two signals necessary for T cell activation as well as in the negative regulation of IL-2 synthesis.
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PMID:Inhibition and activation of interleukin 2 synthesis by direct modification of guanosine triphosphate-binding proteins. 282 88

The in vitro stimulation of murine splenic T lymphocytes with concanavalin A (Con A) produced interleukin 2 (IL2). The addition of cyclosporin A (CsA) to the culture resulted in complete inhibition of IL2 production. The Con A stimulation of T lymphocytes induced the breakdown of phosphatidylinositol into inositol trisphosphate and diacylglycerol, each of which could function as the second messengers in the subsequent signal transduction pathway. CsA did not inhibit the production of inositol (poly)phosphates. Further, CsA did not affect Ca2+-calmodulin functions; a) the redistribution of various cytoskeletal proteins as well as Con A-receptor aggregation, and b) the cytosolic Ca2+-calmodulin-dependent enzyme activities. Moreover, the activity of protein kinase C, which has been accepted to be the target of diacylglycerol, was not influenced in the presence of CsA. While the above steps of signal transduction are bypassed by synergy between calcium ionophore and phorbol ester, T lymphocyte activation which was induced by such stimuli was completely inhibited by CsA. These results indicate that CsA does not influence early steps of T lymphocyte activation as bypassed by calcium ionophore and phorbol ester, but rather inhibits later step(s) subsequent to the activation of protein kinase C and Ca2+-calmodulin.
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PMID:Cyclosporin A inhibits late steps of T lymphocyte activation after transmembrane signaling. 283 Feb 52

CD28 is a homodimeric glycoprotein expressed on the surface of a major subset of human T cells that has recently been identified as a member of the immunoglobulin supergene family. The binding of monoclonal antibodies to the CD28 antigen on purified T cells does not result in proliferation; however, previous studies have shown that the combination of CD28 stimulation and protein kinase C activation by phorbol myristate acetate (PMA) results in T-cell proliferation that is independent of both accessory cells and activation of the T-cell receptor-CD3 complex. In the present study, effects of stimulation by anti-CD28 on cell cycle progression and on the interleukin 2 (IL-2) and IL-2 receptor system have been investigated on primary cultures of purified peripheral-blood CD28+ T cells. There was no measurable effect on cell size or on DNA synthesis after stimulation of resting (G0) cells by CD28 alone. After 3 h of activation of T cells by PMA alone, a slight (8%) increase in cell volume occurred that did not progress to DNA synthesis. In contrast, T-cell stimulation by CD28 in combination with PMA resulted in a progressive increase in cell volume in approximately 100% of cells at 12 to 14 h after stimulation. Northern blot (RNA blot) analysis revealed that CD28 stimulation alone failed to cause expression of the alpha chain of the IL-2 receptor or of IL-2 mRNA, and in accord with previous studies, stimulation by PMA alone resulted in the accumulation of IL-2 receptor transcripts but no detectable IL-2 mRNA. In contrast, T-cell stimulation by the combination of CD28 and PMA resulted in the appearance of IL-2 transcripts and enhanced expression of IL-2 receptor mRNA. Functional studies revealed that the proliferation induced by CD28 and PMA stimulation was entirely resistant to cyclosporine, in contrast to T-cell activation induced by the CD3-T-cell receptor complex. Cyclosporine was found not to affect the accumulation of IL-2 mRNA after CD28 plus PMA stimulation, although there was no detectable IL-2 mRNA after stimulation by CD3 in the presence of the drug. Furthermore, stimulation by CD28 in combination with immobilized CD3 antibodies caused a striking enhancement of IL-2 mRNA expression that was, in part, resistant to the effects of cyclosporine. These studies indicate that the CD28 molecule synergizes with protein kinase C activation to induce IL-2 gene expression and demonstrate that stimulation by the CD28 pathway can cause vigorous T-cell proliferation even in the presence of cyclosporine and that cyclosporine does not prevent transcription of 16-2 mRNA, as has been suggested previously. Moreover, these findings suggest that a potential role for the CD28 molecule in vivo may be to augment IL-2 production after stimulation of the CD3-T-cell receptor molecular complex and thereby to amplify an antigen-specific immune response. Finally, these results provide further evidence that the CD28 molecule triggers T-cell proliferation in a manner that differs biochemically from CD3-T-cell receptor-induced proliferation.
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PMID:T-cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression. 283 Apr 95

The binding of interleukin 2 (IL 2) to specific cell surface receptors provides a unique proliferative stimulus to sensitive T-lymphocytes. The purpose of this investigation was to examine the hypothesis that IL 2 stimulus-response coupling in the IL 2-dependent murine T-lymphocyte clone CTLL-2 employed some of the intracellular second messengers used by other growth factors. No evidence was obtained to implicate changes in intracellular Ca2+ concentrations, protein kinase C activation, or stimulation of the Na+/H+ antiporter or the Na+/K+ ATPase as requirements for stimulation by recombinant human IL 2. Pertussis toxin did not inhibit IL 2-driven growth of CTLL-2, and while cholera toxin did inhibit growth, its effect was optimal 6 to 8 hr after addition of IL 2 and could be mimicked by increased intracellular cyclic-AMP. Thus, guanine nucleotide-binding regulatory proteins do not appear to be involved in stimulation by this lymphokine. Together, these data suggest that IL 2 may not use any of the same types of intracellular second messengers generated subsequent to the binding of antigen or mitogen by T-lymphocytes.
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PMID:Does interleukin 2 stimulus-response coupling result in generation of intracellular second messengers? 284 44

The mouse cytotoxic T cell clone (CTLL-2) was able to grow in the presence of culture medium supplemented only with transferrin, 2-mercaptoethanol, and recombinant interleukin 2 (IL-2). This lymphokine stimulated the synthesis of DNA in these cells. Similarly, phorbol esters, which activate protein kinase C, induced DNA synthesis in this clone. Furthermore, this later proliferation was not blocked by anti-IL-2 receptor antibodies, which inhibited IL-2-induced proliferation, suggesting that it was not indirectly due to the secretion of IL-2 by the cells. CTLL-2 cells pretreated with high doses of phorbol esters for 48 h down regulated protein kinase C and were depleted of this enzyme. This was shown by: 1) purification and in vitro assay of protein kinase C; 2) the lack of effect of phorbol esters in the stimulation of the Na+/H+ anti-porter which has been directly linked to the activation of protein kinase C. As expected, those protein kinase C-depleted cells no longer synthesized DNA and proliferated in response to phorbol esters. However, they proliferated identically to control cells in response to IL-2. Therefore, our results suggest two different pathways for T cell proliferation, one which involves protein kinase C and the other which does not.
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PMID:The role of protein kinase C in T lymphocyte proliferation. Existence of protein kinase C-dependent and -independent pathways. 284 66

We have analyzed the effect mediated by prostaglandin E2 (PGE2) and different reagents that increase intracellular cAMP on the expression of the p55 subunit (CD25) of interleukin 2 receptors (IL 2R), on the levels of CD25-specific mRNA and on the expression of high affinity IL 2R. In purified T cells, activated either by an anti-CD3 monoclonal antibody or phytohemagglutinin, the addition of PGE2 (10(-6) M), forskolin (5 X 10(-5) M), cholera toxin (0.2 microgram/ml) or dibutyryl cAMP (dBcAMP) (10(-4) M) decreased the cell surface expression of IL 2R by reducing (40%-78% inhibition) the proportions of CD25+ cells as well as the expression of high affinity IL 2R, detectable after 24 h. Furthermore, it was observed that PGE2 reduced the concentration of IL 2R-specific mRNA after a 6-h period of activation, indicating that its regulatory activity takes place at a pretranslational level. The addition of exogenous recombinant IL 2 only partially reversed the inhibition, thus suggesting that PGE2 and increased intracellular concentration of cAMP directly interfered with CD25 expression and that their effect could not be merely attributed to a lack of IL 2-dependent positive feedback. Cells cultured under the same conditions in the presence of phorbol myristate acetate, that activates protein kinase C, were refractory to the cAMP-mediated regulation. Finally, we demonstrate that both PGE2 and dBcAMP inhibit the generation of inositol metabolites after T cell activation, thus indicating that these reagents interfere with early signal transduction mechanisms which precede the synthesis of IL 2R.
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PMID:Prostaglandin E2 and the increase of intracellular cAMP inhibit the expression of interleukin 2 receptors in human T cells. 284 51

T cells are activated physiologically by triggering the T-cell receptor-CD3 complex. There is evidence that invariant accessory molecules on the T-cell membrane (CD8 and CD4) are involved in the major histocompatibility complex-restricted recognition process. Moreover, binding and crosslinking of these accessory molecules to the T-cell receptor-CD3 complex exerts a positive synergistic signal, as has been shown by stimulation with crosslinked antibodies. Here we demonstrate that stimulation mediated by immobilized anti-CD3/CD8 antibodies differs from stimulation mediated solely by anti-CD3. Whereas interleukin 2 receptor expression and interferon gamma production are seen to a similar extent in both cases, a second signal provided by the additional involvement of CD8 seems to be essential for interleukin 2 production and full interleukin 2 responsiveness in CD8+ T cells. This second signal is much more sensitive to inhibition by 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, an inhibitor of protein kinase C and cGMP/cAMP-dependent kinases. Our results also show that substantial modulation of the T-cell receptor complex and most likely CD3 phosphorylation are not essential for initiating the activation of resting T cells. Instead, we found a 22- to 24-kDa phosphoprotein whose strong phosphorylation correlated reliably with T-cell activation.
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PMID:Activation of human T lymphocytes: differential effects of CD3- and CD8-mediated signals. 297 60

The tumor promoter 12-0-tetradecanoyl-phorbol-13-acetate (TPA) affects a wide variety of cellular functions via its binding to protein kinase C (PKC). The TPA molecule contains a diacylglycerol (DAG)-like structure, which may explain its ability to mimic DAG in PKC activation. Teleocidin (TCD) is a different tumor promoter which can compete with TPA in binding to its cell surface receptors even though structurally unrelated to TPA or DAG. Since TCD may use an additional receptor system and/or be distinguished from TPA in its effect on cells, we compared the effects of TPA and TCD on human peripheral blood lymphocytes (PBL). Both tumor promoters preferentially enhanced cell proliferation of sheep erythrocyte-rosetted lymphocytes, which were enriched for T cells. Additionally, TPA and TCD both induced a high density of cell surface receptors for interleukin 2 (IL2) and transferrin, but not synthesis or production of IL2. However, either of the tumor promoters synergized with T cell mitogens to induce high level IL2 production by PBL. In dose response and kinetic studies, matching concentrations of TPA and TCD induced similar effects in PBL. The results thus demonstrate that TPA and TCD are alike in mitogenic capacity, and suggest that structural similarity between the tumor promoter and DAG, the physiological activator of PKC, is not an essential property for promoting tumors or affecting a wide variety of cellular functions.
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PMID:Teleocidin and phorbol ester tumor promoters exert similar mitogenic effects on human lymphocytes. 299 82


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