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)

Interferon-gamma (IFN-gamma) is a major effector cytokine of the immune system with an expression pattern strictly restricted to cells of the lymphoid lineage. Several years ago, we reported that, during early pregnancy, the trophectoderm of the pig blastocyst, which represents a monolayer of polarized epithelial cells secretes high amount of IFN-gamma in a transient and developmentally regulated manner. In an effort to study the molecular basis of this atypical IFN-gamma gene expression, a pig trophectoderm cell line, TBA B4-3, was established in our laboratory. These cells developed a polarized phenotype with high transepithelial electrical resistance (TER) when grown on a microporous membrane. We found that treatment of polarized TBA B4-3 cells with the strong PKC agonist PMA induced, 3-4 days later, a transient IFN-gamma mRNA expression and vectorial IFN-gamma protein secretion. In order to better understand IFN-gamma gene regulation in TBA B4-3 cells, we examined in this system the effect of several drugs and factors known to affect the inducibility of this cytokine in T lymphocytes, the main source of IFN-gamma in the immunocompetent animal. We found that cyclosporine A (CsA) treatment of TBA B4-3 cells induces a partial inhibition of IFN-gamma secretion, thus indicating a minor role for the calcineurin signaling pathway in IFN-gamma expression. In addition, we found that although PMA alone can induce IFN-gamma secretion, the calcium ionophore A23187 synergizes with PMA for induction. We also analyzed by Southern blot the methylation status of a CpG dinucleotide in the 5' flanking region of IFN-gamma promoter and found that it was unmethylated in TBA B4-3 cells and in several pig epithelial cell lines that do not express IFN-gamma thus indicating the absence of correlation between demethylation and the ability to express IFN-gamma. Taken together, these results indicate that the mechanisms involved in IFN-gamma induction in TBA B4-3 cells are atypical compared to those presently known to operate in the T cell lineage.
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PMID:Atypical mechanisms regulate the PMA-induced expression of IFN-gamma in a porcine trophectoderm cell line. 1273 16

CXCR6, the receptor for the membrane-anchored chemokine, CXCL16, is expressed on a subset of CCR5-bearing memory T cells, and may play a role in recruiting these cells to sites of inflammation. Here, we set out to determine the effect of T cell activation on CXCR6 expression. Highly purified human peripheral blood T cells were cultured for 7-8 days in presence of IL-2 (400 U/ml) to enhance CXCR6 expression. Overnight stimulation with anti-CD3 mAb+anti-CD28 mAb, which resulted in CD69 induction and cytokine (IL-2 and IFN-gamma) production, reduced cell surface expression of CXCR6 by 85% and that of CCR5 by 76%. The Ca(2+) ionophore, ionomycin (125-500 ng/ml), also markedly diminished CXCR6 expression (85%), but without inducing CD69 expression or cytokine production, and reduced CCR5 expression by only 40%. In contrast, the phorbol esters, PdBu or PMA had little effect on CXCR6 expression (23% reduction) but induced CD69 expression and caused a profound down-regulation (92%) of CCR5 expression. Moreover, CCR7, whose expression was low on CXCR6(+) T cells, was little affected by any of these modes of activation. The down-regulation of CXCR6 expression induced by CD3/CD28 activation was blocked by the broad kinase inhibitor, staurosporine, and by the src kinase inhibitor, PP2, but not by the MEK1 inhibitor, U0106. Most interestingly, the calcineurin inhibitor, FK506, consistently inhibited CD3/CD28-induced CXCR6 down-regulation. FK506 also blocked the decrease of CXCR6 expression caused by ionomycin, whereas staurosporine or PP2 had no effect on this decrease. Altogether, these data indicate that CXCR6 expression is down-regulated, independent of CCR5 or CD69 expression and of cytokine induction, by T cell activation signals that involve predominantly the Ca(2+)-dependent calcineurin pathway.
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PMID:Down-regulation of cell surface CXCR6 expression during T cell activation is predominantly mediated by calcineurin. 1291 53

Mechanisms of alcoholic pancreatitis remain unknown. Previously, we showed that ethanol feeding sensitizes rats to pancreatitis caused by CCK-8, at least in part, by augmenting activation of the proinflammatory transcription factor NF-kappaB. To elucidate the mechanism of sensitization, here we investigate the effect of ethanol on Ca(2+)- and PKC-mediated pathways of CCK-induced NF-kappaB activation using an in vitro system of rat pancreatic acini incubated with ethanol. Ethanol augmented CCK-8-induced activation of NF-kappaB, similar to our in vivo findings with ethanol-fed rats. In contrast, ethanol prevented NF-kappaB activation caused by thapsigargin, an agent that mobilizes intracellular Ca(2+) bypassing the receptor. Pharmacological analysis showed that NF-kappaB activation by thapsigargin but not by CCK-8 is mediated through the calcineurin pathway and that the inhibitory effect of ethanol on the thapsigargin-induced NF-kappaB activation could be through inhibiting this pathway. Ethanol augmented NF-kappaB activation induced by the phorbol ester PMA, a direct activator of PKC. Inhibitory analysis demonstrated that Ca(2+)-independent (novel and/or atypical) PKC isoforms are involved in NF-kappaB activation induced by both CCK-8 and PMA in cells treated and not treated with ethanol. The results indicate that ethanol differentially affects the Ca(2+)/calcineurin- and PKC-mediated pathways of NF-kappaB activation in pancreatic acinar cells. These effects may play a role in the ability of ethanol to sensitize pancreas to the inflammatory response and pancreatitis.
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PMID:Ethanol differentially regulates NF-kappaB activation in pancreatic acinar cells through calcium and protein kinase C pathways. 1295 18

The CD40L expressed on activated CD4+ T cells delivers contact-dependent proliferative and anti-apoptotic signals to B lymphocytes. Little is known about molecular mechanisms of constitutive expression of CD40L on some non-Hodgkin's lymphomas, especially about involvement of two signal pathways regulating its expression in normal cells; one involving calcineurin, and the other protein kinase C. We analyzed by flow cytometry the effects of 6-hour stimulation of both pathways (stimuli: PMA and ionomycin) and their inhibitors: cyclosporin A and chelerythrine, on CD40L expression. Two Jurkat clones differing in CD40L surface expression: clone 217.6 (CD40L-) and 217.7 (CD40L+) were studied. Our experiments showed that high level of CD40L expression on the surface of 217.7 cells was reduced after stimulation with PMA. The same effect was observed for combination of PMA and chelerythrine or for PKC inhibitor alone. In 217.6 cells, only chelerythrine used alone induced low level of CD40L expression, while PMA and ionomycin were without effect. These results suggest that CD40L surface expression is mainly dependent on protein kinase C activity. By using PepTag Assay we have confirmed that in both Jurkat clones PKC activity is higher than in normal blood lymphocytes.
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PMID:Modulation of CD40L antigen expression in Jurkat cells: involvement of protein kinase C activity. 1467 64

Barbiturates are frequently used for the treatment of intracranial hypertension after brain injury but their application is associated with a profound increase in the infection rate. The mechanism of barbiturate-induced failure of protective immunity is still unknown. We provide evidence that nuclear factor of activated T cells (NFAT), an essential transcription factor in T cell activation, is a target of barbiturate-mediated immunosuppression in human T lymphocytes. Treatment of primary CD3+ lymphocytes with barbiturates inhibited the PMA and ionomycin induced increase in DNA binding of NFAT, whereas the activity of other transcription factors, such as Oct-1, SP-1, or the cAMP response element-binding protein, remained unaffected. Moreover, barbiturates suppressed the expression of a luciferase reporter gene under control of NFAT (stably transfected Jurkat T cells), and of the cytokine genes interleukin-2 and interferon-gamma that contain functional binding motifs for NFAT within their regulatory promotor domains (human peripheral blood CD3+ lymphocytes). Neither GABA receptor-initiated signaling nor direct interactions of barbiturates with nuclear proteins affected the activity of NFAT. In contrast, barbiturates suppressed the calcineurin-dependent dephosphorylation of NFAT in intact T cells and also inhibited the enzymatic activity of calcineurin in a cell-free system, excluding upstream regulation. Thus, our results demonstrate a novel mechanism of direct inhibition of the calcineurin/calmodulin complex that may explain some of the known immunosuppressive effects associated with barbiturate treatment.
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PMID:Barbiturates directly inhibit the calmodulin/calcineurin complex: a novel mechanism of inhibition of nuclear factor of activated T cells. 1474 77

The effects of norepinephrine in the brain and periphery are terminated primarily by active reuptake of the catecholamine via cocaine- and amphetamine-sensitive norepinephrine transporters (NETs). Activation of protein kinase C (PKC) down-regulates NET by sequestering it from the plasma membrane, although the underlying mechanism is not yet known. Previously, we showed robust expression of endogenous NETs in rat placental trophoblasts (Jayanthi, L. D., Vargas, G., and DeFelice, L. J. (2002) Br. J. Pharmacol. 135, 1927-1934). Here we report a significant reduction in native NET function and surface expression in these cells following phorbol ester (beta-PMA) treatment. The beta-PMA-mediated down-regulation of NET occurs by a rapid sequestration of NETs from the plasma membrane and is calcium-independent. Reversible biotinylation experiments revealed a significant enhancement of NET endocytosis following beta-PMA treatment. Chemical treatments and expression of dominant negative mutants of dynamin 1 and 2 failed to prevent the beta-PMA effect, suggesting a clathrin-independent pathway. In contrast, treatment with the cholesterol-disrupting agent filipin, which blocks caveolae/lipid raft-mediated internalization, completely blocked the beta-PMA-mediated NET sequestration. Discontinuous sucrose density gradient centrifugation revealed NET in the lipid raft fractions. Following beta-PMA treatment, there was reduced NET levels in the lipid raft fractions suggesting that cholesterol-rich lipid rafts mediate PKC-triggered NET internalization. Metabolic labeling and immunoprecipitation studies revealed that NET phosphorylation is stimulated severalfold by PKC activation and protein phosphatase 1/2A inhibition. Together, these findings demonstrate for the first time that in trophoblasts (i) PKC activation regulates NET function and surface expression by an enhanced internalization process that is lipid raft-mediated and (ii) PKC and protein phosphatase(s) modulation regulates NET phosphorylation.
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PMID:Regulated internalization and phosphorylation of the native norepinephrine transporter in response to phorbol esters. Evidence for localization in lipid rafts and lipid raft-mediated internalization. 1497 8

CD3 antigen is a crucial molecule in T cell signal transduction. Although its expression on cell surface is constitutive, dynamic regulation of TCR-CD3 level is probably the most important mechanism allowing T cells to calibrate their response to different levels of stimuli. In our study we examined the role of two main T cell signal transduction pathways in controlling the surface level of CD3 antigen, one based on protein kinase C activity and the other dependent on calcineurin. As an experimental model we used three clones derived from Jurkat cell line, expressing different levels of CD3 antigen surface expression: CD3(low) (217.6), CD3+(217.9) or CD3(low) (217.7). The cells were stimulated with PMA or ionomycin, acting directly on PKC and calcineurin, respectively. Prior to the stimulation cells were incubated with PKC inhibitor--chelerythrine or calcineurin blocker--cyclosporine A. Changes in CD3 surface expression were measured by flow cytometry. Only PMA and chelerythrine were able to change CD3 expression suggesting important involvement of PKC in the regulation of its expression. To confirm these findings, PKC activity was estimated in Jurkat clones. Our data demonstrated that Jurkat clones with different CD3 expression showed also different PKC activities, so we conclude that PKC-dependent pathway is the main way of controlling CD3 level on Jurkat clones.
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PMID:CD3 receptor modulation in Jurkat leukemic cell line. 1504 99

The Na(+)/Cl(-)-dependent, hemicholinium-3-sensitive choline transporter (CHT) provides choline for acetylcholine biosynthesis. Recent studies show that CHT contains canonical protein kinase C (PKC) serine and threonine residues. We examined the ability of PKC and serine/threonine protein phosphatase 1/2A (PP1/PP2A) to regulate CHT function, surface expression, and phosphorylation. In mouse crude striatal and hippocampal synaptosomes, PKC activators beta-phorbol 12-myristate 13-acetate (beta-PMA) and beta-phorbol 12,13-dibutyrate produced time- and concentration-dependent reductions in CHT function. PP1/PP2A inhibitors okadaic acid (OKA) and calyculin A (CL-A) produced a time- and concentration-dependent decrease in CHT function. However, tautomycin (PP1 inhibitor) and cyclosporin A (PP2B inhibitor) failed to alter CHT-mediated choline uptake. Choline transport kinetic studies following beta-PMA, OKA, and CL-A treatment revealed a reduction in the maximal choline transport velocity (V(max)) with no change in K(m) for choline. These modulators also produced no change in the total levels of CHT protein in the crude hippocampal and striatal synaptosomes; however, surface biotinylation studies using the membrane-impermeant N-hydroxysuccinimide-biotin in crude synaptosomes following treatment with beta-PMA, OKA, and CL-A indicate significant reductions of CHT levels in biotinylated fractions. Pretreatment with OKA alone, but not beta-PMA, significantly augmented the phosphorylation level of CHT proteins. Our findings suggest that neuronal PKC and PP1/PP2A activity may establish the level of function and surface expression of CHT. These studies also provide the first evidence that CHT is a phosphoprotein and that the basal PP1/PP2A activity may have a dominant role in controlling the levels of CHT phosphorylation.
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PMID:Regulation of choline transporter surface expression and phosphorylation by protein kinase C and protein phosphatase 1/2A. 1506 33

Interleukin (IL)-8 produced from glioblastoma is suggested to contribute to its own proliferation and progression. Since various external stimuli have been shown to increase intracellular Ca(2+) in glioma cells, we investigated Ca(2+) mobilization-dependent IL-8 expression and effect of cyclosporin A (CsA), an inhibitor of calcineurin (Cn), on the expression and invasive potential of human glioblastoma U251MG cells. Combined treatment with Ca(2+)-ionophore and phorbol-myristate-acetate (A23187/PMA) increased IL-8 mRNA and protein levels. This increase was suppressed by CsA and by another Cn inhibitor FK506. Luciferase reporter gene assay and electrophoretic mobility shift assay revealed that activation of p65-containing nuclear factor-kappaB was essential for A23187/PMA-dependent activation of IL-8 promoter. CsA suppressed the promoter activity by attenuating IkappaB-alpha degradation. U251MG cells expressed IL-8 receptors CXCR-1 and -2, and Matrigel invasion assay revealed that CsA attenuated A23187/PMA-dependent stimulation of invasive potential, probably by inhibiting IL-8 production. In addition, IL-8-dependent proliferation was also suppressed by CsA. Taken together, these results demonstrate the novel inhibitory effects of CsA on glioblastoma cell functions, suggesting CsA as a potential therapeutic adjuvant for glioma treatment.
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PMID:Inhibitory effects of cyclosporin A on calcium mobilization-dependent interleukin-8 expression and invasive potential of human glioblastoma U251MG cells. 1528 17

Recent studies have indicated that caveolae are enriched in a variety of signaling molecules, some of which are associated with cardiomyocyte hypertrophy. Caveolin-3, a major constituent of cardiac caveolae, has been suggested to interact with several signaling molecules. We investigated the morphologic changes of caveolae and caveolin-3 expression in hypertrophied cardiomyocytes induced by an alpha1-adrenergic agonist. Cultured rat neonatal cardiomyocytes were used for the experiments. Phenylephrine induced cellular hypertrophy associated with an increase of the number of caveolae and an up-regulation of caveolin-3. Although PMA increased the number of caveolae and the caveolin-3 expression, the extent of these up-regulations was less than that by phenylephrine. Moreover, ionomycin increased the number of caveolae and up-regulated caveolin-3 as much as phenylephrine. Phenylephrine-induced up-regulations of caveolae and caveolin-3 expression were inhibited by BAPTA, suggesting that the intracellular Ca2+ is involved in those regulations. Inhibitors of calcineurin and Ca2+calmodulin-dependent kinase II attenuated the phenylephrine-induced up-regulation of caveolin-3. In pressure-overloaded rat hearts, caveolin-3 protein levels were increased compared with sham-operated rats. In conclusion, the number of caveolae and the expression of caveolin-3 were up-regulated in rat hypertrophied cardiomyocytes, possibly via the alterations of intracellular Ca2+ and protein kinase C.
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PMID:Behavior of caveolae and caveolin-3 during the development of myocyte hypertrophy. 1572 44


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