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)

Crosslinking of B- or T-cell antigen receptors results in the rapid tyrosine phosphorylation of a number of proteins, including Vav, a protein expressed in cells of the haematopoietic system. Vav contains an array of structural motifs that include Src-homology domains SH2/SH3 and regions of homology to the guanine-nucleotide-exchange protein Dbl, pleckstrin and protein kinase C (refs 5-9). Using the RAG-complementation approach, we have analysed in vivo differentiation and in vitro responses of B- and T-lineage cells generated by injection of embryonic stem cells homozygous for a null mutation in the vav gene into blastocysts of RAG-1- or RAG-2-deficient mice. Here we report that antigen receptor-mediated proliferative responses of B and T cells in vitro are severely reduced in the absence of Vav. We also suggest a direct link between the low proliferative response of Vav-deficient B and T cells and the reduced number of these cells in peripheral lymphoid organs of chimaeric mice.
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PMID:Defective antigen receptor-mediated proliferation of B and T cells in the absence of Vav. 770 Mar 58

The pim-1 gene encodes a serine/threonine protein kinase with expression restricted primarily to cells of hematopoietic lineage and is thought to play a role in the signal transduction events associated with lymphocyte activation. A rapid increase in pim-1 mRNA levels was found after stimulation of normal unseparated PBMCs with phorbol ester (PMA) and a calcium ionophore (ionomycin) with the peak level occurring 4 hr poststimulation. Treatment of PBMCs with ionomycin alone caused only a minimal increase in pim-1 mRNA, whereas treatment with PMA alone induced a large increase in pim-1 mRNA, suggesting that the activation of a signaling pathway involving protein kinase C is responsible for the accumulation of this transcript. In enriched subpopulations of resting alpha/beta-T cells, gamma/delta-T cells, and B cells, pim-1 expression was found to be constitutively expressed, albeit at lower levels in T cells. This basal level of pim-1 expression could be increased by stimulation of alpha/beta-T cells (approx fivefold) and gamma/delta-T cells (approximately sevenfold) with PMA plus ionomycin. In contrast, pim-1 expression was not inducible in B cells. In PBMCs, half-life determination studies showed that turnover of pim-1 mRNA was markedly prolonged as a result of message stabilization induced by PMA plus ionomycin treatment. In addition, stable pim-1 transcripts were also observed in all transformed lymphoid cell lines examined. Taken together, these results suggest that the stability of pim-1 transcripts may be linked to the regulation of cell growth and represent the first direct demonstration that pim-1 expression is indeed regulated in a cell-type-specific manner.
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PMID:Expression of the pim-1 protooncogene: differential inducibility between alpha/beta- and gamma/delta-T cells and B cells. 770

7-Chloro-1,3-dihydroxyacridone (1) reversibly inhibited growth of KB and vero cell lines with IC50's of 35 and 40 microM, respectively, and a topoisomerase II-mediated multidrug resistant KB sub-clone was found to be about three-fold more susceptible to 1. In contrast, two cell lines of lymphoid origin were killed following treatments with 60 microM and at higher concentrations of 1. KB cell growth inhibition correlated with a rapid, reversible suppression of thymidine incorporation. Uridine but not leucine incorporation was also rapidly suppressed. The in vitro activities of DNA topoisomerase II and novel protein kinase C-subtype delta were inhibited at effective concentrations in tissue-culture, but 1 did not stimulate intracellular protein-associated DNA breaks nor interfere initially with topoisomerase II-mediated DNA cleavage in KB cells. In addition to antiproliferative effects against cells, the compound was weakly virustatic for herpes simplex virus type I with an IC50 of 8 microM. Limited studies comparing three 1-congeners and citpressine-I, an acridone alkaloid with reported antiherpes activity, demonstrated that 7-substituted 1,3-dihydroxyacridones are novel antiproliferative agents which share similar biological and biochemical properties.
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PMID:Antiproliferative actions of 7-substituted 1,3-dihydroxyacridones; possible involvement of DNA topoisomerase II and protein kinase C as biochemical targets. 778 3

Internalisation of CD4 is a well-known phenomenon. It occurs in the presence of phorbol myristate acetate (PMA), TPA or gangliosides and is usually completed within 30 min. Here, we describe an internalisation of CD4 molecules induced by low concentrations of high molecular weight dextran sulfate (M(r) 500 kDa) which differs from the classical mode in several ways. Internalisation is demonstrated by flow cytometry after simultaneous and consecutive staining of extracellular and internalised CD4 molecules and by visualisation by electron micrographs. A simple blockage of antibody binding sites on the CD4 molecule (epitope masking) by DS500, as widely believed, is definitely not responsible for the observed effects. DS500-mediated internalisation is a slow and energy-dependent process, where CD4 but not CD 2, 3, 8, 16, 56 and HLA-DR molecules are involved. The reaction reveals a characteristic time and concentration dependency. It does not require activation of protein kinase C (PKC) and cannot be inhibited by cytochalasin D. These results provide some more insight in the behavior of CD4 on lymphoid cell surfaces in response to high molecular weight polyanions such as dextran sulfate.
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PMID:Dextran sulphate induces a PKC and actin independent internalisation of CD4. 782 23

CONTENTS. T-cell activation--Structure of the T-cell antigen receptor--Modular organisation of the T-cell antigen receptor--T-cell antigen receptor-coupled signaling pathways: Activation of protein-tyrosine kinase by the T-cell antigen receptor; Signal transduction in lymphoid cells involves several protein-tyrosine kinases in parallel; Regulation of T-cell antigen receptor signaling by the phosphoprotein phosphatase CD45--Consequences of T-cell antigen receptor-induced tyrosine phosphorylation: Activation of phosphoinositol-lipid-turnover pathways--Activation of phospholipase C-gamma-1: p59fyn or p56lck?--G-protein motif of CD3-gamma: relevance for signal transduction--Association of lipid kinase with the T-cell antigen receptor--Intracellular signaling by phospholipid metabolites and calcium: activation of protein kinase C--Protein kinase C isoenzymes--Heterogenity of protein kinase C and mode of activation--Phospholipid-derived mediators in activation of protein kinase C in T-cells--Role of phospholipase D metabolites in activation of protein kinase C--Polyunsaturated fatty acids and lysophosphatidylcholine as activators of protein kinase C--Potein kinase C and p21ras function in interdependent and distinct signaling pathways during T-cell activation--Raf-1 kinase: regulator or target of protein kinase C?--Summary and perspectives.
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PMID:T-cell antigen receptor-induced signal-transduction pathways--activation and function of protein kinases C in T lymphocytes. 788 88

Expression of mRNA for protein kinase C (PKC)-alpha, -beta, -gamma, -delta, -epsilon, -zeta, and -eta has been shown, by polymerase chain reaction-generated isozyme-specific probes, to be cell-type -and differentiation-stage-specific in mouse hemopoietic cells. Recently, we cloned a 2.2-kb mouse PKC -zeta cDNA. In this study, we used the nearly full-length cDNA PKC-zeta probe to demonstrate that expression of PKC-zeta was significantly elevated in lymphocytic neoplasms at both the mRNA and protein levels. Normal brain, kidney, and liver contain 2.4- and 4.4-kb mRNAs, whereas normal lymphoid organs (spleen, thymus, and lymph nodes) express barely detectable amounts of PKC-zeta. These vanishingly small levels of PKC-zeta mRNA did not increase when polyclonal spleen B-cell proliferation and differentiation were induced in vivo with anti-immunoglobulin D antiserum or in vitro with lipopolysaccharide. In contrast, 2.4-kb transcripts of PKC-zeta are abundant in virtually all neoplastic B-lymphocytic cell lines. Furthermore, additional transcripts of a novel size, about 7 and 8 kb, were found in several mature B-cell lymphomas and plasma cell tumors. Western blot analysis of protein extracts from normal B cells and hemopoietic tumors confirmed that these quantitative differences in PKC-zeta mRNA also exist at the protein level. That is, only trace amounts of PKC-zeta protein were detectable in pro-B cells and pre-B cells, but abundant amounts of this isoform were found in protein extracts from most B-cell lymphomas and plasma cell tumors. These findings suggest that this atypical member of the PKC multigene family participate in the multistep process of malignant transformation of lymphocytes.
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PMID:Association of elevated levels of protein kinase C-zeta mRNA and protein with murine B-lymphocytic neoplasia. 794 1

Thioredoxin (Trx) catalyzes thiol-disulfide oxidoreductions. We and others recently showed that human Trx could function as an autocrine growth factor for human lymphoid cells immortalized by the human T-lymphotrophic virus type I or the Epstein-Barr virus. Here we report that reduced Trx from Escherichia coli generated by NADPH and thioredoxin reductase increases the proliferation of an Epstein-barr virus(+)-B cell line 1G8, which constitutively produces low amounts of human Trx. This proliferative effect involved the activation of protein kinase C through its translocation to the membrane. Staurosporin and calphostin C, two inhibitors of protein kinase C, but not of H8, a protein kinase A inhibitor, were able to block Trx-dependent proliferation. The addition of Trx to 1G8 cells resulted in the formation of inositol 1,4,5-triphosphate and sn-1,2-diacylglycerol by a phosphoinositide-specific phospholipase C, as well as increased free calcium concentration. Diacylglycerol showed a biphasic increase; the first phase, corresponding to an early peak (30 s) of inositol 1,4,5-triphosphate and a second larger, prolonged phase. The second phase was inhibited by propranolol, a specific inhibitor of phosphohydrolase, indicating that it is most likely derived from phosphatidylcholine hydrolysis by the sequential action of phospholipase D and phosphatidic acid phosphohydrolase. Our data suggest that enhanced phosphoinositide-specific phospholipase C activity induced by the dithiol form of Trx in 1G8 cells is associated to protein kinase C activation, and thus plays a role in the permanent growth of Epstein-Barr virus-infected B cells.
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PMID:Thioredoxin increases the proliferation of human B-cell lines through a protein kinase C-dependent mechanism. 796 46

Considerable circumstantial evidence indicates that glycosylphosphatidylinositol (GPI) molecules of mammalian origin are able to mediate signal transduction in lymphoid cells. For example, perturbation of GPI-anchored surface proteins, but not transmembrane forms of these molecules, can lead to the activation of T lymphocytes. GPIs appear also to be precursors of pharmacologically active phosphoinositol-glycans which mediate responses to hormones such as insulin, nerve growth factor and IL-2. Nonetheless, the biochemical mechanisms of signal transduction by GPIs remain obscure. We have shown that structurally defined GPIs of protozoal parasite origin are able to mediate signal transduction in host macrophages and lymphocytes, by substituting for the putative endogenous GPI-based signalling mechanisms of the host. Signalling by parasite GPIs appears to involve the activation of protein tyrosine kinase and protein kinase C. Evidence from other sources indicates that structurally variant GPIs may provide anergic signals to down-regulate host cell function. These phenomena may represent mechanisms by which eukaryotic parasites regulate host cell function, and can explain a variety of pathological and immunological features of protozoal infections. Furthermore, protozoal GPIs may prove to be an informative model system for the analysis of GPI-mediated signal transduction in lymphocytes and macrophages.
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PMID:Signal transduction in host cells mediated by glycosylphosphatidylinositols of the parasitic protozoa, or why do the parasitic protozoa have so many GPI molecules? 808 Dec 38

A mammalian expression vector directing the synthesis of a cytoplasmic single chain Fv version of the Y13-259 anti-Ras antibody was constructed and co-transfected into the human lymphoid cell line Jurkat together with a reporter construct containing the bacterial gene for chloramphenicol acetyl transferase under the transcriptional control of several copies of the binding site for the transcription factor NF-AT. The Ras specific antibody interferes with NF-AT activation upon direct activation of the T-cell antigen receptor, whereas activation by direct protein kinase C stimulation is less sensitive to the anti-Ras antibody. Furthermore, the observed inhibition is dependent on the ratio of antibody to reporter plasmid utilized in the transfection experiments.
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PMID:Intracellular single chain Fv antibody inhibits Ras activity in T-cell antigen receptor stimulated Jurkat cells. 808 1

Ankyrin is a well characterized membrane skeletal protein which has been implicated in the anchorage of specific integral membrane proteins to the spectrin-based membrane skeleton in a number of systems. In this study, the organization of ankyrin was examined in lymphocytes in relation to T cell function. Light and electron microscope immunolocalization studies revealed extensive heterogeneity in the subcellular distribution of ankyrin in murine tissue-derived lymphocytes. While ankyrin can be localized at the lymphocyte plasma membrane, it can also be accumulated at some distance from the cell periphery, in small patches or in a single discrete, nonmembrane-bound structure. Double immunofluorescence studies demonstrated that ankyrin colocalizes with spectrin and with the signal transducing molecule protein kinase C beta (PKC beta) in tissue-derived lymphocytes, suggesting a functional association between these molecules in the lymphocyte cytoplasm. In addition, T lymphocyte activation-related signals and phorbol ester treatment, both of which lead to PKC activation, cause a rapid translocation of ankyrin, together with spectrin and PKC beta, to a single Triton X-100-insoluble aggregate in the cytoplasm. This finding suggests a mechanism for the reported appearance of PKC in the particulate fraction of cells after activation: activated lymphocyte PKC beta may interact with insoluble cytoskeletal elements like ankyrin and spectrin. Further evidence for a link between the subcellular organization of these proteins and PKC activity is provided by the observation that inhibitors of PKC activity cause their concomitant redistribution to the cell periphery. The dynamic nature of lymphocyte ankyrin and its ability to accumulate at sites distant from the plasma membrane are properties which may be unique to the lymphocyte form of the molecule. Its colocalization with PKC beta in the lymphocyte cytoplasm, together with its redistribution in response to physiological signals, suggests that structural protein(s) may play a role in signal transduction pathways in this cell type. Our data support the conclusion that ankyrin is not solely involved in anchorage of proteins at the plasma membrane in lymphoid cells.
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PMID:Dynamic properties of ankyrin in T lymphocytes: colocalization with spectrin and protein kinase C beta. 816 51


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