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)

Bryostatins are macrocyclic lactones isolated from the marine bryozoan Bugula neritina. They are currently evaluated for putative antineoplastic activity. Bryostatins bind and activate protein kinase C (PK-C), the cellular receptor for the phorbol ester, and elicit PK-D-dependent cellular functions. Such functions include the expression of the interleukin-2 receptor (IL-2R). Northern blot hybridization with a human IL-2R and an IL-2 cDNA showed that bryostatin 1 (bryo 1), like the phorbol ester, PMA, activates the IL-2R gene. Activation with bryo 1 or PMA in the presence of a calcium ionophore, A23187, increased IL-2 message. These findings indicate that calcium mobilization is necessary for bryo 1 or PMA induced IL-2 gene expression. Unlike PMA, bryo 1 did not cause a vigorous proliferative response of T-lymphocytes unless A23187 was added to the cultures. A bryostatin congener, bryo 13, was inactive in the above assays. Short-term treatment of T-cells with bryo 1 and PMA resulted in an equivalent down-regulation of surface CD3 and CD4 receptors without affecting the CD8 receptor. Bryo 1 or PMA mediated expression of surface IL-2R and T-cell proliferation induced by bryo 1 or PMA were sensitive to inhibition by the PK-C antagonists staurosporine (Sts) and H-7. In contrast, CD4 and CD3 down-regulation were resistant to H-7, but could be blocked by Sts, although the Sts concentration required to block bryo 1 or PMA-induced down-modulation was 2.5-fold higher than required to inhibit IL-2R expression and T-cell proliferation. These results indicate that bryostatins activate T-cell through PK-C.
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PMID:Activation of T-cells by bryostatins: induction of the IL-2 receptor gene transcription and down-modulation of surface receptors. 221 Sep 11

Phorbol 12-myristate 13-acetate (PMA) can stimulate T-cells via its binding to protein kinase C (PKC). Such a phenomenon occurs when a threshold of concentration as low as 1 nM of PMA is reached. Other phorbol esters possess the ability to stimulate lymphocytes but at higher thresholds of concentration. We show here that the different phorbol ester concentrations needed to induce stimulation and proliferation, estimated by both interleukin-2 receptor (IL-2R) expression and DNA synthesis, correspond very closely to those inducing the modulation of CD4 antigen, confirming a direct relationship between CD4 down-regulation and cellular activation. We estimated the structural features of these different phorbol derivatives in relation to lymphocyte activation and CD4 modulation, and confirm that the ester side chains which give to the phorbol ester derivatives their lipophilic character, discriminate, according to their length, the ability of the different compounds to reach their receptor inside the cell membrane; we also brought some evidence that the polar phorbol nucleus of these compounds is probably responsible for their interaction with the membrane receptor mainly through the hydroxyl group in the C4 position.
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PMID:Lymphocyte mitogenesis and CD4 modulation induced by different phorbol esters: comparative studies. 229 58

Human melanoma-specific, HLA restricted, cytotoxic T-cell lines can be generated by in vitro stimulation and culturing of peripheral lymphocytes, or lymph node cells, with autologous or HLA-A region matched melanomas in the presence of a low concentration (5 U/ml) of IL-2. Stimulation is followed by a period of clonal expansion and differentiation into cytotoxic T-cells specific for melanoma. We investigated the effect of the PKC modulating drug phorbol dibutyrate combined with the calcium ionophore Ionomycin on growth and differentiation of the cell lines. The growth of the T-cell lines was substantially augmented in the presence of the drugs with increases of 10-fold or more in clonal expansion by 3 weeks of culture. The cell lines were IL-2 dependent for growth in the presence or absence of the drugs and the phenotypic distribution remained predominantly CD3+ T-cells of mixed CD4 and CD8 phenotypes. In spite of the increased rate of growth in the presence of the drugs, autologous melanoma-specific cytotoxicity was almost completely abrogated in those cultures. The cells were, however, nonspecifically lytic in the presence of concanavalin A. The melanoma-specific cytotoxic response was completely restored following culture with IL-2 alone. The results suggest that the human tumor-specific cytotoxic T-cell response can be induced and amplified in the presence of immune modulating drugs.
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PMID:Modulation of in vitro autologous melanoma-specific cytotoxic T-cell responses by phorbol dibutyrate and ionomycin. 229 96

The B oligomer of pertussis toxin serves as a weak mitogen in the T lymphocyte, an effect which is associated with an early rise in cytosolic free calcium concentrations, as monitored by Fura-2 fluorescence. Upon co-administration of phorbol dibutyrate, a phorbol ester tumour promotor which activates protein kinase C, pertussis toxin-induced proliferation was synergistically enhanced, as measured by the increased uptake of [3H]thymidine, into cellular DNA. Although phorbol ester co-administration has often been associated with an inhibition of Ca2+-mobilizing pathways, phorbol dibutyrate pretreatment had no inhibitory effect on the pertussis toxin-induced calcium flux and may actually have enhanced this response slightly. Flow cytometric analysis of cell populations expanded by the combined regimen did not provide evidence for the preferential expansion of cells bearing either CD4 or CD8, the T-cell determinants representative of the helper-inducer and cytotoxic-suppressor subsets, respectively. Pertussis toxin and phorbol dibutyrate appear, therefore, to elicit polyclonal stimulation, rather than the selective activation of a given lymphocyte subset. Expression of the transferrin receptor, a marker for nutrient uptake, and CD25, the Tac component of the interleukin-2 (IL-2) receptor, was, however, synergistically enhanced in cells activated by the co-treatment procedure.
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PMID:Interactive effects of pertussis toxin and the phorbol ester tumour promotor, phorbol dibutyrate, on T-lymphocyte mitogenesis and the expression of phenotypic determinants. 246 42

It has long been recognized that T cells in the cerebrospinal fluid (CSF) and other inflammatory compartments cannot be stimulated by mitogen and the reason for this has remained unknown. This question was investigated using mononuclear cells (MNC) isolated from the CSF of subjects with multiple sclerosis and other inflammatory brain diseases which predominantly express the CD4 and CDw29 but not CD45RA determinants. CSF and blood cells were stimulated by either the CD3/T cell receptor complex, the CD2 activation pathway, calcium ionophore, or an activator of protein kinase C, phorbol myristate acetate (PMA). CSF MNC proliferated less than blood MNC following stimulation by phytohemagglutinin in subjects with inflammation in the CSF, but not in subjects with non-inflammatory CNS diseases. Moreover, CSF MNC were not induced to proliferate through stimulation of the CD2 pathway by anti-T11(2) + anti-T11(3) monoclonal antibodies (mAb). This was not due to defects in either interleukin 2 receptors, interleukin 2 secretion, or to T cell pre-activation in vivo. Instead, the refractory activation state of inflammatory CSF T cells was corrected by PMA. That CSF contains predominantly CD4+CDw29+CD45RA- cells suggests that PMA may be co-stimulatory with anti-CD2 mAb to activate this population of T cells. This was confirmed in experiments with sorted T cells from normal subjects. These data suggest that the inability of mitogens or anti-CD2 mAb to stimulate inflammatory CSF T cells, which can be corrected by an inducer of protein kinase C, is related to the relative absence of CD4+CD45RA+ cells in the CSF. Alterations of protein kinase C and protein phosphorylation may exist in inflammatory T cell populations that regulate the immune response.
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PMID:Inflammatory cerebrospinal fluid T cells have activation requirements characteristic of CD4+CD45RA- T cells. 247 60

We have studied whether the decreased lymphocyte proliferative responses of AIDS lymphocytes to stimulation by mitogens and antigens may be overcome when challenged with a combination of calcium ionophore A23187 and phorbol ester PMA. Comparison of the proliferative response of lymphocytes from nine patients with AIDS with the response of lymphocytes from nine control subjects showed that the response of AIDS lymphocytes was severely decreased when stimulated with PHA and no further response could be achieved by stimulation with A23187/PMA. On the other hand, no significant difference between the PHA-induced rise of cytoplasmic free calcium concentration ([Ca2+]1) in normal and AIDS lymphocytes was observed. The percentage of cells expressing IL-2 receptors (CD25) was also normal both after addition of PHA and after addition of A23187/PMA and the expression was normal on both CD4 and CD8 cells. The production of IL-2 in normal lymphocytes stimulated with A23187/PMA was 33 times higher than that after stimulation with PHA. In AIDS lymphocytes the production of IL-2 induced by all activators was severely decreased compared to control subjects, although the production of IL-2 after stimulation with A23187/PMA was higher than that in control lymphocytes after stimulation with PHA. The present study shows that a direct activation of protein kinase C combined with mobilization of cytoplasmic calcium does not overcome the lymphocyte proliferative deficiency of AIDS lymphocytes.
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PMID:Stimulation of AIDS lymphocytes with calcium ionophore (A23187) and phorbol ester (PMA): studies of cytoplasmic free Ca, IL-2 receptor expression, IL-2 production, and proliferation. 249 38

The potent protein kinase C inhibitors staurosporine, H-7, and UCN-01 were investigated for their effects on 12-0-tetradecanoylphorbol-13-acetate (TPA)--mediated CD4 down-regulation and on the augmentation of human immunodeficiency virus (HIV) expression. Staurosporine was the most effective TPA inhibitor for both of these actions. Because of its high cytotoxicity, the effect of H-7 on augmentation of HIV expression could not be determined. UCN-01 had no cytotoxic effect, but caused only little inhibition of the augmentation of HIV expression.
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PMID:Comparison of effects of protein kinase C inhibitors on phorbol ester-induced CD4 down-regulation and augmentation of human immunodeficiency virus replication in human T cell lines. 250 37

We have investigated signaling mechanisms that may underlie the T cell mitogenic properties of the Ca2+ ionophore ionomycin. Ionomycin induces highly purified resting human T cells to proliferate in the presence of monocytes with accompanying IL-2R expression and IL-2 synthesis. Treatment of T cells with ionomycin triggers the hydrolysis of phosphoinositides, as evidenced by the accumulation of the hydrolytic by-products phosphatidic acid and inositol phosphates. Ionomycin also induces the activation of protein kinase C (PKC), as demonstrated by the auto-phosphorylation of PKC and the phosphorylation of the PKC target proteins CD4 and CD8. Ionomycin synergizes with PMA in enhancing the activation of PKC. It is concluded that, in addition to its putative activation of Ca2+/calmodulin-dependent signaling pathways, ionomycin induces the hydrolysis of phosphoinositides and the activation of PKC in human T cells. The synergy of ionomycin with phorbol esters in triggering T cell activation may relate, at least in part, to enhanced activation of PKC.
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PMID:Mechanisms of T cell activation by the calcium ionophore ionomycin. 254 85

Mice homozygous for the lpr gene develop a lymphoproliferative disorder due to expansion of a subset of CD4-CD8- T cells. Triggering of the T-cell receptor in these lpr T cells does not lead to translocation of protein kinase C or phosphorylation of CD3, interleukin-2 production, or proliferation, whereas a combination of phorbol ester and calcium ionophore does. Stimulation with concanavalin A or anti-CD3 induces phosphoinositide hydrolysis. The rise in inositol bisphosphate, inositol triphosphate, and inositol tetrakisphosphate, identified by HPLC, is similar in +/+ and lpr T cells. The concentration of cytoplasmic free calcium ([Ca2+]i), however, under basal and stimulated conditions is significantly lower in lpr T cells. The lower basal [Ca2+]i may explain why induction of proliferation with phorbol ester and calcium ionophore requires a higher concentration of ionophore in these cells than in normal T cells. The lower [Ca2+]i obtained on stimulation may contribute to the activation defect of CD4-CD8- lpr T cells.
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PMID:Defective signal transduction in CD4-CD8- T cells of lpr mice. 255 9

Activated lymphocytes may have potent biologic effects outside the frame of the immune system. In these studies we analyzed the interaction of activated normal human lymphocytes and/or soluble products of lymphocyte activation on the contractile activity of isolated rat atria. The results indicate that phytohemagglutinin activated lymphocytes of the CD4 phenotype exert a positive inotropic effect on spontaneously beating atria. This effect is linked to steps of lymphocyte activation that precede cell division. Soluble factors released to the supernatant of stimulated lymphocytes can substitute for the intact cells. Interleukin-2 (IL-2) appears to be an important component of the active supernatants, as their activity can be reduced by monoclonal anti-IL-2 or by preincubation of the heart tissue with monoclonal anti-IL-2 receptor (anti-Tac). Highly purified IL-2 was active at 10 units/ml. In order to induce a positive inotropic effect at lower doses of natural or recombinant IL-2 (2-3 units/ml), synergic factors were required (2 x 10(-6) M arachidonic acid, AA, or Ca ionophore A 23187). Indirect evidence indicates that IL-2 exerts its biologic effect by turning on the phosphoinositide cycle and activating protein kinase C in the heart tissue target. It is postulated that similar mechanisms may be activated in inflammatory myocardiopathies or during the treatment of cancer with massive doses of IL-2.
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PMID:[The effect of activated lymphocytes on cardiac contractility]. 264 Apr 86


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