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)

Anti-Tac monoclonal antibody identifies the receptor for interleukin 2 (IL 2, or T cell growth factor) present on activated human T lymphocytes. By using tritiated anti-Tac, we now report a sensitive and specific binding assay to evaluate cell surface IL 2 receptor expression. IL 2 receptors on human peripheral blood lymphocytes can be detected within 6 hr after PHA stimulation. PHA-induced receptor expression is inhibited by actinomycin D and cycloheximide, but not by mitomycin C, suggesting a requirement for de novo RNA and protein synthesis, but not DNA synthesis. Scatchard analysis of [3H]-anti-Tac binding to lymphocytes stimulated with PHA for 3 days revealed from 20,000 to 60,000 molecules of antibody bound per cell, and a Kd of 1 to 3 x 10(-10) mol/l. Sequential binding studies of activated human lymphocytes maintained in long-term culture with IL 2 demonstrated a progressive decline in receptor number correlating with diminished growth rate. Restimulation with lectin or antigen increased the number of IL 2 receptors, suggesting that IL 2 dependent immune responses may be regulated, at least in part, by IL 2 receptor expression. Receptor number was also increased by PMA. Moreover, similar effects were produced by incubation with phospholipase C but not interleukin 1. Because both PMA and phospholipase C result in activation of protein kinase C, these data suggest the possibility that activation of protein kinase C may induce IL 2 receptor expression.
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PMID:Regulation of interleukin 2 receptor expression: effects of phorbol diester, phospholipase C, and reexposure to lectin or antigen. 609 66

The present study was performed to investigate the histamine-releasing activity of non-immunological stimuli on cultured mast cell lines in comparison to isolated skin mast cells and basophils as human therapeutic target cells. The ionophore A23187 induced a dose dependent histamine release from all cell populations (enzymatically isolated human skin mast cells, human peripheral basophils and rat basophilic leukemia cells, RBL-1 and RBL-2H3). The lectin concanavalin A and the tripeptide formyl-methionyl-leucyl-phenylalanine activated only basophils, while the neural mediator substance P and compound 48/80 were active only in experiments with skin mast cells. Activators of protein kinase C (different phorbol esters and the non-phorbol mezerein) induced direct histamine release only from basophils. The data provide further evidence for heterogeneity of mast cells and indicate different signal transduction mechanisms following non-immunological activation.
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PMID:Functional comparison of different histamine-containing IgE-receptor positive cells. 752 49

We have previously demonstrated that both human CD4+ and CD8+ T lymphocytes produce enhanced levels of luteinizing hormone-releasing hormone (LHRH) mRNA and peptide upon stimulation with monoclonal antibody directed at the CD3 component of the T cell receptor for antigen (TCR) or mitogenic lectin. In the current study, we define the signaling pathways that control TCR-mediated LHRH production by using agents known to affect distinct signals, and compare the messenger systems required for LHRH response to other T-cell-associated activation responses, such as expression of CD69 and interleukin-2 receptor (IL-2R) molecules and production of interleukin-2 (IL-2). Results indicate that the activation of protein kinase C (PKC) is essential for LHRH production by previously nonstimulated T cells, not increased concentration of cytosolic-free calcium ([Ca2+]i). Phorbol ester (PMA), a direct activator of PKC, provoked LHRH production and cell surface expression of CD69 and IL-2R molecules by T cells, but not IL-2 synthesis. The synthesis of IL-2 by T cells required costimulation with PMA and ionomycin, a Ca2+ ionophore. Consistent with these observations, H7, an inhibitor of PKC, prevented T cells from producing LHRH upon activation with mitogen. However, LHRH production was not suppressed by HA1004, which inhibits all cyclic nucleotide-dependent protein kinases except for PKC. Genistein, a selective inhibitor of protein tyrosine kinase, blocked PMA-induced increase in LHRH production, but not CD69 and IL-2R expression, suggesting that protein tyrosine phosphorylation events distal from PKC activation may play a role in regulating LHRH response.
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PMID:Signal requirements for production of luteinizing hormone releasing-hormone by human T cells. 760 99

We have developed a series of immortal human-human hybrid cell lines that express phenotypic characteristics of primary oligodendrocytes, by fusing a 6-thioguanine-resistant mutant of the human rhabdomyosarcoma RD with adult human oligodendrocytes by a lectin-enhanced polyethylene glycol procedure. Hybrids were selected in an aminopterin-containing media. In contrast to the tumor parent cells, a hybrid clone M03.13 expressed surface immunoreactivity for galactosyl cerebroside and intracellular immunoreactivity for myelin basic protein (MBP), proteolipid protein (PLP), and glial fibrillary acidic protein (GFAP). Serum deprivation or chronic treatment with a protein kinase C activator 4-beta-phorbol 12-myristate 13-acetate (PMA), but not dibutyl cyclic adenosine monophosphate induced coordinate up-regulation or de novo induction of oligodendrocyte phenotypic markers with concomitant down-regulation of GFAP expression. Consistent with immunohistochemical studies, northern blot analysis demonstrated that both MBP and PLP mRNA were up-regulated in MO3.13 cells by PMA treatment. M03.13 cells provide an immortalized clonal model system suitable for study of gene expression subserving oligodendrocyte and astrocyte phenotypes.
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PMID:A human glial hybrid cell line differentially expressing genes subserving oligodendrocyte and astrocyte phenotype. 770 48

1. To understand better the mechanisms which govern the sensitivity of secretory vesicles to a calcium stimulus, we compared the abilities of injected chromaffin granule membranes and of endogenous cortical granules to undergo exocytosis in Xenopus laevis oocytes and eggs in response to cytosolic Ca2+. Exocytosis of chromaffin granule membranes was detected by the appearance of dopamine-beta-hydroxylase of the chromaffin granule membrane in the oocyte or egg plasma membrane. Cortical granule exocytosis was detected by release of cortical granule lectin, a soluble constituent of cortical granules, from individual cells. 2. Injected chromaffin granule membranes undergo exocytosis equally well in frog oocytes and eggs in response to a rise in cytosolic Ca2+ induced by incubation with ionomycin. 3. Elevated Ca2+ triggered cortical granule exocytosis in eggs but not in oocytes. 4. Injected chromaffin granule membranes do not contribute factors to the oocyte that allow calcium-dependent exocytosis of the endogenous cortical granules. 5. Protein kinase C activation by phorbol esters stimulates cortical granule exocytosis in both Xenopus laevis oocytes and X. laevis eggs (Bement, W. M., and Capco, D. G., J. Cell Biol. 108, 885-892, 1989). Activation of protein kinase C by phorbol ester also stimulated chromaffin granule membrane exocytosis in oocytes, indicating that although cortical granules and chromaffin granule membranes differ in calcium responsiveness, PKC activation is an effective secretory stimulus for both. 6. These results suggest that structural or biochemical characteristics of the chromaffin granule membrane result in its ability to respond to a Ca2+ stimulus. In the oocytes, cortical granule components necessary for Ca(2+)-dependent exocytosis may be missing, nonfunctional, or unable to couple to the Ca2+ stimulus and downstream events.
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PMID:Evidence that the ability to respond to a calcium stimulus in exocytosis is determined by the secretory granule membrane: comparison of exocytosis of injected bovine chromaffin granule membranes and endogenous cortical granules in Xenopus laevis oocytes. 771 14

The molecular mechanism of neural induction is still unknown and the identity of the natural inducer remains elusive. It has been suggested that both the protein kinase C and cAMP signal transduction pathways may be involved in mediating its action. Here we provide evidence that Ca2+ is implicated in the process of transduction of the neuralizing signal. We find that an increase in intracellular Ca2+ concentration [Ca2+]i occurs during neural induction provoked in vitro by the lectin Con A in Pleurodeles waltl embryo. We demonstrate that specific L-type Ca2+ channel agonists also trigger neural induction. Conversely, noninducing lectins do not raise [Ca2+]i. Ryanodine and caffeine trigger neural induction. An increase in [Ca2+]i was also observed after treatment with the phorbol 12-myristate 13-acetate, which has been reported to be inductive. The [Ca2+]i increase triggered by phorbol ester and Con A was abolished by staurosporine and by L-type Ca2+ channel antagonists. Our findings demonstrate that the [Ca2+]i increase occurs via L-type Ca2+ channels. We suggest an amplification of this increase by a Ca(2+)-induced Ca2+ release mechanism which involves intracellular ryanodine-sensitive stores. We propose that Ca(2+)-dependent processes controlled by protein kinase C are implicated in the regulation of gene expression in response to neural induction.
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PMID:Increased internal Ca2+ mediates neural induction in the amphibian embryo. 780 92

CD45, the leukocyte-common antigen, is a transmembrane protein tyrosine phosphatase uniquely expressed by cells of hematopoietic origin. We have developed CD4+ and CD8+ T cell clones that are deficient in the expression of CD45 and have previously shown that these cells fail to proliferate in response to antigen or cross-linked CD3. These studies have now been extended to show that stimulation with anti-Thy-1, a mitogenic signal for the CD4+CD45+ and CD8+CD45+ T cells, fails to induce proliferation in the CD45- T cells. Examination of the CD8+CD45- T cells correlates anti-Thy-1 unresponsiveness with a failure to increase in tyrosine phosphorylation. Furthermore, stimulation of CD8+CD45+ T cells with anti-Thy-1 results in an increase in p56lck activity but not in CD8+CD45- T cells. In contrast to the results with anti-Thy-1, both the CD4+CD45- and CD8+CD45- T cells respond to treatment with lectin mitogens, concanavalin A or phytohemagglutinin. Lectin-induced proliferation was inhibited by the addition of cyclosporin A. Treatment of CD45- T cells with PMA and ionomycin also results in proliferation indicating that activation of protein kinase C in conjunction with an increase in intracellular calcium rescues the defect caused by CD45 deficiency. The data suggest that CD45 is required for the activation of tyrosine kinase activity immediate or prior to transmembrane signaling.
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PMID:Activation of CD45-deficient T cell clones by lectin mitogens but not anti-Thy-1. 790 28

Interleukin 5 (IL-5) and Interleukin 3 (IL-3) mRNA levels in human peripheral blood T cells were compared by semi-quantitative polymerase chain reaction (PCR) analysis. Unstimulated T Cells did not express IL-5 and IL-3 mRNA. IL-5 and IL-3 mRNA expression were similarly induced by the lectin concanavalin A (Con A). The protein kinase C (PKC) activator phorbol myristate acetate (PMA) triggered both IL-3 and IL-5 mRNA expression, whereby IL-5 and IL-3 mRNA expression was observed after 9 and 3 h treatment, respectively. Stimulation with calcium ionophore A23187 induced IL-3 mRNA expression, whereas it failed to induce IL-5 mRNA. In contrast to IL-3 mRNA, the expression of IL-5 mRNA was dependent on de novo protein synthesis, since cycloheximide (CHX) blocked the Con A plus PMA induced IL-5 mRNA expression. In contrast, cyclosporin A (CsA) inhibited but failed to completely block the expression of IL-3 and IL-5 mRNA. mRNA studies in T cell subsets revealed that the expression of IL-5 mRNA was restricted to the CD4 positive T cell subset in response to Con A plus PMA stimulation. On the other hand, IL-3 mRNA expression was noticed in both the CD4 and the CD8 positive T cell subset. These data indicate that the selective expression of IL-5 by human T cells can either be explained by activation of a selective intracellular signalling pathway or by selective activation of a T cell subset. Alternatively, both processes could be involved.
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PMID:The regulation of interleukin 5 and interleukin 3 gene expression in human T cells. 791 36

The human hepatoblastoma cell line, HepG2, exhibits an array of stable properties in culture that have made it a popular cell culture model for studies on regulation of liver-specific gene expression and properties of hepatoma cells. In contrast to other hepatoma cell lines, HepG2 cells overexpress a characteristic detergent-extractable, wheat germ lectin-binding protein with apparent molecular mass of 130 kDa. Using an antibody to screen a phage expression library of HepG2 complementary DNA (cDNA), we identified and cloned a 4734 base pair cDNA which codes for a 130-kDa leucine-rich protein (lrp 130) when expressed in transfected cells. The deduced sequence of lrp130 exhibits sequences weakly homologous to the consensus sequence for the ATP binding site in ATP-dependent kinases and the protein kinase C phosphorylation site of the epidermal growth factor receptor. Consistent with the higher levels of expression of lrp130 antigen, Northern hybridization analysis indicated that HepG2 cells express high levels of the major 4.8 kilobase lrp130 mRNA relative to other hepatoma cells. Although currently of unknown function, lrp130 may be of utility as a marker for liver cell lineages represented by the HepG2 cell line.
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PMID:Molecular cloning and expression of the gene for a major leucine-rich protein from human hepatoblastoma cells (HepG2). 801 52

The aminothiol cysteamine at 10(-5) to 10(-4) M concentrations inhibited both the proliferation of mitogenically stimulated human peripheral mononuclear cells and the phorbol myristate acetate-mediated oxidation of 2',7'-dichlorofluorescein within these cells. Both 2',7'-dichlorofluorescein oxidation and the proliferative response were maximally sensitive to cysteamine-induced inhibition during the first 2 h of mitogenic stimulation. This period of sensitivity indicates that cysteamine preferentially arrests cells transiting from G0 to G1 and is the first such demonstration, of an early cell cycle site of arrest for this compound. 2,3-Dimercapto-1-propane-sulfonic acid and WR 1065 were found to be more effective than cysteamine in attenuating T cell replication but not N-acetylcysteine. Aminothiols preferentially inhibited the intracellular oxidation of 2',7'-dichlorofluorescein, rather than the activity of protein kinase C, which initiates the oxidation, indicating that oxidative events are one of a number of crucial and independent events required for the successful transition through G0-G1. Since aminothiols affect both lectin and PMA/ionomycin-directed proliferation, these aminothiol-sensitive events may serve to integrate and regulate common pathways in T cell activation.
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PMID:Thiol-bearing compounds selectively inhibit protein kinase C-dependent oxidative events and proliferation in human T cells. 806 Oct 47


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