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)

Calcineurin and calcium/calmodulin-dependent protein kinase (CaMK) II have been suggested to be the signaling molecules in cardiac hypertrophy. It was not known, however, whether these mechanisms are involved in cardiac hypertrophy induced by pressure overload without the influences of blood-derived humoral factors, such as angiotensin II. To elucidate the roles of calcineurin and CaMK II in this situation, we examined the effects of calcineurin and CaMK II inhibitors on pressure overload-induced expression of c-fos, an immediate-early gene, and protein synthesis using heart perfusion model. The hearts isolated from Sprague-Dawley rats were perfused according to the Langendorff technique, and then subjected to the acute pressure overload by raising the perfusion pressure. The activation of calcineurin was evaluated by its complex formation with calmodulin and by its R-II phosphopeptide dephosphorylation. CaMK II activation was evaluated by its autophosphorylation. Expression of c-fos mRNA and rates of protein synthesis were measured by northern blot analysis and by 14C-phenylalanine incorporation, respectively. Acute pressure overload significantly increased calcineurin activity, CaMK II activity, c-fos expression and protein synthesis. Cyclosporin A and FK506, the calcineurin inhibitors, significantly inhibited the increases in both c-fos expression and protein synthesis. KN62, a CaMK II inhibitor, also significantly prevented the increase in protein synthesis, whereas it failed to affect the expression of c-fos. These results suggest that both calcineurin and CaMK II pathways are critical in the pressure overload-induced acceleration of protein synthesis, and that transcription of c-fos gene is regulated by calcineurin pathway but not by CaMK II pathway.
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PMID:Roles of calcineurin and calcium/calmodulin-dependent protein kinase II in pressure overload-induced cardiac hypertrophy. 1296 38

Calcineurin, a Ca(2+)-calmodulin-dependent protein phosphatase (PP2B) is one of the links between Ca(2+) signals and regulation of gene transcription in cardiac muscle. We studied the Ca(2+) signal specificity of calcineurin activation experimentally and with modelling. In the rat atrial preparation, an increase in pacing frequency increased nuclear activity of the calcineurin-sensitive transcription factor, nuclear factor of activated T-cells (NFAT), 2-fold in a cyclosporin A (CsA)-sensitive manner. In line with this, modelling results predicted that the frequency of cardiac Ca(2+) transients encodes the stimulus for calcineurin activation. We further observed experimentally that calcineurin inhibition by CsA modulated Ca(2+) release in a Ca(2+)-dependent manner. CsA had no effect on [Ca(2+)](i) at a pacing frequency of 1 Hz but it significantly suppressed the amplitude of Ca(2+) transients, systolic [Ca(2+)](i) and time averaged [Ca(2+)](i) at 6 Hz. Calcineurin had a differential role in the expression of immediate-early genes B-type natriuretic peptide (BNP) and c-fos. CsA inhibited the pacing-induced BNP gene expression, whereas pacing alone had no effect on the expression of c-fos. However, in the presence of CsA, c-fos mRNA levels were significantly augmented by increased pacing frequency. These results show that frequency-dependent calcineurin activation has a specific role in [Ca(2+)](i) regulation and gene expression, constantly recruited by varying cardiac Ca(2+) signals.
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PMID:Pacing-induced calcineurin activation controls cardiac Ca2+ signalling and gene expression. 1456 91

Calcineurin, a calcium-regulated protein phosphatase, activates gene expression specific to slow muscle fibers by dephosphorylating a family of the nuclear factor of activated T cells (NFAT), which cooperates with myocyte enhancer factor-2 (MEF2) and AP-1. However, it remains unknown how acute exercise influences this signaling pathway and leads to the development of slow muscle fibers. In the present study, we investigated the effect of moderate acute exercise on mRNA expression of genes in the calcineurin signaling pathway in human skeletal muscle. Five healthy volunteers underwent 1 h bicycle ergometer at 50%VO2max, and vastus lateralis muscle biopsies were collected before and after exercise. Four hours after exercise, alterations in mRNA expression of NFAT 1-3 were observed with a wide variety among subjects, while c-fos mRNA was significantly induced in all subjects. By contrast, the expression of calcineurin, MEF2, and myocyte-enriched calcineurin-interacting protein 1 (MCIP1) remained unchanged. These results suggest that even moderate acute exercise may change mRNA expression of genes in the calcineurin-signaling pathway.
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PMID:Effect of moderate acute exercise on expression of mRNA involved in the calcineurin signaling pathway in human skeletal muscle. 1458 92

Activation of group I metabotropic glutamate receptors (mGluRs) up-regulates transcription factor cyclic AMP response element-binding protein (CREB) and Elk-1 phosphorylation via extracellular signal-regulated kinase 1/2 (ERK1/2) in the striatum in vivo. Protein phosphatase 1/2A further regulates immediate early gene expression by inactivating (dephosphorylating) CREB. In this study, using semi-quantitative immunohistochemical and western blot analyses and in situ hybridization histochemistry, we found that intrastriatal infusion of the protein phosphatase 1/2A inhibitor okadaic acid (0.005, 0.05 and 0.5 nmol) increased CREB and Elk-1 phosphorylation and c-Fos immunoreactivity in the injected dorsal striatum in a dose-dependent manner. In addition, okadaic acid (0.05 and 0.5 nM) increased c-fos mRNA expression in the dorsal striatum in a dose-dependent manner. Intrastriatal infusion of the group I agonist 3,5-dihydroxyphenylglycine (DHPG) at 100 and 250 nM also increased CREB and Elk-1 phosphorylation. Pre-treatment of okadaic acid (0.05 nm) did not alter DHPG-induced increases in the phosphorylation of the two transcription factors. These data suggest that protein phosphatase 1/2A in striatal neurons is tonically active in dephosphorylating CREB and Elk-1 and thus suppressing constitutive c-fos mRNA and protein expression. Inhibition of the phosphatase 1/2A may contribute to the group I mGluR-regulated phosphorylation of these transcription factors and c-fos expression.
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PMID:The protein phosphatase 1/2A inhibitor okadaic acid increases CREB and Elk-1 phosphorylation and c-fos expression in the rat striatum in vivo. 1505 82

Oxidants cause activation of the AP-1 transcription factor in cardiomyocytes. c-Fos, a component of the AP-1 transcription factor, is transiently induced by H2O2 and the induction is sensitive to the protein synthesis inhibitor cycloheximide. With high percentage gel electrophoresis, multiple c-Fos bands were resolved by Western blot analyses, indicating post-translational modification of newly synthesized c-Fos protein after H2O2 exposure. Treatment of immunoprecipitated c-Fos protein with the type 2 serine/threonine phosphatase A (PP2A) and immunoblotting of c-Fos protein with antibodies against phosphorylated serine or threonine demonstrated that c-Fos was phosphorylated at serine residues. A pharmacological inhibitor of JNKs inhibited the formation of multiple c-Fos bands without affecting c-fos transcription. The proteasomal inhibitor MG132 and Proteasome Inhibitor I extended the time course of c-Fos protein elevation. An increase in ubiquitin was detectable in c-Fos protein from H2O2-treated cells. Interestingly, treating the whole cell lysates with PP2A, but not calcineurin (i.e. PP2B), resulted in disappearance of c-Fos protein and MG132 was able to prevent this loss. H2O2 caused an elevation of PP2B and total phosphatase activity. The phosphatase inhibitor okadaic acid, but not PP2B inhibiter cypermethrin, extended the time course of c-Fos protein elevation after H2O2 exposure. These data suggest that JNK-mediated phosphorylation of newly synthesized c-Fos protects the protein from being degraded by the proteasome. PP2B independent dephosphorylation contributes to degradation of c-Fos protein during oxidative stress response of cardiomyocytes.
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PMID:c-Fos phosphorylation induced by H2O2 prevents proteasomal degradation of c-Fos in cardiomyocytes. 1513 64

There is a common mechanism for mechanotransduction in cells, regardless of the cell type. Integrins, interacting with their matrix/environment, mediate increases in intracellular Ca2+ levels and activate MAP kinase cascades to cause ERK1/2 phosphorylation. Phosphorylated ERK1/2 causes the activation of the AP-1 family of transcription factors that are necessary for the pro-growth response. The pro-bone growth response involves upregulation of the genes c-fos, IGF-1, cyclooxygenase, and osteocalcin. In osteocytes, increases in intracellular Ca2+ levels may additionally occur by extracellular Ca2+ influx through a stretch-activated ion channel. Each bone cell appears fine-tuned for the type of stimulus, with accessory mechanotransduction signaling pathways, such as calcineurin-mediated activation of the tissue-specific transcription factor NF-AT, adjusting the outcome of signaling in each case.
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PMID:Molecular regulation of mechanotransduction. 1569 10

To study the molecular mechanisms for load-induced activation of BNP gene expression, increased wall stress was imposed on isolated isovolumetrically beating adult rat hearts by distension of a fluid filled balloon within the left ventricle. The wall stress for 2 h resulted in a 1.6-fold increase in the expression of BNP gene and a 2.0-fold increase of the c-fos gene. The inhibition of transcription by actinomycin D significantly decreased the baseline BNP mRNA levels but the wall stretch-induced increase of the gene expression remained unaffected. In contrast, the protein synthesis inhibitor cycloheximide increased baseline BNP mRNA levels and abolished the load-induced activation of gene expression. Furthermore, we studied the effects of protein kinase C (PKC), calcineurin and protein phosphatase 2A (PP2A) inhibition to characterize the role of intracellular pathways in the stretch-induced gene expression in the left ventricle. The expression of BNP and c-fos genes were not influenced by calcineurin, PP2A and PKC inhibition. In conclusion, we showed that the stretch-induced activation of BNP gene expression by increased left ventricular wall stress is independent of transcriptional mechanisms and dependent on protein synthesis. Moreover, our results suggest that the load-induced activation of BNP gene expression is independent of calcineurin, PKC and PP2A.
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PMID:Posttranscriptional activation of BNP gene expression in response to increased left ventricular wall stress: role of calcineurin and PKC. 1583 27

We evaluated the effects of d-myo-inositol 1,4,5-tris-phosphate on cardiac hypertrophy. d-myo-inositol 1,4,5-tris-phosphate augmented cardiac hypertrophy as evidenced by its effects on DNA synthesis, protein synthesis, and expression of immediate-early genes c-myc and c-fos, beta-myosin heavy chain, and alpha-actin. The administration of d-myo-inositol 1,4,5-tris-phosphate increased the expression of nuclear factor of activated T-cells and cardiac-restricted zinc finger transcription factor (GATA4). Real-time quantitative RT-PCR showed that d-myo-inositol 1,4,5-tris-phosphate-induced GATA4 mRNA was significantly enhanced even in the presence of the calcineurin inhibitor, cyclosporine A. The effect of d-myo-inositol 1,4,5-tris-phosphate was blocked after inhibition of inositol-trisphosphate receptors but not after inhibition of c-Raf/mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (ERK) or p38 mitogen-activated protein kinase pathways. The study shows that d-myo-inositol 1,4,5-tris-phosphate-induced cardiac hypertrophy is mediated by GATA4 but independent from the calcineurin pathway.
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PMID:GATA4-mediated cardiac hypertrophy induced by d-myo-inositol 1,4,5-tris-phosphate. 1625 52

Calcineurin antagonists are known as potent immunosuppressants working particularly on T cells by virtue of their capacity to block nuclear factor of activated T cell (NFAT) activation and translocation to the nucleus. In addition to interleukin (IL)-2 suppression, T helper cell type 1 (Th1) as well as Th2 cytokine transcription is blocked by calcineurin antagonists. Here, we show that calcineurin antagonists such as cyclosporin A (CsA) or tacrolimus can markedly enhance the production of interferon-gamma (IFN-gamma) by human T cells. This increased IFN-gamma production is dependent on T cell receptor (TCR) and CD28 signaling as well as on the presence of IL-12. IL-27, which could mimic the effect of IL-12, was however less potent in inducing IFN-gamma production in the presence of CsA and TCR stimulation. Other cytokines such as IL-23, IL-18, IL-2, or the Th2-related cytokine IL-4 are not able to support a calcineurin antagonist-dependent up-regulation of IFN-gamma. CsA-dependent IFN-gamma production is observable in therapeutic concentrations. The effect is independent of IL-10 or IL-4, as addition of these cytokines could not inhibit the CsA-induced IFN-gamma production. The effect of calcineurin antagonists is associated with an increased c-fos expression and DNA-binding activity of the transcription factor activated protein-1 but not with increased DNA-binding activity of T-bet. Our study further supports the relevance of known calcineurin activities other than NFAT activation. The presented data may help to explain why concomitant infections (resulting in increased IL-12 expression) under therapy with calcineurin antagonists often have a negative impact on the activity of the underlying disease (e.g., autoimmune disease).
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PMID:Critical involvement of IL-12 in IFN-gamma induction by calcineurin antagonists in activated human lymphocytes. 1664 Nov 33

Depolarization of skeletal muscle cells by either high external K(+) or repetitive extracellular field potential pulses induces calcium release from internal stores. The two components of this release are mediated by either ryanodine receptors or inositol 1,4,5-trisphosphate (IP(3)) receptors and show differences in kinetics, amplitude, and subcellular localization. We have reported that the transcriptional regulators including ERKs, cAMP/Ca(2+)-response element binding protein, c-fos, c-jun, and egr-1 are activated by K(+)-induced depolarization and that their activation requires IP(3)-dependent calcium release. We presently describe the activation of the nuclear transcription factor NF-kappaB in response to depolarization by either high K(+) (chronic) or electrical pulses (fluctuating). Calcium transients of relative short duration activate an NF-kappaB reporter gene to an intermediate level, whereas long-lasting calcium increases obtained by prolonged electrical stimulation protocols of various frequencies induce maximal activation of NF-kappaB. This activation is independent of extracellular calcium, whereas calcium release mediated by either ryanodine or IP(3) receptors contribute in all conditions tested. NF-kappaB activation is mediated by IkappaBalpha degradation and p65 translocation to the nucleus. Partial blockade by N-acetyl-l-cysteine, a general antioxidant, suggests the participation of reactive oxygen species. Calcium-dependent signaling pathways such as those linked to calcineurin and PKC also contribute to NF-kappaB activation by depolarization, as assessed by blockade through pharmacological agents. These results suggest that NF-kappaB activation in skeletal muscle cells is linked to membrane depolarization and depends on the duration of elevated intracellular calcium. It can be regulated by sequential activation of calcium release mediated by the ryanodine and by IP(3) receptors.
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PMID:NF-kappaB activation by depolarization of skeletal muscle cells depends on ryanodine and IP3 receptor-mediated calcium signals. 1721 26


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