Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclosporin A-sensitive promoter activity that is induced by the T cell antigen receptor was identified in the region between base pairs -147 and -17 of the mouse interleukin (IL)-4 gene. Here, we identify a transcriptional factor, NF(P), that binds a sequence from -75 to -69 (ATTTTCC) of the mouse IL-4 gene which corresponds to the human IL-4 gene P sequence. Expression of NF(P) was associated with positive regulation of the IL-4 gene and cyclosporin A sensitivity. The P sequence is homologous to the binding site for the positive transcriptional regulator of the IL-2 gene nuclear factor of activated T cells (NFAT). Binding of NF(P) to the P sequence was completely inhibited by an oligonucleotide corresponding to the NFAT binding site. Like NFAT, NF(P) was also found in the cytosol of resting T cells but translocated to the nucleus via a cyclosporin A-sensitive mechanism after T cell activation. Overexpression of a constitutively active calcineurin caused translocation of NF(P) from the cytosol to the nucleus. NF(P) purified on an oligonucleotide affinity column was 90 kDa, which is smaller than the 120-kDa reported for cNFAT. Purified NF(P) did not bind the NFAT consensus sequence, even in the presence of AP-1 protein. Our results suggest that the NF(P) molecule is not identical to the cNFAT molecule.
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PMID:Activation of the interleukin-4 gene is controlled by the unique calcineurin-dependent transcriptional factor NF(P). 803 12

We have studied the TCR mediated signal transduction pathways involved in transcriptional regulation of the mouse IL-4 gene. The sequences extending from base pair -766 to +63 of the IL-4 gene were inserted upstream of a luciferase indicator gene. Transcriptional activity was observed when the construct, [pIL-4(-766)], was transfected into either the IL-4 producing cell line, EL-4, or the IL-4 non-producing T cell hybridoma, 68-41, but not in the L929 fibroblast cell line. By analysis of deletion mutants of pIL-4(-766), we identified a transcriptional regulatory element that is tightly associated with a signal coming from the TCR and which controls inducible activation of the IL-4 promoter. By analysis of deletion mutants of pIL-4(-766), this latter element was found between base pairs -147 to -17. Electrophoretic mobility shift assays indicated that expression of a nuclear binding protein with binding sites between base pairs -84 and -55 could be induced. By competition and mutation analysis, the binding motif of this protein was determined to be AAAATTTTCC. Stimulation with ionomycin alone was sufficient to induce activity in pIL-4(-766). Cyclosporin A inhibited both the IL-4 promoter activity and activation of the inducible nuclear protein. Transient over-expression of a constitutively active form of the Ca2+/calmodulin-regulated protein phosphatase, calcineurin was sufficient to cause activation of pIL-4(-766) without any additional stimulus. These results indicate that the signaling requirements for activation of upstream positive regulatory elements of the IL-4 gene are distinct from those of the IL-2 gene. Ca2+ mobilization is sufficient to activate the IL-4 promoter, whereas IL-2 gene transcription requires both Ca2+ mobilization and protein kinase C activation.
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PMID:The Ca2+/calmodulin-activated, phosphoprotein phosphatase calcineurin is sufficient for positive transcriptional regulation of the mouse IL-4 gene. 815 95

Autocrine stimulation of the IL-2 receptor (IL-2R) is required for commitment of a T cell to enter the cell cycle and may involve transmission of the IL-2R signal to cell cycle control proteins. Candidates for such proteins are the D-type cyclins which are expressed in G1. Short-term cultures of primary human T cells were used to show that expression of cyclins D2 and D3 is regulated by IL-2 in a concentration- and time-dependent manner. Cyclin D2 RNA was induced rapidly to peak levels well before initiation of DNA synthesis and gradually declined during the remainder of G1. Cyclin D3 RNA and protein showed a slower induction during G1 to maximal levels as cells initiated DNA synthesis that remained high throughout S phase. Induction of cyclins D2 and D3 was independent of the cyclosporin A-sensitive calcineurin pathway and of rapamycin-sensitive pathways, despite the ability of rapamycin to severely inhibit entry into S phase. These observations suggest that cyclins D2 and D3 may monitor the IL-2R signal but that their induction does not guarantee entry into S phase. Rapamycin was found to target a pathway late in G1 that is distal to induction of D-type cyclin gene expression but proximal to DNA replication, perhaps involving the function of the D-type cyclin proteins or their associated kinases.
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PMID:IL-2-dependent induction of G1 cyclins in primary T cells is not blocked by rapamycin or cyclosporin A. 826 27

Previous studies have suggested that gangliosides have an important role in cell signaling and recognition. However, their specific function in these processes has not been clearly defined. A mAb, R24, that reacts specifically with a cell surface ganglioside (GD3) has been demonstrated to stimulate proliferation of T cells derived from human peripheral blood. In this study, we have investigated the mechanisms by which the R24 mAb affects T cell functions. We have observed that the R24 mAb stimulates GD3+ T cell proliferation, cytotoxicity, and surface marker expression of IL-2R alpha-chain, IL-2R beta-chain, HLA-DR, CD11a, and CD11c. Additionally, IFN-gamma activity but not IL-1, IL-2, or IL-4 activity was present in culture supernatants 72 h after R24 stimulation. In some donors, increased IL-6 and TNF-alpha activity also was detected after R24 treatment. Furthermore, R24 treatment resulted in translocation of c-rel, but little or no NF kappa B p50 or p65, from the cytoplasm to the nucleus and an increase of NF kappa B binding complexes containing c-rel and p50. This treatment also caused increased tyrosine phosphorylation of specific protein substrates. R24-stimulated increases in proliferation, cytotoxicity, and cell surface protein expression could be blocked by cyclosporin and staurosporin, indicating that cyclophilin/calcineurin and protein kinase C may be involved in the R24 signaling pathway. Additionally, herbimycin A, a tyrosine kinase inhibitor, blocked the R24-stimulated increase in proliferation but not cytotoxicity at concentrations consistent with specificity for tyrosine kinases. These results suggest that multiple biochemical pathways are involved in the activation of human T cells by R24.
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PMID:Increased proliferation, cytotoxicity, and gene expression after stimulation of human peripheral blood T lymphocytes through a surface ganglioside (GD3) 828 32

In the IL-2-dependent murine cytotoxic T cell line CTLL-2, IL-2 induced a rapid and transient decrease in Co(2+)-trypsin-treated activity of protein phosphatase PP1. The PP1 activity declined to a minimum level, being 70% of control value, in 20 min after the addition of IL-2 but recovered to the control level within 45 min. The decrease of PP1 activity was dependent on IL-2 concentration and occurred specifically in cytosolic fraction. Similar alteration was observed in IL-2 sensitive murine T-lymphoblasts. Neither activity of protein phosphatase PP2A nor PP2C showed alteration during the IL-2 stimulation. These results suggest that PP1 plays an important role in early events of the intracellular growth signaling from the IL-2 receptor.
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PMID:IL-2 induces transient and specific decrease in cytosolic protein phosphatase PP1 activity in murine T cell lines. 839 34

Binding of human recombinant interleukin-1 beta (IL-1 beta) to the cell surface receptors of EL-4 6.1 murine T-cells results in enhanced phosphorylation of several cellular proteins. Staurosporine abolished the enhanced phosphorylation in response to IL-1 for some of these proteins, suggesting that protein kinase C (PKC) was at least partially responsible. PKC-beta was translocated from the cytosol to the plasma membrane between 2 and 15 min after IL-1 binding. Activation of PKC-beta was enhanced by the protein phosphatase inhibitor okadaic acid. In fact, okadaic acid inhibited dephosphorylation of the PKC-specific peptide GS (Pro-Leu-Ser-Arg-Thr-Leu-Ser-Val-Ala-Ala-Lys-Lys). On the other hand, okadaic acid also led to elevation of IL-1-induced trans/autophosphorylation of PKC-beta. Accordingly, IL-1 induction of interleukin-2 synthesis was markedly enhanced by okadaic acid in EL-4 cells. These data suggest that activation of PKC-beta contributes to enhanced phosphorylation of cellular proteins in IL-1-treated cells and support the importance of protein phosphorylation and dephosphorylation in the regulation of IL-1-induced IL-2 synthesis in EL-4 6.1 T-cells.
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PMID:Interleukin-1-induced signaling in T-cells. Evidence for the involvement of phosphatases PP1 and PP2A in regulating protein kinase C-mediated protein phosphorylation and interleukin-2 synthesis. 840 43

T2, an extract of Tripterygium wilfordii Hook F, has been reported to be effective in the treatment of a variety of autoimmune diseases, including rheumatoid arthritis. Previous studies have shown that T2 inhibited mitogen- or antigen-induced proliferation of human peripheral blood T cells and B cells, IL-2 production by T cells and Ig production by B cells. In contrast, T2 did not affect monocyte functions, such as IL-1 production and antigen presentation. The current studies sought to localize the immunosuppressive action of T2 more precisely. Results show that T2 prevented [3H]-uridine uptake by mitogen-stimulated T cells and arrested them in the early GI phase of the cell cycle. The inhibitory effects of T2 could be partially overcome by costimulating PHA activated T cells with PMA and completely nullified by costimulation with PMA plus a monoclonal antibody to CD28. Moreover, T2 had no effect on expression of IL-2R or the transferrin receptor (CD71), but inhibited production of a number of cytokines, including IL-2 and IFN-gamma by activated T cells. T2 suppressed IL-2 mRNA levels, but not IL-2R mRNA levels, in activated T cells. T2-mediated inhibition reflected suppression of IL-2 gene transcription as indicated by suppression of the expression of a reporter gene driven by the IL-2 promoter. T2 had little inhibitory effect on either IL-2 gene expression or cell cycle progression when added after initial mitogenic stimulation, indicating that an early step in the cascade of activation events was inhibited. However, initial activation events including protein tyrosine phosphorylation, the generation of diacylglycerol, IP3, and the translocation of protein kinase C were not inhibited by T2. Moreover, T2 did not inhibit the phosphatase activity of calcineurin. These results have localized the effect of T2 to a step in the T cell activation cascade after initial second messenger generation, tyrosine phosphorylation and protein kinase activation, but before IL-2 gene transcription.
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PMID:The Chinese herbal remedy, T2, inhibits mitogen-induced cytokine gene transcription by T cells, but not initial signal transduction. 855 49

We have studied the signal requirements for human IL-4 promoter activation in Jurkat T cells by the use of DNA transfection assays with vectors carrying the IL-4 promoter linked to a reporter gene. Stimulation with calcium (Ca2+) ionophores (ionomycin), but not with phorbol esters (phorbol myristate acetate, PMA) or cyclic AMP elevating agents (prostaglandin E2, PGE2), induced the transcriptional activity of the IL-4 promoter by approximately 3-fold. Costimulation with ionomycin and PGE2 resulted in the same level of IL-4 promoter activity as the stimulation with ionomycin alone. In contrast, costimulation with ionomycin and PMA decreased the activity of the IL-4 promoter by approximately 40% compared to stimulation with ionomycin alone. Induction of Il-4 promoter by ionomycin was partially inhibited (approximately 50% inhibition) in the presence of as high as 2 microgram/ml cyclosporin A (CsA), an inhibitor of the Ca+/calmodulin-dependent phosphatase calcineurin. Under the same conditions, only 0.1 microgram/ml of CsA inhibited by >95% the transactivation of the IL-2 promoter in response to ionomycin and PMA. Transfection of a deletion mutant of the calcineurin catalytic subunit (delta CaM-AI) known to have Ca2+-independent, constitutive phosphatase activity increased IL-4 promoter activity by approximately 14-fold. Stimulation with ionomycin of cells transfected with low doses of delta CaM-AI, further induced IL-4 promoter activity by approximately 2-fold. These results identify the Ca2+-signaling system as a key component of the signal transduction pathway leading to IL-4 promoter activation in Jurkat T cells and suggest a major role of calcineurin in its regulation.
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PMID:Signal requirements for interleukin 4 promoter activation in human T cells. 859 37

The transcription factor, Nuclear Factor of Activated T cells (NFAT) is a major target for p21ras and calcium signalling pathways in the IL-2 gene and is induced by p21ras signals acting in synergy with calcium/calcineurin signals. One p21ras effector pathway involves the MAP kinase ERK-2, and we have examined its role in NFAT regulation. Expression of dominant negative MAPKK-1 prevents NFAT induction. Constitutively active MAPKK-1 fully activates ERK-2 and the transcription factor Elk-1, but does not substitute for activated p21ras and synergize with calcium/calcineurin signals to induce NFAT. Expression of dominant negative N17Rac also prevents TCR and p21ras activation of NFAT, but without interfering with the ERK-2 pathway. The transcriptional activity of the NFAT binding site is mediated by a complex comprising a member of the NFAT group and AP-1 family proteins. The induction of AP-1 by p21ras also requires Rac-1 function. Activated Rac-1 could mimic activated p21ras to induce AP-1 but not to induce NFAT. Moreover, the combination of activated MAPKK-1 and Rac-1 could not substitute for activated p21ras and synergize with calcium signals to induce NFAT. Thus, p21ras regulation of NFAT in T cells requires the activity of multiple effector pathways including those regulated by MAPKK-1/ERK-2 and Rac-1.
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PMID:Multiple p21ras effector pathways regulate nuclear factor of activated T cells. 867 Aug 97

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


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