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)

Induction of the Epstein-Barr virus (EBV) lytic cycle by crosslinking surface immunoglobulin is inhibited by the immunosuppressants cyclosporin A (CsA) and FK506. This correlates with the ability of CsA to inhibit Ca2+-dependent transcription of the lytic cycle switch gene BZLF1. It is shown here that CsA sensitivity maps to three sites (ZIA, ZIB and ZID) that bind the serum response factor-related protein MEF2D. A synthetic promoter containing multiple copies of a MEF2D site from Zp, in conjunction with a CREB/AP-1 site (ZII) from Zp, exhibits CsA-sensitive inducibility. Furthermore, the Zp MEF2D sites were functionally interchangeable with MEF2 sites derived from heterologous promoters. While no evidence of a NFAT family member binding to either the MEF2 or CREB/AP-1 sites was obtained, it could be demonstrated that CsA-sensitive induction of Zp was mediated by calcineurin and NFATc2 in synergy with either phorbol ester or especially with the EBV-induced Ca2+/calmodulin-dependent kinase type IV/Gr. These studies identify Zp as prototypic of a novel class of CsA-sensitive and NFAT-dependent promoters defined by the presence of MEF2 sites.
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PMID:Cyclosporin A-sensitive induction of the Epstein-Barr virus lytic switch is mediated via a novel pathway involving a MEF2 family member. 900 75

Ca(2+) induction of a subset of cellular and viral immediate-early activation genes in lymphocytes has been previously mapped to response elements recognized by the MEF2 family of transcription factors. Here, we demonstrate that Ca(2+) activation of MEF2 response elements in T lymphocytes is mediated in synergy by two Ca(2+)/calmodulin-dependent enzymes, the phosphatase calcineurin, and the kinase type IV/Gr (CaMKIV/Gr), which promote transcription by the MEF2 family members MEF2A and MEF2D. Calcineurin up-regulates the activity of both factors by an NFAT-dependent mechanism, while CaMKIV/Gr selectively and independently activates MEF2D. These results identify MEF2 proteins as effectors of a pathway of gene induction in T lymphocytes which integrates diverse Ca(2+) activation signals and may be broadly operative in several tissues.
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PMID:Ca(2+)-dependent gene expression mediated by MEF2 transcription factors. 1061 5

T-cell antigen receptor (TCR)-induced thymocyte apoptosis is mediated by calcium-dependent signal transduction pathways leading to the transcriptional activation of members of the Nur77 family. The major calcium- and calcineurin-responsive elements in the Nur77 promoter are binding sites for myocyte enhancer factor-2 (MEF2). It has been shown that nuclear factor of activated T cells (NFAT) interacts with MEF2D and enhances its transcriptional activity, offering a plausible mechanism of activation of MEF2D by calcineurin. We report here that NFATp synergizes with MEF2D to recruit the coactivator p300 for the transcription of Nur77. Surprisingly, the enhancement of transcriptional activity of MEF2D by NFATp does not require its DNA-binding activity, suggesting that NFATp acts as a coactivator for MEF2D. Transient co-expression of p300, MEF2D, NFATp and constitutively active calcineurin is sufficient to recapitulate TCR signaling for the selective induction of the endogenous Nur77 gene. These results implicate NFAT as an important mediator of T-cell apoptosis and suggest that NFAT is capable of integrating the calcineurin signaling pathway and other pathways through direct protein-protein interaction with other transcription factors.
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PMID:Integration of calcineurin and MEF2 signals by the coactivator p300 during T-cell apoptosis. 1094 15

Calcineurin-dependent pathways have been implicated in the hypertrophic response of skeletal muscle to functional overload (OV) (Dunn, S.E., J.L. Burns, and R.N. Michel. 1999. J. Biol. Chem. 274:21908-21912). Here we show that skeletal muscles overexpressing an activated form of calcineurin (CnA*) exhibit a phenotype indistinguishable from wild-type counterparts under normal weightbearing conditions and respond to OV with a similar doubling in cell size and slow fiber number. These adaptations occurred despite the fact that CnA* muscles displayed threefold higher calcineurin activity and enhanced dephosphorylation of the calcineurin targets NFATc1, MEF2A, and MEF2D. Moreover, when calcineurin signaling is compromised with cyclosporin A, muscles from OV wild-type mice display a lower molecular weight form of CnA, originally detected in failing hearts, whereas CnA* muscles are spared this manifestation. We also show that OV-induced growth and type transformations are prevented in muscle fibers of transgenic mice overexpressing a peptide that inhibits calmodulin from signaling to target enzymes. Taken together, these findings provide evidence that both calcineurin and its activity-linked upstream signaling elements are crucial for muscle adaptations to OV and that, unless significantly compromised, endogenous levels of this enzyme can accommodate large fluctuations in upstream calcium-dependent signaling events.
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PMID:Matching of calcineurin activity to upstream effectors is critical for skeletal muscle fiber growth. 1106 66

This study tested the hypothesis that calcineurin signaling is modulated in skeletal muscle cells by fluctuations in nerve-mediated activity. We show that dephosphorylation of NFATc1, MEF2A, and MEF2D transcription factors by calcineurin in all muscle types is dependent on nerve activity and positively correlated with muscle usage under normal weightbearing conditions. With increased nerve-mediated activity, calcineurin dephosphorylation of these targets was found to be potentiated in a way that paralleled the higher muscle activation profiles associated with functional overload or nerve electrical stimulation conditions. We also establish that muscle activity must be sustained above native levels for calcineurin-dependent dephosphorylation of MEF2A and MEF2D to be transduced into an increase in MEF2 transcriptional function, suggesting that calcineurin cooperates with other activity-linked events to signal via these proteins. Finally, examination of individual fiber responses to overload and nerve electrical stimulation revealed that calcineurin-MEF2 signaling occurs in all fiber types but most readily in fibers that are normally least active (i.e. those expressing IIx and IIb myosin heavy chain (MHC)), suggesting that signaling via this phosphatase is also dependent upon the activation history of the muscle cell.
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PMID:Nerve activity-dependent modulation of calcineurin signaling in adult fast and slow skeletal muscle fibers. 1155 50

Cabin1 binds calcineurin and myocyte enhancer factor 2 (MEF2) through its COOH-terminal region. In cell lines, these interactions were shown to inhibit calcineurin activity after T cell receptor (TCR) signaling and transcriptional activation of Nur77 by MEF2. The role of these interactions under physiological conditions was investigated using a mutant mouse strain that expresses a truncated Cabin1 lacking the COOH-terminal calcineurin and MEF2 binding domains. T and B cell development and thymocyte apoptosis were normal in mutant mice. In response to anti-CD3 stimulation, however, mutant T cells expressed significantly higher levels of interleukin (IL)-2, IL-4, IL-9, IL-13, and interferon gamma than wild-type T cells. The enhanced cytokine gene expression was not associated with change in nuclear factor of activated T cells (NF-AT)c or NF-ATp nuclear translocation but was preceded by the induction of a phosphorylated form of MEF2D in mutant T cells. Consistent with the enhanced cytokine expression, mutant mice had elevated levels of serum immunoglobulin (Ig)G1, IgG2b, and IgE and produced more IgG1 in response to a T cell-dependent antigen. These findings suggest that the calcineurin and MEF2 binding domain of Cabin1 is dispensable for thymocyte development and apoptosis, but is required for proper regulation of T cell cytokine expression probably through modulation of MEF2 activity.
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PMID:Deletion of calcineurin and myocyte enhancer factor 2 (MEF2) binding domain of Cabin1 results in enhanced cytokine gene expression in T cells. 1171 52

TCR signaling leading to thymocyte apoptosis is mediated through the expression of the Nur77 family of orphan nuclear receptors. It has been shown that the Nur77 promoter is activated by at least two signaling pathways, one mediated by calcium and the other by protein kinase C (PKC). MEF2D has been known to regulate Nur77 expression in a calcium- dependent manner. The mechanism by which calcium regulates MEF2D is through dissociation of calcium-sensitive MEF2 corepressors (Cabin1/HDACs, HDAC4/5) and the association with calcineurin-activated transcription factor NF-AT and the coactivator p300. However, little is known about how PKC activates the Nur77 promoter. Herein, we report that PKCtheta targets AP-1 like response element in the Nur77 promoter where JunD constitutively binds. PKCtheta triggers mitogen-activated protein kinase-inediated phosphorylation of JunD, and increases transcriptional activity of JunD, cooperatively with p300. Menin is identified as the transcriptional corepressor for JunD via recruitment of mSin3-istone deacetylases. In fact, Menin represses PKCtheta/p300-mediated transcriptional activity of JunD in T cell. Its dynamic regulation of histone modifiers with JunD is responsible for PKCq-synergistic effect on Nur77 expression in T cell.
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PMID:Menin represses JunD transcriptional activity in protein kinase C theta-mediated Nur77 expression. 1626 71

A eukaryotic protein is often subject to regulation by multiple modifications like phosphorylation, acetylation, ubiquitination, and sumoylation. How these modifications are coordinated in vivo is an important issue that is poorly understood but is relevant to many biological processes. We recently showed that human MEF2D (myocyte enhancer factor 2D) is sumoylated on Lys-439. Adjacent to the sumoylation motif is Ser-444, which like Lys-439 is highly conserved among MEF2 proteins from diverse species. Here we present [corrected] several lines of evidence to demonstrate that Ser-444 of MEF2D is required for sumoylation of Lys-439. Histone deacetylase 4 (HDAC4) stimulated this modification by acting through Ser-444. In addition, phosphorylation of Ser-444 by Cdk5, a cyclin-dependent kinase known to inhibit MEF2 transcriptional activity, stimulated sumoylation. Opposing the actions of HDAC4 and Cdk5, calcineurin (also known as protein phosphatase 2B) dephosphorylated Ser-444 and inhibited sumoylation of Lys-439. This phosphatase, however, exerted minimal effects on the phosphorylation catalyzed by ERK5, an extracellular signal-regulated kinase known to activate MEF2D. These results identify [corrected] an essential role for Ser-444 in MEF2D sumoylation and reveal [corrected] a novel mechanism by which calcineurin selectively "edits" phosphorylation at different sites, thereby reiterating that interplay between different modifications represents a general mechanism for coordinated regulation of eukaryotic protein functions in vivo.
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PMID:Control of MEF2 transcriptional activity by coordinated phosphorylation and sumoylation. 1635 33

Extracellular signal-regulated kinase-1 and -2 (ERK1/2) are activated by dual threonine and tyrosine phosphorylation of a TEY motif. The highly related kinase ERK5 is also activated by phosphorylation at a TEY motif. Inactivation of ERK1/2 is achieved by distinct members of the dual-specificity protein phosphatase (DUSP) family, which are responsible for the specific, regulated de-phosphorylation of the TEY motif. These include both nuclear (DUSP5) and cytoplasmic (DUSP6) enzymes. DUSP6, a candidate tumour suppressor gene, is thought to be highly specific for inactivation of ERK1/2 but several reports have suggested that it may also inactivate ERK5. Here we have compared the ability of DUSP6 to regulate the ERK1/2 and ERK5 protein kinases. We find that DUSP6 binds to ERK1/2 in both yeast and human cells but fails to bind to ERK5. Recombinant ERK2 can induce catalytic activation of DUSP6 whereas ERK5 cannot. Ectopic expression of DUSP6 can de-phosphorylate a co-expressed ERK2 construct but does not de-phosphorylate ERK5. Finally, expression of DUSP6 blocks the MEK1-driven activation of GAL4-ELK1, an ERK1/2-regulated transcription factor, but fails to block the MEK5-driven activation of GAL4-MEF2D, an ERK5-regulated transcription factor. These results demonstrate that even upon over-expression DUSP6 fails to inactivate ERK5, confirming that it is indeed an ERK1/2-specific DUSP.
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PMID:DUSP6/MKP-3 inactivates ERK1/2 but fails to bind and inactivate ERK5. 1828 Jan 12

Fetal cardiac gene reactivation is a hallmark of pathological cardiac hypertrophy (PCH) driven by cardiac transcription factors (TFs) such as nuclear factor of activated T-cells (NFATs). Nuclear import of dephosphorylated NFATs catalyzed by calcineurin (CaN) is a well-established hypertrophic mechanism. Here we report that NFATc4 expression is also up-regulated by newly expressed protein kinase D3 (PKD3) to induce PCH. In both in vitro and in vivo cardiac hypertrophic models, the normally undetectable PKD3 was profoundly up-regulated by isoproterenol followed by overt expression of cardiac TFs including NFATc4, NK family of transcription factor 2.5 (Nkx2.5), GATA4 and myocyte enhancer factor 2 (MEF2). Using gene silencing approaches, we demonstrate PKD3 is required for increasing the expression of NFATc4, Nkx2.5, and GATA4 while PKD1 is required for the increase in MEF2D expression. Upstream induction of PKD3 is driven by nuclear entry of CaN-activated NFATc1 and c3 but not c4. Therefore, PKD3 is a pivotal mediator of the CaN-NFATc1/c3-PKD3-NFATc4 hypertrophic signaling cascade and a potential new drug target for the PCH.
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PMID:Protein kinase D3 is a pivotal activator of pathological cardiac hypertrophy by selectively increasing the expression of hypertrophic transcription factors. 2197 Oct 46


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