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 four Ca(2+)-dependent NFATc proteins are both signal transducers and transcription factors that reside in the cytoplasm until dephosphorylation by calcineurin. Dephosphorylation exposes nuclear import sequences and sends NFATc proteins into the nucleus where they assemble with nuclear partners into NFAT transcription complexes. Recent genetic studies have indicated that calcineurin-NFAT signaling is a major determinant of vertebrate morphogenesis and development. Mice lacking calcineurin activity show a complete block in positive selection of CD4 and CD8 double-positive thymocytes, yet the role of the NFATc proteins in T cell development has been controversial. In this study, we address the requirement for NFATc3 in T cell development by generating NFATc3 conditional knockout mice. We show that specific deletion of NFATc3 in thymocytes causes a partial block at the double-negative stage 3 and also a partial block in positive selection. Furthermore, the defect does not become more pronounced when NFATc2 is also absent, consistent with the fact that NFATc2-null mice do not have a T cell developmental defect. Expression of a nuclear (and constitutively active) NFATc1 even at subphysiological levels can rescue the transition of double-negative to double-positive thymocytes in RAG-null mice, but is unable to rescue development of CD4 and CD8 single-positive cells. In addition to NFATc3, this suggests a role for NFATc1 in T cell development. Our studies indicate that the signals that direct positive selection likely use both NFATc1 and NFATc3 downstream of calcineurin.
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PMID:Selective role of NFATc3 in positive selection of thymocytes. 1757 27

The calcium-dependent transcription factor NFATc3, which is a member of the nuclear factor of activated T cells (NFAT) family of transcription factors, is critical for embryonic vascular development and differentiation. Despite its potential importance, nothing is known about NFATc3 regulation in the brain microcirculation. In the present study, we sought to investigate the role that glutamate, possibly through astrocytic communication, plays in the control of NFATc3 regulation in pericytes from parenchymal microvessels. Coronal cortical slices from neonatal rats were subjected to electrical field stimulation or were treated with the metabotropic glutamate receptor agonist (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD). NFATc3, glial fibrillary acidic protein (an astrocyte-specific marker), and platelet-derived growth factor-beta-receptor (a pericyte-specific marker) were detected by immunofluorescence. Electrical field stimulation induced NFATc3 nuclear accumulation in pericytes. This response was dependent on neuronal activity and group I metabotropic glutamate receptor (mGluR) activation. In addition, t-ACPD significantly increased NFATc3 nuclear accumulation in both astrocytes and pericytes. NFATc3 nuclear accumulation in pericytes was prevented when astrocytic function was abolished with the gliotoxin L-alpha-aminoadipate or by the inhibition of calcineurin, cyclooxygenase, and nitric oxide synthase. This is the first study to report NFATc3 expression in pericytes from parenchymal microvessels and in astrocytes from native tissue. Our results suggest a model by which glutamate, via mGluR activation, may regulate gene transcription in pluripotent vascular pericytes.
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PMID:Activity-dependent NFATc3 nuclear accumulation in pericytes from cortical parenchymal microvessels. 1788 10

Skeletal muscle atrophy is a prominent and disabling feature in many chronic diseases. Prevention or reversal of muscle atrophy by stimulation of skeletal muscle growth could be an important therapeutic strategy. Glycogen synthase kinase 3beta (GSK-3beta) has been implicated in the negative regulation of skeletal muscle growth. Since myogenic differentiation is an essential part of muscle growth, we investigated if inhibition of GSK-3beta is sufficient to stimulate myogenic differentiation and whether this depended on regulation of the transcription factor nuclear factor of activated T-cells (NFAT). In both myogenically converted mouse embryonic fibroblasts and C2C12 myoblasts, deficiency of GSK-3beta protein (activity) resulted in enhanced myotube formation and muscle-specific gene expression during differentiation, which was reversed by reintroduction of wild type but not kinase-inactive (K85R) GSK-3beta. In addition, GSK-3beta inhibition restored myogenic differentiation following calcineurin blockade, which suggested the involvement of NFAT. GSK-3beta-deficient mouse embryonic fibroblasts or myoblasts displayed enhanced nuclear translocation of NFATc3 and elevated NFAT-sensitive promoter transactivation, which was reduced by reintroducing wild type, but not K85R GSK-3beta. Overexpression of NFATc3 increased muscle gene promoter transactivation, which was abolished by co-expression of wild type GSK-3beta. Finally, stimulation of muscle gene expression observed following GSK-3beta inhibition was strongly attenuated in NFATc3-deficient myoblasts, indicating that this response requires NFATc3. Collectively, our data demonstrate negative regulation of myogenic differentiation by GSK-3beta through a transcriptional mechanism that depends on NFATc3. Inhibition of GSK-3beta may be a potential strategy in prevention or treatment of muscle atrophy.
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PMID:Glycogen synthase kinase 3 suppresses myogenic differentiation through negative regulation of NFATc3. 1797 34

In order to exert their activity, transcription factors must be transported to the nucleus. Certain transcription factors have also been found on mitochondria. Here, the localization of RelB and NFATx in the mitochondrial fractions of normal thymocytes and thymic lymphoma cells is shown for the first time. CREB was only found in the nucleus, while p50 (NFkappaB) was found in both the nucleus and the cytoplasm, but outside the mitochondria. The translocation of transcription factors to the mitochondria is differentially regulated. Unlike RelB, which is always present in the mitochondrial fraction, NFATx appeared on the mitochondria in cells treated with ionomycin together with an immunosuppressant and inhibitor of calcineurin (FK506). This data reveals that the mitochondrial localization of some transcription factors is precisely controlled by a calcium signal sensitive to FK506 in T cells.
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PMID:The mitochondrial localization of RelB and NFATx in immature T cells. 1846 95

Calcineurin/NFAT signaling is involved in multiple aspects of skeletal muscle development and disease. The myogenic basic helix-loop-helix transcription factors, MyoD, myogenin, Myf5, and MRF4 specify the myogenic lineage. Here we show that calcineurin/NFAT (nuclear factor of activated T cells) signaling is required for primary myogenesis by transcriptional cooperation with the basic helix-loop-helix transcription factor MyoD. Calcineurin/NFAT signaling is involved in myogenin expression in differentiating myoblasts, where the myogenic regulatory factor MyoD synergistically cooperates with NFATc2/c3 at the myogenin promoter. Using gel shift and chromatin immunoprecipitation assays, we identified two conserved NFAT binding sites in the myogenin promoter that were occupied by NFATc3 upon skeletal muscle differentiation. The transcriptional integration between NFATc3 and MyoD is crucial for primary myogenesis in vivo, as myogenin expression is weak in myod:nfatc3 double null embryos, whereas myogenin expression is unaffected in embryos with null mutations for either factor alone. Thus, the combined findings provide a novel transcriptional paradigm for the first steps of myogenesis, where a calcineurin/NFATc3 pathway regulates myogenin induction in cooperation with MyoD during myogenesis.
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PMID:Cooperative synergy between NFAT and MyoD regulates myogenin expression and myogenesis. 1867 76

Transient outward K+ current (I to) downregulation following sustained tachycardia in vivo is usually attributed to tachycardiomyopathy. This study assessed potential direct rate regulation of cardiac I(to) and underlying mechanisms. Cultured adult canine left ventricular cardiomyocytes (37 degrees C) were paced continuously at 1 or 3 Hz for 24 hours. I to was recorded with whole-cell patch clamp. The 3-Hz pacing reduced I to by 44% (P<0.01). Kv4.3 mRNA and protein expression were significantly reduced (by approximately 30% and approximately 40%, respectively) in 3-Hz paced cells relative to 1-Hz cells, but KChIP2 expression was unchanged. Prevention of Ca2+ loading with nimodipine or calmodulin inhibition with W-7, A-7, or W-13 eliminated 3-Hz pacing-induced I to downregulation, whereas downregulation was preserved in the presence of valsartan. Inhibition of Ca2+/calmodulin-dependent protein kinase (CaMK)II with KN93, or calcineurin with cyclosporin A, also prevented I to downregulation. CaMKII-mediated phospholamban phosphorylation at threonine 17 was increased in 3-Hz paced cells, compatible with enhanced CaMKII activity, with functional significance suggested by acceleration of the Ca2+i transient decay time constant (Indo 1-acetoxymethyl ester microfluorescence). Total phospholamban expression was unchanged, as was expression of Na+/Ca2+ exchange and sarcoplasmic reticulum Ca2+-ATPase proteins. Nuclear localization of the calcineurin-regulated nuclear factor of activated T cells (NFAT)c3 was increased in 3-Hz paced cells compared to 1-Hz (immunohistochemistry, immunoblot). INCA-6 inhibition of NFAT prevented I to reduction in 3-Hz paced cells. Calcineurin activity increased after 6 hours of 3-Hz pacing. CaMKII inhibition prevented calcineurin activation and NFATc3 nuclear translocation with 3-Hz pacing. We conclude that tachycardia downregulates I to expression, with the Ca2+/calmodulin-dependent CaMKII and calcineurin/NFAT systems playing key Ca2+-sensing and signal-transducing roles in rate-dependent I to control.
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PMID:Mechanisms underlying rate-dependent remodeling of transient outward potassium current in canine ventricular myocytes. 1881 10

CHP2 (calcineurin B homologous protein 2) was initially identified as a tumor-associated antigen highly expressed in hepatocellular carcinoma. Its biological function remains largely unknown except for a potential role in transmembrane Na(+)/H(+) exchange. In the present study, we observed that ectopic expression of CHP2 promoted the proliferation of HEK293 cells, whereas knockdown of endogenous CHP2 expression in HepG2 inhibited cell proliferation. When inoculated into nude mice, CHP2 transfected HEK293 cells displayed markedly increased oncogenic potential. In analysis of the underlying molecular mechanisms, we found that like calcineurin B, CHP2 was able to bind to and stimulate the phosphatase activity of calcineurin A. In accord with this, CHP2-transfected cells showed increased nuclear presence of NFATc3 (nuclear factor of activated T cells) and enhanced NFAT activity. Finally, both accelerated cell proliferation and NFAT activation following CHP2 transfection could be suppressed by the calcineurin inhibitor cyclosporine A, suggesting an intrinsic connection between these events. Taken together, our results highlighted a potential role of CHP2 in tumorigenesis and revealed a novel function of CHP2 as an activator of the calcineurin/NFAT signaling pathway.
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PMID:CHP2 activates the calcineurin/nuclear factor of activated T cells signaling pathway and enhances the oncogenic potential of HEK293 cells. 1881 28

Many excitable cells express L-type Ca(2+) channels (LTCCs), which participate in physiological and pathophysiological processes ranging from memory, secretion, and contraction to epilepsy, heart failure, and hypertension. Clusters of LTCCs can operate in a PKCalpha-dependent, high open probability mode that generates sites of sustained Ca(2+) influx called "persistent Ca(2+) sparklets." Although increased LTCC activity is necessary for the development of vascular dysfunction during hypertension, the mechanisms leading to increased LTCC function are unclear. Here, we tested the hypothesis that increased PKCalpha and persistent Ca(2+) sparklet activity contributes to arterial dysfunction during hypertension. We found that PKCalpha and persistent Ca(2+) sparklet activity is indeed increased in arterial myocytes during hypertension. Furthermore, in human arterial myocytes, PKCalpha-dependent persistent Ca(2+) sparklets activated the prohypertensive calcineurin/NFATc3 signaling cascade. These events culminated in three hallmark signs of hypertension-associated vascular dysfunction: increased Ca(2+) entry, elevated arterial [Ca(2+)](i), and enhanced myogenic tone. Consistent with these observations, we show that PKCalpha ablation is protective against the development of angiotensin II-induced hypertension. These data support a model in which persistent Ca(2+) sparklets, PKCalpha, and calcineurin form a subcellular signaling triad controlling NFATc3-dependent gene expression, arterial function, and blood pressure. Because of the ubiquity of these proteins, this model may represent a general signaling pathway controlling gene expression and cellular function.
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PMID:The control of Ca2+ influx and NFATc3 signaling in arterial smooth muscle during hypertension. 1883 65

In heart, pore-forming Kv4 alpha channel subunits underlie the K(+) transient outward current (I(to)). Expression of Kv4 is greater in left ventricular epicardial (EPI) than in endocardial (ENDO) cells, resulting in larger I(to) in EPI than in ENDO cells. In adult ventricular myocytes, the transcription factor NFATc3 suppresses Kv4 expression. NFATc3 activity is higher in ENDO than in EPI cells and this has been proposed to contribute to heterogeneous Kv4 expression across the left ventricular free wall. Here, we tested the hypothesis that regional activation of NFATc3 signaling dissipates the gradient of I(to) density across the mouse left ventricle during chronic activation of beta adrenergic signaling. [Ca(2+)](i), calcineurin, and NFAT activity were larger in ENDO than in EPI myocytes. Infusion of the beta adrenergic receptor agonist isoproterenol increased [Ca(2+)](i), calcineurin, and NFAT activity in EPI, but not in ENDO myocytes, leading to equalization of these parameters in EPI and ENDO cells. This was accompanied by dissipation of the transmural gradient in Kv4.2 expression and I(to) density. Unlike wild type, ENDO or EPI myocytes from beta1 adrenergic receptor-null and NFATc3-null mice did not undergo changes in I(to) density during isoproterenol infusion. Collectively, these data suggest that calcineurin and NFATc3 signaling contributes to the loss of heterogeneous Kv4 expression, and hence I(to) density, in the mouse left ventricle during chronic beta adrenergic stimulation.
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PMID:NFATc3-dependent loss of I(to) gradient across the left ventricular wall during chronic beta adrenergic stimulation. 1902 24

Schwann cells develop from multipotent neural crest cells and form myelin sheaths around axons that allow rapid transmission of action potentials. Neuregulin signaling through the ErbB receptor regulates Schwann cell development; however, the downstream pathways are not fully defined. We find that mice lacking calcineurin B1 in the neural crest have defects in Schwann cell differentiation and myelination. Neuregulin addition to Schwann cell precursors initiates an increase in cytoplasmic Ca2+, which activates calcineurin and the downstream transcription factors NFATc3 and c4. Purification of NFAT protein complexes shows that Sox10 is an NFAT nuclear partner and synergizes with NFATc4 to activate Krox20, which regulates genes necessary for myelination. Our studies demonstrate that calcineurin and NFAT are essential for neuregulin and ErbB signaling, neural crest diversification, and differentiation of Schwann cells.
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PMID:Calcineurin/NFAT signaling is required for neuregulin-regulated Schwann cell differentiation. 1917 36


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