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 transcription factor NFATc1 may be involved in slow skeletal muscle gene expression. NFATc1 translocates from cytoplasm to nuclei during slow fiber type electrical stimulation of skeletal muscle fibers because of activation of the Ca(2+)-dependent phosphatase calcineurin, resulting in nuclear factor of activated T-cells (NFAT) dephosphorylation and consequent exposure of its nuclear localization signal. Here, we find that unstimulated adult skeletal muscle fibers exhibit a previously unanticipated nucleocytoplasmic shuttling of NFATc1 without appreciable nuclear accumulation. In resting fibers, the nuclear export inhibitor leptomycin B caused nuclear accumulation of NFATc1 (but not of isoform NFATc3) and formation of NFATc1 intranuclear bodies independent of calcineurin. The rate of nuclear uptake of NFATc1 was 4.6 times lower in resting fibers exposed to leptomycin B than during electrical stimulation. Inhibitors of glycogen synthase kinase and protein kinase A or of casein kinase 1 slowed the decay of nuclear NFATc1 after electrical stimulation, but they did not cause NFATc1 nuclear uptake in unstimulated fibers. We propose that two nuclear translocation pathways, one pathway mediated by calcineurin activation and NFAT dephosphorylation and the other pathway independent of calcineurin and possibly independent of NFAT dephosphorylation, determine the distribution of NFATc1 between cytoplasm and nuclei in adult skeletal muscle.
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PMID:Activity- and calcineurin-independent nuclear shuttling of NFATc1, but not NFATc3, in adult skeletal muscle fibers. 1643 3

Calpain, a Ca(2+)-dependent cysteine protease, in vitro converts calcineurin (CaN) to constitutively active forms of 45 kDa and 48 kDa by cleaving the autoinhibitory domain of the 60 kDa subunit. In a mouse middle cerebral artery occlusion (MCAO) model, calpain converted the CaN A subunit to the constitutively active form with 48 kDa in vivo. We also confirmed increased Ca(2+)/CaM-independent CaN activity in brain extracts. The generation of constitutively active and Ca(2+)/CaM-independent activity of CaN peaked 2 h after reperfusion in brain extracts. Increased constitutively active CaN activity was associated with dephosphorylation of dopamine-regulated phosphoprotein-32 in the brain. Generation of constitutively active CaN was accompanied by translocation of nuclear factor of activated T-cells (NFAT) into nuclei of hippocampal CA1 pyramidal neurons. In addition, a novel calmodulin antagonist, DY-9760e, blocked the generation of constitutively active CaN by calpain, thereby inhibiting NFAT nuclear translocation. Together with previous studies indicating that NFAT plays a critical role in apoptosis, we propose that calpain-induced CaN activation in part mediates delayed neuronal death in brain ischemia.
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PMID:Generation of constitutively active calcineurin by calpain contributes to delayed neuronal death following mouse brain ischemia. 1680 17

The growth and function of organs such as pancreatic islets adapt to meet physiological challenges and maintain metabolic balance, but the mechanisms controlling these facultative responses are unclear. Diabetes in patients treated with calcineurin inhibitors such as cyclosporin A indicates that calcineurin/nuclear factor of activated T-cells (NFAT) signalling might control adaptive islet responses, but the roles of this pathway in beta-cells in vivo are not understood. Here we show that mice with a beta-cell-specific deletion of the calcineurin phosphatase regulatory subunit, calcineurin b1 (Cnb1), develop age-dependent diabetes characterized by decreased beta-cell proliferation and mass, reduced pancreatic insulin content and hypoinsulinaemia. Moreover, beta-cells lacking Cnb1 have a reduced expression of established regulators of beta-cell proliferation. Conditional expression of active NFATc1 in Cnb1-deficient beta-cells rescues these defects and prevents diabetes. In normal adult beta-cells, conditional NFAT activation promotes the expression of cell-cycle regulators and increases beta-cell proliferation and mass, resulting in hyperinsulinaemia. Conditional NFAT activation also induces the expression of genes critical for beta-cell endocrine function, including all six genes mutated in hereditary forms of monogenic type 2 diabetes. Thus, calcineurin/NFAT signalling regulates multiple factors that control growth and hallmark beta-cell functions, revealing unique models for the pathogenesis and therapy of diabetes.
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PMID:Calcineurin/NFAT signalling regulates pancreatic beta-cell growth and function. 1698 14

Calcineurin (CaN) assists T-cell activation, growth and differentiation of skeletal and cardiac myocytes, memory, and apoptosis. It also activates transcription of the nuclear factor of activated T-cells (NFAT) family including hypertrophic target genes. It has been reported that the modulatory calcineurin-interacting protein (MCIP) inhibits the CaN activity and thereby reduces the hypertrophic response. However, it has been shown that MCIP facilitates or permits the hypertrophic response under some stress conditions such as isoproterenol infusion or pressure overload by transverse aortic constriction. As there is no direct experimental evidence that can explain these paradoxical phenomena, there has been a controversy concerning the functional role of MCIP in developing the hypertrophic response. It is therefore crucial to establish a hypothesis that can clearly explain these phenomena. Towards this end, we propose in this paper a hypothesis that is based on available experimental evidence as well as mathematical modeling and computer simulations. We hypothesize that there is a threshold in the nuclear NFAT concentration above which MCIP is switched on. Below this threshold, the inhibition of active CaN by MCIP is negligible, while the activated protein kinase increases the dissociation rate of the CaN/MCIP complex. This leads to an augmentation of active CaN. This mechanism realizes the positive effect (i.e., removing any negative feedback) of MCIP in the hypertrophic response. On the other hand, the over-expression of active CaN increases nuclear NFAT to values above the threshold, while CaN is inhibited through binding of MCIP (expressed by the nuclear NFAT). This mechanism realizes the introduction of a negative feedback mechanism. To unravel this switching feedback mechanism, we have developed a mathematical model for which computer simulations are in agreement with the existing experimental data. The simulations demonstrate how the apparently paradoxical behavior can emerge as a result of cellular conditions.
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PMID:Switching feedback mechanisms realize the dual role of MCIP in the regulation of calcineurin activity. 1704 57

Calcium is a key element in intracellular signaling in skeletal muscle. Changes in intracellular calcium levels are thought to mediate the fast-to-slow transformation of muscle fiber type. One factor implicated in gene regulation in adult muscle is the nuclear factor of activated T-cells (NFAT) isoform c1, whose dephosphorylation by the calcium/calmodulin-dependent phosphatase calcineurin facilitates its nuclear translocation. Here, we report that differentiated C2C12 myotubes predominantly expressing fast-type MyHCII protein undergo fast-to-slow transformation following calcium-ionophore treatment, with several transcription factors and a transcriptional coactivator acting in concert to upregulate the slow myosin heavy chain (MyHC) beta promoter. Transient transfection assays demonstrated that the calcineurin/NFATc1 signaling pathway is essential for MyHCbeta promoter activation during transformation of C2C12 myotubes but is not sufficient for complete fast MyHCIId/x promoter inhibition. Along with NFATc1, myocyte enhancer factor-2D (MEF-2D) and the myogenic transcription factor MyoD transactivated the MyHCbeta promoter in calcium-ionophore-treated myotubes in a calcineurin-dependent manner. To elucidate the mechanism involved in regulating MyHCbeta gene expression, we analyzed the -2.4-kb MyHCbeta promoter construct for cis-regulatory elements. Using electrophoretic mobility shift assays (EMSAs), chromatin immunoprecipitation assays (ChIP), and nuclear complex coimmunoprecipitation (NCcoIP) assays, we demonstrated calcium-ionophore-induced binding of NFATc1 to a NFAT consensus site adjacent to a MyoD-binding E-box. At their respective binding sites, both NFATc1 and MyoD recruited the transcriptional coactivator p300, and in turn, MEF-2D bound to the MyoD complex. The calcium-ionophore-induced effects on the MyHCbeta promoter were shown to be calcineurin-dependent. Together, our findings demonstrate calcium-ionophore-induced activation of the beta MyHC promoter by NFATc1, MyoD, MEF-2D, and p300 in a calcineurin-dependent manner.
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PMID:Activation of the beta myosin heavy chain promoter by MEF-2D, MyoD, p300, and the calcineurin/NFATc1 pathway. 1711 65

Bradykinin produced at sites of tissue injury and inflammation elicits acute pain and alters the sensitivity of nociceptive neurons to subsequent stimuli. We tested the hypothesis that bradykinin could elicit long-lasting changes in nociceptor function by activating members of the nuclear factor of activated T-cells (NFAT) family of transcription factors. Bradykinin activation of B2 receptors evoked concentration-dependent (EC50 = 6.0 +/- 0.3 nM) increases in intracellular Ca2+ concentration ([Ca2+]i) in a proportion of dorsal root ganglion neurons in primary culture. These [Ca2+] increases were sensitive to inhibition of phospholipase C (PLC) and depletion of Ca2+ stores. In neurons expressing a green fluorescent protein (GFP)-NFAT4 fusion protein, a 2-min exposure to bradykinin induced the translocation of GFP-NFAT4 from the cytoplasm to the nucleus. Translocation was partially inhibited by the removal of extracellular Ca2+ and was blocked by inhibition of calcineurin. Furthermore, bradykinin triggered a concentration-dependent increase in NFAT-mediated transcription of a luciferase gene reporter (EC50 = 24.2 +/- 0.1 nM). This depended on the B2 receptor, PLC activation, and inositol triphosphate-mediated Ca2+ release. Transcription was not inhibited by capsazepine. Finally, as indicated by quantitative reverse transcription-polymerase chain reaction, bradykinin elicited an increase in cyclooxygenase mRNA. This increase was sensitive to calcineurin and B2 receptor inhibition. These findings suggest a mechanism by which short-lived bradykinin-mediated stimuli can enact lasting changes in nociceptor function and sensitivity.
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PMID:Bradykinin-induced nuclear factor of activated T-cells-dependent transcription in rat dorsal root ganglion neurons. 1748 65

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) play key roles in the development of inflammation-induced hyperalgesia by triggering the expression of pro-nociceptive genes within primary afferent and spinal neurons. However, the mechanisms by which neurotrophins elicit gene expression remain largely unknown. Recently, neurotrophins have been shown to activate members of the calcineurin (CaN)-regulated, nuclear factor of activated T-cells (NFATc) family of transcription factors within brain. Thus, we hypothesized that NFATc transcription factors couple neurotrophin signaling to gene expression within primary afferent and spinal neurons. In situ hybridization revealed NFATc4 mRNA within the dorsal root ganglion and spinal cord. In cultured dorsal root ganglion cells, NGF triggered NFAT-dependent transcription in a CaN-sensitive manner. Further, increased BDNF expression following NGF treatment relied on CaN, thereby suggesting that NGF regulates BDNF transcription via activation of NFATc4. Within cultured spinal cells, BDNF also activated CaN-dependent, NFAT-regulated gene expression. Interestingly, BDNF stimulation increased the expression of the pro-nociceptive genes cyclooxygenase-2, neurokinin-1 receptor, inositol trisphosphates receptor type 1, and BDNF itself, through both NFAT-dependent and NFAT-independent transcriptional mechanisms. Our results suggest that regulation of pro-nociceptive genes through activation of NFAT-dependent transcription is one mechanism by which NGF and BDNF signaling contributes to the development of persistent pain states.
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PMID:Neurotrophin activation of NFAT-dependent transcription contributes to the regulation of pro-nociceptive genes. 1748 77

The Forkhead box protein P3 (FOXP3) is a master cell lineage modulator in CD4(+)CD25(+) natural regulatory T cell (Treg) development. The Treg set of cells, also called T suppressor cells, play an essential role in natural Treg-mediated suppression of various types of immune cells. Suppression can be manifest by a cell-cell contact set of events, and recent evidence also supports soluble mediators. FOXP3 was previous identified as a passive transcriptional repressor which associates with nuclear factor of activated T-cells, cytoplasmic, and calcineurin-dependent 2 (NFATc2) as well as several other transcriptional factors including nuclear factor kappa-B (NFkappaB) and acute myeloid leukemia 1(AML1)/runt-related transcription factor 1(RUNX1). We found FOXP3 could actively repress transcription by recruiting distinct histone acetyltransferases and histone deacetylases to function as a co-repressor complex. The identification of enzymatic factors operative as essential participants in FOXP3-mediated transcriptional repression provides a practical basis for therapeutically modulating the activity of FOXP3 in immune suppression. Here we briefly summarize recent progress in our understanding of the biochemistry of FOXP3-mediated transcriptional regulation.
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PMID:FOXP3 actively represses transcription by recruiting the HAT/HDAC complex. 1759 52

In endothelial cells, binding of vascular endothelial growth factor (VEGF) to VEGF receptor 2 leads to the activation of the serine/threonine phosphatase calcineurin, dephosphorylation of the nuclear factor of activated T-cells (NF-AT) transcription factors, translocation of NF-AT to the nucleus, and expression of angiogenesis-related genes such as Cox-2. Down syndrome candidate region 1 (DSCR1) is transactivated by NF-AT nuclear translocation, and subsequently inhibits calcineurin activity, forming a negative feedback loop. While DSCR1 has a clearly defined role as an endogenous inhibitor of VEGF-calcineurin-mediated angiogenesis in endothelial cells, the function of the DSCR1 family member, DSCR1-like 1 (DSCR1-L1), has not yet been investigated in endothelial cells. Here we show that a panel of pro-angiogenic factors, including VEGF, basic fibroblast growth factor (bFGF), angiopoietin 1, hepatocyte growth factor, as well as triiodo-l-thyronine (T(3)), does not induce DSCR1-L1 up-regulation in endothelial cells, while VEGF potently up-regulates DSCR1. To investigate the effects of DSCR1-L1 on endothelial cell function, we cloned the gene into a lentiviral vector and overexpressed DSCR1-L1 in human umbilical vein endothelial cells. Constitutive DSCR1-L1 overexpression prevented the nuclear translocation of NF-ATc1 in response to VEGF, underscoring its role as a calcineurin inhibitor. Additionally, DSCR1-L1-transduced cells inhibited VEGF-induced endothelial cell migration, proliferation, and tube formation by 36, 77, and 39%, respectively, compared to cells infected with control virus. Overexpression of DSCR1-L1 in the transformed endothelial cell line Sven 1 ras also resulted in decreased proliferation. Our findings demonstrate that DSCR1-L1 is constitutively expressed in endothelial cells and acts similar to DSCR1 in inhibiting calcineurin activity and restraining VEGF-mediated angiogenesis.
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PMID:Down syndrome candidate region 1-like 1 (DSCR1-L1) mimics the inhibitory effects of DSCR1 on calcineurin signaling in endothelial cells and inhibits angiogenesis. 1761 Sep 1

We recently demonstrated that a constitutively active form of calcineurin (CaN) is generated by calpain-mediated limited proteolysis following brain ischemia. The calpain-induced CaN activation mediated delayed neuronal death through translocation of nuclear factor of activated T-cells (NFAT) into nuclei after brain ischemia. We also previously demonstrated that activation of forkhead in rhabdomyosarcoma (FKHR), a forkhead transcription factor and substrate of protein kinase-B (Akt), mediated ischemia-induced neuronal death through Fas-ligand expression in gerbil hippocampus. FKHR activation occurred through decreased Akt activity and concomitant dephosphorylation mediated by undefined phosphatases. In this study, we show that phosphorylated Ser-256 of FKHR is dephosphorylated by constitutively active CaN and that in turn FKHR forms a complex with CaN that is translocated into nuclei after brain ischemia. After nuclear translocation of NFAT and FKHR, both NFAT and FKHR stimulated expression of Fas-ligand by binding to its promoter region. Consistent with activation of the Fas-ligand promoter by FKHR dephosphorylation, Fas-ligand expression increased 2 days after ischemia/reperfusion, and treatment with the CaN inhibitor FK506 inhibited that expression. These results suggest that FKHR is a downstream target of CaN and that constitutively active CaN mediates delayed neuronal death through Fas-ligand expression via up-regulation of both NFAT and FKHR transcriptional activity in brain ischemia.
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PMID:Constitutively active calcineurin mediates delayed neuronal death through Fas-ligand expression via activation of NFAT and FKHR transcriptional activities in mouse brain ischemia. 1766 23


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