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)

Prostaglandin G/H synthase (PGHS) is one of the key enzymes in prostaglandin synthesis. Regulation of the mRNA expression of the two isozymes PGHS-1 and PGHS-2 was investigated in mesangial cells. PGHS-1 was constitutively expressed and not modulated by any of the stimuli used. PGHS-2 was induced by the platelet products serotonin (5-HT) and thromboxane A2 (used as its analogue U46619), but not by ATP. Expression of PGHS protein was regulated correspondingly; whereas PGHS-1 protein was constitutively expressed, PGHS-2 protein was virtually absent in unstimulated cells, but could increasingly be induced by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), 5-HT, or fetal calf serum. Induction of PGHS-2 mRNA was transient with a peak after 2-3 h. Stimulated mRNA levels persisted for more than 6 h when transcription was inhibited by actinomycin D or when translation was inhibited by cycloheximide. As shown by specific inhibitors, 5-HT signal transduction was mediated by 5-HT2 receptors, which couple to phospholipase C via pertussis toxin-sensitive G-proteins. Induction of PGHS-2 mRNA by 5-HT was dependent on protein kinase C. Down-regulation of the enzyme by prolonged incubation with TPA abolished 5-HT-induced PGHS-2 mRNA expression. Short time activation of protein kinase C by TPA induced PGHS-2 mRNA expression. On the other hand, TPA given immediately before 5-HT decreased the 5-HT-induced PGHS-2 mRNA expression, indicating a negative feedback. The immunosuppressive drug cyclosporin A reduced induction of PGHS-2 mRNA expression by 5-HT, indicating interference with the signaling cascade, most likely with the Ser/Thr phosphatase calcineurin. Involvement of Tyr phosphorylation in 5-HT signaling was shown by the Tyr kinase inhibitor genistein, which inhibited the induction, while the Tyr phosphatase inhibitor vanadate by itself was able to induce PGHS-2 mRNA expression, which was further augmented when vanadate was combined with 5-HT. PGHS-2 mRNA expression is thus tightly regulated in mesangial cells and therefore allows modulation at various levels by physiological and pharmacological stimuli.
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PMID:Signal transduction pathways responsible for serotonin-mediated prostaglandin G/H synthase expression in rat mesangial cells. 808 94

Increased production of prostaglandins by the gestational tissues is pivotal for the initiation and maintenance of human labour. A major source of prostaglandins in the pregnant human uterus is the amnion membrane, which synthesizes increased amounts of prostaglandin E2 (PGE2) at parturition. We have found that the activity of prostaglandin endoperoxide H2 synthase (PGHS), the enzyme catalyzing the committing step of prostanoid biosynthesis, increases significantly in the amnion at term and preterm labour, and also prior to the onset of clinical labour at term. Furthermore, the abundance of the mRNA encoding the inducible PGHS-2 isoenzyme was higher in the amnion after spontaneous delivery that before labour. The level of the constitutive PGHS-1 mRNA remained unchanged. In addition, we found a significant positive correlation between PGHS activity and the level of PGHS-2 mRNA, but not of PGHS-1 mRNA, in the individual tissue samples, also indicating that PGHS-2 was selectively induced in the amnion membrane at labour. The regulation of PGHS expression by agonists was studied using primary cultures of amnion cells. Glucocorticoid treatment enhanced the activity of PGHS and the level of PGHS-2 mRNA in the cultured cells, without affecting PGHS-1 mRNA abundance. The stimulation was glucocorticoid specific and was blocked by the glucocorticoid receptor antagonist RU486, suggesting that it was mediated by the glucocorticoid receptor. Inhibition of protein synthesis did not block the accumulation of PGHS-2 mRNA showing that the steroid acted directly, without inducing an intervening protein. Protein kinase C activator and protein phosphatase inhibitor compounds and epidermal growth factor also promoted PGHS-2 mRNA expression, demonstrating the involvement of protein kinase dependent mechanisms in PGHS-2 regulation. However, the role of these effectors in the in vivo control of PGHS-2 expression remains to be determined.
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PMID:Regulation of prostaglandin endoperoxide H2 synthase in term human gestational tissues. 904 57

Prostaglandin H2 synthase (PGHS)-1 and PGHS-2 expression was examined in primary cultures of human amnion cells, an in vitro model of amnion tissue. Epidermal growth factor (EGF), the protein kinase C (PKC) activating phorbol ester TPA, and the protein phosphatase inhibitor, okadaic acid (OA), stimulated PGHS activity and the level of PGHS-2 mRNA, but did not affect the level of PGHS-1 mRNA. In situ hybridization suggested that the same population of cells responded to EGF, TPA and OA. Okadaic acid promoted PGHS activity independently of PKC. EGF stimulated the activity of extracellular signal-regulated protein kinase (Erk) and N-terminal c-Jun kinase (Jnk). OA increased Jnk activity but had no effect on Erk activity, while TPA had no influence on either Erk or Jnk activity. PD098059, a selective inhibitor of the Erk-activating kinase MEK, blocked the stimulation of PGHS expression by EGF, but did not decrease stimulation in response to OA. Herbimycin A, a tyrosine kinase inhibitor, suppressed the stimulation of PGHS activity and PGHS-2 mRNA abundance by all three stimulants, and blocked signalling via the Erk and Jnk mitogen-activated protein kinase pathways. Thus, growth factor stimulation, PKC activation and protein phosphatase inhibition induced the expression of PGHS-2 in primary amnion cells by distinct regulatory mechanisms involving tyrosine kinase(s). Tyrosine kinase inhibitors may constitute a new category of PGHS-2 inhibitors that act by blocking the expression of the enzyme.
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PMID:Regulation of prostaglandin H2 synthase-2 expression in primary human amnion cells by tyrosine kinase dependent mechanisms. 951 44

1. FK506 and cyclosporin A (CsA) are immunosuppressive drugs, that specifically inhibit T-cell activation via calcineurin inhibition. This study was undertaken to investigate whether calcineurin inhibitors exert analgesic actions in rat adjuvant-induced arthritis (AIA), an animal model of rheumatoid arthritis (RA). 2. AIA was induced in female Lewis rats. Single doses of FK506 and CsA were orally administered to arthritic rats 17 days after arthritis induction. Intensity of hyperalgesia was assessed by measuring the pain threshold of hind paws. Tumor necrosis factor (TNF)-alpha, IL-1beta and PGE(2) levels in paw extracts were determined by ELISA. TNF activity was measured by L929 cell cytotoxicity assay. IL-1beta and cyclooxygenase (COX) mRNA expression in arthritic paws were measured by RT-PCR. 3. Single doses of FK506 and CsA markedly reduced joint hyperalgesia 24 h after drug administration, without affecting inflammation in an advanced stage of AIA. 4. The calcineurin inhibitors partially reduced the elevated level of TNF-alpha in arthritic paws, however, the analgesic effects of these drugs were not associated with the reduction in TNF-alpha level. 5. Moreover, treatment with anti-rat TNF-alpha antibody did not affect the hyperalgesia, when TNF-alpha activity was suppressed in arthritic paws by that treatment. 6. Both calcineurin inhibitors reduced the elevated level of IL-1beta in arthritic paws to a normal level, 24 h after drug administration. 7. FK506 reduced IL-1beta and COX-2 mRNA expression and PGE(2) level in arthritic paws. 8 In conclusion, calcineurin inhibitors rapidly reduce joint hyperalgesia probably by downregulating IL-1beta, but not TNF-alpha, in AIA. Our findings may provide a new strategy for the treatment of pain in RA.
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PMID:Calcineurin inhibitors exert rapid reduction of inflammatory pain in rat adjuvant-induced arthritis. 1283 66

We have previously reported that nuclear factor of activated T cells (NFATs) play an important role in the regulation of vascular smooth muscle cell migration and proliferation by receptor tyrosine kinase and G protein-coupled receptor agonists, platelet-derived growth factor-BB and thrombin, respectively. To understand the role of NFATs in vascular disease, we have now studied the involvement of these transcription factors in neointima formation in a rat carotid artery balloon injury model. The levels of NFATc1 in injured right common carotid arteries were increased at 72 h, 1 week, and 2 weeks after balloon injury compared with its levels in uninjured left common carotid arteries. Intraperitoneal injection of cyclosporine A (CsA), a pharmacological inhibitor of the calcineurin-NFAT activation pathway, suppressed balloon injury-induced neointima formation by 40%. Similarly, adenoviral-mediated expression of GFPVIVIT, a competent peptide inhibitor of the calcineurin-NFAT activation pathway, in injured arteries also reduced neointima formation by about 40%. Furthermore, CsA and GFPVIVIT attenuated balloon injury-induced neointimal smooth muscle cell proliferation as determined by bromodeoxyuridine staining. Platelet-derived growth factor-BB induced the expression of COX-2 in cultured VSMC in a time- and NFAT-dependent manner. COX-2 expression was also increased in the right common carotid artery in a time-dependent manner after balloon injury as compared with its levels in uninjured left common carotid artery and both CsA and GFPVIVIT negated this response. Together these results for the first time demonstrate that NFATs play a critical role in neointima formation via induction of expression of COX-2.
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PMID:Blockade of nuclear factor of activated T cells activation signaling suppresses balloon injury-induced neointima formation in a rat carotid artery model. 1568 47

Cyclooxygenase (COX) is a key enzyme in prostaglandin (PG) synthesis. Up-regulation of COX-2 expression is responsible for increased PG release during inflammatory conditions and is thought to be also involved in allergic states. In this study, we demonstrate that in human T, B and natural killer lymphocytes from allergic patients, COX-2 expression became induced upon cell challenge with specific allergens and that this process is presumably IgE dependent and occurs after CD23 receptor ligation. This induction took place at both mRNA and protein levels and was accompanied by PGD2 release. IgE-dependent lymphocyte treatment elicited, in parallel, an activation of the MAPK p38 and extracellular signal-regulated kinase 1/2, an enhancement of calcineurin (CaN) activity, and an increase of the DNA-binding activity of the nuclear factor of activated T cells and of NF-kappaB, with a concomitant decrease in the levels of the cytosolic inhibitor of kappaB, IkappaB. In addition, specific chemical inhibitors of MAPK, such as PD098059 and SB203580, as well as MG-132, an inhibitor of proteasomal activity, abolished allergen-induced COX-2 up-regulation, suggesting that this process is mediated by MAPK and NF-kappaB. However, induction of COX-2 expression was not hampered by the CaN inhibitor cyclosporin A. We also examined the effect of a selective COX-2 inhibitor, NS-398, on cytokine production by human lymphocytes. Treatment with NS-398 severely diminished the IgE-dependently induced production of IL-8 and TNF-alpha. These results underscore the relevant role of lymphocyte COX-2 in allergy and suggest that COX-2 inhibitors may contribute to the improvement of allergic inflammation through the reduction of inflammatory mediator production by human lymphocytes.
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PMID:Induction of cyclooxygenase-2 expression by allergens in lymphocytes from allergic patients. 1599 64

We determined the functional implications of calcium-sensing receptor (CaR)-dependent, Gq- and Gi-coupled signaling cascades, which work in a coordinated manner to regulate activity of nuclear factor of activated T cells and tumor necrosis factor (TNF)-alpha gene transcription that cause expression of cyclooxygenase (COX)-2-derived prostaglandin E2 (PGE2) synthesis by rat medullary thick ascending limb cells (mTAL). Interruption of Gq, Gi, protein kinase C (PKC), or calcineurin (CaN) activities abolished CaR-mediated COX-2 expression and PGE2 synthesis. We tested the hypothesis that these pathways contribute to the effects of CaR activation on ion transport in mTAL cells. Ouabain-sensitive O2 consumption, an in vitro correlate of ion transport in the mTAL, was inhibited by approximately 70% in cells treated for 6 h with extracellular Ca2+ (1.2 mM), an effect prevented in mTAL cells transiently transfected with a dominant negative CaR overexpression construct (R796W), indicating that the effect was initiated by stimulation of the CaR. Pretreatment with the COX-2-selective inhibitor, NS-398 (1 microM), reversed CaR-activated decreases in ouabain-sensitive O2 consumption by approximately 60%, but did not alter basal levels of ouabain-sensitive O2 consumption. Similarly, inhibition of either Gq, Gi, PKC, or CaN, which are components of the mechanism associated with CaR-stimulated COX-2-derived PGE2 synthesis, reversed the inhibitory effects of CaR on O2 consumption without affecting basal O2 consumption. Our findings identified signaling elements required for CaR-mediated TNF production that are integral components regulating mTAL function via a mechanism involving COX-2 expression and PGE2 production.
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PMID:Calcium-sensing receptor signaling pathways in medullary thick ascending limb cells mediate COX-2-derived PGE2 production: functional significance. 1868 86

The nuclear factor of activated T cells (NFAT) transcription factors are regulated by calcium/calcineurin signals and play important roles in T cells, muscle, bone, and neural tissue. NFAT is expressed in the epidermis, and although recent data suggest that NFAT is involved in the skin's responses to ultraviolet radiation (UVR), the wavelengths of radiation that activate NFAT and the biological function of UV-activated NFAT remain undefined. We demonstrate that NFAT transcriptional activity is preferentially induced by UVB wavelengths in keratinocytes. The derived action spectrum for NFAT activation indicates that NFAT transcriptional activity is inversely associated with wavelength. UVR also evoked NFAT2 nuclear translocation in a parallel wavelength-dependent fashion and both transcriptional activation and nuclear translocation were inhibited by the calcineurin inhibitor cyclosporin A. UVR also evoked NFAT2 nuclear translocation in three-dimensional skin equivalents. Evidence suggests that COX-2 contributes to UV-induced carcinogenesis. Inhibiting UV-induced NFAT activation in keratinocytes, reduced COX-2 protein induction, and increased UV-induced apoptosis. COX-2 luciferase reporters lacking functional NFAT binding sites were less responsive to UVR, highlighting that NFAT is required for UV-induced COX-2 induction. Taken together, these data suggest that the proinflammatory, antiapoptotic, and procarcinogenic functions of UV-activated COX-2 may be mediated, in part, by upstream NFAT signaling.
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PMID:NFAT regulates induction of COX-2 and apoptosis of keratinocytes in response to ultraviolet radiation exposure. 1870 88

Mitogen-activated protein kinase phosphatase (MKP)-1 is a protein phosphatase that regulates the activity of p38 mitogen-activated protein (MAP) kinase and c-Jun NH2-terminal kinase (JNK) and, to lesser extent, p42/44 extracellular signal-regulated kinase. Studies with MKP-1(-/-) mice show that MKP-1 is a regulating factor suppressing excessive cytokine production and inflammatory response. The data on the role of MKP-1 in the regulation of inflammatory gene expression in human cells are much more limited. In the present study, we investigated the effect of MKP-1 on the expression of interleukin (IL)-6, IL-8 and cyclooxygenase (COX)-2 in response to stimulation with cytokines (tumor necrosis factor, IL-1beta, and interferon-gamma; 10 ng/ml each) in A549 human lung epithelial cells. Cytokines enhanced p38 and JNK phosphorylation and MKP-1 expression. p38 MAP kinase inhibitors 4-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-2-yl] phenol (SB202190) and 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3(4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl)urea (BIRB 796) inhibited cytokine-induced phosphorylation of p38 substrate MAP kinase-activated protein kinase 2 and expression of IL-6, IL-8, and COX-2. An aminopyridine-based JNK inhibitor, N-(4-amino-5-cyano-6-ethoxypyridin-2-yl)-2-(2,5-dimethoxyphenyl)acetamide (JNK inhibitor VIII), inhibited phosphorylation of a JNK substrate c-Jun but did not have any effect on IL-6, IL-8, or COX-2 expression. Down-regulation of MKP-1 with small interfering RNA enhanced p38 and JNK phosphorylation and increased IL-6, IL-8, and COX-2 expression in A549 cells. In conclusion, cytokine-induced MKP-1 expression was found to negatively regulate p38 phosphorylation and the expression of IL-6, IL-8, and COX-2 in human pulmonary epithelial cells. Our results suggest that MKP-1 is an important negative regulator of inflammatory gene expression in human pulmonary epithelial cells, and compounds that enhance MKP-1 may have anti-inflammatory effects and control inflammatory response in the human lung.
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PMID:Mitogen-activated protein kinase phosphatase-1 negatively regulates the expression of interleukin-6, interleukin-8, and cyclooxygenase-2 in A549 human lung epithelial cells. 2008 8

Sphingolipid metabolites regulate cell fate by acting on specific cellular targets. Although the influence of sphingolipids in cellular signaling has been well recognized, the exact molecular targets and how these targets influence cellular signaling mechanisms remain poorly understood. Toward this goal, we used affinity chromatography coupled with proteomics technology and identified acidic leucine-rich nuclear phosphoprotein-32A (ANP32A), an inhibitor of protein phosphatase 2A (PP2A) as a direct target of sphingosine, N,N'-dimethyl sphingosine (DMS) and phytosphingosine but not dihydrosphingosine or sphingosine 1-phosphate. Treatment of human umbilical vein endothelial cells (HUVEC) with DMS, which is not phosphorylated by sphingosine kinases, led to the activation of PP2A activity. Suppression of ANP32A with siRNA enhanced basal and DMS-activated PP2A activity suggesting that the sphingoid base binds to and relieves the inhibitory action of ANP32A on the PP2A complex. Indeed, DMS relieved the ANP32A-mediated inhibition of PP2A enzyme complex in vitro. Interestingly, DMS treatment induced the p38 stress-activated protein kinase (SAPK) and expression of cyclooxygenase (COX)-2 transcript and protein. Knockdown of ANP32A expression further induced p38 SAPK and COX-2. These data identify ANP32A as a novel molecular target of sphingoid bases that regulates cellular signaling events and inflammatory gene expression.
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PMID:Sphingosine interaction with acidic leucine-rich nuclear phosphoprotein-32A (ANP32A) regulates PP2A activity and cyclooxygenase (COX)-2 expression in human endothelial cells. 2055 41


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