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)

The T lymphocytes that expand with age in the peripheral lymphoid organs of autoimmune disease-prone mice homozygous for the lpr mutation display deficient activation and proliferation in response to mitogenic lectins or antigen. In the present study, an attempt was made to correlate the deficient agonist-induced proliferation of these lpr T cells with early transmembrane signaling events mediated by receptor-coupled phosphoinositide hydrolysis. lpr T cells were capable of binding the agonistic lectin, phytohemagglutinin, in a normal manner. In addition, they expressed on their surface the antigen-specific T cell receptor-CD3 complex, which is required for T cell activation, albeit at a lower density than that found on congenic +/+ T cells. Furthermore, lpr T cells contained normal levels of the Ca2+- and phospholipid-dependent enzyme, protein kinase C, and the enzyme was translocated from the cytosol to the particulate fraction upon phorbol ester treatment. On the other hand, the lpr T cells displayed a markedly deficient agonist-induced phosphoinositide hydrolysis in comparison with their congenic +/+ counterparts, as indicated by the minimal accumulation of the phosphoinositide-derived second messengers, inositol phosphates and diacylglycerol. The defective step(s) in transmembrane signaling was bypassed by a combination of phorbol ester plus Ca2+ ionophore, which reconstituted proliferative responses of lpr T cells to normal levels, suggesting that: (a) the phosphoinositide signaling pathway plays an obligatory role in T cell activation; and (b) signaling events subsequent to phosphoinositide hydrolysis are, for the most part, intact in lpr T cells. The deficient step(s) in lpr T cell activation precedes, therefore, the generation of phosphoinositide-derived second messengers and could be due to defective function of the T cell receptor-CD3 complex, GTP-binding proteins, and/or phosphoinositide-specific phosphodiesterase. It remains to be determined whether the deficient signaling event(s) in lpr T cells is a direct pathologic consequence of the lpr gene, or rather, reflects the immature status of a normally minor thymic subset that is aberrantly exported and expanded in lpr mice.
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PMID:Lpr T cell hyporesponsiveness to mitogens linked to deficient receptor-stimulated phosphoinositide hydrolysis. 283 Nov 96

When L3T4+ cloned murine helper T lymphocytes (HTL) are stimulated with antigen or immobilized anti-T cell receptor (TCR) monoclonal antibodies (mAb) at concentrations which are optimal for proliferation, anti-L3T4 mAb inhibits activation as measured by proliferation and lymphokine production. Under similar conditions, IL 2-independent proliferation of Lyt-2+ cloned murine cytolytic T lymphocytes (CTL) stimulated by anti-TCR mAb is inhibited by anti-Lyt-2 antibodies. Proliferation of cloned HTL and CTL cells stimulated by IL 2 is not affected by the anti-L3T4 and anti-Lyt-2 mAb. The inhibition of TCR-induced activation of the T cell clones is not due to interference with the binding of the anti-TCR mAb. Stimulation of the TCR has been proposed to induce lymphokine secretion and proliferation by T cells through a pathway involving the activation of protein kinase C and the stimulation of an increase in the concentration of intracellular free calcium. However, proliferation of T cells stimulated by PMA (which activates protein kinase C) plus the calcium ionophore A23187 (which increases the concentration of intracellular free calcium) is not affected by mAb reactive with the Lyt-2 or L3T4 structures. If TCR stimulation does indeed activate T cells by activating protein kinase and increasing intracellular free calcium, then our data suggest that anti-L3T4 and anti-Lyt-2 mAb inhibit TCR-driven proliferation at some step before the activation of protein kinase C and the stimulation of a rise in intracellular free calcium concentration. Our results suggest that anti-L3T4 and anti-Lyt-2 mAb interfere with early biochemical processes induced by stimulation of the TCR. In HTL, which proliferate via an autocrine pathway, anti-L3T4 mAb appears to inhibit proliferation by interfering with signaling events involved in lymphokine production. Inhibition of IL 2-independent proliferation of Lyt-2+ cells by anti-Lyt-2 mAb appears to occur by a different mechanism. The precise molecular basis for the interference of each cell type has not yet been characterized.
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PMID:Antibodies to the L3T4 and Lyt-2 molecules interfere with antigen receptor-driven activation of cloned murine T cells. 295 46

Three monoclonal antibodies reactive with different structural domains of the T3-T cell receptor complex of the human T cell leukemia line, HPB-ALL, were previously shown to activate a membrane potential-sensitive, La3+-inhibitable Ca2+ influx (Oettgen, H. C., Terhorst, C., Cantley, L. C., and Rosoff, P. M. (1985) Cell 40, 583-590). OKT3 (anti-T3), WT-31 (anti-receptor constant region), and T40/25 (anti-receptor variable region) also enhance the activity of the Na+/H+ exchanger in these cells. The associated rise in pHi was dependent on the presence of external Ca2+ and Na+, was inhibited by dimethylamiloride and La3+, and was maintained for at least 20 min. Phorbol esters, which are co-mitogenic in T cells and activate protein kinase C, also stimulated the exchanger, but by a mechanism not requiring an elevation in cytoplasmic Ca2+; the rise in pHi rapidly peaked and returned to baseline levels within 20 min. Pretreatment with phorbols prevented an increase in pHi by OKT3 although a transient additive effect was observed when the two were added simultaneously. Receptor function was maintained in the presence of phorbol esters as OKT3 still stimulated a Ca2+ influx. These data demonstrate the existence of two interdependent pathways to activate Na+/H+ exchange in T lymphocytes and suggest a pathway of internal regulation of antigen-activated signal transduction.
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PMID:Stimulation of the T3-T cell receptor-associated Ca2+ influx enhances the activity of the Na+/H+ exchanger in a leukemic human T cell line. 299 91

The cyclic undecapeptide cyclosporine A (CsA) is a potent immunosuppressive agent that inhibits the initial activation of T lymphocytes. This agent appears to be most effective in blocking the action of mitogens such as concanavalin A and the calcium ionophore A23187, which cause an influx of Ca2+, but not those that may act by alternate mechanisms. These observations suggest that CsA may block a Ca2+-dependent step in T cell activation. We have shown that stimulation of the T3-T cell receptor complex-associated Ca2+ transporter activates the Na+/H+ antiport (Rosoff, P. M., and L. C. Cantley, 1985, J. Biol. Chem., 260: 14053-14059). The tumor-promoting phorbol esters, which are co-mitogenic for T cells, activate the exchanger by a separate pathway which is mediated by protein kinase C. Both the rise in intracellular Ca2+ and intracellular pH may be necessary for the successful triggering of cellular activation. In this report we show that CsA blocks the T3-T cell receptor-stimulated, Ca2+ influx-dependent activation of Na+/H+ exchange, but not the phorbol ester-mediated pathway in a transformed human T cell line. CsA inhibited mitogen-stimulation of interleukin-2 production in a separate cell line. CsA also inhibited vasopressin stimulation of the antiporter in normal rat kidney fibroblasts, but had no effect on serum or 12-O-tetradecanoyl phorbol 13-acetate stimulation. CsA did not affect serum or vasopressin or serum stimulation of normal rat kidney cell proliferation. CsA also had no effect on lipopolysaccharide or phorbol ester stimulation of Na+/H+ exchange activity or induction of differentiation in 70Z/3 pre-B lymphocytes in which these events are initiated by the protein kinase C pathway. These data suggest that mechanisms of activation of Na+/H+ exchange that involve an elevation in cytosolic Ca2+ are blocked by CsA but that C kinase-mediated regulation is unaffected. The importance of the Na+/H+ antiport in the regulation of growth and differentiation of T cells is discussed.
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PMID:Cyclosporine A inhibits Ca2+-dependent stimulation of the Na+/H+ antiport in human T cells. 301 82

Quiescent normal human T cells express low levels of steady-state c-myc mRNA as a result of low constitutive promoter utilization, a block to transcriptional elongation within the gene, and rapid degradation of c-myc mRNA in the cytoplasm. Following the activation of the T cell receptor (TCR)/CD3 complex, quiescent T cells are induced to express c-myc mRNA. Two intracellular pathways, one involving protein kinase C activation and the other mediated by increased intracellular calcium concentration, are activated by TCR/CD3 receptor stimulation. These two pathways, which can be activated by phorbol myristate acetate (PMA) and ionomycin respectively, appear to play complementary roles in the transcriptional induction of c-myc gene expression by the antigen receptor complex. Ionomycin treatment of quiescent cells leads to enhanced c-myc expression primarily as a result of increased transcriptional initiation. In contrast, PMA contributes to c-myc expression, at least in part, by decreasing the block to transcriptional elongation present within the gene. Both the PMA- and ionomycin-mediated induction of c-myc expression can be independently enhanced by stabilization of c-myc mRNA in the cytoplasm. These observations demonstrate that multiple mechanisms co-operate to regulate c-myc gene expression during normal T cell activation.
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PMID:Multiple mechanisms regulate c-myc gene expression during normal T cell activation. 305 65

We have studied the activation of interleukin 1 (IL 1)-dependent and IL 1-independent T cell lines, specifically their capacity to produce and secrete interleukin 2 (IL 2). The IL 1-dependent T cell lymphoma LBRM33-1A5.47, which requires phytohemagglutinin (PHA) and IL 1 to produce IL 2, was compared with the IL 1-independent T cell lymphoma LBRM33-5A4 and T cell hybridomas DO-11.10/S4.4 and 3DO-54.8. The latter hybridomas do not require exogenous IL 1 to produce IL 2 in response to mitogens or ovalbumin (OVA)/I-Ad. Even though IL 1 is not required by these IL 1-independent T cell lines, we tested whether IL 1 could modulate their response but found no significant effect of exogenous IL 1. We then studied the activation of these T cell lines by the calcium ionophore A23187 and phorbol myristate acetate (PMA). In the case of the IL 1-dependent line LBRM33-1A5.47, there was a strong response when both A23187 and PMA were used simultaneously. We subsequently found that A23187 can replace PHA, and PMA can replace IL 1 in the activation of this cell line to IL 2 production. These observations suggest that the signal(s) provided by PHA and IL 1 involve at least in part a calcium flux, and activation of protein kinase C. Parallel experiments with the use of the IL 1-independent T cell lines showed a strong response to both agents when used simultaneously. A modest response observed to A23187 alone was always enhanced by the addition of PMA. No response was observed to PMA alone. IL 1-rich P388D1 supernatant could replace the enhancing effect of PMA in the response of the IL 1-independent T cell lines. We suggest that the activating signals provided by A23187 and PMA are at least part of the sequence of events that lead to production of IL 2 in either IL 1-dependent or IL 1-independent T cell lines. In IL 1-independent T cell lines, however, both of the activating signals studied may be delivered through stimulation of the Antigen-MHC T cell receptor.
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PMID:Activation of IL 1-dependent and IL 1-independent T cell lines by calcium ionophore and phorbol ester. 307 93

Cell surface expression of CD4, an invariant membrane glycoprotein, is characteristic of the MHC class II-restricted T cell helper/inducer subset. Although the specificity and restriction patterns of T lymphocytes are determined by the T cell receptor for antigen, CD4 might represent an additional "interaction" molecule that is required to strengthen the interaction between T cells, antigen, and antigen-presenting cells. In this manuscript, we have shown that the cell surface expression of CD4 is correlated with activation of T cells. Data presented in this paper have demonstrated, for the first time, that antigenic stimulation of human T cell clones caused a decrease in the expression of the CD4 marker (as well as to the CD3 marker) to about 50% of the constitutive level. As previously demonstrated, PMA caused modulation of CD4 and CD3, which suggested that phosphorylation by protein kinase C played a crucial role in the regulation of the expression of both markers. The parallel down-regulation of CD3 and CD4 after antigen stimulation suggested that both markers might be members of a multimolecular complex mediating T cell activation.
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PMID:Modulation of CD4 by antigenic activation. 310 Jun 38

The human T cell hybrid II23 was isolated from fusions between human peripheral blood lymphocytes which had been stimulated with phytohemagglutinin (PHA) and a subline of the human T cell line CEM called CEM.TET1. This hybrid does not constitutively express detectable levels of interleukin 2 (IL 2) receptors but can be induced to express receptors by stimuli shown to activate T cells. Antibody to CD3 (a component of the T cell receptor) coupled to agarose or PHA (greater than 3 micrograms/ml) induced both IL 2 production and receptor expression on II23 cells. Phorbol 12-myristate 13-acetate (PMA) induced IL 2 receptor expression on II23 cells but not IL 2 secretion. Because PMA is a known activator of the Ca2+/phospholipid-dependent enzyme protein kinase C, proteins of stimulated and unstimulated cells were analyzed by two-dimensional gel electrophoresis for changes in phosphoprotein patterns. A Mr 70,000 protein with a pI of 6.2 was phosphorylated in hybrids stimulated by PMA, anti-CD3 antibody coupled to agarose or PHA, i.e. by the same stimuli which induce IL 2 receptors on these cells. The immunosuppressive drug cyclosporin A inhibited IL 2 release without altering induction of IL 2 receptors or phosphorylation of the Mr 70,000 protein. The 70-kDa protein was located in the cytosol, where it remained phosphorylated for at least 4 h after stimulation. A protein with the same migratory properties on two-dimensional gels was similarly phosphorylated after stimulation of normal peripheral blood T lymphocytes, indicating that the phenomenon was not due to hybridization or transformation. This 70-kDA protein may therefore be involved in the pathway which leads to the transcription and expression of IL 2 receptors.
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PMID:Phosphorylation of a Mr 70,000 protein is associated with interleukin 2 receptor expression. 312 93

The 10B4 system of human T cells seems to constitute a member of T cell receptor complex. We have analyzed the mechanisms by which a monoclonal antibody against the 10B4 molecule activates human peripheral T cells. The 10B4 antibody together with goat anti-mouse immunoglobulin antibody induced significant increase of DNA and RNA syntheses in T cells with peak responses on day 9 and on day 7, respectively. This activation process is mediated by interleukin 2 (IL-2) and its receptor (IL-2R), because (1) IL-2 activity was detected in the culture supernatants, (2) the percentage of IL-2R positive cells increased during the culture period, with a peak on day 9, and (3) the 10B4-induced T cell proliferation was inhibited by anti IL-2R antibody. Blocking studies with pharmacological agents showed that in the 10B4-induced system, a protein kinase C (PK-C) inhibitor, palmitoylcarnitine, blocked DNA synthesis, RNA synthesis, IL-2 production and IL-2R expression whereas a Ca ion channel blocker, verapamil, inhibited DNA synthesis, RNA synthesis, IL-2 production but not IL-2R expression. It is thus concluded that PK-C activation is required for IL-2 production and IL-2R expression and that channel-mediated Ca ion influx is important for IL-2 production but may not be needed for IL-2R expression.
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PMID:[On the mechanisms of human T cell proliferation induced by the 10B4 molecule]. 312 16

Levels of mRNA of the T cell antigen receptors (TcR) in human thymocytes are differentially regulated in response to distinct intracellular signals. Activation of protein kinase C by the phorbol ester, tetradecanoyl phorbol acetate or other phorbol esters increases the levels of the alpha and beta T cell receptor (TcR-alpha, TcR-beta) mRNA, whereas an increase in cytosolic free Ca2+, induced by ionomycin or other Ca2+ ionophores, results in a decrease of alpha and beta TcR mRNA levels. In contrast, ionomycin increases the expression TcR-gamma mRNA whereas tetradecanoyl phorbol acetate prevents this induction. Our results suggest the existence of two opposing intracellular pathways that control expression of TcR-alpha and TcR-beta mRNA levels, on the one hand and TcR-gamma mRNA, on the other. These results provide the first evidence for antagonistic actions of protein kinase C and cytosolic-free Ca2+ on gene expression.
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PMID:Antagonistic effects of calcium ionophores and phorbol esters on T cell receptor mRNA levels in human thymocytes. 325 35


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