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)

A few protein targets were found to display a specific high-affinity interaction with the immunosuppressant cyclosporin A (CsA): cytosolic cyclophilins (CyP)A, B, C, D, E containing from 122 to 174 amino acid residues in a polypeptide chain, and secreted forms of CyP; CyP-40, 40-kDa CsA-binding polypeptide complexed with steroid receptor (SR); CyP-related 150-kDa receptor of natural killer (NK) cells; interleukin 8 (IL-8); actin; a family of molecular chaperones hsp70 and P-glycoprotein (P-GP). All CyPs possess peptidyl-prolyl cis-trans isomerase activity (PPIase) and may serve as ATP-independent molecular chaperone proteins. The CsA-CyP complexes are specific inhibitors of Ca(2+)-and calmodulin-dependent protein phosphatase calcineurin (CaN). The inhibition of CaN blocks the activation of genes of IL-2, IL-2R, IL-4, etc. in T cells. In addition, immunosuppressive and/or antiinflammatory activity of CsA can be executed via CyP-40 and hsp 70 complexed with SR, and following the interaction with CyP-related receptor of NK and with IL-8. CsA binding to CyPC, P-GP and actin may throw light on the biochemical events leading to nephrotoxicity and graft vessel disease, two major side effects produced by CsA. The discovery of the interaction of human immunodeficiency virus type 1 (HIV-1) Gag protein with CyP and effective disruption of this interaction by CsA may be important for our understanding of the pathology caused by this immunosuppressive virus and will inspire therapeutic strategies to nip HIV in the bud. Bacterial immunophilins (ImPs) contribute to the virulence of pathogenic microorganisms. Elucidation of molecular mechanisms of microbial ImPs' action in the pathogenesis of bacterial infections may lead to new strategies for designing antibacterial drugs.
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PMID:Some new aspects of molecular mechanisms of cyclosporin A effect on immune response. 754 42

Adult T cell leukemia-derived factor (ADF), which is identical to a disulfide reducing enzyme human thioredoxin (TRX), is produced and released by activated or virus-infected lymphocytes. Here we report that, in peripheral blood mononuclear cells (PBMC) stimulated with phytohemagglutinin (PHA), ADF/TRX mRNA was induced within 8 h after stimulation as detected by in situ hybridization study. To analyze the mechanism of ADF/TRX induction during T cell activation, the effects of immunosuppressants including FK506, rapamycin (Rap) and cyclosporin A (CsA) on ADF/TRX expression were investigated by immunoblot analysis. ADF/TRX induction in PBMC by PHA, Con A or OKT3 mAb was almost completely suppressed by FK506. Whereas CsA also inhibited ADF/TRX expression in OKT3 mAb-stimulated PBMC, Rap failed to affect it in spite of exhibiting growth inhibition. In addition, exogenous IL-2 could not increase ADF/TRX production in FK506-treated PBMC or in PHA blasts. These results indicate that ADF/TRX induction in T cell activation depends on calcineurin-dependent events in the early phase and that IL-2 production is not directly involved in ADF/TRX induction. Furthermore, when recombinant ADF (rADF) was added to a culture of PBMC 1 h before the addition of PHA and FK506, the action of FK506 was partially reversed as determined by [3H]thymidine incorporation and viable cell counts. These results suggest that ADF/TRX produced and released from PBMC may be a crucial event in lymphocyte activation, and that FK506 and CsA may exert the immune suppression partly through inhibiting the induction of the endogenous reducing factor ADF/TRX.
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PMID:Suppression of adult T cell leukemia-derived factor/human thioredoxin induction by FK506 and cyclosporin A: a new mechanism of immune modulation via redox control. 757 7

Calcineurin, a Ca2+/calmodulin-dependent phosphatase, has recently been identified as a common target for cyclophilin A-cyclosporin A and FK506 binding protein 12-FK506 complexes. This study has examined the structure activity relationships of cyclosporin A (CsA) and three functionally distinct analogues, [MeBm2t]1-CsA, D-diaminobutyryl-8-CsA (Dab8-CsA), and D-diaminopropyl-8-CsA (Dap8-CsA). Immunosuppressive potency in T cell activation models, NF kappa B activation, and IL-2 mRNA transcription has been compared with analogue affinity for cyclophilin A and inhibition of calcineurin phosphatase activity. CsA, Dap8-CsA, and Dab8-CsA bind to cyclophilin A with a similar affinity (Ki 4 to 5 nM as measured by inhibition of prolyl cis-trans isomerase activity), however, Dap8-CsA and Dab8-CsA inhibit T cell activation less than CsA. Although [MeBm2t]-CsA has weak affinity for cyclophilin A (Ki 540 nM), its immunosuppressive potency is similar to that of CsA. Both cyclophilin A-CsA and cyclophilin A-[MeBm2t]1-CsA complexes inhibit calcineurin phosphatase activity in vitro (Ki 114 and 67 nM, respectively). In Jurkat cells exposed to CsA or the analogues for 2 h, endogenous calcineurin phosphatase activity in cell lysates was inhibited by CsA and [MeBm2t]1-CsA (drug concentrations causing 50% reduction in 32PO4 release of 8 and 55 nM, respectively) in proportion to inhibition of T cell activation, IL-2 mRNA transcription, and NF kappa B activation. Dap8-CsA and Dab8-CsA had a minimal effect on endogenous calcineurin phosphatase activity in Jurkat cell lysates. These findings correlate the functional activity of CsA and structural analogues with calcineurin phosphatase activity and support calcineurin as a target for drug action. The Dap8 and Dab8 modifications of CsA, occurring in residue 8, which is exposed to solvent in the cyclophilin A-CsA complex, appears to significantly alter complex affinity for calcineurin.
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PMID:Immunosuppressive activity of [MeBm2t]1-, D-diaminobutyryl-8-, and D-diaminopropyl-8-cyclosporin analogues correlates with inhibition of calcineurin phosphatase activity. 768 Jun 83

The immunosuppressants cyclosporin and FK506 block the calcium-dependent signal-transduction pathway emanating from the T-cell receptor, thereby inhibiting the activation of helper T cells. Using these drugs as probes, chemists and biologists have uncovered several intracellular signaling molecules bridging the generation of second-messenger Ca2+ ion and the transcriptional activation of IL-2, among which are calmodulin, calcineurin and the nuclear factor of activated T cells (NF-AT). Hence, Ca2+ binds to calmodulin, leading to the binding of calmodulin to calcineurin; the activated calcineurin, in turn, may dephosphorylate the cytoplasmic subunit of NF-AT, resulting in its translocation from the cytoplasm into the nucleus to form a competent transcriptional activator. As described by Jun Liu these drugs manifest their effects in an unprecedented fashion. They do not directly intercept intracellular signaling molecules. Instead, they form tight complexes with two different classes of abundant cytosolic receptors called immunophilins upon entering the cell, and consequently inhibit their peptidyl prolyl cis-trans isomerase activities. The two structurally distinct immunophilin-drug complexes bind to, and inhibit, the phosphatase activity of calcineurin.
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PMID:FK506 and cyclosporin, molecular probes for studying intracellular signal transduction. 769 Oct 65

The immunosuppressants ciclosporin and FK506 block the Ca(2+)-dependent signal-transduction pathway emanating from the T-cell receptor, thereby inhibiting the activation of helper T cells. Using these drugs as probes, chemists and biologists have uncovered several intracellular signalling molecules bridging the generation of second-messenger Ca2+ ions and the transcriptional activation of IL-2, among which are calmodulin, calcineurin and the nuclear factor of activated T cells (NF-AT). Hence, Ca2+ binds to calmodulin, leading to the binding of calmodulin to calcineurin; the activated calcineurin, in turn, may dephosphorylate the cytoplasmic subunit of NF-AT, resulting in its translocation from the cytoplasm into the nucleus to form a competent transcriptional activator. As described by Jun Liu, these drugs manifest their effects in an unprecedented fashion. They do not directly intercept intracellular signalling molecules. Instead, they form tight complexes with two different classes of abundant cytosolic receptors called immunophilins upon entering the cell, and consequently inhibit their peptidyl prolyl cis-trans isomerase activities. The two structurally distinct immunophilin-drug complexes bind to, and inhibit, the phosphatase activity of calcineurin.
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PMID:FK506 and ciclosporin: molecular probes for studying intracellular signal transduction. 769 52

We have previously shown that prostaglandin E2 and other cAMP elevating agents inhibit the nuclear transcription of the human IL-2 gene by interfering with a Ca(2+)-sensitive T cell signal transduction pathway. Calcineurin, a Ca2+/calmodulin-dependent 2B protein phosphatase, is an essential component of the T cell receptor signal transduction pathway leading to IL-2 gene expression. We have therefore tested the hypothesis that this phosphatase may be a target for the inhibitory effects of cAMP on IL-2 gene transcription. We report here that PGE2 markedly reduces the IL-2 promoter activity that is induced by a constitutively active form of calcineurin. In contrast to the complete inhibition of promoter activity produced by the immunosuppressants cyclosporin A and FK-506, this partial block suggests that PGE2 modulates downstream events needed for lymphokine gene activation. Overexpression of calcineurin in Jurkat cells decreases their apparent sensitivity to the inhibitory effects of PGE2 consistent with the fact that this enzyme plays a physiological role in dephosphorylating substrates of cAMP-dependent kinases in several tissues. These results provide evidence that cAMP-dependent pathways may antagonize calcineurin-regulated cascades for T cell activation in vivo, and suggest crosstalk between the Ca2+ and the cAMP signaling pathways during T cell activation.
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PMID:Prostaglandin E2 and other cyclic AMP elevating agents inhibit interleukin 2 gene transcription by counteracting calcineurin-dependent pathways. 769 57

Glucocorticoids (GC) inhibit IL-2 gene transcription by interfering with the binding of the nuclear factor activator protein-1 on the IL-2 promoter. Calcineurin, a Ca2+/calmodulin-dependent protein phosphatase, is an essential component of the T cell antigen receptor signal transduction pathway leading to IL-2 gene transcription. Therefore, we have asked whether this phosphatase may also be regulated by GC. Jurkat T cells were cotransfected with plasmids containing the intact IL-2 promoter or its NF-AT and Oct-1 motifs, and a deletion mutant (delta CaM-AI) of calcineurin known to have Ca(2+)-independent constitutive phosphatase activity. Cotransfection of IL-2 promoter with delta CaM-AI allowed the activation of IL-2 promoter in the presence of phorbol ester alone. Under these conditions dexamethasone (Dex; 10(-6) M) inhibited IL-2 promoter activation by 50-60%. The inhibitory effect of Dex was specific, as demonstrated by experiments using an unrelated promoter (simian virus 40) and estradiol. Furthermore, it was completely reversed in the presence of excess amounts of the glucocorticoid antagonist RU 486, which suggests that it is mediated through the glucocorticoid receptor. Overexpression of calcineurin via delta CaM-AI in Jurkat cells decreased their apparent sensitivity to Dex (approximately 5-fold increase in IC50). Similar results were obtained with the NF-AT and Oct-1 constructs, which are also known to be activated by calcineurin. Thus, in addition to their known inhibitory effects on activator protein-1, GC also inhibit calcineurin-dependent pathways for T cell activation.
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PMID:Glucocorticoids regulate calcineurin-dependent trans-activating pathways for interleukin-2 gene transcription in human T lymphocytes. 776 70

Engagement of the T cell receptor for antigen activates phospholipase C resulting in an increase in intracellular free calcium concentration ([Ca2+]i) and activation of protein kinase C (PKC). Increased [Ca2+]i activates Ca2+/calmodulin-dependent kinases including the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaM-K II), as well as calcineurin, a type 2B protein phosphatase. Recent studies have identified calcineurin as a key enzyme for interleukin (IL)-2 and IL-4 promoter activation. However, the role of CaM-K II remains unknown. We have used mutants of these kinases and phosphatases (gamma B*CaM-K and delta CaM-AI, respectively) to explore their relative role in cytokine gene transcription and their interactions with PKC-dependent signaling systems. gamma B*CaM-K and delta CaM-AI, known to exhibit constitutive Ca(2+)-independent activity, were cotransfected (alone or in combination) in Jurkat T cells with a plasmid containing the intact IL-2 promoter driving the expression of the chloramphenicol acetyltransferase reporter gene. Cotransfection of gamma B*CaM-K with the IL-2 promoter construct downregulated its transcription in response to stimulation with ionomycin and phorbol myristate acetate (PMA). The inhibitory effect of CaM-K II on IL-2 promoter was associated with decreased transcription of its AP-1 and NF-AT transactivating pathways. Under the same conditions, delta CaM-AI superinduced IL-2 promoter activity (approximately twofold increase). When both mutants were used in combination, gamma B*CaM-K inhibited the induction of the IL-2 promoter by delta CaM-AI. Similar results were obtained when a construct containing the IL-4 promoter also was used. gamma B*CaM-K also downregulated the activation of AP-1 in response to transfection with a constitutively active mutant of PKC or stimulation with PMA. These results suggest that CaM-K II may exert negative influences on cytokine gene transcription in human T cells, and provide preliminary evidence for negative cross-talk with the calcineurin- and PKC-dependent signaling systems.
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PMID:Calcium/calmodulin-dependent protein kinase II downregulates both calcineurin and protein kinase C-mediated pathways for cytokine gene transcription in human T cells. 786 38

Interleukin-1 (IL-1) has potent immunoregulatory and inflammatory functions. Its activity is mediated by an 80-kDa receptor on the cell surface and leads to activation of other genes. The underlying molecular events are largely unknown. We investigated the role of phosphatases in activation of the IL-2 gene in EL4 thymoma cells. We found that the protein phosphatase PP1 and PP2A inhibitor okadaic acid (OA) alone was able to significantly stimulate IL-2 production by the IL-1-responsive EL4 subline EL4 5D3 and also by the IL-1-nonresponsive EL4 subline EL4D6/76. In the IL-1-responsive cell line OA strongly synergized with phorbol myristate acetate (PMA) and IL-1. In the IL-1-nonresponsive cell line OA synergized with PMA but not with IL-1. Under suboptimal conditions of PMA/OA synergy an additional synergistic effect of IL-1 was shown. This was true for IL-2 and IL-6 production. Sphingomyelinase or sphingosine had no detectable effect. The kinetics of OA- and PMA-induced expression of IL-2 mRNA and IL-2 protein was different. PMA induced maximal expression between 6 and 12 h and was almost undetectable at 24 h. OA-induced expression was first obvious at 12 h and continued longer than 36 h. In both cases IL-1 caused no shift in kinetics, but potentiated the effects of the different tumor promoters. Utilizing IL-2 promoter-CAT constructs we showed in transfection experiments that the synergistic effect was also evident on the transcriptional level. We conclude from the data that phosphatases play an important role for IL-2 expression and that IL-1 can use additional pathways of activation that are different from events induced by PMA or OA.
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PMID:Activation of the mouse IL-2 gene by okadaic acid: synergy with interleukin-1. 794 25

The promoters of IL-2 and IL-4 genes contain multiple binding sites for octamer factors. In peripheral T lymphocytes and several T cell lines, both the ubiquitous Oct factor Oct-1 and the lymphocyte-specific factor Oct-2 are expressed and bind to the IL-2 and IL-4 promoters. Prominent octamer binding sites of IL-2 and IL-4 promoters are their upstream promoter sites (UPS) which share 14 identical nucleotides. Multiple copies of the IL-2 and IL-4 UPS act as inducible enhancers in T cells, and their induction is inhibited by the immunosuppressant cyclosporin A (CsA). Closely linked to the octamer site, the IL-2 UPS contains a non-canonical AP-1 binding (TRE) site, and mutation in either site to a non-functional factor binding site impairs the induction of the IL-2 promoter. The binding of AP-1 and octamer factors to the IL-2 UPS DNA overlaps, and the tight association and functional cooperation of octamer with AP-1 factors is of crucial importance for the inducible IL-2 UPS activity. Introduction of five or ten spacer nucleotides between both IL-2 UPS sites results in a drastic reduction of inducible UPS activity, both in the loss of suppression by CsA and stimulation by the Ca(2+)-dependent phosphatase calcineurin. Within the IL-4 UPS the Oct and TRE-like motifs are separated by a binding site of nuclear factor of activated T cells (NF-AT). This site shares nine out of ten bp with an IL-2 NF-AT site. The strong binding of NF-ATp to the IL-4 UPS site suppresses the simultaneous binding of Oct factors to the IL-4 UPS. Because the two other Oct binding sites of IL-4 promoter show a similar sequence configuration, the binding of NF-AT seems to prevent the simultaneous binding of Oct factors to the IL-4 promoter. By contrast, both classes of factors bind simultaneously to the IL-2 promoter, and their tight association with AP-1 enhances the IL-2 promoter activity.
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PMID:Octamer factors exert a dual effect on the IL-2 and IL-4 promoters. 798 59


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