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)

Human cloned CD8+ cytotoxic T lymphocytes permeabilized with alpha-toxin of Staphylococcus aureus can be triggered by the guanosine triphosphate (GTP) analogue GTP gamma S to release the contents of their granula by exocytosis. To localize the guanosine nucleotide-binding protein (G-protein) activated by GTP gamma S in the sequence of events after T-lymphocyte triggering we have used several inhibitors of T-cell activation that inhibit early stages in T-cell triggering. The protein kinase C-inhibitor staurosporine, the immunosuppressants cyclosporin A and FK-506 and genistein, an inhibitor of tyrosine kinases, all inhibited esterase release triggered in intact cells by anti-T-cell receptor antibodies but not GTP gamma S-induced release from permeabilized cells. Cyclosporin A, FK-506 and genistein also blocked exocytosis triggered in intact cells by a combination of phorbolester and the calcium ionophore A23187. In addition, cytochalasin B, an inhibitor of actin polymerization, inhibited exocytosis in intact cells but enhanced exocytosis from permeabilized cells. These data show that the G-protein effecting exocytosis is localized distally in the cascade of events after T-cell activation.
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PMID:Functional localization of an exocytosis-triggering G-protein in human cytotoxic T lymphocytes. 138 35

To clarify the mechanism of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced macrophage-like differentiation of HL-60 cells, we investigated the correlation between the effects of protein kinase C (PKC) inhibitors on the induction of markers of TPA-induced differentiation and those on suggested critical steps of the differentiation. H-7, sphingosine, and trifluoroperazine significantly suppressed TPA-induced cell adhesion but their effects on the induction of acid phosphatase and nonspecific esterase differed among the inhibitors. The three inhibitors failed to affect on TPA-induced annexin I expression. In contrast, staurosporine markedly suppressed the induction of all these markers. The effects of the inhibitors on some suggested critical steps of the differentiation, a rapid phosphorylation of specific proteins, a rapid membrane association of PKC, and down-regulation of PKC at 18 h after addition of TPA, were not correlated with those on the differentiation marker induction. Only the effect of the inhibitors on up-regulation of PKC-alpha was closely correlated with TPA-induced annexin I expression; staurosporine inhibited up-regulation of PKC-alpha but other inhibitors did not similarly affect the induction of annexin I expression. These results suggest that PKC-alpha is intimately related to macrophage-like differentiation of HL-60 cells by TPA.
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PMID:Differentiation of HL-60 cells by phorbol ester is correlated with up-regulation of protein kinase C-alpha. 144 57

alpha CD3 induced the generation of activated killer cells from resting T cells. Pretreatment of the splenic responders with PMA, a phorbol ester, depleted protein kinase C and induced unresponsiveness to the generation of alpha CD3-induced activated killer (CD3-AK) cells. Addition of exogenous IL-4 (1 U/ml) restored the cytotoxic response, with the maximal effect achieved with 30 to 100 U/ml. The phenotypes of CD3-AK cells maintained in IL-2 or in IL-4, with or without PMA, were the same: Thy1+ and CD8+. These results were reproduced with purified T cells and purified CD8+ cells, indicating that both the effectors and precursors were CD8+ cells and IL-4 had a selective effect to upregulate the CD8+ cells. Similar results were obtained by using SSP (staurosporine), another PKC inhibitor. At 2 days prior to testing, switching the lymphokine added to 2-week PMA- and IL-2-maintained CD3-AK cells reversed their cytolytic activity: switching from IL-2 to IL-4 restored cytolytic activity, and switching from IL-4 to IL-2 reduced cytolytic activity. The cytolytic activity of these CD3-AK cells correlated with their ability to produce BLT-esterase. In the absence of PMA, CD3-AK cells cultured in either IL-2 or IL-4 were cytolytic and contained high levels of BLT-esterase. In contrast, in the presence of PMA, only the IL-4-maintained CD3-AK cells were cytolytic and produced significant amounts of BLT-esterase. The effect of IL-4 was abrogated by the alpha IL-4 antibody 11B11, which reduced the cytolytic activity of CD3-AK and the ability to produce BLT-esterase. The requirement of IL-2 was less stringent and its major role appeared to be maintaining the cell growth. These findings indicate that IL-4 may participate in the regulation of a PKC-independent pathway for the generation of CD3-AK cells by regulating the production of cytolytic granules.
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PMID:IL-4 regulation of a protein kinase C independent pathway for the generation of alpha CD3-induced activated killer cells. 153 52

A cell line (TI-1) has been established from the peripheral blood of a patient with acute myeloid leukemia (M2). A typical TI-1 cell displayed many abnormalities of its chromosomes, but not the Philadelphia (Ph1) chromosome. Light and electron microscopic examination and histochemical analysis indicated that the TI-1 cells were undifferentiated blast cells, but immunologic marker studies suggested that these cells had myeloid characteristics. The proliferation of TI-1 cells was dependent on the concentration of fetal bovine serum (FBS). Their doubling time was 13.8 hours when they were cultured in a medium containing 10% FBS. Phorbol-12 myristate 13-acetate (PMA) induced the TI-1 cells to differentiate into monocyte-like cells, as judged by their morphologic similarity to monocytes, their adhesion to the culture dish, and their increase of both nitroblue tetrazolium (NBT)-reducing ability and nonspecific esterase (NSE)-activity. PMA significantly inhibited the proliferation and DNA synthesis of TI-1 cells in a dose-dependent manner. The PMA-induced differentiation was significantly inhibited by the protein kinase C inhibitors (H-7, staurosporine). Hemin induced the TI-1 cells to differentiate into erythroid cells. The number of hemoglobin-producing cells and hemoglobin production was increased by hemin treatment. Hemin also inhibited the proliferation of the TI-1 cells. Thus, the TI-1 cell represents a bipotent, granulo-monocytoid, and erythroid cell line. The TI-1 cell line will be a useful model for monocytoid and erythroid differentiation.
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PMID:Characterization, growth, and differentiation of a human myeloid leukemia cell line, TI-1 cell. 161 Oct 97

A GALT-derived B lymphoma, T560, that bears IgAR is described. T560 is IgG2a kappa +, Ia+, B220+, J11d+, Thy-1-, CD3-, CD4-, CD5-, Mac 1-, Mac 2-, nonspecific esterase negative and binds bromelain-treated mouse RBC but not SRBC or ORBC. It presents antigen, secretes IL-1, IL-4 and IL-6 but not IL-2, IL-5 or TGF beta and appears to be related to the Lyt 1+(CD5) lineage of B cells though it lacks Lyt 1. T560 bears IgAR that, on the cell surface, are completely cross-inhibited by low concentrations of IgM and by high concentrations of IgG2a and IgG2b. They do not appear to represent a cell-surface form of galactosyl transferase. They are inducible by high concentrations of IgA, sensitive to trypsin and insensitive to neuraminidase. They are down-regulated by activation of PKC with PMA, but their recovery is not inhibited by cycloheximide, indicating that they are not degraded or shed. They may either lose their affinity for IgA or be internalized without degradation. Seventy percent of IgA receptor activity is lost when T560 is treated with PI-PLC; part of this loss of activity is due to activation of PKC and is inhibited by staurosporine, but approximately 30% of it is not protected by staurosporine indicating that some, or all, of the IgA receptor of T560 is connected to the cell membrane via a GPI linker. The T560 IgA receptor could be related to the poly-Ig or M cell receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Sensitivity of receptors for IgA on T560, a murine B lymphoma, to phorbol myristate acetate and to phosphatidylinositol-specific phospholipase C. 165 5

Recent reports indicate that the protein kinase inhibitor H7 is capable of inducing both morphological and functional differentiation of a number of neural cell types. This investigation demonstrates that H7 potentiates the neurogenic properties of nerve growth factor (NGF) in PC12 cells with a concomitant change in the accumulation of the beta II-protein kinase C (beta IIPKC) isoform protein without changes in either alpha or gamma. However, NGF alone stimulates a coordinate increase in all three isoforms. The assay of acetylcholine esterase as a functional marker of neuronal differentiation demonstrates that H7 alone is not capable of stimulating morphological or functional differentiation in PC12 cells. H7 synergizes with NGF through a PKC-dependent pathway and by differential expression of PKC subtypes. The expression of the PKC transcripts for alpha, beta II, and gamma all undergo simultaneous yet differential changes in their patterns of expression during treatment with H7 and/or NGF. These data suggest that isoform switching is regulated primarily at the protein level. Last, these findings suggest that expression of PKC isoforms is tightly coupled with neuronal differentiation and may play a role in the maintenance of the differentiated state.
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PMID:Differential expression of PKC isoforms and PC12 cell differentiation. 173 52

DL-1,2-Dioctanoylglycerol (1,2-DiC8) added to human peripheral resting T lymphocytes was rapidly metabolized to produce octanoic acid and further to small molecules, probably by the action of diacylglycerol lipase and/or nonspecific esterase. Only a small portion was converted to the corresponding phosphatidic acid or was isomerized to 1,3-DiC8 before being metabolized. The uptake of 1,2-DiC8 by the cell was apparently fast, and the rate of disappearance of 1,2-DiC8 was dependent on the cell densities; at a higher density of T lymphocytes 1,2-DiC8 was removed quickly, whereas at a lower cell density 1,2-DiC8 remained for a longer period of time. With a fixed amount of 1,2-DiC8 added, the extent of interleukin 2 receptor alpha-subunit (IL-2R alpha) expression was inversely related to the cell density and proportional to the duration of exposure of the cells to 1,2-DiC8. Repeated doses of 1,2-DiC8 potentiated IL-2R alpha expression. In contrast, a single dose of phorbol 12-myristate 13-acetate caused T-lymphocyte activation to similar extents irrespective of the cell density, probably because the phorbol ester was not metabolized and remained in membranes. The available evidence supports a proposal made in a previous paper and indicates that the sustained activation of protein kinase C for at least the first 3-4 hr is essential for the activation of resting T lymphocytes.
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PMID:Metabolic rate of membrane-permeant diacylglycerol and its relation to human resting T-lymphocyte activation. 192 30

The metabolism of biologically active inositol phosphates in developed ovarian follicles from Xenopus laevis was investigated. Techniques used were microinjection of tracer into the intact oocyte coupled by gap junctions to follicle cells, as well as addition of tracer to homogenates of ovarian follicles and to homogenates of oocytes stripped of outer follicle-cell layers. Metabolism was similar to that previously described for other types of cell and tissue, with several unusual features. Homogenates of ovarian follicles were shown to contain an apparent 3'-phosphomonoesterase capable of converting [3H]Ins(1,3,4,5)P4 predominantly into a substance with h.p.l.c. elution characteristics of Ins(1,4,5)P3. In intact ovarian follicles, little Ins(1,4,5)P3 was formed but the esterase was activated by the phorbol ester activator of protein kinase C, PMA (phorbol 12-myristate 13-acetate; 60 nM), as well as by acetylcholine (200 microM). In follicle homogenates, this enzyme also appeared to be active in converting [3H]Ins(1,3,4)P3 into a substance eluting as Ins(1,4)P2. The apparent 3'-phosphomonoesterase activity was not inhibited by intracellular (or higher) levels of Mg2+. Although PMA activated this enzyme in intact oocytes relative to 5'-phosphomonoesterase activation, it did not enhance overall metabolism, in contrast with reports on other tissues. Compared with the processing of inositol phosphates injected into the intact follicle, homogenization in simulated intracellular medium appeared to alter the activity and/or accessibility of several enzymes. The metabolism of inositol phosphates appears to occur predominantly in the follicle cells surrounding the oocyte, as collagenase treatment followed by defolliculation greatly diminished the rates of metabolism of several inositol phosphates. The presence in Xenopus ovarian follicles of a 3'-phosphomonoesterase activated by protein kinase C in addition to the well-known 3'-kinase suggests that, by forming a reversible interconversion between Ins(1,4,5)P3 and Ins(1,3,4,5)P4, this tissue may have the potential to prolong stimulatory signals on binding of appropriate agonists to receptors.
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PMID:Metabolism of the biologically active inositol phosphates Ins(1,4,5)P3 and Ins(1,3,4,5)P4 by ovarian follicles of Xenopus laevis. 216 Aug 8

Phorbol esters induce the human HL-60 promyelocytic cell line to differentiate along a monocytic pathway. This induction of differentiation may involve phorbol ester-induced activation of the phospholipid- and calcium-dependent protein kinase C. Bryostatin 1, a macrocyclic lactone, has been shown to compete with phorbol esters for binding to protein kinase C. We have confirmed that bryostatin 1 translocates activity of protein kinase C from the cytosolic to membrane fractions of HL-60 cells. The present results also demonstrate that bryostatin 1 (10 nmol/L) induces monocytic differentiation of HL-60 cells as determined by adherence, growth inhibition, appearance of monocyte cell surface antigens, and alpha-naphthyl acetate esterase staining. Furthermore, bryostatin 1 (10 nmol/L) downregulated c-myc expression and induced c-fos, c-fms, and tumor necrosis factor transcripts. These changes in gene expression induced by bryostatin 1 are similar to those associated with phorbol ester-induced monocytic differentiation of HL-60 cells. In contrast, exposure to a higher concentration of bryostatin 1 (100 nmol/L) had less of an effect on growth inhibition of HL-60 cells and changes in gene expression. Moreover, 100 nmol/L bryostatin 1 antagonized the cytostatic effects and adherence induced by phorbol esters. Our results thus suggest that bryostatin 1 activates HL-60 cell protein kinase C and that this effect is associated with induction of monocytic differentiation.
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PMID:Bryostatin 1 activates protein kinase C and induces monocytic differentiation of HL-60 cells. 245 68

In our study we investigated the effect of pretreatment of bulk CTL and CTL clones with immobilized anti-CD3 antibody (Ab) or PMA. Primary CTL and CTL clones were cultured in dishes coated with anti-CD3 Ab or in medium containing PMA (5 nM) and assayed for Ag-specific or Ag-nonspecific "redirected" cytolysis using FcR+ P815 cells as targets. Cytotoxic activity of bulk CTL and five of six CTL clones tested in this study were inhibited by prolonged (longer than 6 h) pretreatment with immobilized anti-CD3 Ab or PMA, whereas proliferation of CTL clones or expression of surface CD3 molecules were not. The intracellular granule enzyme (N-alpha-benzyloxycarbonyl-L-lysine thiobenzyl ester esterase) activity of CTL clones was not reduced under these suppressive conditions, indicating that the incompetence of CTL is not merely due to depletion of cytolytic granules by chronic stimulation. The suppressed cytotoxicity could be recovered by culturing CTL without perturbation of CD3 molecules for 24 h. In one exceptional clone, BM10-37, pretreatment with immobilized anti-CD3 Ab or PMA did not suppress the cytotoxic activity. Immunostaining of intracellular protein kinase C (PKC) revealed that PKC was depleted after prolonged treatment with immobilized anti-CD3 Ab or PMA in those susceptible CTL clones but not in the resistant BM10-37. These findings lead us to conclude that prolonged stimulation of CD3 of CTL results in depletion of PKC and that PKC may be essential for signal transduction to deliver a lethal hit to the target cells.
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PMID:Cytotoxic T lymphocyte unresponsiveness induced by prolonged treatment with immobilized anti-CD3 antibody. Association of impairment of cytolytic activity with temporary depletion of intracellular protein kinase C. 253 Feb 77


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