Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Carbon dioxide is produced as a by-product of cellular respiration by all aerobic organisms and thus serves for many animals as an important indicator of food, mates, and predators. However, whether free-living terrestrial nematodes such as Caenorhabditis elegans respond to CO2 was unclear. We have demonstrated that adult C. elegans display an acute avoidance response upon exposure to CO2 that is characterized by the cessation of forward movement and the rapid initiation of backward movement. This response is mediated by a cGMP signaling pathway that includes the cGMP-gated heteromeric channel TAX-2/TAX-4. CO2 avoidance is modulated by multiple signaling molecules, including the neuropeptide Y receptor NPR-1 and the calcineurin subunits TAX-6 and CNB-1. Nutritional status also modulates CO2 responsiveness via the insulin and TGFbeta signaling pathways. CO2 response is mediated by a neural circuit that includes the BAG neurons, a pair of sensory neurons of previously unknown function. TAX-2/TAX-4 function in the BAG neurons to mediate acute CO2 avoidance. Our results demonstrate that C. elegans senses and responds to CO2 using multiple signaling pathways and a neural network that includes the BAG neurons and that this response is modulated by the physiological state of the worm.
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PMID:Acute carbon dioxide avoidance in Caenorhabditis elegans. 1852 55

We identify Balpha (PPP2R2A) and Bdelta (PPP2R2D), two highly related members of the B family of regulatory subunits of the protein phosphatase PP2A, as important modulators of TGF-beta/Activin/Nodal signalling that affect the pathway in opposite ways. Knockdown of Balpha in Xenopus embryos or mammalian tissue culture cells suppresses TGF-beta/Activin/Nodal-dependent responses, whereas knockdown of Bdelta enhances these responses. Moreover, in Drosophila, overexpression of Smad2 rescues a severe wing phenotype caused by overexpression of the single Drosophila PP2A B subunit Twins. We show that, in vertebrates, Balpha enhances TGF-beta/Activin/Nodal signalling by stabilising the basal levels of type I receptor, whereas Bdelta negatively modulates these pathways by restricting receptor activity. Thus, these highly related members of the same subfamily of PP2A regulatory subunits differentially regulate TGF-beta/Activin/Nodal signalling to elicit opposing biological outcomes.
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PMID:Two highly related regulatory subunits of PP2A exert opposite effects on TGF-beta/Activin/Nodal signalling. 1869 6

Chronic allograft nephropathy is characterized by an increase over time of interstitial fibrosis, tubular atrophy, fibrointimal thickening, arteriolar hyalinosis and glomerulosclerosis, resulting in progressive renal dysfunction. It is mainly caused by calcineurin inhibitors-induced nephrotoxicity, which is related to an imbalance between vasoconstrictor and vasodilator factors. Cyclosporine A-induced nephrotoxicity is particularly due to the activation of pro-apoptotic genes leading to tubular atrophy with tubular cell apoptosis and to hemodynamic changes inducing interstitial fibrosis by the activation of factors stimulating the fibroblast proliferation (TGFbeta, Endothelin-A and Plasminogen activator inhibitor-1). Calcineurin inhibitors (CNI) treatment monitoring is essentially based on histology, but a better follow-up of drug exposure post-transplantation leading to a regular and rapid adjustment of the doses to avoid extended periods of overexposure, could enable to decrease their nephrotoxicity and improve graft survival in treated patients. CNIs dose reduction or conversion to proliferating signal inhibitors may be a therapeutic alternative.
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PMID:[Monitoring of calcineurin inhibitors induced-nephrotoxicity]. 1870 92

Calcineurin is an important intracellular signaling molecule which can be inhibited by cyclosporin resulting in immune suppression and nephrotoxicity. Previously, we reported that homozygous loss of the alpha isoform of calcineurin impairs kidney development and function and mimics many features of cyclosporin nephrotoxicity. However, early lethality of null mice prevented further study of renal changes. Alternatively, we examined aged heterozygous (CnAalpha(+/-)) mice. In addition to renal dysfunction and inflammation, we find that CnAalpha(+/-) mice spontaneously develop tertiary lymphoid aggregates in the kidney, small intestine, liver, and lung. Lymphoid aggregates contain both T cells and B cells and exhibited organization suggestive of tertiary lymphoid organs (TLOs). Kidney function and TLO formation were highly correlated suggesting that this process may contribute to nephrotoxicity. Consistent with previous findings, transforming growth factor (TGF)-beta is significantly increased in CnAalpha(+/-) mice. Neutralization of TGF-beta attenuated TLO formation and improved kidney function. In conclusion, we report that haploinsufficiency of CnAalpha causes uregulation of TGF-beta which contributes to chronic inflammation and formation of TLOs. While the process that leads to TLOs formation in transplant allografts is unknown, TLOs are associated with poor clinical prognosis. This study suggests that calcineurin inhibition itself may lead to TLO formation and that TGF-beta may be a novel therapeutic target.
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PMID:TGF-beta upregulation drives tertiary lymphoid organ formation and kidney dysfunction in calcineurin A-alpha heterozygous mice. 1912 56

The use of the calcineurin inhibitors cyclosporine and tacrolimus led to major advances in the field of transplantation, with excellent short-term outcome. However, the chronic nephrotoxicity of these drugs is the Achilles' heel of current immunosuppressive regimens. In this review, the authors summarize the clinical features and histologic appearance of both acute and chronic calcineurin inhibitor nephrotoxicity in renal and nonrenal transplantation, together with the pitfalls in its diagnosis. The authors also review the available literature on the physiologic and molecular mechanisms underlying acute and chronic calcineurin inhibitor nephrotoxicity, and demonstrate that its development is related to both reversible alterations and irreversible damage to all compartments of the kidneys, including glomeruli, arterioles, and tubulo-interstitium. The main question--whether nephrotoxicity is secondary to the actions of cyclosporine and tacrolimus on the calcineurin-NFAT pathway--remains largely unanswered. The authors critically review the current evidence relating systemic blood levels of cyclosporine and tacrolimus to calcineurin inhibitor nephrotoxicity, and summarize the data suggesting that local exposure to cyclosporine or tacrolimus could be more important than systemic exposure. Finally, other local susceptibility factors for calcineurin inhibitor nephrotoxicity are reviewed, including variability in P-glycoprotein and CYP3A4/5 expression or activity, older kidney age, salt depletion, the use of nonsteroidal anti-inflammatory drugs, and genetic polymorphisms in genes like TGF-beta and ACE. Better insight into the mechanisms underlying calcineurin inhibitor nephrotoxicity might pave the way toward more targeted therapy or prevention of calcineurin inhibitor nephrotoxicity.
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PMID:Calcineurin inhibitor nephrotoxicity. 1921 75

In vitro chondrocyte expansion is required for several cell-based approaches for the repair of chondral lesions. During expansion, loss of chondrogenic phenotype takes place (dedifferentiation). The objective of this study was to investigate calcineurin (Cn) as a potential target to improve chondrocyte phenotype for cartilage repair purposes. Cn activity in human articular chondrocytes was significantly increased during dedifferentiation and decreased during redifferentiation in vitro. Inhibition of Cn activity by FK506 increased the expression of chondrogenic markers collagen type 2, aggrecan, and SOX9 in culture-expanded cells. Addition of FK506 increased endogenous transforming growth factor 2 (TGF) beta1 expression on both mRNA and protein level. The effect of FK506 on chondrogenic markers was abolished by addition of anti-TGFbeta1 antibody, indicating that the endogenous TGFbeta1 was necessary to increase chondrogenic marker expression. We also showed that chondrocyte redifferentiation by TGFbeta requires calcium influx and does not depend on changes in Cn activity. In conclusion, inhibition of Cn activity by FK506 increases the expression of chondrogenic markers via endogenous TGFbeta1 production in human articular chondrocytes. Cn inhibitors might be an alternative for the application of (recombinant) TGFbeta, to promote chondrocyte phenotype for cell-based cartilage repair procedures.
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PMID:Calcineurin inhibitors promote chondrogenic marker expression of dedifferentiated human adult chondrocytes via stimulation of endogenous TGFbeta1 production. 1960 38

Smad anchor for receptor activation (SARA) is known as Smad cofactor that interacts directly with Smad2/3 and functions to recruit Smad2/3 to the TGF-beta receptor. SARA plays an essential role in TGF-beta-induced Smad2 activation and it may modulate TGF-beta signaling through regulating the balance between Smad2 and Smad3. SARA also functions as an anchor for catalytic subunit of protein phosphatase 1 (PP1c) and maybe involved in the dephosphorylation of TGF-beta type I receptor (TbetaR-I) mediated by Smad7. The expression of SARA changes as the development of epithelial to mesenchymal transition (EMT) and fibrosis and it plays a critical role in the maintenance of epithelial cell phenotype. Modulation of SARA may provide a new therapeutic approach to TGF-beta-mediated EMT and fibrosis.
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PMID:Smad anchor for receptor activation (SARA) in TGF-beta signaling. 2051 59

The aim of this study was to define copy number alterations in a rare laryngeal type basaloid squamous cell carcinoma (laryngeal BSCC) using high throughput array comparative genomic hybridization. This is the first genome wide screening of a laryngeal BSCC describing the unique events of DNA copy number changes. By Nimble-Gen Whole Genome Tiling Array CGH (consisting of 72,000 probes) we were able to identify 3,777 genes altered by copy number changes (1,726 genes with copy number gains and 2,051 genes with copy number with losses). The resolution of the array allowed us to identify a new alteration at the 17q21.31 region covering the DUSP3 gene which encodes the dual-specific protein phosphatase. Functional studies of the altered genes (Database for Annotation, Visualization and Integrated Discovery v6.7 analysis) highlighted molecular pathways including chemokine signaling, cell cycle, adherent junction-, VEGF- and TGF-beta signaling pathways that might be disrupted by copy number alterations in laryngeal BSCC.
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PMID:Array CGH analysis of the rare laryngeal basaloid squamous cell carcinoma: a case report. 2307 66


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