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)

Monocytes-macrophages which serve as host immune cells to kill pathogens can often be "activated" after exposing to viruses, bacteria, cytokines as well as chemical substances, However, it is paradoxical that highly activated macrophages can be induced to become the suppressor ones by live microbes, microbial products, tumor, and autoimmune disease, although the mechanism remains unknown. Our previous experimental studies have shown that immuno-suppressor activities of suppressor macrophages on T, B and NK cells can be prevented by the treatment with LPS or supernatant in vitro from mitogen-stimulated lymphocytes, while, at the same time, the tumoricidal activities of those macrophages can be kept or even enhanced following the same treatment. This phenomenon was then termed as "immune modulation" For the understanding of its mechanism, we are now undertaking signal transduction in modulated macrophages. Since mitogen-activated protein kinase (MAPK) is an integration point of different signal transduction pathways, its cascade and regulation of activation are being investigated extensively by the assay of electrophoresis mobility shift. Recent results suggested that interaction of ligand-receptor triggers protein tyrosine kinase(PTK) activation leading to Ras-GTP binding with Raf-1 to phosphorylate MAPK kinase (MAPKK), the specific activator of MAPK. It is reported that PKC-alpha can directly phosphorylate or activate Raf-1 in NIH3 T3 cells. Raf-1 (74 KDa), with an intrinsic serine (Ser)-threonine (The) kinase activity, becomes hyperphosphorylated after activation which can be followed by gel mobility shift test. It has also been shown that a variety of extracellular factors stimulate a pair of MAPK p44 and MAPK p42 of MAPK family members. A significant property of activation of ERK 1 and ERK 2 is the requirement for the phosphorylation of both Thr-183 and Tyr-185 (at TEY motif) within in its protein kinase subdomain VIII. More recently, two other MAPK subtypes, p38 MAPK (mammalian equivalents of HOG1 in yeast) and JNK MAPK have been discovered. The requirement for activation of p38 MAPK for both Thr-180 and Tyr-182 (at TGY motif) has been shown. p38 MAPK is important in certain transcriptional regulatory pathways, since it can phosphorylate the following transcriptional factors: 1) Elk at Ser 383/389 for binding with SRE motif; 2). ATF 2 at Ser 69/71, forming a complex with Myc for DNA binding at CRE motif; 3) Max at Ser-62 to combine DNA of E-Box motif. p38 MAPK can be activated by LPS, inflammatory cytokines, such as TNF and IL-1, osmolarity. To examine the possibility that whether activation of Raf-1 and ERK 1, ERK2 and p38 MAPK can be regulated directly or/and differently by PKC and PKA pathways, herbimycin A (Ki = 0.9 mumol/L), a potent PTK inhibitor (J. Immunol. 155:3944-4003, 1995) at 2 mumol/L concentration was utilized to block Ras/Raf-1/MAPK cascade. After pre-incubation of macrophages with herbimycin A for 30 min or 90 min, cells were treated with LPS (10 micrograms/ml) and PMA (100 nmol/L) for 15 min. No inhibition of phosphorylation of Raf-1, MAPK p44 and MAPK p42 in response to LPS and PMA was observed (Fig. 1 and 3). However, forskolin, a cAMP inducer for protein kinase A (PKA) activation, inhibited the phosphorylation of LPS- and PMA-stimulated Raf-1, MAPK p44 and MAPK p42 (Fig. 2 and 4). Similarly, in agreement with a very recent report from David, M et al in NIH, in which they indicated that forskolin (30 mumol/L) inhibited IFN-beta-stimulated ERK activity by U 266 cells (J. Biol. Chem. 271: 4585-4588 1996), we found that the levels of phosphorylations of Raf-1 and ERK1 and ERK2 were declined when forskolin (30 mumol/L) was added to macrophages for 20 min at 37 degrees C prior to the stimulation by LPS and PMA. Interestingly, under the same condition, forskolin (30 mumol/L) stimulated the phosphorylation of LPS- and PMA-triggered p38 MAPK of murine peritoneal suppressor macrophages, suggesting that activatio
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PMID:[Studies on cell signaling immunomodulated murine peritoneal suppressor macrophages: LPS and PMA mediate the activation of RAF-1, MAPK p44 and MAPK p42 and p38 MAPK]. 1068 11

The paper presents a review of data on the localization of interferons (IFNs) and IFN system genes and their relationship with human diseases, mainly cancer. Genes of interferon system proteins are located at the sites of breakpoints of the structural chromosome aberrations in cancer. Thus, any of them are rearranged or translocated in various tumor types. As the activity of these genes plays a role in cancer development, their rearrangements may be one of the crucial points in the pathogenesis of some cancer types. Besides, they also take part in organism immunity against viral infections. Transfection experiments with IFN system genes have proved the influence of these genes on cancer behavior and may serve as a basis for clinical gene therapy. IFN-alpha and IFN-beta genes are located at 9p21-22, the site of frequent homozygotic deletions in cancer. Their loss sensitizes cells to the growth inhibitory actions of exogenous IFNs. The IFN-gamma gene, a representative of class II genes, is located at 12q24.1. Transfection of class II IFNs genes to cancer cell lines causes cell proliferation arrest and augments the expression of HLA antigens, which may be clinically useful in stimulating the immune destruction of tumor cells. The interferon regulatory factor 1 (IRF-1) gene is located at 5q31, the site of common deletions in myelodysplastic syndromes (MDS) and secondary leukemias. The loss of heterozygosity of this gene was found in MDS, which proves that IRF-1 may be a tumor suppressor. A transfection of its gene causes neoplastic transformation arrest. The double-stranded RNA-activated protein kinase (PKR) gene is located at 2p21-22, a region which is frequently rearranged in leukemia. Transfection of a wild type PKR gene reverses neoplastic transformation caused by transfection of a mutated PKR gene, proving that PKR acts as a dominant negative cancer suppressor.
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PMID:The genes of interferons and interferon-related factors: localization and relationships with chromosome aberrations in cancer. 1080 49

Virus infection triggers innate responses to host cells including production of type I interferon (IFN). Since IFN production is also induced by treatment with poly(I:C), viral double-stranded (ds) RNA has been postulated to play a direct role in the process. In the present study, we investigated the effect of dsRNA binding proteins on virus-induced activation of the IFN-beta gene. We found that PACT, originally identified as protein activator for dsRNA-dependent protein kinase (PKR) and implicated in the regulation of translation, augmented IFN-beta gene activation induced by Newcastle disease virus. Concomitantly with the augmented activity of IFN-beta enhancer, increased activity of NF-kappaB and IRF-3 and IRF-7 was observed. For the observed effect, the dsRNA-binding activity of PACT was essential. We identified residues of PACT that interact with a presumptive target molecule to exert its function. Furthermore, PACT colocalized with viral replication complex in the infected cells. Thus the observed effect of PACT is novel and PACT is involved in the regulation of viral replication and results in a marked increase of cellular IFN-beta gene expression.
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PMID:PACT, a double-stranded RNA binding protein acts as a positive regulator for type I interferon gene induced by Newcastle disease virus. 1140 90

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

Lipopolysaccharide (LPS) impairs classical swine fever virus (CSFV) replication in monocytic cells, which are primary targets for CSFV and mediators of virus-induced immunomodulation. Although soluble antiviral factors including interferons (IFN) were not detected, IFN-alpha and IFN-beta mRNA were induced. The serine threonine protein kinase inhibitor 2-aminopurine, impeded this antiviral activity. These results indicate that the LPS-induced antiviral state employs signaling pathways, in which the double-stranded RNA-dependent protein kinase (PKR) is actively involved.
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PMID:Lipopolysaccharide-induced impairment of classical swine fever virus infection in monocytic cells is sensitive to 2-aminopurine. 1168 17

Interferon alfa (IFN-alpha) is currently the only well-established therapy for viral hepatitis. However, its effectiveness is much reduced (<10%) in alcoholic patients. The mechanism underlying this resistance is not fully understood. In this study, we examined the expression of IFN-alpha signaling components and its inhibitory factors in 9 alcoholic liver disease (ALD) and 8 healthy control liver tissues. In comparison with normal control livers, expression of IFN-beta, IFN-alpha receptor 1/2, Jak1, and Tyk2 remained unchanged in ALD livers, whereas expression of IFN-alpha, signal transducer and activator of transcription factor 1 (STAT1), and p48 were up-regulated and expression of STAT2 was down-regulated. Expression of antiviral MxA a karyophilic 75 kd protein induced by IFN in mouse cells carrying the influenza virus resistance allele Mx(+) and 2'-5' oligoadenylate synthetase (OAS) proteins was not regulated, whereas expression of double-stranded RNA-activated protein kinase (PKR) was decreased by 55% in ALD livers. Three families of inhibitory factors for the JAK-STAT signaling pathway were examined in ALD livers. Members of the suppressor of cytokine signaling (SOCS) family, including SOCS 1, 2, 3, and CIS, and the protein tyrosine phosphatases, including Shp-1, Shp-2, and CD45, were not up-regulated in ALD livers, whereas the phosphorylation of and protein levels of p42/44 mitogen-activated protein kinase (p42/44MAP kinase) were increased about 3.9- and 3.2-fold in ALD livers in comparison with normal control livers, respectively. In conclusion, these findings suggest that chronic alcohol consumption down-regulates STAT2 and PKR, but up-regulates p42/44 mitogen-activated protein kinase (p42/44MAP kinase), which may cause down-regulation of IFN-alpha signaling in the liver of ALD patients.
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PMID:Expression of interferon alfa signaling components in human alcoholic liver disease. 1182 19

We have investigated the mechanisms by which prior exposure of mouse macrophages to lipopolysaccharides (LPS) induces a state of low responsiveness to subsequent exposure to IFN-gamma. We demonstrate that induction of this state requires both de novo gene expression and the suppression of phosphorylation events that lead to activation of transcription factor Stat1 alpha. These observations are mechanistically consistent with the known induction of suppressors of cytokine signaling (SOCS)-1 and SOCS-3 proteins by LPS. In this regard, we demonstrate that overexpression of either SOCS protein suppresses induction of the mouse inducible nitric oxide synthase (iNOS) gene promoter: apparently by suppressing interactions between Stat1 alpha and IFN-gamma activated sites present in both the iNOS, and interferon regulatory factor-1, gene promoters. The induction of SOCS-1 and SOCS-3 by LPS or IFN-beta (an autocrine/paracrine mediator of LPS-induced SOCS-1 mRNA synthesis)occurs by way of multiple protein kinase pathways that include protein tyrosine kinases, protein kinase C, and mitogen-activated protein kinases. These results provide insight that may allow discrimination between LPS-induced inhibition of macrophage functions that are detrimental to the host (e.g. continued exposure to LPS) versus those that might potentially be beneficial (e.g. exposure to subsequent agonists that induce more specific macrophage functions).
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PMID:Low responsiveness to IFN-gamma, after pretreatment of mouse macrophages with lipopolysaccharides, develops via diverse regulatory pathways. 1187 Jun 15

Toll-like receptor 2 (TLR2) agonists induce a subset of TLR4-inducible proinflammatory genes, which suggests the use of differential signaling pathways. Murine macrophages stimulated with the TLR4 agonist Escherichia coli lipopolysaccharide (LPS), but not with TLR2 agonists, induced phosphorylation of signal transducer and activator of transcription 1alpha (STAT1alpha) and STAT1beta, which was blocked by antibodies to interferon beta (IFN-beta) but not IFN-alpha. All TLR2 agonists poorly induced IFN-beta, which is encoded by an immediate early LPS-inducible gene. Thus, the failure of TLR2 agonists to induce STAT1-dependent genes resulted, in part, from their inability to express IFN-beta. TLR4-induced IFN-beta mRNA was MyD88- and PKR (double-stranded RNA-dependent protein kinase)-independent, but TIRAP (Toll-interleukin 1 receptor domain-containing adapter protein)-dependent. Together, these findings provide the first mechanistic basis for differential patterns of gene expression activated by TLR4 and TLR2 agonists.
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PMID:TLR4, but not TLR2, mediates IFN-beta-induced STAT1alpha/beta-dependent gene expression in macrophages. 1189 92

Alpha/beta interferons (IFN-alpha/beta) are potent, endogenous antiviral cytokines that suppress the replication of RNA and DNA viruses, including herpes simplex virus type 1 (HSV-1). The present study compared the efficacies of IFN-alpha/beta transgenes, including IFN-alpha1, -alpha4, -alpha5, -alpha6, -alpha9, and -beta, against HSV-1 infection. L929 cells transfected with the IFN-alpha/beta transgenes produced similar levels of IFN, as measured by bioassay and enzyme-linked immunosorbent assay. In addition, transfected cells were less susceptible to HSV-1 infection than were cells transfected with a plasmid vector control. The murine IFN-beta plasmid construct exhibited the greatest reduction, while the murine IFN-alpha5 transgene showed a modest inhibitory effect in viral titers recovered from the supernatants of transfected, infected L929 cultures. Consistent with this observation, the IFN-beta transgene antagonized viral transcript levels, including infected cell protein 27, thymidine kinase, and glycoprotein B, to a greater extent than did the IFN-alpha transgenes at 6 to 10 h postinfection as determined by real-time PCR. Cells transfected with the IFN-alpha4, IFN-alpha9, or IFN-beta transgenes showed the greatest reduction in viral protein expression relative to the other transfected cells, which was associated with increased STAT1 expression. The absence of the IFN-responsive protein kinase R (PKR) gene completely abrogated the antiviral induction by all IFN-alpha/beta against HSV-1. In the absence of RNase L, viral yields were increased 10-fold, but the antiviral effect of IFN was either unaffected or enhanced. These results suggest that the predominant IFN-mediated, antiviral pathway during HSV-1 infection taken by IFN-alpha/beta in L929 cells utilizes PKR.
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PMID:Differential effect of murine alpha/beta interferon transgenes on antagonization of herpes simplex virus type 1 replication. 1205 Mar 68

Interferon (IFN) therapy is used worldwide as the best available treatment for hepatitis C virus (HCV) infection; however, little is known about how IFN or other drugs work against liver diseases. The effect of 6 drugs (glycyrrhizin, ursodeoxycholic acid, ribavirin, methylprednisolone, IFN-alpha, and IFN-beta) on HCV RNA translation from the HCV internal ribosome entry site (IRES) was investigated, using a bicistronic reporter containing the HCV IRES. IFNs suppressed both cap-dependent and HCV IRES-dependent translation, with HCV IRES-dependent translation being more significantly suppressed. In contrast to HCV IRES, IFN did not suppress either foot-and-mouth disease virus IRES-dependent or encephalomyocarditis virus IRES-dependent translation more than it suppressed cap-dependent translation. Moreover, dominant inhibition of HCV IRES-dependent over cap-dependent translation depended neither on the double-stranded RNA-activated protein kinase activation nor on La protein function. These results indicate a novel antiviral effect of IFNs against HCV.
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PMID:Interferons specifically suppress the translation from the internal ribosome entry site of hepatitis C virus through a double-stranded RNA-activated protein kinase-independent pathway. 1213 50


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