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)

An anti-T cell receptor (TcR) monoclonal antibody (mAb), LC4, directed against a human leukemic T cell line, SUP-T13, caused DNA fragmentation ("apoptosis") and cell death upon binding to this cell line. Cross-linking of receptor molecules was necessary for this effect since F(ab')2, but not Fab', fragments of LC4 could induce cell death. Five anti-CD3 mAb tested also caused apoptosis, but only when they were presented on a solid phase. Interestingly, soluble anti-CD3 mAb induced calcium flux and had an additive effect on the calcium flux and interleukin 2 receptor expression induced by LC4, but these anti-CD3 mAb reversed the growth inhibition and apoptosis caused by LC4. The calcium ionophore A23187, but not the protein kinase C activator phorbol 12-myristate 13-acetate (PMA), also induced apoptosis, suggesting that protein kinase C activation alone does not cause apoptosis, although PMA is growth inhibitory. These results suggest that two distinct biological phenomena can accompany stimulation of the TcR/CD3 complex. In both cases, calcium flux and interleukin 2 receptor expression is induced, but only in one case is apoptosis and cell death seen. The signal initiating apoptosis can be selectively prevented by binding CD3 portion of the receptor in this cell line. This difference in signals mediated by the TcR/CD3 complex may be important in explaining the process of thymic selection, as well as in choosing anti-TcR mAb for therapeutic use.
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PMID:DNA fragmentation and cell death mediated by T cell antigen receptor/CD3 complex on a leukemia T cell line. 253 Oct 90

This study was designed to determine the effect of the phenothiazine chlorpromazine (CPZ) on the activation of human thymocytes. We provide evidence that CPZ inhibits the accumulation of mRNA specific for the lymphokines, interleukin 2, interferon-gamma, tumor necrosis factor alpha and the proto-oncogene c-myc; by contrast, the accumulation of mRNA specific for the alpha chain of the interleukin 2 receptor and the subsequent early expression of Tac antigen on the cell surface is not inhibited by CPZ. The inhibition of the expression of lymphokine-specific mRNA results in a decrease in interferon-gamma synthesis and in inhibition of thymocyte proliferation as determined by the incorporation of [3H]thymidine. In addition, we show that activation of protein kinase C (PKC) in human thymocytes by 12-O-tetradecanoyl phorbol 13-acetate (TPA) causes the phosphorylation of a protein of a molecular mass of approximately 75 kDa. The function of this protein is as yet not defined, but it is possible that it plays a role in the transduction of the signals to the nucleus which in turn elicit the expression of the genes coding for c-myc and for the lymphokines required for thymocyte activation. We also demonstrate that CPZ, like the immunosuppressant drug cyclosporin A does not inhibit the phosphorylation of the 75-kDa protein which is induced by the activation of PKC by TPA and does not affect phosphoinositide breakdown, indicating that it exerts its effect at a site distal to the activation of PKC. These observations demonstrate that CPZ has an immunoregulatory function in addition to its psychotropic activity.
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PMID:Inhibition by chlorpromazine of lymphokine-specific mRNA expression in human thymocytes. 255 Feb 48

Many cytokines have been documented to have a multiplicity of biological effects by acting on a variety of cells. In order to determine whether human BCGF-II acts on any cells in addition to normal B cells, the effect of human BCGF-II on murine thymocytes, human peripheral blood T cells, a human natural killer-like cell line, YT, and Epstein-Barr virus (EBV)-transformed B-cell lines was further examined. BCGF-II augmented incorporation of [3H]thymidine by murine thymocytes in combination with suboptimal doses (0.5 microgram/ml) of concanavalin A (Con A) but not at lower doses (0.1 microgram/ml) of Con A, a concentration usually used for interleukin 1 (IL-1) assays. BCGF-II could not induce proliferation or Tac antigen (Ag) expression on normal peripheral blood T cells stimulated with OKT3 antibody. Both proliferation and Tac Ag expression on YT cells were also augmented by BCGF-II. BCGF-II induced both high- and low-affinity IL-2 receptor (IL-2R) on YT cells as determined by 125I-IL-2-binding assay. Two of seven EBV-transformed B-cell lines tested (ORSON and AUM cells) in response to BCGF-II exhibited augmentation of proliferation and cell surface Tac Ag expression. BCGF-II in the presence of low doses (0.1 microgram/ml) of phorbol myristate acetate (PMA) also induced Tac Ag mRNA (3.5 and 1.5 kb) in these B-cell lines. The IL-2R induced on these B-cell lines, however, consisted mostly of low-affinity receptors. Both Tac Ag and its mRNA in these B-cell lines were not induced by Forskolin but by PMA, suggesting that this induction may involve protein kinase C. The present study shows that human BCGF-II can stimulate YT cells, murine thymocytes, and some EBV-transformed B-cell lines but not peripheral blood T cells. Consequently, BCGF-II can induce the growth and differentiation of a number of cell types in addition to normal B cells.
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PMID:A major 50-kDa human B-cell growth factor-II induces both Tac antigen expression and proliferation by several types of lymphocytes. 282 95

The proliferative responses of natural killer (NK) cells to 12-O-tetradecanoylphorbol-13-acetate (TPA), which directly activates protein kinase c(PKC), and to the Ca2+ ionophores A23817 and ionomycin, known to enhance the intracellular calcium, have been investigated. Highly purified large granular lymphocytes (LGL) were cultured for 12-30 hr in the presence of TPA, ionomycin, or A23817. TPA alone (1-20 ng/ml) triggered rapid LGL proliferation, whereas the calcium ionophores were ineffective. The addition of either calcium ionophore to suboptimal doses or TPA (0.1-0.5 ng/ml) resulted in a synergistic effect on LGL proliferation. Under these conditions high levels of IL-2 activity were released by the LGL. Phenotypic analysis revealed the rapid loss of the Fc gamma receptors (CD16) on LGL and the induction of the expression of IL-2 (CD25) and transferrin receptors and of HLA-DR, but not of CD3. Removal of extracellular Ca2+ by addition of EGTA at the beginning of the culture greatly depressed LGL proliferation and IL-2 production, and blocked phenotypic changes, such as the expression of Tac antigen. Finally, progression to the proliferative phase of LGL, activated by TPA alone or with ionomycin, was completely abrogated by a hyperimmune anti-IL-2 antiserum.
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PMID:Proliferative effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) and calcium ionophores on human large granular lymphocytes (LGL). 283 70

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

Tac antigen (as a measure of the IL 2 receptor) acquisition and regulation by IL 2, an antigen-receptor agonist (anti-T3), phorbol esters, and phytohemagglutinin (PHA) were studied. Phorbol esters stimulated de novo acquisition of Tac antigen, which was associated with the subcellular redistribution of protein kinase C (PK-C) from cytosol to particulate membranes of human T lymphocytes. PHA and anti-T3 (alpha-T3) antibody also stimulated a transient redistribution and activation of PK-C that reached a maximum within 20 min after stimulation. Both phorbol esters and alpha-T3 could increase Tac expression and stimulate PK-C translocation on 5 and 12 day activated T cells that were at the G0/G1 stage of the cell cycle due to IL 2 deprivation. Tac antigen-specific mRNA was seen in the nucleus within 2 hr after stimulation. In contrast, IL 2 alone could only increase Tac expression and stimulate PK-C translocation on day 5 but not day 12 activated T cells. IL 2 synergizes with alpha-T3 and phorbol ester for the regulation of Tac expression. Although IL 2 increased expression of Tac, the majority if not all of these receptors possessed low affinity for IL 2. These data suggest that the activation of PK-C is a common transmembrane signal shared by IL 2 and antigen stimulation. The results also imply that PK-C activation is necessary for the regulation of Tac antigen expression.
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PMID:Association of protein kinase C activation with IL 2 receptor expression. 300 92

Mouse thymocytes treated with the lectin Concanavalin A do not proliferate nor do they develop responsiveness to interleukin 2. Co-treatment with Concanavalin A and either lectin-activated splenocyte conditioned medium or phorbol ester caused increased interleukin 2 receptor expression and proliferation. Under these conditions, lectin alone stimulated a 3.4 fold increase in phosphatidylinositol turnover which was unaffected by the presence of conditioned medium. Phosphorylation of a 55 kD protein was stimulated in response to conditioned medium or phorbol ester, but not lectin. These results indicate that stimulation of phosphoinositide turnover is not sufficient to activate thymocytes, and suggest that costimulating factors activate a kinase which is distinct from protein kinase C, or alternatively, activate protein kinase C through a process which is not coupled to phosphoinositide turnover.
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PMID:Stimulation of phosphatidylinositol turnover by concanavalin A is not sufficient to activate mouse thymocytes. 302 88

A B cell-specific monoclonal antibody (anti-Ba) was prepared. In two-color FACS analysis the anti-Ba reacted with a subpopulation of Ig+ or B1+ cells obtained from tonsils, but did not react with most B1+ cells derived from PBL. Activation of B cells from PBL with TPA or anti-mu induced Ba expression and the addition of PHA-conditioned supernatant with anti-mu-enhanced Ba expression. Other B cell activators, such as Staphylococcus aureus Cowan I (Staph-A) or PWM plus T cells, could induce Ba expression. Ba expression was observed 6 hr after stimulation and reached a peak level at 72 hr. Ba expression was strictly restricted to B cells. H-7, a specific inhibitor of protein kinase C (C-kinase), displayed a dose-dependent inhibitory effect on Ba expression, showing dependency on C-kinase for Ba expression. Anti-Ba inhibited B cell proliferation induced by anti-mu and B-BCGF distinct from BSF-1. The results presented in this study suggest that the Ba antigen on B cells may be comparable to the Tac antigen on T cells.
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PMID:Expression and function of an early activation marker restricted to human B cells. 308 51

Tac antigen, the receptor for human interleukin 2 (IL-2), contains in its intracytoplasmic region a serine residue (Ser-247) that is seemingly the predominant site of protein kinase C-mediated phosphorylation. A number of studies on growth factor receptors have suggested the importance of phosphorylation in receptor structure, function, and regulation. In this study, we generated site-directed mutations in the Tac antigen cDNA to generate mutant receptors in which Ser-247 or Thr-250, a probable site of minor phosphorylation, was replaced with another amino acid that is not accessible to phosphorylation. Study of the expression of these mutant genes in a T-lymphoid cell line has provided no evidence as to the essential role of the above-mentioned residues in determining the degree of receptor affinity, its ability for signal transduction, and phorbol ester-mediated regulation of the receptor. Our results strongly suggest the existence of an IL-2 receptor "complex" in which the Tac antigen is associated with another molecule(s) that is involved in receptor structure, function, and regulation.
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PMID:Intracytoplasmic phosphorylation sites of Tac antigen (p55) are not essential for the conformation, function, and regulation of the human interleukin 2 receptor. 309 87

Human peripheral blood T lymphocytes were treated with phorbol myristate acetate (PMA), an activator of protein kinase C (PKC) activity, and with the calcium ionophore A23187. The resulting accumulation of specific mRNA for interleukin 2 (IL-2) and interleukin 2 receptor (IL-2R), as well as IL-2 secretion and membrane IL-2R expression were examined. At low concentrations (0.1 microM), A23187 synergized maximally with PMA to induce proliferation, to increase IL-2R mRNA levels and the expression of membrane IL-2R, and to produce a low but sufficient accumulation of IL-2 mRNA and IL-2 secretion. A high concentration of A23187 (1.0 microM) did not show any synergism for the accumulation of IL-2R mRNA, membrane IL-2R expression and inhibited the proliferation of PMA co-stimulated T cells. It did, however, induce maximum accumulation of IL-2 mRNA and IL-2 secretion.
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PMID:Regulation of interleukin 2 and interleukin 2 receptor gene expression in human T cells: I. Effect of Ca2+-ionophore on phorbol myristate acetate co-stimulated cells. 311 57


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