Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interferon (IFN)-gamma and macrophages (Mphi) play key roles in acute, persistent, and latent murine cytomegalovirus (MCMV) infection. IFN-gamma mechanisms were compared in embryonic fibroblasts (MEFs) and bone marrow Mphi (BMMphi). IFN-gamma inhibited MCMV replication in a signal transducer and activator of transcription (STAT)-1alpha-dependent manner much more effectively in BMMphi (approximately 100-fold) than MEF (5-10-fold). Although initial STAT-1alpha activation by IFN-gamma was equivalent in MEF and BMMphi, microarray analysis demonstrated that IFN-gamma regulates different sets of genes in BMMphi compared with MEFs. IFN-gamma inhibition of MCMV growth was independent of known mechanisms involving IFN-alpha/beta, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase RNA activated (PKR), RNaseL, and Mx1, and did not involve IFN-gamma-induced soluble mediators. To characterize this novel mechanism, we identified the viral targets of IFN-gamma action, which differed in MEF and BMMphi. In BMMphi, IFN-gamma reduced immediate early 1 (IE1) mRNA during the first 3 h of infection, and significantly reduced IE1 protein expression for 96 h. Effects of IFN-gamma on IE1 protein expression were independent of RNaseL and PKR. In contrast, IFN-gamma had no significant effects on IE1 protein or mRNA expression in MEFs, but did decrease late gene mRNA expression. These studies in primary cells define a novel mechanism of IFN-gamma action restricted to Mphi, a cell type key for MCMV pathogenesis and latency.
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PMID:Novel cell type-specific antiviral mechanism of interferon gamma action in macrophages. 1118

Excessive proinflammatory cytokine and NO production by activated microglia play a role in neurodegenerative disorders. To investigate whether the neuroprotectant N-acetyl-O-methyldopamine (NAMDA) downregulates genes associated with microglial activation, we measured gene expression of TNF-alpha, IL-1beta, inducible nitric oxide synthase (NOS2), and an associated cofactor synthesis gene, GTP cyclohydrolase I (GTPCH) in LPS-stimulated microglia cells in the presence or absence of NAMDA. The temporal pattern of cytokine gene expression showed that LPS (0.2 microg/ml) increased TNF-alpha and IL-1beta gene expression at 1 and 3 h, which was repressed by cotreatment of NAMDA. Similarly, LPS also induced GTPCH and NOS2 gene expression at 3 and 6 h, and cotreatment of NAMDA repressed the induction with parallel reduction of nitrite, an oxidative metabolite of nitric oxide. Since transcription factor NF-kappaB is involved in regulating expression of these genes, the effects of NAMDA on NF-kappaB nuclear translocation and DNA binding in immunostimulated microglia were investigated. We found that neither LPS-induced NF-kappaB translocation nor DNA binding activity was affected by cotreatment with NAMDA in BV-2 microglia. On the other hand, NAMDA increased intracellular cAMP levels and potentiated LPS-induced phosphorylated cAMP-responsive element binding protein (pCREB) expression. Treatment with adenosine 3'5'-cyclic monophosphothioate, a specific inhibitor of cAMP-dependent protein kinase (PKA), reversed not only NAMDA-induced pCREB upregulation but also NAMDA-induced repression of TNF-alpha and IL-1beta gene transcription. The data demonstrate that NAMDA represses LPS-induced proinflammatory cytokines gene expression via a cAMP-dependent protein kinase pathway. Thus, repressing proinflammatory cytokines and NOS2 gene expression in activated microglia by NAMDA may provide new therapeutic strategies for ischemic cerebral disease as well as other neurodegenerative diseases.
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PMID:Repression of proinflammatory cytokine and inducible nitric oxide synthase (NOS2) gene expression in activated microglia by N-acetyl-O-methyldopamine: protein kinase A-dependent mechanism. 1124 31

Imidazoline compounds have been considered for the treatment of type 2 diabetes. We have now investigated the effects of imidazolines on interleukin (IL)-1beta-induced beta-cell apoptosis and the signal transduction pathways involved. Inhibition of Ca2+ influx into beta-cells by D-600, a blocker of voltage-gated L-type Ca2+ channels, suppressed IL-1beta-induced apoptosis. Our data show that calcineurin, Ca2+/calmodulin-dependent serine/threonine protein phosphatase 2B, is responsible for the effect of Ca2+ on beta-cell apoptosis. We also demonstrate that IL-1beta-mediated apoptosis correlates with expression of inducible nitric oxide synthase (iNOS) and the increase in intracellular production of nitric oxide. An inhibitor of cGMP-dependent protein kinase (PKG), KT5823, suppressed IL-1beta-induced apoptosis, suggesting the involvement of a PKG-dependent pathway in the apoptotic process. One of the major findings in this study is that imidazoline compounds RX871024 and efaroxan, suggested as prototypes of a new generation of drugs against type 2 diabetes, can protect against IL-1beta-induced apoptosis in pancreatic beta-cells, possibly by their inhibition of the expression of iNOS, a key element in the IL-1beta-induced apoptotic pathway in pancreatic beta-cells. These data suggest that imidazoline compounds should be explored as a potential therapeutic agent for the treatment of both type 1 and type 2 diabetes.
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PMID:Imidazoline compounds protect against interleukin 1beta-induced beta-cell apoptosis. 1127 6

This study has demonstrated the mechanism of protein kinase A (PKA)-dependent inhibition of astrocytic nitric oxide production and inducible NO synthase mRNA expression induced by lipopolysaccharide. In C6 glioma cells, the stimulation with lipopolysaccharide (LPS; 1 microg/ml) evoked increases of nitric oxide (NO) production, NO synthase (iNOS) mRNA expression, phosphorylation of p38 mitogen activated protein kinase (p-p38), and the activation of NF kappa B. LPS-induced NO production and iNOS mRNA expression were inhibited by the pretreatment with forskolin (FSK; 5 microM) in a dose-dependent manner, and which were reversed by PKA inhibition by compound H89. Furthermore, LPS-induced increases of p-p38, but not activation of NF kappa B, were also reduced by FSK and H89 reversed the FSK-induced inhibition response. The dose-dependent inhibition of NO production and iNOS mRNA expression by compound SB203580 (p38 inhibitor) suggests the participation of p38 in PKA-dependent inhibition of LPS-induced NO production and iNOS mRNA expression. However, the activation of NF kappa B by LPS also not affected by SB203580. Therefore, our results suggest that, in C6 glioma cells, LPS-induced NO production and iNOS gene expression may be regulated by PKA pathway through the reduction of activity of p38 kinase. This inhibitory role of PKA may not involve the activation of NF kappa B.
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PMID:Forskolin inhibits expression of inducible nitric oxide synthase mRNA via inhibiting the mitogen activated protein kinase in C6 cells. 1131 70

Nitric oxide (NO) levels are increased after exposure of cultured proximal tubule cells (PTC) to non-haem iron, potentially contributing to PTC injury in disease states associated with increased iron exposure, including proteinuric renal disease. The mechanisms underlying this observed increase were investigated. After 3 h exposure to 400 microM nitrilotriacetate (NTA)-Fe, inducible nitric oxide synthase (iNOS) mRNA expression was significantly increased, with a corresponding increase in iNOS protein after 12 h. The nuclear binding activity of NFkappaB with 400 microM NTA-Fe was increased, and pyrrolidine dithiocarbamate (PDTC), an antioxidant inhibitor of NFkappaB, prevented both activation of NFkappaB and NO production in response to NTA-Fe. Inhibition of protein tyrosine kinase reduced iNOS mRNA, iNOS protein levels and NO production in response to NTA-Fe. The effect of tyrosine kinase inhibition on NFkappaB activation was variable, with herbimycin but not genistein having an inhibitory effect. Activation of either protein kinase A or C increased iNOS mRNA and protein levels, and NO production in response to NTA-Fe, whereas only the protein kinase C activator phorbol dibutyrate (PDBu) had a stimulatory effect on NFkappaB activation. The protein kinase A activator forskolin did not alter iron-induced activation of NFkappaB. These data suggest that the observed increase in NO production by PTC in response to iron is due to increased transcription of iNOS. The transcriptional regulation of this response is complex and involves NFkappaB, protein tyrosine kinase and the protein kinases A and C.
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PMID:Molecular mechanisms by which iron induces nitric oxide synthesis in cultured proximal tubule cells. 1134 Mar 4

Both nitric oxide (NO) and prostaglandin E2 (PGE2) are known to play an important role in cartilage metabolism. The present study investigated the novel intercellular mechanism of inducible NO synthase (iNOS) induction mediated by PGE2 in articular chondrocytes. Bovine articular chondrocytes were stimulated by cyclic adenosine monophosphate (cAMP) elevating agents like PGE2 in the presence of interleukin-1 alpha (IL-1 alpha). NO generation was measured by using the Griess reaction. Inducible NOS mRNA was semi-quantitated by reverse transcription-polymerase chain reaction (RT-PCR). While little NO was released from articular chondrocytes in the presence of PGE2 or direct adenylate cyclase activator such as forskolin, synergistic augmentation of NO generation was observed when chondrocytes were stimulated by PGE2 or forskolin in combination with IL-1 alpha. Further expression of iNOS mRNA by stimulation of PGE2 in the presence of IL-1 alpha simultaneously was also detected by RT-PCR in comparison with the mRNA induction by IL-1 alpha stimulation alone. These results indicated that PGE2 might modulate the articular cartilage metabolism by augmentation of chondrocyte NO synthesis in inflammatory process through cAMP-protein kinase A system.
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PMID:Effect of prostaglandin E2 on nitric oxide synthesis in articular chondrocytes. 1135 27

The protection conferred by ischemic preconditioning (PC) of myocardium occurs in a bimodal time course. The early cardioprotection wanes rapidly and is succeeded by a delayed phase of protection. This "second window" lasts for up to 72 hours, depending on species and end-point. A widely adopted paradigm for delayed PC is the following: 1) freely diffusible molecules or radicals, generated during the PC period, act in autocrine and/or paracrine manner as triggers of cellular adaptation; 2) they cause the activation of a protein kinase signal cascade; 3) the activated kinases phosphorylate important substrate proteins. In the case of delayed PC, it is thought that the phosphorylation of transcription factors, initiating the synthesis of late appearing effector proteins that promote cell survival during subsequent ischemia, may be a crucial event. Investigation of the proximal components of this sequence has altered our perceptions of several biological mediators, previously thought to be short acting, including adenosine, NO, free radicals and bradykinin. Signal transduction components include protein kinase C, tyrosine kinases and various mitogen- and stress-activated protein kinases but their patterns of regulation are complex and as yet poorly defined. Gene expression is modified in a regulated fashion to induce new proteins that promote cell repair and to protect against subsequent ischemia-reperfusion insult. It is likely that the complex nature of the preconditioning stimulus causes the activation of a variety of transcription factors, regulating a large number of target genes. So far, attention has focussed on a small number of protein products as potential distal mediators of delayed preconditioning. These include the heat shock proteins, manganese superoxide dismutase, inducible nitric oxide synthase, the ATP-sensitive potassium channel and cyclo-oxygenase-2.
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PMID:Delayed preconditioning of myocardium: current perspectives. 1151 89

Administration of bacterial lipopolysaccharide (LPS) to laboratory animals and cultured macrophages is known to induce the production of nitric oxide (NO) from inducible nitric oxide synthase (iNOS). Here we show that pre-treatment with Ginkgo biloba extract (EGb 761) suppresses the in vivo production of NO (measured by the Griess reaction) after challenge with LPS. In order to begin to understand the mechanism of this inhibition, we evaluated in vitro effects of EGb 761 and its flavonoid component, quercetin, on LPS-treated RAW 264.7 macrophages. Pre-treatment with EGb 761 or quercetin dose-dependently inhibited NO release. Both substances scavenged NO generated from the decomposition of sodium nitroprusside. Western analysis showed that EGb 761 and quercetin inhibited LPS-induced levels of iNOS protein. Northern blotting demonstrated that EGb 761 and quercetin decreased LPS-induced iNOS mRNA levels without altering the half-life. Activation of mitogen activated protein kinases (MAPKs) and the redox-sensitive transcription factors, nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1) are key events in the signal transduction pathways mediating iNOS induction. In our studies, both EGb 761 and quercetin inhibited p38 MAPK activity, which is necessary for iNOS expression in LPS-stimulated RAW 264.7 macrophages. However, differences in the response of NF-kappaB, AP-1, and Jun N-terminal kinase/stress activated protein kinase (JNK/SAPK) and its downstream substrates to EGb 761 and quercetin suggest that quercetin is not the sole component responsible for the in vivo inhibition of LPS-induced iNOS activation by EGb 761.
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PMID:Effects of Ginkgo biloba extract (EGb 761) and quercetin on lipopolysaccharide-induced release of nitric oxide. 1151 63

During periods of acute rejection, transplanted hearts have increased nitric oxide (NO) production and depressed contractile function. Myocytes isolated from rejecting hearts exhibit parallel increases in NO production and reduced shortening, indicating that the contractile dysfunction of the transplanted heart is intrinsic to the myocytes. We tested the hypothesis that the contractile dysfunction of the rejecting heart is due to an NO-mediated inhibition of the L-type calcium current. Ventricular myocytes isolated from rejecting rat hearts (allografts) expressed inducible nitric oxide synthase (iNOS) and produced substantially more NO than did myocytes isolated from non-rejecting rat hearts (isografts). Aminoguanidine, an inhibitor of iNOS, reduced NO production by allograft myocytes, but was without effect on NO production by isograft myocytes. In the absence of exogenous l -arginine (the precursor of NO), the calcium current was identical in allograft and isograft myocytes. In the presence of l -arginine, the calcium current was reduced in allograft myocytes compared to isograft myocytes. Superfusion of the myocytes with either aminoguanidine or KT5823 (an inhibitor of the cyclic GMP-dependent protein kinase) reversed the depression of the calcium current in allograft myocytes, but neither inhibitor had an effect on calcium current in isograft myocytes. These results indicate that increased production of NO by myocytes isolated from rejecting hearts leads to a reduction in the calcium current. This mechanism may contribute substantially to the contractile dysfunction of rejecting transplanted hearts.
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PMID:Myocytes isolated from rejecting transplanted rat hearts exhibit a nitric oxide-mediated reduction in the calcium current. 1154 47

Tremendous progress has been made in understanding the molecular basis of the antiviral actions of interferons (IFNs), as well as strategies evolved by viruses to antagonize the actions of IFNs. Furthermore, advances made while elucidating the IFN system have contributed significantly to our understanding in multiple areas of virology and molecular cell biology, ranging from pathways of signal transduction to the biochemical mechanisms of transcriptional and translational control to the molecular basis of viral pathogenesis. IFNs are approved therapeutics and have moved from the basic research laboratory to the clinic. Among the IFN-induced proteins important in the antiviral actions of IFNs are the RNA-dependent protein kinase (PKR), the 2',5'-oligoadenylate synthetase (OAS) and RNase L, and the Mx protein GTPases. Double-stranded RNA plays a central role in modulating protein phosphorylation and RNA degradation catalyzed by the IFN-inducible PKR kinase and the 2'-5'-oligoadenylate-dependent RNase L, respectively, and also in RNA editing by the IFN-inducible RNA-specific adenosine deaminase (ADAR1). IFN also induces a form of inducible nitric oxide synthase (iNOS2) and the major histocompatibility complex class I and II proteins, all of which play important roles in immune response to infections. Several additional genes whose expression profiles are altered in response to IFN treatment and virus infection have been identified by microarray analyses. The availability of cDNA and genomic clones for many of the components of the IFN system, including IFN-alpha, IFN-beta, and IFN-gamma, their receptors, Jak and Stat and IRF signal transduction components, and proteins such as PKR, 2',5'-OAS, Mx, and ADAR, whose expression is regulated by IFNs, has permitted the generation of mutant proteins, cells that overexpress different forms of the proteins, and animals in which their expression has been disrupted by targeted gene disruption. The use of these IFN system reagents, both in cell culture and in whole animals, continues to provide important contributions to our understanding of the virus-host interaction and cellular antiviral response.
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PMID:Antiviral actions of interferons. 1158 85


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