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)

Tropisetron, an antagonist of serotonin type 3 receptor, has been investigated in chronic inflammatory joint process. Since T cells play a key role in the onset of several inflammatory diseases, we have evaluated the immunosuppressive activity of tropisetron in human T cells, discovering that this compound is a potent inhibitor of early and late events in TCR-mediated T cell activation. Moreover, we found that tropisetron specifically inhibited both IL-2 gene transcription and IL-2 synthesis in stimulated T cells. To further characterize the inhibitory mechanisms of tropisetron at the transcriptional level, we examined the DNA binding and transcriptional activities of NF-(kappa)B, NFAT and AP-1 transcription factors in Jurkat T cells. We found that tropisetron inhibited both the binding to DNA and the transcriptional activity of NFAT and AP-1. We also observed that tropisetron is a potent inhibitor of PMA plus ionomycin-induced NF-(kappa)B activation but in contrast TNF(alpha)-mediated NF-(kappa)B activation was not affected by this antagonist. Finally, overexpression of a constitutively active form of calcineurin indicated that this phosphatase may represent one of the main targets for the inhibitory activity of tropisetron. These findings provide new mechanistic insights into the anti-inflammatory activities of tropisetron, which are probably independent of serotonin receptor signalling and highlight their potential to design novel therapeutic strategies to manage inflammatory diseases.
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PMID:The 5-HT3 receptor antagonist tropisetron inhibits T cell activation by targeting the calcineurin pathway. 1592 94

We recently reported that p38 MAPK regulates TNF-induced endothelial apoptosis via phosphorylation and downregulation of Bcl-xL. Here, we describe that such apoptosis includes p38 MAPK-mediated, protein phosphatase 2A (PP2A)-dependent, downregulation of the MEK-ERK pathway. Inhibition of PP2A with fostriecin or calyculin A significantly increased MEK phosphorylation, as did exposure to the p38 MAPK inhibitor SB203580. Inhibition of MEK potentiated TNF-induced caspase-3 activity and cell death, and both those events were suppressed by treatment with fostriecin or calyculin A. Immunoprecipitation experiments revealed an association between p38 MAPK, PP2A and MEK, and the results of a phosphatase assay suggested that PP2A is a downstream target of p38 MAPK. Importantly, phosphorylation of Bad at Ser-112 was found to be regulated by p38 MAPK and PP2A. In summary, the present findings indicate a novel p38 MAPK-mediated apoptosis pathway, involving activation of Bad via PP2A-dependent inhibition of the MEK-ERK pathway.
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PMID:p38 MAPK regulates phosphorylation of Bad via PP2A-dependent suppression of the MEK1/2-ERK1/2 survival pathway in TNF-alpha induced endothelial apoptosis. 1597 58

Because nuclear factor of activated T cells (NFAT) has been implicated in TNF production as well as osmoregulation and salt and water homeostasis, we addressed whether calcium-sensing receptor (CaR)-mediated TNF production in medullary thick ascending limb (mTAL) cells was NFAT dependent. TNF production in response to addition of extracellular Ca(2+) (1.2 mM) was abolished in mTAL cells transiently transfected with a dominant-negative CaR construct (R796W) or pretreated with the phosphatidylinositol phospholipase C (PI-PLC) inhibitor U-73122. Cyclosporine A (CsA), an inhibitor of the serine/threonine phosphatase calcineurin, and a peptide ligand, VIVIT, that selectively inhibits calcineurin-NFAT signaling, also prevented CaR-mediated TNF production. Increases in calcineurin activity in cells challenged with Ca(2+) were inhibited after pretreatment with U-73122 and CsA, suggesting that CaR activation increases calcineurin activity in a PI-PLC-dependent manner. Moreover, U-73122, CsA, and VIVIT inhibited CaR-dependent activity of an NFAT construct that drives expression of firefly luciferase in transiently transfected mTAL cells. Collectively, these data verify the role of calcineurin and NFAT in CaR-mediated TNF production by mTAL cells. Activation of the CaR also increased the binding of NFAT to a consensus oligonucleotide, an effect that was blocked by U-73122 and CsA, suggesting that a calcineurin- and NFAT-dependent pathway increases TNF production in mTAL cells. This mechanism likely regulates TNF gene transcription as U-73122, CsA, and VIVIT blocked CaR-dependent activity of a TNF promoter construct. Elucidating CaR-mediated signaling pathways that regulate TNF production in the mTAL will be crucial to understanding mechanisms that regulate extracellular fluid volume and salt balance.
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PMID:NFAT regulates calcium-sensing receptor-mediated TNF production. 1638 Apr 62

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) belongs to the TNF superfamily of proteins. It is highly expressed on natural killer cells, cytotoxic T lymphocytes, and monocytes after stimulation, and plays a critical role in immune surveillance. Two splice variants of TRAIL were identified recently that show no proapoptotic activity. Phosphorylation level in splicing factors, serine-arginine-rich (SR) and heterogeneous ribonucleoproteins (hnRNPs) govern the mRNA splicing of several apoptosis-related genes. We characterized the apoptotic stimuli-mediated alternative splicing pattern of TRAIL and investigated the possible underlying mechanism of alternative splicing. Etoposide and cycloheximide induced alternative splicing, whereas staurosporine (a broad kinase inhibitor) blocked both constitutive and alternative splicing. De novo ceramide synthesis and subsequent protein phosphatase-1 (PP-1) activation enhanced the alternative splicing, as did TNF-alpha but not interferon alpha (IFN-alpha) stimulation. We demonstrated that TRAIL alters gene expression through mRNA splicing and may change proapoptotic potential in response to cytokine stimulation.
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PMID:Activation of protein phosphatase causes alternative splicing of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL): potential effect on immune surveillance. 1758 76

We evaluated the contribution of calcium-sensing receptor (CaR)-mediated G(i)-coupled signaling to TNF production in medullary thick ascending limb (mTAL) cells. A selective G(i) inhibitor, pertussis toxin (PTX), but not the inactive B-oligomer binding subunit, abolished CaR-mediated increases in TNF production. The inhibitory effect of PTX was partially reversed by using an adenylate cyclase inhibitor. CaR-mediated TNF production also was partially reversed by a cAMP analog, 8-Br-cAMP. IP(1) accumulation was CaR dependent and blocked by PI-PLC; partial inhibition also was observed with PTX. CaR increased calcineurin (CaN) activity by approximately threefold, and PTX prevented CaR-mediated increases in CaN activity, an nuclear factor of activated T cells (NFAT)-cis reporter construct, and a TNF promoter construct. The interaction between G(i) and PKC was determined, as we previously showed that CaR-mediated TNF production was CaN and NFAT- mediated and G(q) dependent. CaR activation increased PKC activity by twofold, an effect abolished by transient transfection with a dominant negative CaR construct, R796W, or pretreatment with PTX. Inhibition with the pan-specific PKC inhibitor GF 109203X (20 nM) abolished CaR-mediated increases in activity of CaN, an NFAT reporter, and a TNF promoter construct. Collectively, the data suggest that G(i)-coupled signaling contributes to NFAT-mediated TNF production in a CaN- and PKC-dependent manner and may be part of a CaR mechanism to regulate mTAL function. Moreover, concurrent G(q) and G(i) signaling is required for CaR-mediated TNF production in mTAL cells via a CaN/NFAT pathway that is PKC dependent. Understanding CaR-mediated signaling pathways that regulate TNF production in the mTAL is crucial to defining novel mechanisms that regulate extracellular fluid volume and salt balance.
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PMID:CaR activation increases TNF production by mTAL cells via a Gi-dependent mechanism. 1803 44

The considerable interindividual differences in efficacy and side effects of commonly used medications in Crohn's disease are partly owing to genetic polymorphisms. Many genetic variants have been studied in genes possibly involved in the metabolism or mechanism of action of therapeutic agents such as glucocorticosteroids, azathioprine/6-mercaptopurine, methotrexate, calcineurin inhibitors or anti-TNF agents. However, the only test translated into clinical practice is thiopurine S-methyltransferase (TPMT) genotyping for hematological toxicity of thiopurine treatment. To date, there are no other meaningful applications for pharmacogenomics in clinical practice of Crohn's disease. In the future, designed therapeutic trials should possibly permit the development of predictive models including genotypic markers, such as that proposed for the clinical outcome after infliximab therapy, which includes an apoptotic pharmacogenetic index. The recent identification of new susceptibility genes provides additional candidate markers that have possible effects on the outcomes of therapies, and prioritizes new therapeutic targets, such as the IL-23 pathway. Further innovative approaches might be relevant for the pharmacogenetic investigation of gene variants implied in innate immune pattern recognition and autophagy.
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PMID:Pharmacogenetics of Crohn's disease. 1859 52

In the present study, we demonstrate the biological activity of esterified caffeic acid with methyl vanillate also termed as caffeic acid methyl vanillate ester (CAMVE). CAMVE potentiates TNF-induced cell death as analyzed by cell viability assay and blocks inflammatory stimuli-induced nuclear transcription factor kappaB (NF-kappaB) activation and NF-kappaB-dependent genes expression. CAMVE-mediated inhibition of NF-kappaB or induction of cell death is not cell type specific. CAMVE inhibits cell proliferation by inhibiting G1 to S phase progression. It suppresses TNF-induced Bcl-2 expression and potentiates chemotherapeutic agents-mediated cell death. CAMVE enhances intracellular free Ca(2+) and thereby activates calcineurin. Calcineurin, in turns, activates nuclear transcription factor NF-AT and its dependent genes such as FasL, which induces cell death. The data demonstrate that CAMVE is one of the combinatorial products, which is able to inhibit NF-kappaB regulated genes and cell proliferation. The combinatorial synthesis of novel caffeic ester derivatives can be a useful approach to generate potent chemotherapeutic agents and designing CAMVE as potent therapeutic agent for combination therapy may be useful to treat tumors.
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PMID:Novel caffeic acid ester derivative induces apoptosis by expressing FasL and downregulating NF-KappaB: Potentiation of cell death mediated by chemotherapeutic agents. 1903 29

Fibrocytes are collagen-type-I-producing cells that arise at low frequency from hematopoietic cells. We have analyzed in mice which leukocyte subsets are required for generation of fibrocytes and show that murine fibrocytes develop from the subpopulation of CD11b(+) CD115(+) Gr1(+) monocytes under the control of CD4(+) T cells. In the absence of CD4(+) T cells, differentiation of fibrocytes was markedly reduced in vitro and in vivo. In the presence of CD4(+) T cells, the characteristics of T-cell activation critically determined development of fibrocytes. Polyclonal activation of CD4(+) T cells induced the release of soluble factors that completely prevented the outgrowth of fibrocytes and could be identified as IL-2, TNF, IFN-gamma, and IL-4. Application of IL-2 and TNF significantly reduced the appearance of fibrocytes and the severity of fibrosis in the model of unilateral ureteral obstruction. In contrast, activation of CD4(+) T cells in the presence of calcineurin inhibitors, but not mTOR inhibitors, markedly enhanced the outgrowth of fibrocytes and renal deposition of collagen I. Taken together, we show that differentiation of fibrocytes is critically dependent on CD4(+) T cells and that the context of T-cell activation determines whether development of fibrocytes is supported or blocked. Our data may have implications for prevention of organ fibrosis in autoimmune diseases and transplantation.
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PMID:CD4+ T cells control the differentiation of Gr1+ monocytes into fibrocytes. 1981 30

Genes encoding apoptosis-inducing proteins are postulated to be candidate tumour suppressors. The identification of such proteins may benefit the early diagnosis and therapy of tumours. In the present study, we characterized the function of a novel human BMSC (bone marrow stromal cell)-derived protein {IPP5 [inhibitor-5 of PP1 (protein phosphatase 1)]} by large-scale random sequencing of a human BMSC cDNA library. hIPP5 (human IPP5) cDNA encodes a protein of 116 amino acid residues, which shares high homology with human PPI-1 (inhibitor-1 of PP1). The effect of IPP5 on apoptosis and the underlying molecular mechanisms were investigated by overexpression of IPP5 in HeLa cells, a human cervical carcinoma cell line. Our results showed that overexpression of active mutant IPP5 inhibited anchorage-dependent growth and induced apoptosis in HeLa cells, which may be attributed to the up-regulation of p21(waf/cip1) (a 21 kDa cell-cycle regulatory protein), p53 and Bcl-2-antagonist/killer, and down-regulation of Bcl-2 and Bcl-X(L). We also showed that the expression of active mutant IPP5 in HeLa cells was further enhanced on TNF (tumour necrosis factor) treatment and overexpression of active mutant IPP5 sensitized HeLa cells to TNF-induced JNK (c-Jun N-terminal kinase) and p38 activation as well as TNF-mediated apoptosis. Thus overexpression of active mutant IPP5 may increase cell susceptibility to TNF-induced apoptosis by the activation of p38 and JNK pathways. In addition, IPP5 active mutant could interact with PP1alpha as demonstrated by the co-precipitation assay.
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PMID:Effect of IPP5, a novel inhibitor of PP1, on apoptosis and the underlying mechanisms involved. 1987 72

There is increasing evidence that p38 MAPK, which is classified as a stress-activated kinase, also participates in cell cycle regulation, functioning as a suppressor of cell proliferation and tumorigenesis. We conducted a study of p38 MAPK phosphorylation during liver regeneration in mice to determine whether p38 MAPK activation or inactivation may correlate with events that lead to DNA replication after partial hepatectomy (PH), and whether p38 MAPK activation may be required for hepatocyte DNA replication in vivo and in culture. We report that active p38 (Pi-p38 MAPK) is present in normal liver, is rapidly inactivated starting 30 min after PH, and is re-activated by 12h. Although levels of Pi-MKK 3/6, the upstream kinases that activate p38 MAPK increase after PH, the expression of the dual protein phosphatase 1 is also elevated, and may be responsible for Pi-p38 MAPK dephosphorylation after PH. Inactivation and re-activation of p38 MAPK inversely correlates with the stimulation of protein synthesis and translation pathways, as indicated by activation of p70S6 kinase, increases in the phosphorylation of initiation factor elF-4E and translational repressor, 4E-BP. The activity of a p38 MAPK downstream substrate, MAPKAPK2 (MK2), did not reflect the changing levels of Pi-p38 MAPK during liver regeneration. Pi-p38 MAPK may be involved in TNF-stimulated DNA replication of murine hepatocytes in culture, but is not necessary for hepatocyte DNA replication after PH. Our results suggest that p38 MAPK inactivation plays a permissible role in DNA replication during liver regeneration and is consistent with a role for p38 MAPK in the maintenance of hepatocyte cell cycle arrest in adult liver.
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PMID:Inactivation of p38 MAPK during liver regeneration. 2070 92


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