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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The phenotype of mitogen-activated protein kinase-activated protein kinase-2 (MK2) knockout mice revealed the essential role of this enzyme in post-transcriptional regulation of lipopolysaccharide-induced expression of cytokines such as tumour necrosis factor (TNF)-alpha, interleukin-6 and interferon-gamma, at the level of mRNA stability and translation. In the case of TNF-alpha, this regulation depends on the AU-rich element in TNF-alpha mRNA. In addition to cytokine expression, MK2 is also essential for cell migration in vitro. Although the role of MK2 in cytokine expression depends mainly on catalytic activity, its role in cell migration is also dependent on a proline-rich N-terminal motif. However, the molecular mechanisms involved and the relevant protein targets for MK2 are not completely defined. Here we discuss the possible mechanisms by which two potential target proteins of MK2, small heat-shock protein 25/27 (Hsp25/27) and tristetraprolin, could contribute to our understanding of the above regulation.
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PMID:Is MK2 (mitogen-activated protein kinase-activated protein kinase 2) the key for understanding post-transcriptional regulation of gene expression? 1244 Sep 54

Interferon-induced protein of 10 kDa (IP-10) induces antitumor immunity. Cyclooxygenase-2 and its metabolite prostaglandin E2 (PGE2) are overexpressed in tumor cells, which may suppress antitumor immunity. We examined the in vitro effects of cyclooxygenase-2 inhibitor NS398 on IP-10 production in human epidermoid carcinoma A431. NS398 enhanced interferon-gamma-induced IP-10 secretion, mRNA expression, and promoter activation in A431, and exogenous PGE2 antagonized the enhancement. Interferon-stimulated response element (ISRE) on IP-10 promoter was responsible for the transcriptional regulation by NS398 and PGE2. NS398 enhanced interferon-gamma-induced transcription through ISRE and binding of signal transducer and activator of transcription 1alpha (STAT1alpha to ISRE in A431, and PGE2 antagonized the enhancement. NS398 enhanced interferon-gamma-induced tyrosine phosphorylation of STAT1alpha, Janus tyrosine kinase 1, and Janus tyrosine kinase 2, and PGE2 antagonized the enhancement. PGE2-mediated suppression of IP-10 synthesis was counteracted by adenylate cyclase inhibitor SQ22536 and protein kinase A inhibitor H-89, and PGE2 receptor EP4 antagonist AH23848B. AH23848B, SQ22536, and H-89 counteracted the PGE2-mediated suppression of ISRE-dependent transcription, STAT1alpha binding to ISRE, and tyrosine phosphorylation of STAT1alpha, Janus tyrosine kinase 1, and Janus tyrosine kinase 2. PGE2 increased intracellular cAMP level and protein kinase A activity in A431 pretreated with NS398, and AH23848B blocked the effects of PGE2. These results suggest that A431-derived PGE2 may generate cAMP signal via EP4 in A431, which may activate protein kinase A, and may resultantly inhibit interferon-gamma-induced STAT1alpha activation and IP-10 synthesis. The results also suggest that NS398 may restore IP-10 synthesis by preventing PGE2 production in A431 and thus may be therapeutically useful for skin cancer.
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PMID:Cyclooxygenase-2 inhibitor enhances whereas prostaglandin E2 inhibits the production of interferon-induced protein of 10 kDa in epidermoid carcinoma A431. 1244 96

Activation of CD4(+) T cells is governed by interplay between stimulatory and inhibitory receptors; predominance of stimulatory signals favors autoimmune reactions. In patients with rheumatoid arthritis, expression of the critical costimulatory molecule, CD28, is frequently lost. Instead, CD4(+)CD28(null) T cells express killer immunoglobulin-like receptors (KIRs) with a preferential expression of the stimulatory receptor, CD158j. The frequency of CD4(+)CD28(null) T cells in rheumatoid arthritis (RA) correlates with the risk for more severe disease. Moreover, the KIR2DS2 gene, which encodes for CD158j, is a genetic risk factor for rheumatoid vasculitis. CD158j signals through the adaptor molecule, KARAP/DAP12, to positively regulate cytotoxic activity in NK cells. However, the majority of CD4(+)CD28(null) T cell clones lacked the expression of KARAP/DAP12. Despite the absence of KARAP/DAP12, CD158j was functional and augmented interferon-gamma production after T cell receptor stimulation. Cross-linking of CD158j resulted in selective phosphorylation of c-Jun NH(2)-terminal protein kinase (JNK) and its upstream kinase, MKK4 that led to the expression of ATF-2 and c-Jun, all in the absence of extracellular signal-regulated kinase (ERK)1/2 phosphorylation. Mutation of the lysine residue within the transmembrane domain of CD158j abolished JNK activation, suggesting that an alternate adaptor molecule was being used. CD4(+)CD28(null) T cells expressed DAP10 and inhibition of phosphatidylinositol 3-kinase, which acts downstream of DAP10, inhibited JNK activation; however, no interaction of DAP10 with CD158j could be detected. Our data suggest that CD158j in T cells functions as a costimulatory molecule through the JNK pathway independent of KARAP/DAP12 and DAP10. Costimulation by CD158j may contribute to the autoreactivity of CD4(+)CD28(null) T cells in RA.
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PMID:Selective activation of the c-Jun NH2-terminal protein kinase signaling pathway by stimulatory KIR in the absence of KARAP/DAP12 in CD4+ T cells. 1259 2

Regulatory RNAs are noncoding RNAs that can regulate gene expression. Our previous results showed that regulatory RNAs can induce the production of interleukin-1, interleukin-2, interleukin-8, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma, and Fas ligand (FasL). These cytokines and FasL are involved in host defense mechanisms against tumors. B16-F10 melanoma cells are highly metastatic to the lungs and we showed that lymphocytes treated with the regulatory B16-RNA reduce significantly the number of metastatic nodules. We also found that B16-RNA activates RNA-dependent protein kinase (PKR) and the active B16-RNA fraction is polyadenylated with a sedimentation coefficient of 18S. Our findings suggest that the antitumor activity of B16-RNA is mediated by PKR through activation of the transcription factor NF-kappaB. Thus, B16-RNA may act as a regulatory RNA and may regulate gene expression at transcriptional level. This study provides the rationale for the use of B16-RNA as an immunomodulator in melanoma.
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PMID:Antitumor activity induced by regulatory RNA: possible role of RNA-dependent protein kinase and nuclear factor-kappaB. 1268 31

Atopic asthma is a chronic inflammatory disorder of the airways where upon exposure to allergens, the body mounts an immune response. This disease is associated with an increase in the number of Th2 (T helper type 2) cells and Th2 cytokines and a decrease in the number of Th1 (T helper type 1) cells and Th1 cytokines. Histamine plays an important role in the pathogenesis of atopic asthma through differential regulation of T helper lymphocytes. Histamine enhances the secretion of Th2 cytokines such as IL-4 (interleukin-4), IL-5, IL-10 and IL-13 and inhibits the production of Th1 cytokines IL-2 and IFNgamma (interferon-gamma) and monokine IL-12. It has been shown that histamine can modulate the cytokine network through upregulation of PGE(2) (prostaglandin E(2)) and NO (nitric oxide). Histamine also affects cytokine production via H2 receptors and through the activation of PKA (protein kinase A). We have also demonstrated that the Jak-STAT (Janus kinase-signal transducers and activators of transcription) pathway is involved in histamine-mediated regulation of Th2 cytokines IL-5, IL-10, IL-13 and Th1 cytokine IFNgamma. While standard treatment of asthma consists of beta-receptor agonists and inhaled corticosteroids, the elucidation of histamine's control over the cytokine network and the Th1/Th2 balance provides a basis for the potential use of antihistamines in the prevention and treatment of atopic asthma. Several other anti-allergic agents to modulate the Th1/Th2 balance are under current investigation based on this paradigm. These include cytokines, cytokine antagonists, anti-IgE, and vaccinations. As more advances are made in our understanding of histamine and its control over the Th1/Th2 balance, the use of new therapeutic targets such as these will play a prominent role in disease management.
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PMID:Effects of histamine on Th1/Th2 cytokine balance. 1281 Mar 48

Using cultured rat alveolar NR 8383 macrophages, this study investigated the effect of YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole], a soluble guanylyl cyclase (sGC) activator, on the production of tumor necrosis factor-alpha (TNF alpha). YC-1 enhanced lipopolysaccharide and interferon-gamma (LPS/IFN gamma)-induced TNF alpha formation in a concentration- and time-dependent fashion. YC-1 also caused an increasing effect on the TNF alpha mRNA level, suggesting that the transcriptional process was involved. However, further studies suggested that cyclic GMP did not mediate the potentiation of YC-1 on TNF alpha release, because (a) the sGC inhibitor and the protein kinase G inhibitor failed to block the effect; and (b) the cyclic GMP analogues, on the contrary, concentration-dependently diminished LPS/IFN gamma-induced TNF alpha synthesis. In agreement with this finding, YC-1 produced changes in cell function but no changes in cyclic GMP and cyclic AMP levels or sGC activity. Pretreatment of the cells with cyclooxygenase inhibitors, a p38 mitogen-activated protein kinase inhibitor, a mitogen-activated protein kinase kinase (MEK) inhibitor, and a tyrosine kinase inhibitor did not attenuate the potentiation of TNF alpha release by YC-1. Cycloheximide prevented the YC-1-enhanced TNF alpha formation, implying that new protein synthesis was required. Interestingly, protein kinase C inhibitors enhanced the potentiation of YC-1 to a greater extent. Nevertheless, a protein kinase C activator, phorbol 12-myristate 13-acetate, failed to suppress the potentiation of TNFalpha production by YC-1. In summary, potentiation of TNF alpha release by YC-1 in LPS/IFN gamma-activated alveolar macrophages is an additional mode of action of this compound that is independent of the elevation of cyclic GMP. Thus, caution needs to be used in attributing the YC-1-mediated response to the activation of sGC.
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PMID:Potentiation of tumor necrosis factor-alpha expression by YC-1 in alveolar macrophages through a cyclic GMP-independent pathway. 1281 75

Our previous studies using differential mRNA display have shown that interferon-gamma-inducible GTPase (IGTP), was up-regulated in coxsackievirus B3 (CVB3)-infected mouse hearts. In order to explore the effect of IGTP expression on CVB3-induced pathogenesis, we have established a doxycycline-inducible Tet-On HeLa cell line overexpressing IGTP and have analyzed activation of several signaling molecules that are involved in cell survival and death pathways. We found that following IGTP overexpression, protein kinase B/Akt was strongly activated through phosphorylation, which leads to phosphorylation of glycogen synthase kinase-3 (GSK-3). Furthermore, in the presence of CVB3 infection, the intensity of the phosphorylation of Akt was further enhanced and associated with a delayed activation of caspase-9 and caspase-3. These data indicate that IGTP expression appears to confer cell survival in CVB3-infected cells, which was confirmed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt cell viability assay. However, the ability of IGTP to induce phosphorylation of Akt and to promote cell survival was attenuated by the phosphotidylinositol-3 kinase (PI3-K) inhibitor LY294002. Transient transfection of the cells with a dominant negative Akt construct followed by doxycycline induction and CVB3 infection reversed Akt phosphorylation to basal levels and returned caspase-3 activity to levels similar to those when the PI3-K inhibitor LY294002 was added. Moreover, IGTP expression inhibited viral replication and delayed CVB3-induced cleavage of eukaryotic translation initiation factor 4G, indicating that IGTP-mediated cell survival relies on not only the activation of PI3-K/Akt, inactivation of GSK-3 and suppression of caspase-9 and caspase-3 but also the inhibition of viral replication.
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PMID:Overexpression of interferon-gamma-inducible GTPase inhibits coxsackievirus B3-induced apoptosis through the activation of the phosphatidylinositol 3-kinase/Akt pathway and inhibition of viral replication. 1281 92

The aim of this study was to determine whether cyclic AMP (cAMP) pathways alter the nitric oxide (NO) production mediated by inducible NO synthase (iNOS) in adipocytes. The treatment of 3T3-L1 cells, a model of white adipocytes, with the combination of lipopolysaccharide (L), tumor necrosis factor-alpha (T), and interferon-gamma (I) synergistically induced iNOS, leading to the production of NO. Enhancers of intracellular cAMP (dibutyryl cAMP, forskolin, and IBMX) inhibited the NO production elicited by LTI, whereas H89, a specific inhibitor of PKA, stimulated the NO production in 3T3-L1 cells. In rat brown adipocyte cell line, the combined treatment with LT synergistically elicited the NO production, and the cAMP analogues further enhanced it. Forskolin inhibited the NO production in 3T3-L1 cells, but enhanced it in brown adipocytes, in a dose-dependent manner. The changes in NO production paralleled the change in iNOS mRNA and protein level in both cell types. The activation of NF-kappaB by LTI/LT was blocked in 3T3-L1 cells, but enhanced in brown adipocytes, by the co-treatment with cAMP analogues. The protein level of 1-kappaBalpha, a NF-kappaB stabilizer, changed reciprocally to that of NF-kappaB activity in each cell type. These results suggest that cAMP regulates iNOS expression in adipocytes through modulating NF-kappaB activity. The differential regulation of iNOS in 3T3-L1 cells from that in the brown adipocytes indicates that intracellular signal pathways activated by cAMP are different between the cell types.
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PMID:Differential effects of cyclic AMP on induction of nitric oxide synthase in 3T3-L1 cells and brown adipocytes. 1282 59

Previous results with p9-RNA, obtained from lymph nodes of animals immunized with the peptide p9 of HIV-1, suggested that its effects on lymphocytes could be mediated by RNA-dependent protein kinase (PKR). Here we report that p9-RNA activates PKR leading to the degradation of the inhibitor I-kappaB alpha and the concomitant nuclear factor kappa B (NF-kappaB) activation. The fractionation of p9-RNA by affinity chromatography indicates that the poly A(+) p9-RNA is the fraction responsible for PKR activation. We also found that p9-RNA induces the production of interferon-gamma (IFN-gamma), but not interleukin (IL-4) since only IFN-gamma gene promoter contains NF-kappaB binding site. This study provides the first evidence that transcriptional control of gene expression by regulatory RNAs can be mediated by PKR through NF-kappaB activation. A model for the mechanism of action of poly A(+) p9-RNA is proposed.
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PMID:Regulatory RNA induces the production of IFN-gamma, but not IL-4 in human lymphocytes: role of RNA-dependent protein kinase (PKR) and NF-kappaB. 1284 50

To explore the mechanism by which morphine promotes the incidence of HIV infection, we evaluated the regulatory role of morphine on the interferon-gamma (IFN-gamma) promoter in activated T cells from wild type and mu-opioid receptor knockout mice. Our results show that morphine inhibited anti-CD3/CD28-stimulated IFN-gamma promoter activity in a dose-dependent manner. Chronic morphine treatment of T cells increased intracellular cAMP. To evaluate the role of cAMP in morphine's modulatory function, the effects of dibutyryl cyclic AMP and forskolin were investigated. Both dibutyryl cyclic AMP and forskolin treatment inhibited IFN-gamma promoter activity. Treatment with pertussis toxin, but not with a protein kinase A inhibitor, antagonized morphine's inhibitory effects. Morphine inhibited phosphorylation of ERK1/2 and p38 MAPK; in addition, morphine treatment in the presence of either ERK1/2 or p38 MAPK inhibitor (PD98059 or SB203580) resulted in an additive inhibition of IFN-gamma promoter activity. The transcription factor activator protein-1, NF-kappaB, and nuclear factor of activated T cells (NFAT) were negatively regulated by morphine. Overexpression of NF-kappaB p65 rescued the inhibitory effect of morphine on IFN-gamma promoter activity. However, only when NFATc1 was co-overexpressed with c-fos was the inhibitory effect of morphine on IFN-gamma promoter counteracted. The inhibitory effects of morphine were not observed in T cells obtained from mu-opioid receptor knockout mice, suggesting that morphine modulation of IFN-gamma promoter activity is mediated through the mu-opioid receptor. In summary, our data indicate that morphine modulation of IFN-gamma promoter activity is mediated through two distinct cAMP-dependent pathways, the NF-kappaB signaling pathway and the ERK1/2, p38 MAPK, AP-1/NFAT pathway.
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PMID:Morphine negatively regulates interferon-gamma promoter activity in activated murine T cells through two distinct cyclic AMP-dependent pathways. 1284 91


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