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)

Hydrogen peroxide (H2O2), a reactive oxygen species, is assumed to have a detrimental effect on neuronal plasticity. Indeed, H2O2 suppresses long-term potentiation (LTP) in hippocampal slices of normal rats and wild-type (wt) mice. Transgenic mice overexpressing superoxide dismutase (SOD) 1 (tg-SOD), which maintain high ambient H2O2, have also been shown to be impaired in their ability to express hippocampal LTP. Paradoxically, H2O2, at a concentration (50 microm) that blocks LTP in wt mice, actually enhanced LTP in slices of 2-month-old tg-SOD mice. H2O2-dependent LTP in tg-SOD was blocked by the protein phosphatase calcineurin inhibitor FK506, but not by rapamycin, an FK-binding protein 12 (FKBP12) inhibitor or by 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7), a serine-kinase inhibitor. Interestingly, wt and tg-SOD mice expressed similar levels of the antioxidant enzyme catalase and similar activity of glutathione peroxidase. An opposite situation was found in 2-year-old mice. Aged wt mice were impaired in LTP in a manner that could be reversed by the addition of H2O2. Surprisingly, aged tg-SOD mice exhibited larger LTP than that found in wt mice, but this was now reduced by 50 microm H2O2. Both young tg-SOD and aged control mice displayed altered protein phosphatase activity, compared with that of young controls; moreover, FK506 inhibited LTP in old tg-SOD as well as in old wt mice treated with H2O2. These data promoted a dual role for H2O2 in the regulation of LTP, and proposed that it is mediated by the protein phosphatase calcineurin.
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PMID:Paradoxical actions of hydrogen peroxide on long-term potentiation in transgenic superoxide dismutase-1 mice. 1461 95

Cyclosporin A (CsA) suppresses immune reaction by inhibiting calcineurin activity after forming complex with cyclophilins and is currently widely used as an immunosuppressive drug. Cyclophilin A (CypA) is the most abundantly and ubiquitously expressed family member of cyclophilins. We previously showed that CsA toxicity is mediated by ROS generation as well as by inhibition of peptidyl-prolyl cis-trans isomerase (PPIase) activity of CypA in CsA-treated myoblasts [FASEB J. 16 (2002) 1633]. Since CsA-induced nephrotoxicity is the most significant adverse effect in its clinical utilization, we here investigated the role of CsA inhibition of CypA PPIase activity in its nephrotoxicity using transgenic mouse models. Transgenic mice of either wild type (CypA/wt) or R55A PPIase mutant type (CypA/R55A), a dominant negative mutant of CypA PPIase activity, showed normal growth without any apparent abnormalities. However, CsA-induced nephrotoxicity was virtually suppressed in CypA/wt mice, but exacerbated in CypA/R55A mice, compared to that of littermates. Also, life expectancy was extended in CypA/wt mice and shortened in CypA/R55A mice during CsA administration. Besides, CsA-induced nephrotoxicity was inversely related to the levels of catalase expression and activity. In conclusion, our data provide in vivo evidence that supplement of CypA PPIase activity allows animal's resistance toward CsA-induced nephrotoxicity.
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PMID:Transgenic mice overexpressing cyclophilin A are resistant to cyclosporin A-induced nephrotoxicity via peptidyl-prolyl cis-trans isomerase activity. 1504 94

The rice Oryza sativa selenium-binding protein homologue (OsSBP) gene encodes a homologue of mammalian selenium-binding proteins, and it has been isolated as one of the genes induced by treating a plant with a cerebroside elicitor from rice blast fungus. The possible role of OsSBP in plant defense was evaluated by using a transgenic approach. Plants overexpressing OsSBP showed enhanced resistance to a virulent strain of rice blast fungus as well as to rice bacterial blight. The expression of defense-related genes and the accumulation of phytoalexin after infection by rice blast fungus were accelerated in the OsSBP overexpressors. A higher level of H(2)O(2) accumulation and reduced activity of such scavenging enzymes as ascorbate peroxidase and catalase were seen when the OsSBP-overexpressing plants were treated with the protein phosphatase 1 inhibitor, calyculin A. These results suggest that the upregulation of OsSBP expression conferred enhanced tolerance to different pathogens, possibly by increasing plant sensitivity to endogenous defense responses. Additionally, the OsSBP protein might have a role in modulating the defense mechanism to biotic stress in rice.
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PMID:Enhanced resistance to blast fungus and bacterial blight in transgenic rice constitutively expressing OsSBP, a rice homologue of mammalian selenium-binding proteins. 1511 17

Reactive oxygen intermediates (ROI) have been viewed traditionally as damaging to the cell. However, a predominance of evidence has shown that ROI can also function as important activators of key cellular processes, and ROI have been shown to play a vital role in cell signaling networks. The calcium/calmodulin-dependent protein kinases (CaM kinases) are a family of related kinases that are activated in response to increased intracellular calcium concentrations. In this report we demonstrate that hydrogen peroxide treatment results in the activation of both CaM kinase II and IV in Jurkat T lymphocytes. Surprisingly, this activation occurs in the absence of any detectable calcium flux, suggesting a novel means for the activation of these kinases. Treatment of Jurkat cells with phorbol 12-myristate 13-acetate (PMA), which does not cause a calcium flux, also activated the CaM kinases. The addition of catalase to the cultures inhibited PMA-induced activation of the CaM kinases, suggesting that similar to hydrogen peroxide, PMA also activates the CaM kinases via the production of ROI. One mechanism by which this likely occurs is through oxidation and consequential inactivation of cellular phosphatases. In support of this concept, okadaic acid and microcystin-LR, which are inhibitors of protein phosphatase 2A (PP2A), induced CaM kinase II and IV activity in these cells. Overall, these results demonstrate a novel mechanism by which ROI can induce CaM kinase activation in T lymphocytes.
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PMID:Redox regulation of the calcium/calmodulin-dependent protein kinases. 1529 13

Reactive oxygen species (ROS) trigger a biomolecular alteration that causes functional and structural changes. In renal transplantation, there is an increase in oxidative phenomena related to endothelial dysfunction, inflammation, and atherosclerosis, the main cause of cardiovascular complications and chronic allograft failure. The present study was designed to assess the oxidative state of transplant patients with stable renal function, in order to establish differences in oxidative, biochemical, and clinical parameters between patients treated with tacrolimus versus cyclosporine. We studied 67 stable kidney transplant patients treated with calcineurin inhibitors who were not receiving cholesterol-lowering therapy, and 14 healthy subjects. Data were collected on biochemical parameters: lipid profile (apoA, apoB, total cholesterol and fractions, and triglycerides); urea; and creatinine; oxidative parameters: malondialdehyde (MDA) as a lipid peroxidation marker, glutathione peroxidase (GPx), catalase, superoxide dismutase (SOD), glutathione reductase (GR), and antibodies against oxidized LDL; and clinical variables. Transplanted patients showed a higher oxidative status (MDA increase and GPx decrease) than healthy subjects. The oxidative status did not differ between the cyclosporine and tacrolimus cohorts. Some factors during the posttransplant period, such as delayed graft function, cytomegalovirus infection, and microalbuminuria, which may damage renal function, produce a decreased antioxidant capacity (lower GPx).
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PMID:Modulation factors of oxidative status in stable renal transplantation. 1586 26

Intracellular reduction and oxidation pathways regulate protein functionality through both reversible and irreversible mechanisms. The Cdc25 phosphatases, which control cell cycle progression, are potential subjects of oxidative regulation. Many of the more potent Cdc25 phosphatase inhibitors reported to date are quinones, which are capable of redox cycling. Therefore, we used the previously characterized quinolinedione Cdc25 inhibitor DA3003-1 [NSC 663284 or 6-chloro-7-(2-morpholin-4-yl-ethylamino)-quinoline-5,8-dione] and a newly synthesized congener JUN1111 [7-(2-morpholin-4-yl-ethylamino)-quinoline-5,8-dione] to test the hypothesis that quinone inhibitors of Cdc25 regulate phosphatase activity through redox mechanisms. Like DA3003-1, JUN1111 selectively inhibited Cdc25 phosphatases in vitro in an irreversible, time-dependent manner and arrested cells in the G1 and G2/M phases of the cell cycle. It is noteworthy that both DA3003-1 and JUN1111 directly inhibited Cdc25B activity in cells. Depletion of glutathione increased cellular sensitivity to DA3003-1 and JUN1111, and in vitro Cdc25B inhibition by these compounds was sensitive to pH, catalase, and reductants (dithiothreitol and glutathione), consistent with oxidative inactivation. In addition, both DA3003-1 and JUN1111 rapidly generated intracellular reactive oxygen species. Analysis of Cdc25B by mass spectrometry revealed sulfonic acid formation on the catalytic cysteine of Cdc25B after in vitro treatment with DA3003-1. These results indicate that irreversible oxidation of the catalytic cysteine of Cdc25B is indeed a mechanism by which these quinolinediones inactivate this protein phosphatase.
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PMID:Redox regulation of Cdc25B by cell-active quinolinediones. 1615 9

Diabetes mellitus causes multiple cardiovascular complications. Previous studies have shown that prolonged exposure (96 h) of human umbilical vein endothelial cells (HUVECs) to hyperglycemia causes a significant increase in apoptosis. We report here that this increase in apoptosis is associated with an increase in Ca(2+) current (whole cell patch-clamp recorded) resulting from Ca(2+) entry mediated by store-operated channels (SOCs). The number of apoptotic cells after prolonged high glucose (HG, 30 mmol/L) exposure was significantly reduced in the presence of the SOC inhibitor 2-APB or of La(3+). A marked increase (approximately 80%) in Ca(2+)-dependent calcineurin (CN-A) phosphatase activity also occurred after prolonged HG exposure. Prolonged HG exposure-induced increase in CN-A activity was prevented by 2-APB, and selective CN-A phosphatase inhibition by FK506 or calmodulin inhibition by calmidazolium decreased HG-induced apoptosis. Blocking hydrogen peroxide production using catalase or inhibiting the tyrosine kinase pp60(src) during prolonged exposure to HG, resulted in a marked decrease in apoptosis and was further associated with a significant reduction in CN-A phosphatase activity. The results demonstrate a significant role for Ca(2+) entry in HG-induced apoptosis in HUVECs, and suggest that this role is mediated via H(2)O(2) generation and the action of the Ca(2+)-activated protein phosphatase calcineurin.
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PMID:High glucose-induced apoptosis through store-operated calcium entry and calcineurin in human umbilical vein endothelial cells. 1624 95

The enzyme catalase (EC 1.11.1.6) is inactivated by light and must be continuously replaced by new synthesis in order to maintain a constant enzyme activity in leaves. In winter rye leaves (Secale cereale L.) posttranscriptional mechanisms determine the rate of new catalase synthesis, including a light-controlled reversible modification of the catalase cat1 mRNA by methylation which greatly enhanced its translation efficiency. The specificity and regulation of this mRNA activation were further investigated. The translation efficiency of the rye cat1 mRNA was much more enhanced by N-7 methylation of the cap than that of an lhcb transcript. Investigations with truncated rye cat1 mRNAs indicated that the translational enhancement resulting from N-7 cap methylation did not require the presence of specific sequences of cat1 5'- and 3'-untranslated regions. Translational activation of the cat1 mRNA in rye leaves was independent of photosynthesis and most effectively induced by blue light. Peroxides (H(2)O(2), tertiary butyl hydroperoxide) and conditions enforcing an H(2)O(2) accumulation in the leaves (aminotriazole, paraquat) also caused an activation of the cat1 mRNA. A search for further signalling systems controlling the replenishment of inactivated catalase in light suggested that an inositol-1,4,5-triphosphate-mediated liberation of Ca(2+) from internal stores and a protein phosphatase played some role. However, these signalling systems did not affect the activation of the cat1 mRNA. After removal of Ca(2+) by EGTA the cat1 mRNA was rapidly degraded.
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PMID:Mode of translational activation of the catalase (cat1) mRNA of rye leaves (Secale cereale L.) and its control through blue light and reactive oxygen. 1634 7

Cdc25B protein phosphatase represents an attractive potential therapeutic target for small molecule intervention because of its central role in positively regulating cyclin dependent kinases and thus cell proliferation, as well as its elevated levels observed in many human tumors. Among the most potent previously identified Cdc25 inhibitors have been quinoline quinones, which have a rich legacy as therapeutic agents but have also been associated with nonspecific interactions. In this study, we have interrogated the structure-activity relationship of a focused series of C2-, C3-, or C4-modified quinoline-5,8-quinones on Cdc25B inhibition in vitro. Substitution at the C3-position in this small chemical series were slightly superior to substitutions at the C3-position. For all compounds, recombinant human Cdc25B was approximately 5-fold more sensitive compared to recombinant human PTP1B. Two compounds inhibited HeLa cell growth with IC50 values of approximately 2 microM. Consistent with other para-quinones, some members of this series generated intracellular reactive oxygen species and the in vitro enzyme inhibition was mitigated by addition of reductants or catalase. These results indicate that chemical modifications on the pyridine core are tolerated, providing additional sites for future structural modification of this biologically active pharmacophore.
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PMID:Biological evaluation of newly synthesized quinoline-5,8-quinones as Cdc25B inhibitors. 1678 52

Curcumin is a naturally occurring compound which is known to induce heme oxygenase 1 (HO-1), although the underlying mechanism has not been fully elucidated. This study investigates in detail the mechanism of HO-1 induction by curcumin in human hepatoma cells. There was increasing toxicity of curcumin at concentrations higher than 10 microM. Curcumin was found to induce HO-1 at doses of 10 to 25 microM. At both non-toxic and toxic doses, HO-1 induction was found to correlate with production of reactive oxygen species (ROS), suggesting a causative relationship. This was reinforced by the finding that pretreatment with the antioxidants N-acetylcysteine, vitamin E and catalase prevented HO-1 induction by curcumin. ROS production appeared to be mitochondrial in origin, and curcumin treatment resulted in depolarisation of the mitochondrial membrane potential. Nrf2 was induced by curcumin treatment, which was also partly ROS dependent. Using siRNA, Nrf2 was demonstrated to contribute to HO-1 induction. A panel of kinase inhibitors was used to examine the contribution of MAP kinases to the induction of HO-1 by curcumin. PKC and p38 MAPK activity are required for full induction of HO-1. Furthermore, curcumin also inhibited protein phosphatase activity. In conclusion, curcumin treatment results in ROS generation, activation of Nrf2 and MAP kinases and the inhibition of phosphatase activity in hepatocytes, and when curcumin is not administered in toxic doses, these multiple pathways converge to induce HO-1.
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PMID:Curcumin induces heme oxygenase 1 through generation of reactive oxygen species, p38 activation and phosphatase inhibition. 1714 61


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