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)

The immunosuppressant drugs cyclosporin A and FK506 bind to small, predominantly soluble proteins cyclophilin and FK506 binding protein, respectively, to mediate their pharmacological actions. The immunosuppressant actions of these drugs occur through binding of cyclophilin-cyclosporin A and FK506 binding protein-FK506 complexes to the calcium-calmodulin-dependent protein phosphatase, calcineurin, inhibiting phosphatase activity. Utilizing immunohistochemistry, in situ hybridization and autoradiography, we have localized protein and messenger RNA for FK506 binding protein, cyclophilin and calcineurin. All three proteins and/or messages exhibit a heterogenous distribution through the brain and spinal cord, with the majority of the localizations being neuronal. We observe a striking co-localization of FK506 binding protein and calcineurin in most brain regions and a close similarity between calcineurin and cyclophilin. FK506 binding protein and cyclophilin localizations largely correspond to those of calcineurin, although cyclophilin is enriched in some brain areas that lack calcineurin. The dramatic similarities in localization of FK506 binding proteins and cyclophilins with calcineurin suggest related functions.
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PMID:The immunophilins, FK506 binding protein and cyclophilin, are discretely localized in the brain: relationship to calcineurin. 753 Mar 48

FK506 and cyclosporin A (CsA) are immunosuppressive agents that inhibit IL-2 production by activated T cells, but only CsA inhibits IgE activation-induced cytokine transcripts in mouse IL-3-dependent, bone marrow-derived mast cells (BMMC). We previously associated the resistance of BMMC to FK506 with a deficiency in the expression of FK506 binding protein (FKBP) 12, a molecule that forms a complex with FK506 capable of inhibiting calcineurin phosphatase activity in vitro. In this report, we establish that FKBP12 mediates FK506 inhibition of both calcineurin phosphatase activity and IgE activation-induced cytokine transcripts in a Kirsten murine sarcoma virus-immortalized mast cell line that is FKBP12 deficient. Overexpression of FKBP12 by transfection enhanced the ability of FK506 to inhibit calcineurin phosphatase activity (IC50 = 2 nM), compared with cells transfected with the expression vector alone (IC50 > 30 nM). The IC50 value for FK506 inhibition of IgE activation-induced transcripts for TNF-alpha decreased from 40 nM in vector control cells to 10 nM in FKBP12 transfectants. Similarly, the IC50 value for inhibition of IL-6 transcripts decreased from > 1000 nM in vector control cells to 35 nM in FKBP12 transfectants. In contrast, activation-elicited release of the secretory granule mediator beta-hexosaminidase was only partially inhibited by FK506 at 1000 nM, regardless of the levels of FKBP12 expressed by the cells. Thus, FKBP12 is the dominant cytosolic protein that mediates FK506 inhibition of TNF-alpha and IL-6 transcripts.
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PMID:The complex of FK506-binding protein 12 and FK506 inhibits calcineurin phosphatase activity and IgE activation-induced cytokine transcripts, but not exocytosis, in mouse mast cells. 753 Jul 43

Recent data on the molecular mechanism of some immunosuppressive drugs provide strong support for the fascinating postulate that CSA and FK506 work by binding to immunophilins and then, as a drug-immunophilin complex, inhibiting the calcium-activated protein phosphatase, calcineurin. This inhibition could result in an altered modification pattern of the cytoplasmic components of transcription factors, thereby disturbing their nuclear translocation, which is a prerequisite for proper IL-2 transcription. It looks as if, with the immunosuppressive microbial metabolites as molecular probes, the pieces of this complex signal transduction puzzle are starting to fit together! Once the details of the chain of events along the T-cell signaling pathways are known, the molecular structures involved will provide new tools to be used in the search for and the rational design of new and improved therapeutic agents.
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PMID:Molecular mechanisms of immunosuppressive agents. 753 Oct 51

The ability of the immunosuppressive agent FK506 to affect growth of the epidermal growth factor-receptor (EGF-R) overexpressing cell line, A431, was compared with that of the structurally unrelated immunosuppressive compound, cyclosporin A (CyA). Both were shown to inhibit growth, although neither of them caused down-regulation of the EGF-R or affected epidermal growth factor (EGF)-induced tyrosine phosphorylation of the EGF-R. Inhibition of growth was not specific to EGF-R pathways, as both FK506 and CyA also inhibited EGF- and platelet-derived growth factor (PDGF)-induced DNA synthesis in fibroblasts. In all assays FK506 was less potent than CyA even though it is 10-100 times more potent as an immunosuppressive agent. The role of calcineurin in CyA- or FK506-induced growth inhibition was investigated using the synthetic pyrethroid insecticides: cypermethrin, deltamethrin and fenvalerate, which are known calcineurin inhibitors. Failure of these agents to block cell growth or influence growth factor-induced mitogenesis indicated that the biochemical pathway(s) by which CyA or FK506 inhibited cell growth did not depend solely on inhibition of calcineurin.
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PMID:Growth inhibitory effects of FK506 and cyclosporin A independent of inhibition of calcineurin. 753 76

The nephrotoxic potential of the macrolide immunosuppressants, FK506 and rapamycin, was compared with that of cyclosporin (CsA) in male Wistar rats. FK506 induced a reduction of creatinine clearance, hypomagnesemia and hyperuricemia as previously described for CsA. In contrast, equidosed rapamycin did not alter the glomerular filtration rate. FK506 caused proximal tubular epithelial changes consisting of atrophy, vacuolization, inclusion bodies, microcalcification and focal mononuclear interstitial infiltrate as described for CsA. The most striking alteration was hypertrophy of the juxtaglomerular apparatus (JGA). The percentage of renin-containing JGA and the extent of renin immunoreactivity along afferent vessels were significantly increased in FK506- and CsA-treated rats. By contrast, no renal morphologic lesions were found in rapamycin-treated animals. Renal cortical extracts contained abundant cyclophilin and FK506-binding protein (FKBP), the main intracytoplasmic receptors for CsA and FK506, respectively. Furthermore, we demonstrated that receptor bound CsA and FK506, but not rapamycin, formed complexes with the phosphatase calcineurin, as shown previously for lymphocytes. Thus, it is hypothesized that both the immunosuppressive and toxic effects of FK506 and CsA, but not of rapamycin, are mediated through an immunophilin-drug-calcineurin complex. The renal substrate of calcineurin, which mediates renal vasoconstriction is yet to be identified.
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PMID:Nephrotoxicity of immunosuppressants in rats: comparison of macrolides with cyclosporin. 753 90

Stimulation of B and T cells via the antigen receptor, by phorbol ester or by phorbol ester and ionomycin, leads to nuclear translocation of the inducible transcription factor NF-kappa B, comprising the p50 and p65 rel-related polypeptides. In this report we show that c-rel is a component of the antigen receptor-induced kappa B binding proteins in both B and T cells. Whereas NF-kappa B can be induced by phorbol ester alone, optimal induction of c-rel requires stimulation by both phorbol ester and ionomycin, the dual signal that is necessary for proliferation of untransformed lymphocytes. Furthermore, c-rel induction is blocked by the immunosuppressive drug FK506 that is known to inhibit B and T cell activation. c-rel-dependent transactivation of the interleukin-2 receptor alpha chain (IL-2R alpha) promoter is augmented by coexpression of calcineurin, suggesting the involvement of a calcineurin-dependent intracellular pathway. Our results identify c-rel as a target of immunosuppressive agents and illustrate the similarity of activation pathways in both B and T cells.
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PMID:FK506 inhibits antigen receptor-mediated induction of c-rel in B and T lymphoid cells. 753 76

The goal of this study was to identify the differences of intracellular signals between the processes of thymic positive and negative selection. The activation of calcineurin, a calcium- and calmodulin-dependent phosphatase, is known to be an essential event in T cell activation via the T cell receptor (TCR). The effect of FK506, an inhibitor of calcineurin activation, on positive and negative selection in CD4+CD8+ double positive (DP) thymocytes was examined in normal mice and in a TCR transgenic mouse model. In vivo FK506 treatment blocked the generation of mature TCRhighCD4+CD8- and TCRhighCD4-CD8+ thymocytes, and the induction of CD69 expression on DP thymocytes. In addition, the shutdown of recombination activating gene 1 (RAG-1) transcription and the downregulation of CD4 and CD8 expression were inhibited by FK506 treatment suggesting that the activation of calcineurin is required for the first step (or the very early intracellular signaling events) of TCR-mediated positive selection of DP thymocytes. In contrast, FK506-sensitive calcineurin activation did not appear to be required for negative selection based on the observations that negative selection of TCR alpha beta T cells in the H-2b male thymus (a negative selecting environment) was not inhibited by in vivo treatment with FK506 and that there was no rescue of the endogenous superantigen-mediated clonal deletion of V beta 6 and V beta 11 thymocytes in FK506-treated CBA/J mice. DNA fragmentation induced by TCR activation of DP thymocytes in vitro was not affected by FK506. In addition, different effects of FK506 from Cyclosporin A on the T cell development in the thymus were demonstrated. The results of this study suggest that different signaling pathways work in positive and negative selection and that there is a differential dependence on calcineurin activation in the selection processes.
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PMID:T cell receptor-mediated signaling events in CD4+CD8+ thymocytes undergoing thymic selection: requirement of calcineurin activation for thymic positive selection but not negative selection. 753 85

The immunosuppressive drugs FK506 and rapamycin bind to a family of intracellular proteins termed FK506-binding proteins (FKBP). FK506 and rapamycin inhibit lymphocyte-activation pathways by forming complexes with an FKBP; subsequently, the drug/FKBP complexes interact with target molecules involved in signal transduction. A key target of FK506/FKBP12 complexes is calcineurin, a calcium- and calmodulin-dependent serine/threonine phosphatase. In mammalian cells, rapamycin treatment is associated with inhibition of the activity of several cellular serine/threonine kinases, including p70 S6 kinase. These kinases may function in signaling pathways involving TOR gene producs, which have been shown to interact with rapamycin/FKBP12 complexes in vitro. To determine if FKBP12 mediates the effects of both FK506 and rapamycin in mammalian cells, we overexpressed FKBP12 in a murine mast cell line. Increased expression of FKBP12 resulted in increased sensitivity to FK506 and rapamycin, as measured by inhibition of calcineurin activity and p70 S6 kinase activity, respectively. In contrast, overexpression of FKBP25 had no effect on sensitivity to either drug. Two distinct point mutations in FKBP12, one altering a hydrophobic residue within the drug-binding pocket and the other changing a charged surface residue of FKBP12, abrogated its ability to mediate sensitivity to FK506 and rapamycin. These results establish that FKBP12 can mediate sensitivity to both FK506 and rapamycin in mammalian cells.
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PMID:FK506 binding protein 12 mediates sensitivity to both FK506 and rapamycin in murine mast cells. 753 90

The effect of cyclosporin A on induction of nitric oxide synthase in rat aortic smooth muscle cells was examined. A combination of interleukin-1 alpha (100 U/mL) and tumor necrosis factor--alpha (5000 U/mL) induced accumulation of nitrite/nitrate, the stable end products of nitric oxide, in culture media within 48 hours. Cyclosporin A inhibited this nitrite/nitrate accumulation in a concentration-dependent manner with an IC50 of 4 x 10(-7) mol/L when applied simultaneously with the cytokines. The expression of inducible nitric oxide synthase messenger RNA (mRNA) induced by the combination of interleukin-1 alpha and tumor necrosis factor-alpha was inhibited by the cyclosporin A cotreatment. Cyclosporin A did not decrease inducible nitric oxide synthase mRNA stability in the presence of transcription inhibitor actinomycin D (5 micrograms/mL). Induction of nitrite/nitrate production by the combination of tumor necrosis factor-alpha and bacterial lipopolysaccharide or that of interleukin-1 alpha and interferon gamma (100 U/mL) was also inhibited by cyclosporin A cotreatment. Another inhibitor of calcineurin, FK506 (up to 10(-6) mol/L), had no effect on the induction of nitrite/nitrate production, suggesting the possibility that the inhibitory effect of cyclosporin A may be exerted by means of a novel pathway other than inhibition of calcineurin. These results indicate that cyclosporin A inhibits inducible nitric oxide synthase induction at the mRNA level and that inducible nitric oxide synthase in vascular smooth muscle cells can be a target for cyclosporin A, providing a possible mechanism for the interference of the drug with the balance of vasoactive substances.
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PMID:Cyclosporin A inhibits nitric oxide synthase induction in vascular smooth muscle cells. 753 14

Gene transcription can be induced by cAMP and Ca2+ through distinct protein kinases phosphorylating the transcription factor CREB, which binds to cAMP response elements (CREs) in various genes. Induction of gene transcription by Ca2+ has been shown recently to depend on the Ca2+/calmodulin-dependent protein phosphatase calcineurin in pancreatic islet cells. This study investigates the role of calcineurin in CRE-directed gene transcription after stimulation by cAMP. Reporter fusion genes under the transcriptional control of CREs were transiently transfected into the cell line HIT. Pharmacological evidence suggests that cAMP stimulates CRE-mediated transcription through a Ca(2+)-dependent mechanism. The immunosuppressive drugs cyclosporin A and FK506 inhibited CRE-mediated transcription stimulated by cAMP. At the same concentrations they also inhibited calcineurin phosphatase activity. Reversal of calcineurin inhibition by rapamycin or overexpression of calcineurin led to disinhibition of CRE-mediated gene transcription. Immunoblots with a phosphoCREB-specific antibody showed that cyclosporin A and FK506 do not interfere with CREB phosphorylation at serine 119 stimulated with cAMP or membrane depolarization. These results indicate that in HIT cells stimulation of CRE-mediated transcription depends not only on the activity of protein kinases phosphorylating CREB but also on the Ca2+/calmodulin-dependent protein phosphatase calcineurin that is necessary for the transcriptional competence of phosphorylated CREB.
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PMID:Involvement of the Ca(2+)-dependent phosphatase calcineurin in gene transcription that is stimulated by cAMP through cAMP response elements. 753 40


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