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)

In order to understand the mechanisms underlying the T lymphocyte dysfunction associated to allogeneic bone marrow transplantation (BMT), we assessed two different protein kinase C (PKC) dependent events in T cells from BMT recipients: the PKC-dependent membrane expression and function of the CD69 early activation antigen; and the rapid phorbol ester-induced phosphorylation of PKC protein substrates in lysates from T cells permeabilized with digitonin, in the presence of (gamma-32P)ATP. Most BMT recipient T cells detectably expressed the CD69 surface antigen after 24 h of stimulation with either phorbol 12-myristate 13-acetate (PMA) or anti-CD3 MoAb and PMA, thus indicating that PKC activity is sufficient to induce de novo gene expression. Nevertheless, it is noteworthy that the fluorescent staining intensity with anti-CD69 MoAbs was significantly lower in BMT recipient T cells than in normal T lymphocytes, although no clear-cut correlation was found between the expression of CD69 and the proliferative capacity. However, the pattern of PMA-induced phosphoproteins analysed as early as 1 min after PKC activation in T cells from BMT recipients displaying a low response to mitogenic stimuli, was undistinguishable from that detected in T cells from healthy subjects. In all cases a major 110-kD phosphoprotein was observed, which was inducible with PMA, phorbol 12,13-dibutyrate (PDBu), 1-oleoyl-2-acetylglycerol (OAG) and a phorbol-ester-related activator of PKC (mezerein); moreover, its phosphorylation was blocked by pretreating cells with the PKC inhibitor H-7. Altogether our results suggest that the depressed mitogenic responses, which were also observed in the present study when T cells were stimulated via CD69, cannot be simply attributed to a defective PKC activity.
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PMID:Analysis of different protein kinase C-dependent events in T cells from allogeneic bone marrow transplantation recipients. 154 33

CD40 and CD43 are two cell-surface glycoproteins that appear to be functionally involved in the growth stimulation of human B cells. Whereas CD40 is structurally similar to the NGF receptor and is present on all resting B cells, CD43 displays no homology to other known proteins and is expressed only on a subpopulation of these cells. To further understand the extra- and intracellular signals regulating these molecules and in which stage of activation they may play a role, we used various activation strategies and studied their expression on tonsillar B cells. As expected, activation of protein kinase C by TPA increased both CD40 and CD43. In contrast, a rise in intracellular Ca2+, e.g. by ionomycin, did not influence the expression of these antigens. However, in the presence of TPA, ionomycin further up-regulated CD43 but not CD40. Anti-IgM behaved similarly to ionomycin suggesting that the effect of this reagent was due primarily to its ability to increase intracellular Ca2+. Of three interleukins (IL-2, IL-4 and IL-6) only IL-4 had a significant effect when used alone in that it up-regulated CD40 but not CD43. However, in the presence of anti-IgM, both IL-2 and IL-4 synergistically up-regulated the two antigens. Complementation of antigen receptor stimulation with TPA or IL-4 increased CD40 during the first 24 h, whereas up-regulation of CD43 did not occur until 24 to 48 h after stimulation. With regard both to up-regulation in response to different stimuli and to kinetics, CD40 expression paralleled that of the early activation antigen CD23, whereas CD43 was induced in parallel with the transferrin receptor (CD71). Taken together, our results suggests that the expression of CD40 and CD43 is regulated by different intracellular signals and that CD40 may be important during early activation, whereas CD43 may have its major function during later stages of B-cell differentiation. These assumptions are in line with the observations that CD40 antibodies can directly activate resting B cells and that CD43 are retained on plasma cells.
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PMID:Expression of CD40 and CD43 during activation of human B lymphocytes. 170 62

The ability of tumor necrosis factor (TNF)-alpha to activate T lymphocytes in combination with other stimuli has been studied. TNF was strongly co-mitogenic with low doses of anti-CD3 antibodies or phorbol esters (those which are strong activators of protein kinase C, PKC) but poorly with phytohemagglutinin or concanavalin A. No synergism was seen with the calcium ionophore A23187. TNF was co-mitogenic with several phorbol esters known to activate PKC but was uneffective with inactive phorbol esters such as methyl-phorbol 12-myristate 13-acetate. Furthermore, H-7 a known inhibitor of PKC, inhibited the proliferative response of T cells induced by esters plus TNF. This effect took place at low doses of TNF and was also observed with purified T lymphocytes indicating that the effect of TNF was not dependent on accessory cells. This proliferative effect of TNF was inhibited by an anti-interleukin 2 receptor (IL2R) antibody, MAR 108, which blocks IL2 binding to its receptor. Although PKC activation induced CD25 (IL2R) expression but very little IL2 synthesis, TNF did not synergize by augmenting the synthesis of this lymphokine in peripheral blood lymphocytes stimulated with phorbol esters. By contrast, TNF strongly increased the membrane level of CD25 and to a lesser extent that of the activation antigen, 4F2, over the levels already induced by phorbol esters on T cells. More interestingly, TNF significantly increased the number of high-affinity IL2R on purified T cells in the presence of phorbol 12,13-dibutyrate. Our results indicate that TNF is co-mitogenic with those stimuli which strongly activate PKC and suggest that TNF may play a role on T cell activation increasing the number of effective IL2/IL2R interactions when these are limiting.
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PMID:Synergy of tumor necrosis factor with protein kinase C activators on T cell activation. 231 52

We previously reported that the coculture of cloned, allospecific human T helper (Th) cells with allogenic B cells bearing the relevant major histocompatibility complex class II antigen induces expression of the B cell activation antigen CD23 (BLAST-2) on a fraction of the B cells. To determine if Th cell-induced CD23 expression defines a distinct subset of human B cells, allospecific Th cells were cultured with B cell fractions isolated on discontinuous Percoll gradients. Our results show that the majority of high density resting B cells, those bearing surface IgD and little of the 4F2 activation antigen, express high intensity CD23 after culture with relevant allospecific Th cells. Essentially all of the low density, presumably in vivo-activated, B cell subpopulation and a fraction of the high density B cell pool remain CD23 negative after repeated culture with relevant allospecific Th cells. We utilized the CD23 induction assay to investigate a potential synergistic effect in B cell activation mediated by Th cell signaling and antigen analog-induced cross-linking of B cell surface Ig receptors. These studies show that phorbols known to result in PKC activation, one of the biochemical consequences of sIg-mediated B cell signaling, enhance both the intensity of CD23 expression and the percentage of cells expressing CD23 after allospecific Th cell or IL-4 interaction with high density, but not low density B cells. Finally, we show that while Th-induced B cell activation, as measured by CD23 expression, is a property of high density B cells, induction of Th cell proliferation is a property of the low density B cell population. These results suggest that the antigen-specific interaction between Th cells and resting B cells may serve to activate the B cell in preference to the T cell.
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PMID:T helper cell-induced CD23 (BLAST-2) expression: an activation marker for the high density fraction of human B cells. 252 58

The expression of the CD9 pre-B acute lymphoblastic leukemia (ALL)-associated antigen was studied. CD9-positive B cells were enriched in the in vivo-activated buoyant B cell population isolated from tonsils. Small tonsil B cells activated in vitro with either PWM, phorbol 12-myristate 13-acetate (TPA), or anti-Ig plus low Mr B cell growth factor (BCGF) also demonstrated increased CD9 expression. The peak of CD9 expression (30-40% positive cells) occurred after 4-6 days of activation. The kinetics of increased CD9 expression was similar to that of the 4F2 activation antigen. CD9 antigen expression on tonsillar B cells as well as on pre-B leukemic cell lines was associated with protein kinase C activation. Two phorbols that activate protein kinase C (TPA; phorbol 12,13-dibutyrate) induced expression of the CD9 antigen whereas a phorbol analogue that does not activate C kinase (4-alpha-phorbol 12,13-didecanoate) and an analogue that is a very weak agonist (phorbol 12-myristate 13-acetate-4-0-methyl ether) were unable to induce CD9 expression on tonsil B cells or on the cell lines. The effect of the anti-CD9 monoclonal antibody, DU-ALL-1, on B cell mitogenesis was studied. Dense or buoyant tonsillar B cells were cultured in the presence or absence of DU-ALL-1 antibody plus PWM, anti-Ig, and BCGF, DU-ALL-1 antibody did not inhibit or augment the mitogenic response of resting or activated B cells. These results indicate that the CD9 pre-B ALL antigen is present on a population of normal activated tonsillar B cells and that its induction of expression is associated with protein kinase C activation.
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PMID:Expression of CD9 antigen on normal activated human B cells. 267 48

When platelets bind certain specific ligands they are induced to secrete the contents of their cytoplasmic granules and to aggregate. Studies of the molecular events accompanying this vital physiological response have led to a greater understanding of cell activation in general since the pathways involved are common to a number of cell types. By contrast most of the information about the cell surface molecules that initiate signal transduction has emerged from work on T lymphocyte activation, a process essential to the initiation of the immune response. We have described an activation antigen on T lymphocytes that is involved in the differentiation of these cells. In the present report it is demonstrated that the antigen is expressed on the platelet membrane with about 1,200 copies/platelet. A monoclonal antibody detecting this antigen stimulates platelet secretion and aggregation with a half-maximal response at approximately 10(-8) M. Characterization of the antigen, termed PTA1, reveals a glycoprotein of Mr 67,000 showing extensive N-linked carbohydrate, much of which appears to be heavily sialated. The amino-terminal sequence of PTA1, EEVLWHTSVPFAEXMSLEXVYPSM, indicates that the protein has not previously been characterized. Preliminary investigation of the mechanism by which PTA1 mediates platelet activation suggests involvement of protein kinase C and the 47-kDa protein of platelets is rapidly phosphorylated upon antibody-mediated activation. During this process PTA1 is also phosphorylated, as it is following platelet activation by the other agonists, collagen, thrombin, and 12-O-tetradecanoylphorbol 13-acetate. These results provide the first example of a cell surface glycoprotein that is directly involved in both platelet and T lymphocyte activation.
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PMID:Characterization of a novel membrane glycoprotein involved in platelet activation. 276 31

AIM is an activation inducer molecule selectively expressed by activated lymphocytes through which agonistic proliferative signals can be triggered. The relationship between the expression of AIM with the activation of protein kinase C (PKC) has been studied. Different activators of PKC such as the active phorbol esters, phorbol myristate acetate and phorbol dibutyrate, or the phorbol-related ester mezerein were able to induce AIM expression on peripheral blood lymphocytes as assessed by immunofluorescence flow cytometry. Moreover, the expression of this activation antigen was also induced by treatment of peripheral blood lymphocytes either with dioctanoyl-rac-glycerol, a synthetic analogue of diacylglycerol, the physiological mediator of PKC activation. Further indirect evidence that AIM expression was dependent on the activation of PKC was obtained by blockade of the induction of its expression in cells treated with H7, an inhibitor of PKC. The AIM expression can be detected as early as 3 h after addition of phorbol esters and it requires active RNA and protein synthesis. The activation of PKC appears to be also required in the proliferative response induced by anti-AIM monoclonal antibody (mAb) in conjunction with phorbol esters. Agents such as phorbol myristate acetate, phorbol dibutyrate or mezerein but not the inactive phorbol ester methyl-phorbol myristate acetate induced a high proliferation of peripheral blood lymphocytes in the presence of anti-AIM mAb. In addition, we have demonstrated that the anti-AIM mAb is not sufficient by itself to induce cellular proliferation once the AIM antigen is expressed at the cell surface, requiring the simultaneous stimulation of the PKC to trigger high proliferative responses. Furthermore, the anti-AIM mAb did not appear to exert its effect on proliferation by rapidly increasing the intracytoplasmic Ca2+ levels. Taken together all these results indicate that the expression and function of AIM antigen is dependent on the activation of PKC.
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PMID:Expression and function of AIM, an activation inducer molecule of human lymphocytes, is dependent on the activation of protein kinase C. 278 11

The tumor promotor 12-O-tetradecanoylphorbol-13-acetate (TPA) has diverse effects on lymphoid cell function. Two of the early effects were the induction of early activation antigen EA1 and the down-regulation of certain T cell differentiation antigens (CD3, CD4, CD7). The mechanisms of these TPA effects were investigated. It was confirmed that EA1 expression was dependent on protein kinase C (PKC) activation. Synthetic diacylglycerols were capable of inducing EA1 expression. In addition, inhibition of PKC by the kinase inhibitor, H7, led to the inhibition of EA1 expression induced by TPA and synthetic diacylglycerols. In contrast, down-regulation of T cell differentiation antigens by TPA was not dependent on PKC activation. Synthetic diacylglycerols did not induce down-regulation of T cell antigens and H7 had no effect on the down-regulation of T cell antigens induced by TPA. These data would suggest that TPA exerted its effects on T cell function by mechanisms in addition to the activation of PKC alone. One possible mechanism would be the activation of the calmodulin-dependent pathway(s) since its inhibition resulted in the reversal of TPA-induced down-regulation of the T cell differentiation antigens.
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PMID:Dissociation of TPA-induced down-regulation of T cell antigens from protein kinase C activation. 326 13

Tissue distribution and expression on mitogen and virally stimulated lymphocytes render the ACT35 molecule a human lymphocyte activation antigen which as yet could not be clustered. Expression cloning of the ACT35 antigen from a pCDM8 library of the HUT-102 cell line revealed strong homology of the cDNA and its encoded protein sequence with the formerly described rat OX40 antigen. The 1.4-kb nucleotide sequence and the deduced 277-amino acid sequence of the single transmembrane protein were 65% and 63% identical, in human and in rat, respectively. Conservation included one N-linked glycosylation site and one protein kinase C phosphorylation site. When expressed in COS-1 cells, the cDNA presented properties comparable to the native ACT35 antigen and the rat OX40 molecule (relative molecular mass 48,000). Thus, the ACT35 protein corresponds to the hitherto unknown human OX40 antigen and is, therefore, another member of the tumor necrosis factor/nerve growth factor receptor (TNFR/NGFR) family. After applying fluorescence in situ hybridization, the human ACT35/OX40 gene could be mapped to chromosome band 1p36 and is, thus, linked to the genes for TNFR II and CD30.
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PMID:The human OX40 homolog: cDNA structure, expression and chromosomal assignment of the ACT35 antigen. 751 Feb 40

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


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