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 influence of interleukin-7 (IL-7) on V(D)J recombination was investigated directly in the V(D)J recombination competent pre-B-cell line 38B9. The addition of IL-7 to the medium reduced the V(D)J recombination rate by 52-64%. This reduction was insensitive to the addition of cyclosporin A, indicating that the repression by IL-7 is not mediated by phosphatase 2B. The repression mechanism of IL-7 did not synergize with those of the protein kinase C activator 12-O-Tetradecanoylphorbol-13-acetate (TPA) and the intracellular Ca2+ mobilizer thapsigargin. The actin of IL-7 blocked by the addition of the protein kinase A stimulator caffeine and the synthetic glucocorticoid dexamethasone. IL-7 did not change the m-RNA levels of the V(D)J recombination activating genes RAG-1 and RAG-2, therefore IL-7 must exert its influence on V(D)J recombination either by post-transcriptional regulation of the RAG genes or by the regulation of other genes that are involved in V(D)J recombination. Although IL-7 may be necessary for the induction of and maintenance of V(D)J recombination during some stages of lymphocyte precursor development, it reduces the V(D)J recombination activity in pre-B cells.
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PMID:The influence of IL-7 V(D)J recombination. 901 23

The adherence of tumour cells to microvascular endothelium is believed to be a necessary step in their migration to sites of metastasis. It has been proposed that this process occurs when cell surface molecules on tumour cells bind to complementary sites on endothelial cells. The expression of these endothelial-derived cell adhesion molecules appears to be modulated by cytokines, a broad class of protein mediators which play important roles in immune and inflammatory reactions. It has been found by ourselves and others that exposure of endothelium to some cytokines augments the adhesion of inflammatory cells as well as tumour cells in in vitro assays. We used a murine model consisting of P815 mastocytoma cells and microvascular endothelium and found that pretreatment of endothelial monolayers with TNF-alpha, IL-1, LPS or PMA augmented the number of tumour cells that attach in a dose-dependent fashion. FACS analysis showed that the change in binding was due to an increase in the expression of VCAM-1 on the surface of the endothelial cell. Methylxanthines (caffeine and theophylline) as well as "classical" calcium-mobilizing agents (ionomycin and thapsigargin) inhibited the expression of VCAM-1 in MME. We also studied the possible mechanisms of TNF-alpha signal transduction in endothelial cells. We examined the involvement of protein kinases in the TNF-alpha effect. Although we found that inhibitors of PKC could inhibit the TNF-alpha effect, our studies suggest that the "classical" PKC pathway is not completely responsible for signaling since TNF-alpha did not cause translocation of PKC to the cell membrane and its effect could not be completely mimicked by PMA. We also studied the effect of TGF-beta on the binding of tumour cells to endothelium. Exposure of endothelium to TGF-beta led to the inhibition of both basal and TNF-alpha enhanced binding of P815 cells. Inhibitors of G-proteins do not abolish TGF-beta action, and PKC and PKA activators elicit an opposite effect. However, TGF-beta-mediated inhibition of both basal binding and TNF-alpha-enhanced P815 binding to endothelium is completely abolished in the presence of the protein phosphatase inhibitor okadaic acid suggesting that TGF-beta elicits its effect by stimulating protein phosphatase activity.
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PMID:Effect of cytokines on tumour cell-endothelial interactions. 934 51

In the yeast Saccharomyces cerevisiae, Na+ efflux is mediated by the Ena1 ATPase, and the expression of the ENA1 gene is regulated by the Ppz1 and Ppz2 Ser/Thr protein phosphatases. On the contrary, in the fission yeast Schizosaccharomyces pombe, effective output of Na+ is attributed to the H+/Na+ antiporter encoded by the sod2 gene. We have isolated a S. pombe gene (pzh1) that encodes a 515-amino-acid protein that is 78% identical, from residue 193 to the COOH terminus, to the PPZ1 and PPZ2 gene products. Bacterially expressed Pzh1p shows enzymatic characteristics virtually identical to those of recombinant Ppz1p. When expressed in high-copy number from the PPZ1 promoter, the pzh1 ORF rescues the caffeine-induced lytic defect and slightly decreases the high salt tolerance of S. cerevisiae ppz1delta mutants. Disruption of pzh1 yields viable S. pombe cells and has virtually no effect on tolerance to caffeine or osmotic stress, but it renders the cells highly tolerant to Na+ and Li+, and hypersensitive to K+. Although lack of pzh1 results in a 2-3-fold increase in sod2 mRNA, the pzh1 mutation significantly increases salt tolerance in the absence of the sod2 gene, suggesting that the phosphatase also regulates a Sod2-independent mechanism. Therefore, the finding of a PPZ-like protein phosphatase involved in the regulation of salt tolerance in fission yeast reveals unexpected aspects of cation homeostasis in this organism.
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PMID:Regulation of salt tolerance in fission yeast by a protein-phosphatase-Z-like Ser/Thr protein phosphatase. 942 1

We studied spiking neurons isolated from turtle retina by the whole cell version of the patch clamp. The studied cells had perikaryal diameters > 15 microns and fired multiple spikes in response to depolarizing current steps, indicating they were ganglion cells. In symmetrical [Cl-], currents elicited by puffs of 100 microM gamma-aminobutyric acid (GABA) were inward at a holding potential of -80 mV. All of the GABA-evoked current was blocked by SR95331 (20 microM), indicating that it was mediated by a GABAA receptor. The GABA-evoked currents were unaltered by eliciting a transmembrane calcium current either just before or during the response to GABA. On the other hand caffeine (10 mM), which induces Ca2+ release from intracellular stores, inhibited the GABA-evoked current on average by 30%. The caffeine effect was blocked by introducing the calcium buffer bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA) into the cell but was unaffected by replacing [Ca2+]o with equimolar cobalt. Thapsigargin (10 microM), an inhibitor of intracellular calcium pumps, and ryanodine (20 microM), which depletes intracellular calcium stores, both markedly reduced a caffeine-induced inhibition of the GABA-evoked current. Another activator of intracellular calcium release, inositol trisphosphate (IP3; 50 microM), also progressively reduced the GABA-induced current when introduced into the cell. Dibutyryl adenosine 3'5'-cyclic monophosphate (cAMP; 0.5 mM), a membrane-permeable analogue of cAMP, did not reduce GABA-evoked currents, suggesting that cAMP-dependent kinases are not involved in suppressing GABAA currents, whereas calmidazolium (30 microM) and cyclosporin A (20 microM), which inhibit Ca/calmodulin-dependent phosphatases, did reduce the caffeine-induced inhibition of the GABA-evoked current. Alkaline phosphatase (150 micrograms/ml) and calcineurin (300 micrograms/ml) had a similar action to caffeine or IP3. Antibodies directed against the ryanodine receptor or the IP3 receptor reacted with the great majority of neurons in the ganglion cell layer. We found that these two antibodies colocalized in large ganglion cells. In summary, intracellular calcium plays a role in reducing the currents elicited by GABA, acting through GABAA receptors. The modulatory action of calcium on GABA responses appears to work through one or more Ca-dependent phosphatases.
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PMID:Calcium released from intracellular stores inhibits GABAA-mediated currents in ganglion cells of the turtle retina. 974 25

We have investigated the mechanism of mitochondrial-nuclear crosstalk during cellular stress in mouse C2C12 myocytes. For this purpose, we used cells with reduced mitochondrial DNA (mtDNA) contents by ethidium bromide treatment or myocytes treated with known mitochondrial metabolic inhibitors, including carbonyl cyanide m-chlorophenylhydrazone (CCCP), antimycin, valinomycin and azide. Both genetic and metabolic stresses similarly affected mitochondrial membrane potential (Deltapsim) and electron transport-coupled ATP synthesis, which was also accompanied by an elevated steady-state cytosolic Ca2+ level ([Ca2+]i). The mitochondrial stress resulted in: (i) an enhanced expression of the sarcoplasmic reticular ryanodine receptor-1 (RyR-1), hence potentiating the Ca2+ release in response to its modulator, caffeine; (ii) enhanced levels of Ca2+-responsive factors calineurin, calcineurin-dependent NFATc (cytosolic counterpart of activated T-cell-specific nuclear factor) and c-Jun N-terminal kinase (JNK)-dependent ATF2 (activated transcription factor 2); (iii) reduced levels of transcription factor, NF-kappaB; and (iv) enhanced transcription of cytochrome oxidase Vb (COX Vb) subunit gene. These cellular changes, including the steady-state [Ca2+]i were normalized in genetically reverted cells which contain near-normal mtDNA levels. We propose that the mitochondria-to-nucleus stress signaling occurs through cytosolic [Ca2+]i changes, which are likely to be due to reduced ATP and Ca2+ efflux. Our results indicate that the mitochondrial stress signal affects a variety of cellular processes, in addition to mitochondrial membrane biogenesis.
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PMID:Retrograde Ca2+ signaling in C2C12 skeletal myocytes in response to mitochondrial genetic and metabolic stress: a novel mode of inter-organelle crosstalk. 992 12

Chronic treatment with cyclosporin A (CsA) has been reported (H. S. Banijamali, M. H. ter Keurs, L. C. Paul, and H. E. ter Keurs. Cardiovasc. Res. 27: 1845-1854, 1993; I. Kingma, E. Harmsen, H. E. ter Keurs, H. Benediktsson, and L. C. Paul. Int. J. Cardiol. 31: 15-22, 1991) to induce reversible alterations of contractile properties in rat hearts. To define the molecular mechanisms underlying the physiological alterations, the Ca2+-release channel (CRC) and Ca2+-ATPase from sarcoplasmic reticulum in rats were examined. Ryanodine binding to whole homogenates of rat hearts shows time- and dose-dependent alterations in CRC properties by CsA. On 3 wk of treatment with 15 mg CsA. kg body wt-1. day-1, 1) maximal ryanodine binding (Bmax) decreased, 2) the dissociation constant of ryanodine (Kd) increased, 3) caffeine sensitivity of CRC increased, and 4) ruthenium red sensitivity of CRC decreased. On the other hand, Bmax and Kd of ryanodine binding in rat skeletal muscles were not changed. Ryanodine-sensitive oxalate-supported Ca2+ uptake in whole homogenates was lower in CsA-treated rat hearts than in control hearts, whereas total Ca2+ uptake in the presence of 500 M ryanodine was not changed. Functional experiments with rapamycin and Western blot analysis suggest that the CsA-induced alteration of ryanodine binding is due at least in part to an upregulation of calcineurin. The heart muscle-specific alterations of CRC could be responsible for the previously reported contractile changes of CsA-treated rat hearts.
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PMID:Cyclosporin A treatment alters characteristics of Ca2+-release channel in cardiac sarcoplasmic reticulum. 1007 69

Thirty-two protein phosphatase (PPase) genes were identified in the genome nucleotide sequence of Saccharomyces cerevisiae. We constructed S. cerevisiae disruptants for each of the PPase genes and examined their growth under various conditions. The disruptants of six putative PPase genes, i.e. of YBR125c, YCR079w, YIL113w, YJR110w, YNR022c and YOR090c, were created for the first time in this study. The glc7, sit4 and cdc14 disruptants were lethal in our strain background. The remaining 29 PPase gene disruptants were viable at 30 degrees C and 37 degrees C, but only one disruptant, yvh1, showed intrinsic cold-sensitive growth at 13 degrees C. Transcription of the YVH1 gene was induced at 13 degrees C, consistent with an idea that Yvh1p has a specific role for growth at a low temperature. The viable disruptants grew normally on nutrient medium containing sucrose, galactose, maltose or glycerol as carbon sources. The ppz1 disruptant was tolerant to NaCl and LiCl, while the cmp2 disruptant was sensitive to these salts, as reported previously, and none of the other viable PPase disruptants exhibited the salt sensitivity. When the viable disruptants were tested for sensitivity to drugs, i.e. benomyl, caffeine and hydroxyurea, ppz1 and ycr079w disruptants exhibited sensitivity to caffeine.
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PMID:A series of protein phosphatase gene disruptants in Saccharomyces cerevisiae. 1057 63

We have characterized LUV1/RKI1/TCS3/VPS54, a novel yeast gene required to maintain normal vacuolar morphology. The luv1 mutant was identified in a genetic screen for mutants requiring the phosphatase calcineurin for vegetative growth. luv1 mutants lack a morphologically intact vacuole and instead accumulate small vesicles that are acidified and contain the vacuolar proteins alkaline phosphatase and carboxypeptidase Y and the vacuolar membrane H(+)-ATPase. Endocytosis appears qualitatively normal in luv1 mutants, but some portion (28%) of carboxypeptidase Y is secreted. luv1 mutants are sensitive to several ions (Zn(2+), Mn(2+), and Cd(2+)) and to pH extremes. These mutants are also sensitive to hygromycin B, caffeine, and FK506, a specific inhibitor of calcineurin. Some vacuolar protein-sorting mutants display similar drug and ion sensitivities, including sensitivity to FK506. Luv1p sediments at 100,000 x g and can be solubilized by salt or carbonate, indicating that it is a peripheral membrane protein. A Green Fluorescent Protein-Luv1 fusion protein colocalizes with the dye FM 4-64 at the endosome, and hemagglutinin-tagged Luv1p colocalizes with the trans-Golgi network/endosomal protease Kex2p. Computer analysis predicts a short coiled-coil domain in Luv1p. We propose that this protein maintains traffic through or the integrity of the early endosome and that this function is required for proper vacuolar morphology.
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PMID:Luv1p/Rki1p/Tcs3p/Vps54p, a yeast protein that localizes to the late Golgi and early endosome, is required for normal vacuolar morphology. 1088 79

The gene pzl-1 from the filamentous fungus Neurospora crassa encodes a putative Ser/Thr protein phosphatase that is reminiscent of the Ppz1/Ppz2 and Pzh1 phosphatases from Saccharomyces cerevisiae and Schizosaccharomyces pombe, respectively. The entire PZL-1 protein, as well as its carboxyl-terminal domain, have been expressed in Escherichia coli as active protein phosphatases. To characterize its cellular role, PZL-1 was also expressed in Sz. pombe and in S. cerevisiae. Expression of PZL-1 in S. cerevisiae from the PPZ1 promoter was able to rescue the altered sensitivity to caffeine and lithium ions of a ppz1 strain. Furthermore, high copy number expression of PZL-1 alleviated the lytic phenotype of a S. cerevisiae slt2/mpk1 mitogen-activated protein (MAP) kinase mutant, similarly to that described for PPZ1, and mimicked the effects of high levels of Ppz1 on cell growth. Expression of PZL-1 in fission yeast from a weak version of the nmt1 promoter fully rescued the growth defect of a pzh1Delta strain in high potassium, but only partially complemented the sodium-hypertolerant phenotype. Strong overexpression of the N. crassa phosphatase in Sz. pombe affected cell growth and morphology. Therefore, PZL-1 appears to fulfil every known function carried out by its S. cerevisiae counterpart, despite the marked divergence in sequence within their NH(2)-terminal moieties.
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PMID:Functional analysis of the Neurospora crassa PZL-1 protein phosphatase by expression in budding and fission yeast. 1116 54

Temperature-induced bleaching in symbiotic cnidarians is a result of the detachment and loss of host cells containing symbiotic algae. We tested the hypothesis that host cell detachment is evoked through a membrane thermotropic event causing an increase in intracellular calcium concentration, [Ca(2+)](i), which could then cause collapse of the cytoskeleton and perturb cell adhesion. Electron paramagnetic resonance measurements of plasma membranes from the tropical sea anemone Aiptasia pulchella and the Hawaiian coral Pocillopora damicornis labeled with 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) revealed no membrane thermotropic event. In addition, intracellular imaging using Fura-2AM as well as labeling anemones with (45)Ca revealed no significant change in [Ca(2+)](i). However, bleaching could be evoked at ambient temperature with 25 mmol l(-1) caffeine without affecting [Ca(2+)](i). [Ca(2+)](i) could be altered with ionomycin in isolated host cells, but ionomycin could not induce bleaching in A. pulchella. As caffeine can affect levels of intracellular protein phosphorylation, the ability of other agents that alter intracellular levels of protein phosphorylation to evoke bleaching was investigated. The protein phosphatase inhibitor vanadate could induce bleaching in A. pulchella. Two-dimensional gels of (32)P-labeled proteins from cold-shocked, caffeine-treated and control anemones show that both temperature shock and caffeine alter the array of phosphorylated host soluble proteins. We conclude that cnidarian bleaching is linked to a temperature-induced alteration in protein phosphorylation.
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PMID:Cellular mechanisms underlying temperature-induced bleaching in the tropical sea anemone Aiptasia pulchella. 1170 95


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