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)

Growth suppression of normal human keratinocytes by high Ca2+ or TGFbeta was shown to be mediated by p21WAF1/CIP1 and Sp1 [Pardali, K., et al. (2000) J. Biol. Chem. 275, 29244-29256; Santini, M. P., Talora, C., Seki, T., Bolgan, L. & Dotto, G. P. (2001) Proc. Nat. Acad. Sci. USA 98, 9575-9580; Al-Daraji, W. I., Grant, K. R., Ryan, K., Saxton, A., & Reynolds, N. J. (2002) J. Invest. Dermatol. 118, 779-788]. We previously demonstrated that S100C/A11 is a key mediator for growth inhibition of normal human epidermal keratinocytes (NHK) triggered by high Ca2+ or TGFbeta [Sakaguchi, M., et al. (2003) J. Cell Biol. 163, 825-835; Sakaguchi, M., et al. (2004) 164, 979-984]. On exposure of NHK cells to either agent, S100C/A11 is transferred to nuclei, where it induces p21WAF1/CIP1 through activation of Sp1/Sp3. In the present study, we found that high Ca2+ activated NFAT1 through calcineurin-dependent dephosphorylation. In growing NHK cells, Krueppel-like factor (KLF)16, a member of the Sp/KLF family, bound to the p21WAF1/CIP1 promoter and, thereby, inhibited the transcription of p21(WAF1/CIP1). Sp1 complexed with NFAT1 in high Ca2+-treated cells or with Smad3 in TGFbeta1-treated cells, but not Sp1 alone, replaced KLF16 from the p21WAF1/CIP1 promoter and transcriptionally activated the p21WAF1/CIP1 gene. Thus, high Ca2+ and TGFbeta1 have a common S100C/A11-mediated pathway in addition to a unique pathway (NFAT1-mediated pathway for high Ca2+ and Smad-mediated pathway for TGFbeta1) for exhibiting a growth inhibitory effect on NHK cells, and both pathways were shown to be indispensable for growth inhibition.
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PMID:Bifurcated converging pathways for high Ca2+- and TGFbeta-induced inhibition of growth of normal human keratinocytes. 1617 1

Although TGF-beta inhibits the production of proinflammatory mediators in vitro and in vivo, its anti-inflammatory activities may be ineffective in early or severe acute inflammatory circumstances. In this study, we suggest a role for oxidative stress on TGF-beta signaling, leading to prevention of its normal anti-inflammatory effects but leaving its Smad-driven effects on cellular differentiation or matrix production unaffected. Stimulation of the RAW 264.7 macrophage cells, human or mouse alveolar macrophages with LPS led to NF-kappaB-driven production of proinflammatory mediators, which were inhibited by TGF-beta. This inhibition was prevented in the presence of hydrogen peroxide. We found that hydrogen peroxide acted by inducing p38 MAPK activation, which then prevented the ERK activation and MAPK phosphatase-1 up-regulation normally induced by TGF-beta. This was mediated through Src tyrosine kinases and protein phosphatase-1/2A. By contrast, hydrogen peroxide had no effects on TGF-beta-induced Smad2 phosphorylation and SBE-luc reporter gene transcription.
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PMID:Oxidants selectively reverse TGF-beta suppression of proinflammatory mediator production. 1639 11

Calcineurin inhibitors are helpful immunosuppressive agents in clinical practice. Thanks to their lower cost respect with new immunosuppressive therapy, calcineurin inhibitors in our country continue being the most used treatment in solid organ transplant recipients or patients with autoimmune disease. In the 80's decade cyclosporine A (CsA) was introduced as the first calcineurin inhibitor transforming the immunosuppression therapy. Up to date, many articles evaluating beneficial and adverse effects of CsA have been published. In this review, basic aspects and actions of CsA are analyzed together with studies from our laboratory that pointed out the pathophysiological role of aldosterone as a mediator of functional and structural changes that are observed in CsA nephrotoxicity. Based in our findings, we proposed that in CsA nephrotoxicity, the aldosterone mediates renal vasoconstriction and enhances TGFbeta expression promoting the development of nefrotoxicity. Finally, results from our laboratory and others allow us to suggest that aldosterone receptors blockade with spironolactone or eplerone could be a pharmacological therapy to reduce or prevent acute and chronic CsA nephrotoxicity in transplant recipients.
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PMID:[Novel action of aldosterone in CsA nephrotoxicity]. 1652 53

ISG15, an interferon-upregulated ubiquitin-like protein, is covalently conjugated to various cellular proteins (ISGylation). In this study, we found that protein phosphatase 2Cbeta (PP2Cbeta), which functions in the nuclear factor kappaB (NF-kappaB) pathway via dephosphorylation of TGF-beta-activated kinase, was ISGylated, and analysis by NF-kappaB luciferase reporter assay revealed that PP2Cbeta activity was suppressed by co-expression of ISG15, UBE1L, and UbcH8. We determined the ISGylation sites of PP2Cbeta and constructed its ISGylation-resistant mutant. In contrast to the wild type, this mutant suppressed the NF-kappaB pathway even in the presence of ISG15, UBE1L, and UbcH8. Thus, we propose that ISGylation negatively regulates PP2Cbeta activity.
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PMID:Negative regulation of protein phosphatase 2Cbeta by ISG15 conjugation. 1687 4

The goal of this research was the assessment of non-genetic and genetic risk factors of renal lesions in children after heart transplants. The research was carried out in 22 pediatric heart transplant recipients who have had a long-term treatment with calcineurin inhibitors. Renal function was assessed directly after the transplantation and then in 3 months intervals with the monitoring of calcineurin inhibitors concentration in the plasma. A significant renal lesion has been confirmed, which was a time-function in all examined patients, although its severity varied. Acute renal insufficiency, transplant rejection and ATG usage in the peri-transplant and the post-transplant periods have not proven to influence the complications mentioned above. The relationship between "high TGFbeta production genotype" and the intensity of nephrotoxicity of calcineurin inhibitors has been confirmed.
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PMID:[The role of some selected risk factors in the development of the nephrotoxicity of immunosuppressive medications used after the heart transplantation in children and young adults]. 1689 85

The repressed transactivator (RTA) yeast two-hybrid system was developed to enable genetic identification of interactions with transcriptional activator proteins. We have devised modifications of this system that enable its use in screening for inhibitors of protein interactions from small molecule compound libraries. We show that inhibition of protein interactions can be measured by monitoring growth in selective medium containing 3-aminotriazole (3-AT) and using this assay have identified inhibitors of four independent protein interactions in screens with a 23,000 small molecule compound library. Compounds found to inhibit one of the tested interactions between FKBP12 and the transforming growth factor beta receptor (TGFbeta-R) were validated in vivo and found to inhibit calcineurin-dependent signaling in T cells. One of these compounds was also found to cause elevated basal expression of a TGFbeta-R/SMAD-dependent reporter gene. These results demonstrate the capability of the RTA small molecule screening assay for discovery of potentially novel therapeutic compounds.
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PMID:Identification of protein interaction antagonists using the repressed transactivator two-hybrid system. 1751 3

Calcineurin is an important regulator of extracellular matrix (ECM) accumulation in the kidney but functions in a cell-specific manner. Previously, we identified a novel role for calcineurin in mesangial cells where calcineurin activity is required for TGFbeta-mediated induction of fibronectin expression. In this study, we examined the role of the calcineurin substrate NFATc in transcriptional regulation of fibronectin. First, inhibition of calcineurin blocks TGFbeta induction of the fibronectin promoter. Moreover, expression of constitutively active calcineurin in mesangial cells is sufficient to increase fibronectin transcription. Next, inhibition of the calcineurin substrate NFATc1 blocked TGFbeta-mediated activation of the fibronectin promoter. Finally, stable expression of a dominant-negative NFATc protein reduced transcriptional activation of the promoter and inhibited TGFbeta-mediated fibronectin expression. In conclusion, TGFbeta activation of calcineurin in mesangial cells results in regulation of ECM accumulation at least in part by direct transcriptional activity of NFATc on the fibronectin promoter.
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PMID:NFATc is required for TGFbeta-mediated transcriptional regulation of fibronectin. 1771 12

CD4(+)CD25(+) regulatory T cells (Tregs) are potent modulators of immune responses. The transcriptional program distinguishing Tregs from the CD4(+)CD25(-) Th cells is unclear. NFAT, a key transcription factor, is reported to interact with forkhead box p3, allowing inhibitory and activating signals in T cells. In the current study, we hypothesize that distinctive NFAT regulation in Tregs as compared with Th cells, may contribute to specific functions of these cells. Tregs express basal levels of cytoplasmic NFATc1 and NFATc2. In contrast to Th cells, anti-CD3-mediated T cell activation did not induce nuclear translocation of NFATc1 or NFATc2 in Tregs. This effect was associated with altered regulation for NFAT in Tregs that included reduced calcium flux, diminished calcineurin activation, and increased activity of glycogen synthase kinase-3beta, a negative regulatory kinase for NFAT in Tregs relative to Th cells. These data suggested that NFAT inhibition in Th cells may induce regulatory function. Indeed, pharmacologically mediated NFAT inhibition induced Th cells to function as Tregs, an effect that was mediated by induction of membrane-bound TGF-beta on Th cells. Collectively, these data suggest that maintaining NFAT at basal levels is a part of the transcriptional program required for Tregs.
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PMID:Regulation of the NFAT pathway discriminates CD4+CD25+ regulatory T cells from CD4+CD25- helper T cells. 1803 93

An F(1) mutagenesis strategy was developed to identify conditional mutations affecting extracellular matrix (ECM) patterning. Tubulogenesis requires coordinated movement of epithelial cells and deposition of a multilayered ECM. In the Drosophila ovary, an epithelium of follicle cells creates the eggshells, including the paired tubular dorsal appendages (DAs) that act as breathing tubes for the embryo. A P-element mutagenesis strategy allowed for conditional overexpression of hundreds of genes in follicle cells. Conditional phenotypes were scored at the level of individual mutant (F(1)) female flies. ECM pattern regulators were readily identified including MAPK signaling gene ets domain lacking (fused DAs), Wnt pathway genes frizzled 3 and osa (long DAs), Hh pathway gene debra (branched DAs), and transcription factor genes sima/HIF-1alpha, ush, lilli, Tfb1, broad, and foxo. In moving cells the [Ca(2+)]/calcineurin pathway can regulate adhesion to ECM while adherens junctions link cells together. Accordingly, thin eggshell and DA phenotypes were identified for the calcineurin regulator calreticulin and the adherens junction component arc. Finally a tubulogenesis defect phenotype was identified for the gene pterodactyl, homologous to the mammalian serine/threonine receptor-associated protein (STRAP) that integrates the TGF-beta and PI3K/AKT signaling pathways. Because phenotypes can be scored in each mutant fly before and after gene induction, this F(1) conditional mutagenesis strategy should allow for increased scale in screens for mutations affecting repeated (reiterated) events in adult animals, including gametogenesis, movement, behavior, and learning.
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PMID:Conditional switches for extracellular matrix patterning in Drosophila melanogaster. 1824 54

The ubiquitination system comprises a highly specific and regulated post-translational mechanism by which the immune response can be modulated, setting the balance between immunity and tolerance. Proteolysis dependent and independent mechanisms have been implicated. Particularly, the role of ubiquitin ligases as modulators of central and peripheral tolerance has brought attention to this system as one of the key elements of a complex regulatory network designed to maintain an active surveillance system. Cbl-b, GRAIL and Itch are the main E3 ligases, considered as negative regulators of the immune response as part of the genetic program induced by the calcium/calcineurin pathway. Other key signaling pathways for the immune response, such as the NF-kappaB and TGF-beta signaling are prone to be modulated by these ubiquitin ligases. Diverse mechanisms have been implicated in the development of anergy associated to E3 ligases, among these, the setting for TCR responsiveness and repression of cytokine transcription are best well characterized. Also, a role as inductors of regulatory T cells has been evidenced for Cbl-b and GRAIL. The defective expression of some of these E3 ligases has been related to the development of autoimmune disease, in experimental murine and human models, remarking its possible pathogenic role.
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PMID:Ubiquitination system and autoimmunity: the bridge towards the modulation of the immune response. 1829 31


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