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 Down syndrome critical region 1 (DSCR1) gene (also known as MCIP1, Adapt78) encodes a regulatory protein that binds to calcineurin catalytic A subunit and acts as a regulator of the calcineurin-mediated signaling pathway. We show in this study that DSCR1 is greatly induced in endothelial cells in response to VEGF, TNF-alpha, and A23187 treatment, and that this up-regulation is inhibited by inhibitors of the calcineurin-NFAT (nuclear factor of activated T cells) signaling pathway as well as by PKC inhibition and a Ca(2+) chelator. We hypothesized that the up-regulation of DSCR1 gene expression in endothelial cells could act as an endogenous feedback inhibitor for angiogenesis by regulating the calcineurin-NFAT signaling pathway. Our transient transfection analyses confirm that the overexpression of DSCR1 abrogates the up-regulation of reporter gene expression driven by both the cyclooxygenase 2 and DSCR1 promoters in response to stimulators. Our results indicate that DSCR1 up-regulation may represent a potential molecular mechanism underlying the regulation of angiogenic genes activated by the calcineurin-NFAT signaling pathway in endothelial cells.
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PMID:VEGF selectively induces Down syndrome critical region 1 gene expression in endothelial cells: a mechanism for feedback regulation of angiogenesis? 1535 55

Evidence from in vivo studies suggests that some inputs to cardiac hypertrophy are opposed by the actions of estrogen. However, the mechanisms of E2 action in this respect are mainly unknown. An important pathway that is utilized by multiple hypertrophic stimuli involves the activation of the tyrosine phosphatase, calcineurin (PP2B). Here we show that 17beta-estradiol (E2) significantly prevents angiotensin II (AngII)- or endothelin-1 (ET-1)-induced new protein synthesis, skeletal muscle actin expression, and increased surface area in cultured rat cardiomyocytes. ET-1 stimulated calcineurin phosphatase activity, resulting in new protein synthesis, and both were prevented by E2. E2 induced the MCIP1 gene, an inhibitor of calcineurin activity, via phosphatidylinositol 3-kinase, transcriptional, and mRNA stability mechanisms. Small interfering RNA for MCIP1 significantly reversed both the E2 restraint of protein synthesis and the inhibition of AngII-induced calcineurin activity. AngII-induced the translocation of the hypertrophic transcription factor, NF-AT, to the nucleus of the cardiomyocyte and stimulated NF-AT transcriptional activity. Both were prevented by E2. AngII also stimulated the activation of ERK and protein kinase C, contributing to cardiac hypertrophy. E2 inhibited these pathways, related to the stimulation of atrial natriuretic peptide production and secretion. Thus, restraint of calcineurin and kinase signaling to the hypertrophic program underlie these important effects of E2.
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PMID:Estrogen inhibits cardiomyocyte hypertrophy in vitro. Antagonism of calcineurin-related hypertrophy through induction of MCIP1. 1589 94

Skeletal muscles are a mosaic of slow and fast twitch myofibers. During embryogenesis, patterns of fiber type composition are initiated that change postnatally to meet physiological demand. To examine the role of the protein phosphatase calcineurin in the initiation and maintenance of muscle fiber types, we used a "Flox-ON" approach to obtain muscle-specific overexpression of the modulatory calcineurin-interacting protein 1 (MCIP1/DSCR1), an inhibitor of calcineurin. Myo-Cre transgenic mice with early skeletal muscle-specific expression of Cre recombinase were used to activate the Flox-MCIP1 transgene. Contractile components unique to type 1 slow fibers were absent from skeletal muscle of adult Myo-Cre/Flox-MCIP1 mice, whereas oxidative capacity, myoglobin content, and mitochondrial abundance were unaltered. The soleus muscles of Myo-Cre/Flox-MCIP1 mice fatigued more rapidly than the wild type as a consequence of the replacement of the slow myosin heavy chain MyHC-1 with a fast isoform, MyHC-2A. MyHC-1 expression in Myo-Cre/Flox-MCIP1 embryos and early neonates was normal. These results demonstrate that developmental patterning of slow fibers is independent of calcineurin, while the maintenance of the slow-fiber phenotype in the adult requires calcineurin activity.
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PMID:Calcineurin is necessary for the maintenance but not embryonic development of slow muscle fibers. 1602 98

Mating and virulence of the human fungal pathogen Cryptococcus neoformans are controlled by calcineurin, a serine-threonine-specific calcium-activated phosphatase that is the target of the immunosuppressive drugs cyclosporine A and FK506. In previous studies, a calcineurin binding protein (Cbp1, Rcn1, Dscr1/Csp1-3/MCIP1-3) that is conserved from yeasts to humans has been identified, but whether this protein functions to regulate calcineurin activity or facilitate calcineurin function as a signaling effector has been unclear. Here we show that, like calcineurin, Cbp1 is required for mating in C. neoformans. By contrast, Cbp1 plays no role in promoting calcineurin-dependent growth at 37 degrees C and is not essential for haploid fruiting. Site-directed mutagenesis studies provide evidence that tandem phosphorylation and dephosphorylation of two serine residues in the conserved SP repeat motif are critical for Cbp1 function. Epistasis analysis supports models in which Cbp1 functions coordinately with calcineurin to direct hyphal elongation during mating. Taken together, these findings provide insights into the roles of Cbp1 as an accessory subunit or effector of calcineurin-specific signaling pathways, which may be features conserved among the calcipressins to govern calcineurin signaling in immune cells, cardiomyocytes, and neurons of multicellular eukaryotes.
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PMID:Calcineurin-binding protein Cbp1 directs the specificity of calcineurin-dependent hyphal elongation during mating in Cryptococcus neoformans. 1615 Dec 46

Heart failure is associated with alterations in cardiac and skeletal muscle energy metabolism resulting in a generalized myopathy. We investigated the molecular and cellular effects of angiotensin-converting enzyme inhibition (ACEi) on skeletal muscle metabolism in infarcted animals. Myocardial infarction (MI) was obtained by left descending coronary artery ligation. Sham, MI, and MI-treated rats (perindopril, 2 mg.kg(-1).day(-1) given 7 days after MI) were studied 1 and 4 mo after surgery. Oxygen consumption of white gastrocnemius (Gas) muscle was studied in saponin-permeabilized fibers, using the main substrates of mitochondrial respiration. mRNA expression of nuclear factors (PGC-1alpha, NRF-2alpha, and mtTFA), involved in the transcription of mitochondrial proteins, and of MCIP1, a marker of calcineurin activation, were also determined. Echocardiographic left ventricular fractional shortening was reduced in both MI and perindopril group after 1 and 4 mo, whereas systemic blood pressure was reduced by 16% only in the MI group after 4 mo. The capacity of Gas to oxidize glutamate-malate, glycerol-triphosphate, or pyruvate (-30%, P < 0.01; -32%, P < 0.05; -33%, P < 0.01, respectively), was greatly decreased. Furthermore, PGC-1alpha (-54%), NRF-2alpha (-45%), and MCIP1 (-84%) gene expression were significantly downregulated. ACEi improved survival, left ventricular function, and blood pressure. Perindopril protected also totally the Gas mitochondrial function and preserved the mRNAs concentration of the mitochondrial transcriptional factors. Moreover, PGC-1alpha correlated with Gas oxidative capacity (r = 0.48), mitochondrial cytochrome-c oxidase (r = 0.65), citrate synthase (r = 0.45) activities, and MCIP1 expression (r = 0.44). Thus ACEi totally prevented MI-induced alterations of skeletal muscle mitochondrial function and protein expression, halting the development of this metabolic myopathy.
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PMID:ACE inhibition prevents myocardial infarction-induced skeletal muscle mitochondrial dysfunction. 1661 54

The RCAN1 protein (previously called calcipressin 1 or MCIP1) binds to calcineurin, a serine/threonine phosphatase (PP2B), and inhibits its activity. Here we demonstrate that regulated overexpression of an RCAN1 transgene (this gene was previously called DSCR1 or Adapt78) also stimulates expression of the GSK-3beta kinase, which can antagonize the action of calcineurin. We also show that GSK-3beta is regulated by RCAN1 at a post-transcriptional level. In humans, high RCAN1 expression is found in the brain, where at least two mRNA isoforms have been reported. Therefore, we further investigated expression of the various RCAN1 isoforms, resulting from differential splicing and alternative promotors in human brain. We detected at least three distinct RCAN1s: RCAN1-1 Short at 31 kDa (RCAN1-1S), RCAN1-1 Long at 38 kDa (RCAN1-1 L), and RCAN1-4. Furthermore, the levels of RCAN1-1S, but not RCAN1-1 L or RCAN1-4 correlated with the levels of GSK-3beta. This suggests that RCAN1-1S might induce production of GSK-3beta in vivo. While RCAN1s can regulate calcineurin and GSK-3beta, it has also been shown that calcineurin and GSK-3beta can regulate RCAN1s. Here we propose a new model (incorporating all these findings) in which cells maintain an equilibrium between RCAN1s, calcineurin, and GSK-3beta.
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PMID:RCAN1 (DSCR1 or Adapt78) stimulates expression of GSK-3beta. 1664 88

In the compensatory state of human left ventricular hypertrophy (LVH), the remodeling processes in the extracellular matrix and the role of calcineurin (Cn) are not completely understood. The present work aimed to analyze the expression and activity of matrix metalloproteinases (MMPs), their endogenous inhibitors (TIMPs), and of Cn in patients with compensated LVH. By semiquantitative RT-PCR, Western blotting, and gelatine zymography, we determined mRNA, protein, and/or enzyme activity levels of MMPs, TIMPs, atrial natriuretic peptide (ANP), Cn subunits, and of the modulatory calcineurin-interacting protein (MCIP) 1. Myocardial samples from patients showing severe aortic stenosis, normal ejection fraction, and compensated LVH were compared with autopsy samples from healthy hearts. LVH patients showed upregulation of CnA-beta mRNA but downregulation of both CnB-alpha mRNA and protein. Total Cn activity (as determined through NF-AT phosphorylation and MCIP1 mRNA expression) was unchanged. There were no differences in gene expression and activities of MMP-2, MMP-9, and of TIMPs 1-4 between LVH patients and controls. As expected, ANP mRNA expression was high in LVH patients. We propose a prominent role for CnB in controlling Cn activity in compensated LVH. At this stage of the disease, MMP and TIMP activities are balanced.
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PMID:Calcineurin and matrix protein expression in cardiac hypertrophy: evidence for calcineurin B to control excessive hypertrophic signaling. 1668 6

Down syndrome candidate region 1 (DSCR1), an endogenous inhibitor of calcineurin, inhibits the expression of genes involved in the inflammatory response. To elucidate the molecular basis of these anti-inflammatory effects, we analyzed the role of DSCR1 in the regulation of NF-kappaB transactivation using glioblastoma cells stably transfected with DSCR1.4 or its truncation mutants (DSCR1.4-(1-133) and DSCR1.4-(134-197)). Overexpression of DSCR1.4 significantly attenuated the induction of cyclooxygenase-2 (COX-2) expression by phorbol 12-myristate 13-acetate (PMA) via a calcineurin-independent mechanism. Experiments using inhibitors of the signaling molecules for NF-kappaB activation showed that NF-kappaB is responsible for the induction of COX-2. Full-length and truncated DSCR1.4 decreased the steady-state activity of NF-kappaB as well as PMA-induced activation of NF-kappaB, which correlated with attenuation of COX-2 induction. DSCR1.4 did not affect the PMA-stimulated phosphorylation or degradation kinetics of IkappaBalpha; however, DSCR1.4 significantly decreased the basal turnover rate of IkappaBalpha and consequently up-regulated its steady-state level. In the same context, knockdown of endogenous DSCR1.4 increased the turnover rate of IkappaBalpha as well as COX-2 induction. These results suggest that DSCR1 attenuates NF-kappaB-mediated transcriptional activation by stabilizing its inhibitory protein, IkappaBalpha.
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PMID:Down syndrome candidate region 1 increases the stability of the IkappaBalpha protein: implications for its anti-inflammatory effects. 1706 74

Down syndrome candidate region 1 (DSCR1) is one of more than 50 genes located in a region of chromosome 21 that has been implicated in Down syndrome. DSCR1 can be expressed as four isoforms, one of which, isoform 4 (DSCR1-4), has recently been found to be strongly induced by vascular endothelial growth factor A (VEGF-A(165)) and to provide a negative feedback loop that inhibits VEGF-A(165)-induced endothelial cell proliferation in vitro and angiogenesis in vivo. We report here that another DSCR1 isoform, DSCR1-1L, is also up-regulated by VEGF-A(165) in cultured endothelial cells and is strongly expressed in several types of pathologic angiogenesis in vivo. In contrast to DSCR1-4, the overexpression of DSCR1-1L induced the proliferation and activation of the transcription factor NFAT in cultured endothelial cells and promoted angiogenesis in Matrigel assays in vivo, even in the absence of VEGF-A. Similarly, small interfering RNAs specific for DSCR1-1L and DSCR1-4 had opposing inhibitory and stimulatory effects, respectively, on these same functions. DSCR1-4 is thought to inhibit angiogenesis by inactivating calcineurin, thereby preventing activation and nuclear translocation of NFAT, a key transcription factor. In contrast, DSCR1-1L, regulated by a different promoter than DSCR1-4, activates NFAT and its proangiogenic activity is inhibited by cyclosporin, an inhibitor of calcineurin. In sum, DSCR1-1L, unlike DSCR1-4, potently activates angiogenesis and could be an attractive target for antiangiogenesis therapy.
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PMID:Down syndrome candidate region 1 isoform 1 mediates angiogenesis through the calcineurin-NFAT pathway. 1711 39

Pressure overload is the major stimulus for cardiac hypertrophy. Accumulating evidence suggests an important role for calcium-induced activation of calcineurin in mediating hypertrophic signaling. Hypertrophy is an important risk factor for cardiovascular morbidity and mortality. We therefore employed an in vitro mechanical stretch model of cultured neonatal cardiomyocytes to evaluate proposed mechanisms of calcium-induced calcineurin activation in terms of inhibition of calcineurin activity and hypertrophy. The protein/DNA ratio and ANP gene expression were used as markers for stretch-induced hypertrophy. Stretch increased the calcineurin activity, MCIP1 gene expression and DNA binding of NFATc as well as the protein/DNA ratio and ANP mRNA in a significant manner. The specific inhibitor of calcineurin, cyclosporin A, inhibited the stretch-induced increase in calcineurin activity, MCIP1 gene expression and hypertrophy. The L-type Ca2+ channel blocker nifedipine and a blocker of the Na+/H+ exchanger (cariporide) both suppressed stretch-dependent enhanced calcineurin activity and hypertrophy. Also application of a blocker of the Na+/Ca2+ exchanger (KB-R7943) was effective in preventing calcineurin activation and increases in the protein/DNA ratio. Inhibition of capacitative Ca2+ entry with SKF 96365 was also sufficient to abrogate calcineurin activation and hypertrophy. The blocker of stretch-activated ion channels, streptomycin, was without effect on stretch-induced hypertrophy and calcineurin activity. The present work suggests that of the proposed mechanisms for the calcium-induced activation of calcineurin (L-type Ca2+ channels, capacitative Ca2+ entry, Na+/H+ exchanger, Na+/Ca2+ exchanger and stretch-activated channels) all but stretch-activated channels are possible targets for the inhibition of hypertrophy.
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PMID:Mechanisms of Ca2+-dependent calcineurin activation in mechanical stretch-induced hypertrophy. 1726 7


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