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)

Activation of immature thymocytes or transformed T lymphocytes via T-cell receptor (TCR)/CD3 signalling can induce programmed cell death (apoptosis). Recent data indicate that anti-CD3/TCR monoclonal antibodies (mAb) also trigger apoptosis in activated (but not resting) mature peripheral blood T lymphocytes. Here we report that triggering of resting CD4-CD8-TCR alpha beta+ and/or TCR gamma delta+ via the alternative CD2-dependent activation pathway is able to induce programmed cell death. A pair of mitogenic anti-CD2 mAb provoked a dramatic rise in [Ca2+]i that was almost entirely sustained by extracellular fluxes, and the inhibition of membrane [Ca2+/Mg2+] ATPase. The resulting endonuclease activation was able to induce DNA fragmentation, as revealed by propidium iodide staining and gel electrophoresis. Induction of apoptosis was prevented by the presence of interleukin-4 (IL-4) as well as by endonuclease inactivation with 100 microM ZnCl2, but enhanced by the contemporary block of protein kinase C. Thus it seems that in resting T lymphocytes the strong calcium signal delivered by the alternative CD2 activation pathway may act as a negative apoptotic signal in both alpha beta and gamma delta T cells with low (non-major histocompatibility complex restricted) antigenic affinity, so limiting the extension of polyclonal T-cell growth.
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PMID:IL-4 is able to reverse the CD2-mediated negative apoptotic signal to CD4-CD8- alpha beta and/or gamma delta T lymphocytes. 855 74

The murine retrovirus SL3-3 is a potent inducer of T-cell lymphomas when inoculated into susceptible newborn mice. The proviral integration site sequences were surveyed in tumor DNAs by a simple two-step PCR method. From 20 SL3-3-induced tumors a total of 39 provirus-host junctions were amplified and sequenced. Seven showed homology to known sequences. These included the known common integration site c-myc as well as genes not previously identified as targets of provirus integration, namely N-ras and the genes coding for major histocompatibility complex class 11 E-beta, protein kinase C-eta, and T-cell receptor beta-chain. Among these genes, the integrations in c-myc as well as the one in N-ras were found to be clonal. One of the remaining 32 proviral integration site sequences that show no similarities to known sequences may represent a common integration site, as 2 of the 20 tumors demonstrated clonal provirus insertion into this region.
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PMID:Sequence tags of provirus integration sites in DNAs of tumors induced by the murine retrovirus SL3-3. 864 44

Human CD4+ T cells, activated by allogeneic monocytes in a primary mixed lymphocyte reaction in the presence of exogenous interleukin (IL) 10, specifically failed to proliferate after restimulation with the same alloantigens. A comparable state of T cell unresponsiveness could be induced by activation of CD4+ T cells by cross-linked anti-CD3 monoclonal antibodies (mAbs) in the presence of exogenous IL-10. The anergic T cells failed to produce IL-2, IL-5, IL-10, interferon gamma, tumor necrosis factor alpha, and granulocyte/macrophage colony-stimulating factor. The IL-10-induced anergic state was long-lasting. T cell anergy could not be reversed after restimulation of the cells with anti-CD3 and anti-CD28 mAbs, although CD3 and CD28 expression was normal. In addition, restimulation of anergized T cells with anti-CD3 mAbs induced normal Ca2+ fluxes and resulted in increased CD3, CD28, and class II major histocompatibility complex expression, indicating that calcineurin-mediated signaling occurs in these anergic cells. However, the expression of the IL-2 receptor alpha chain was not upregulated, which may account for the failure of exogenous IL-2 to reverse the anergic state. Interestingly, anergic T cells and their nonanergic counterparts showed comparable levels of proliferation and cytokine production after activation with phorbol myristate acetate and Ca2+ ionophore, indicating that a direct activation of a protein kinase C-dependent pathway can overcome the tolerizing effect of IL-10. Taken together, these data demonstrate that IL-10 induces T cell anergy and therefore may play an important role in the induction and maintenance of antigen-specific T cell tolerance.
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PMID:Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells. 869 Nov 22

Treatment of mice with multiple topical applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) or diacylglycerol resulted in a preferential decrease in epidermal protein kinase C-beta 2 (PKC-beta 2) compared with PKC-alpha as determined by western analysis. When PKC-alpha was decreased by 40%, PKC-beta 2 could no longer be detected, suggesting that PKC-beta 2 is more sensitive to downregulation, and/or specific epidermal cell types that contain PKC-beta 2 are more sensitive to TPA/diacylglycerol. To address this issue, we isolated Langerhans cells (LCs) from epidermal cell suspensions with immunomagnetic beads and an antibody to the class II major histocompatibility complex. Northern blot analysis revealed a PKC-beta 2 signal in isolated LCs that was 40-fold greater than that observed in unfractionated epidermal cells, and no PKC-beta 2 signal was detected in epidermal cells depleted of LCs, indicating that PKC-beta 2 is expressed exclusively in LCs within the epidermis. Western blot analysis confirmed the presence of PKC-beta 2 in LCs. PKC-beta 2 was highly sensitive to downregulation, because a single application of TPA resulted in a 90% loss of PKC-beta 2 within 6 h without a decrease in the number of LCs. To determine whether the decreased level of PKC-beta 2 within LCs was associated with an alteration in contact hypersensitivity, we treated mice with only a single application of TPA, and 6 hours later mice were sensitized with 2,4-dinitrofluorobenzene on the same dorsal area. Subsequent challenge revealed a 60% decrease in contact hypersensitivity in TPA-treated mice. These data indicate that (i) within the epidermis, PKC-beta 2 is highly sensitive to downregulation and is exclusively expressed in LCs, and (ii) the downregulation of PKC-beta 2 is associated with impaired LC function with respect to contact hypersensitivity.
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PMID:Epidermal protein kinase C-beta 2 is highly sensitive to downregulation and is exclusively expressed in Langerhans cells: downregulation is associated with attenuated contact hypersensitivity. 875 70

Mature peripheral T cells closely regulate their intercellular interactions by modulating integrin adhesion functions. The ability of members of the integrin family to mediate intercellular adhesion is dependent on signals from within the cells (inside-out signaling) that increase the avidity of integrins for their ligands. These changes in avidity are independent of the quantitative changes on the number of receptors, and there is evidence to suggest that phosphorylation events play a predominant role in the regulation of the avidity state of the integrins. Whether such regulatory mechanisms are operative during T cell development had hitherto been an opened question. In the present work, we have used an in vitro adhesion assay between thymocytes and target cells expressing VLA-4 and LFA-1 counter ligands to determine how thymocytes can discriminate between integrin-specific signals during T cell development. Our findings are that VLA-4, but not LFA-1, is constitutively expressed in its high-avidity state during the early stages of T cell development, and that the high-avidity state of thymocytes for VCAM-1-expressing cells is closely regulated by signaling through protein kinase C and protein tyrosine kinase pathways. At later stages of development, mature thymocytes prior to leaving the thymus turn off both VLA-4 and LFA-1 adhesion functions. Our results show that the low-affinity state of integrins on peripheral mature T cells is established before mature thymocytes leave the thymus. Only when mature T cells recognize antigenic peptides in the context of major histocompatibility complex in the periphery will they turn on the adhesion function of VLA-4 and/or LFA-1 integrins.
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PMID:Modulation of integrin-mediated intercellular adhesion during the interaction of thymocytes with stromal cells expressing VLA-4 and LFA-1 ligands. 881 45

Less than 5% of immature CD4/CD8 double-positive (DP) thymocytes are positively selected to survive and differentiate into single-positive CD4 and CD8 T cells, while self-reactive DP thymocytes undergo apoptosis (negative selection). Both positive and negative selection events are active processes that involve signaling through the T cell receptors (TCRs) and through some accessory molecules. The two events differ quantitatively in the strength of the interaction between TCR and peptide/major histocompatibility complex molecules. We established an in vitro model of positive selection that can be analyzed quantitatively. Positive selection is likely to inhibit glucocorticoid-induced apoptosis in DP thymocytes. Proper crosslinking of TCR together with CD4, CD8, or LFA-1 inhibits the death, and its inhibitory activity is mimicked by proper combinations of ionomycin, a calcium ionophore, and phorbol myristate acetate (PMA), a protein kinase C (PKC) activator. The drug concentrations are within narrow ranges, and are lower than those which are required for the proliferation of mature T cells. Transient stimulation with the combinations of ionomycin and PMA induces differentiation and commitment of isolated DP thymocytes to the CD4 or CD8 T cell lineage in suspension cultures. The level of PKC activity appears to determine the lineage to commit. Functional mature T cells are induced from the committed cells upon secondary stimulation. Activation of calcineurin, a Ca2+/calmodulin-dependent protein phosphatase, also appears to be essential for positive selection as well as for the inhibition of glucocorticoid-induced apoptosis. Negative selection and the regulation of mature T cell apoptosis through TCR and steroid receptors are also discussed.
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PMID:Regulation of T cell apoptosis via T cell receptors and steroid receptors. 894 21

We noticed that B cell receptor ligation or phorbol 12-myristate 13-acetate treatment induced intracellular vesicles containing major histocompatibility complex (MHC) class II and invariant chain (Ii), and increased the amount of transmembrane p12 Ii fragments coimmunoprecipitated with class II molecules. To determine the influence of protein kinase C activation on the MHC class II presentation pathway, we analyzed the subcellular distribution of Ii, the induction of SDS-stable forms of class II molecules, and their ability to present different antigens. Ii chains visualized with luminal and cytoplasmic directed antibodies appeared in early endosomal compartments accessible to transferrin in response to phorbol 12-myristate 13-acetate treatment, whereas transmembrane Ii degradation products equivalent to the p12 Ii fragments were colocalized with the B cell receptors internalized after cross-linking. Protein kinase C activation delayed in parallel the formation of SDS-stable forms of class II molecules and reduced the presentation of antigenic determinants requiring newly synthesized class II alphabeta-Ii complexes. These data indicate that B cell activation affects Ii processing and MHC class II peptide loading in endosomal compartments intersecting the biosynthetic pathway.
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PMID:Selective modulation of the major histocompatibility complex class II antigen presentation pathway following B cell receptor ligation and protein kinase C activation. 901 17

Lymphocytes employ a complex assembly of signaling elements that have been organized on a spatiotemporal map to define their role in stimulating both proliferation and apoptosis. The antigen/major histocompatibility complex (MHC) initiates the sequence by organizing the assembly of an active T-cell receptor (TCR) complex responsible for transmitting information down various signaling cassettes (e.g., the IP3/Ca2+, DAG/PKC, ras/MAPK, and the PI 3-K pathways). It is proposed that CD28 may exert its costimulatory action by facilitating the assembly of an effective scaffold of signaling elements within the TCR complex. The absence of costimulation through CD28 seems to result in the assembly of a defective scaffold that reverses slowly and may thus account for the state of unresponsiveness responsible for peripheral T-cell tolerance. The signaling cassettes activated by the TCR and CD28 then engage cytosolic factors that transmit information into the nucleus to activate the genes that code for the IL-2 and Fas signaling pathways. The IL-2 and Fas receptors employ additional signaling cassettes (e.g., the JAK/STAT and the sphingomyelinase/ceramide pathways) to mediate their effects on proliferation and apoptosis, respectively. Information concerning these signaling systems is beginning to provide therapeutic strategies to manipulate the immune system to overcome human immunodeficiency virus (HIV) infection, autoimmune diseases, and graft rejection.
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PMID:Lymphocyte activation in health and disease. 909 51

The signal transduction events which govern major histocompatibility complex-unrestricted tumour cell destruction by nonspecific killer T lymphocytes induced with anti-CD3 antibody have not yet been determined. In this study we used pharmacologic inhibitors to investigate the role of protein tyrosine kinases (PTK) and protein kinase C (PKC) in this process. The PTK-inhibitors herbimycin A, genistein, and methyl 2,5-dihydroxycinnamate blocked anti-CD3-activated killer T (AK-T) lymphocyte-mediated killing of tumour target cells. The PKC-inhibitors staurosporine, calphostin C, and myristoylated PKC pseudosubstrate peptide, as well as PKC desensitization by phorbol 12-myristate 13-acetate pretreatment, also suppressed the cytolytic effector function of AK-T lymphocytes. Lack of tumoricidal activity was not due to reduced AK-T lymphocyte binding to tumour target cells but was associated with the abrogation of granule exocytosis, indicating that PTK and PKC are involved in the postbinding process which results in delivery of the 'lethal hit' by AK-T lymphocytes.
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PMID:Inhibition of protein tyrosine kinases or protein kinase C prevents nonspecific killer T lymphocyte-mediated tumoricidal activity. 919 76

We investigated the function of the evolutionary conserved X2 box in the promoter of the HLA-DRA gene from the human major histocompatibility complex (MHC) in resting and activated B cells. NF-X2, which contains members of the AP-1/ATF/CREB families of transcription factors, interacts with the X2 box (5'-TGCGTCA-3') from positions -97 to -91 in the DRA promoter. In resting Raji cells, little to no binding to the X2 box was observed. In sharp contrast, in B cells treated with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), strong interactions between the X2 box and NF-X2 containing c-Fos were observed. As determined by transient expression and RNA analyses, the activation of protein kinase C (PKC) also increased rates of transcription from the wild-type DRA promoter but not from a DRA promoter bearing clustered point mutations in the X2 box. Since the co-expression with a dominant negative c-Fos abolished the responsiveness to TPA, we conclude that activated transcription of the DRA gene depends on interactions between the X2 box and NF-X2, which contains c-Fos.
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PMID:Role of the X2 box in activated transcription from the DRA promoter in B cells. 921 34


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