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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We established three sister cell lines, NALM-30, NALM-31 and NALM-32, with biphenotypic features carrying myeloperoxidase mRNA and protein with complex Philadelphia (Ph) chromosome, t(9;22;10)(q34;q11;q22), from a patient with Ph-positive acute leukemia in relapse. Epstein-Barr virus nuclear antigen was negative. The morphological appearance of the cell lines is that of immature lymphoid cells. Expression of myeloid- and lymphoid-associated surface membrane antigens on these cells was detected allowing for the classification of "biphenotypic" leukemia. Immunophenotypically, the established cell lines reported here fulfill the European Group for the Immunological Characterization of Leukemias (EGIL) criteria for B-lineage derivation, however, surface and cytoplasmic immunoglobulin chains were negative. Whereas TGF-beta R (CD105), MCSFR (CD115), SCFR (CD117), IL-4R/IL-13R (CD124) and IL-6R (CD126) were not expressed, the cell lines were mostly positive for IFN-gamma R (CD119), IL-7R (CD127) and FLT-3R (CD135). The NALM-30, NALM-31 and NALM-32 cell lines together with their serial sister cell lines NALM-27 and NALM-28 which were established from the same patient at diagnosis provide unprecedented opportunities for studying a multitude of biological aspects related to normal and neoplastic immature B-lymphocytes.
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PMID:Myeloperoxidase positive acute lymphoblastic leukemia cell lines, NALM-30, NALM-31 and NALM-32, carrying Philadelphia chromosome with biphenotypic characteristics. 1036 60

Intracellular protozoan parasites of the genus Leishmania antagonize host defense mechanisms by interfering with cell signaling in macrophages. In this report, the impact of Leishmania donovani on mitogen-activated protein (MAP) kinases and nitric oxide synthase (NOS) expression in the macrophage cell line RAW 264 was investigated. Overnight infection of cells with leishmania led to a significant decrease in phorbol-12-myristate-13-acetate (PMA)-stimulated MAP kinase activity and inhibited PMA-induced phosphorylation of the MAP kinase substrate and transcription factor Elk-1. Simultaneously, leishmania infection markedly attenuated the induction of c-FOS and inducible nitric oxide synthase (iNOS) expression in response to PMA and gamma interferon (IFN-gamma), respectively. These effects correlated with decreased phosphorylation of p44 and p42 MAP kinases on tyrosine residues. Consistent with the latter finding, lysates prepared from leishmania-infected cells contained an activity that dephosphorylated MAP kinase in vitro, suggesting the possibility of a phosphatase acting in vivo. Attenuation of both MAP kinase activity and c-FOS and iNOS expression was reversed by treatment of macrophages with sodium orthovanadate prior to infection. It was also found that the specific activity of the Src homology 2 domain containing tyrosine phosphatase (SHP-1) toward MAP kinase was markedly increased in leishmania-infected cells. These findings indicate that infection with L. donovani attenuates MAP kinase signaling and c-FOS and iNOS expression in macrophages by activating cellular phosphotyrosine phosphatases. This may represent a novel mechanism of macrophage deactivation during intracellular infection.
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PMID:Activation of phosphotyrosine phosphatase activity attenuates mitogen-activated protein kinase signaling and inhibits c-FOS and nitric oxide synthase expression in macrophages infected with Leishmania donovani. 1041 74

The effect of CD3-CD4 coligation on CD3-mediated activation of normal mouse CD4(+) T lymphocytes has been analyzed in the absence of exogenous lymphokines. If anti-CD3 and anti-CD4 antibodies are adsorbed to culture wells by means of previously adsorbed anti-Ig antibodies (indirect binding), CD3-CD4 coligation inhibits activation measured as cell proliferation or as secretion of IL-2, IL-4, and IFN-gamma. Addition of IL-2, anti-CD28 antibodies, or phorbol esters, but not IL-1, IL-4, or ionomycin, blocked CD4-mediated inhibition and restored the response to levels equal or higher than those of cultures activated by anti-CD3 alone. In contrast, CD3-CD4 coligation by antibodies directly adsorbed to culture wells potentiated anti-CD3-induced activation, either in the absence or in the presence of exogenous costimuli. Similar results were observed when CD4(+) T cells of naive phenotype (CD44(low), CD45RB(high)) were used in the experiments. The analysis of early tyrosine phosphorylation in CD4(+) T cells shows that phosphorylation of many cell substrates is clearly enhanced upon CD3-CD4 coligation using indirectly or directly bound antibodies, yet certain substrates are mainly phosphorylated under inhibitory conditions. Although CD28 ligation does not produce any clear change in the tyrosine phosphorylation pattern in lysates from cells activated by indirectly bound anti-CD3 plus anti-CD4 antibodies, the analysis of active forms of the MAP kinase ERK suggests that downstream signaling pathways involved in IL-2 gene activation can be differentially activated depending on the direct or indirect CD3-CD4 adsorption and CD28 ligation.
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PMID:Antibody-induced CD3-CD4 coligation inhibits TCR/CD3 activation in the absence of costimulatory signals in normal mouse CD4(+) T lymphocytes. 1044 9

Fas (CD95, APO-1) is a member of the TNF receptor family, and engagement of Fas by its ligand, Fas ligand (FasL), can induce apoptotic death of Fas expressing cells. Signaling through Fas has previously been shown to induce apoptosis of CD34+ human hematopoietic progenitor cells after exposure to IFN-gamma or TFN-alpha. In contrast, we found that FasL promoted a significantly increased viability of primitive CD34+CD38- cells. Thus, incubation with FasL for 48 hours reduced cell death from 46 to 29% compared to cells cultured in medium alone as measured by propidium iodide (PI) incorporation (n = 8, p < 0.02). Inhibition of apoptosis was confirmed by morphological analysis and by the Nicoletti technique. Furthermore, by using a delayed addition assay at the single cell level we found that sFasL treatment had a direct viability-promoting effect on CD34(+)CD38(-) cells. The effect of sFasL was completely blocked by NOK-1, a neutralizing mAb against FasL. In agreement with previous reports, FasL alone slightly increased cell death of more mature CD34(-)CD38+ cells, indicating an interesting shift in the responsiveness to FasL during early hematopoiesis.
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PMID:Fas ligand promotes cell survival of immature human bone marrow CD34+CD38- hematopoietic progenitor cells by suppressing apoptosis. 1048 Apr 36

IFN-gamma primes macrophages for antimicrobial activity, increased killing of intracellular pathogens, and Ag processing and presentation to lymphocytes by cooperating with a second signal (provided by LPS or endogenous TNF-alpha) to promote increased proinflammatory cytokine production, NO production, and MHC class II expression. Macrophage-stimulating protein (MSP) suppresses NO production by activated peritoneal macrophages in vitro. Furthermore, targeted deletion of the receptor for MSP, stem cell-derived tyrosine kinase receptor (STK/RON), resulted in increased production of NO by activated macrophages both in vitro and in vivo. Here we demonstrate that expression of STK in RAW264.7 cells resulted in suppression of NO production following IFN-gamma+/- LPS stimulation in the presence of MSP, reflecting a decrease in the levels of inducible NO synthase (iNOS) mRNA and protein, which was confirmed by decreased trans-activation of an iNOS reporter. The iNOS expression is regulated by the coordinate activity of the inducible transcription factors STAT-1, IFN response factor-1, and NF-kappaB. The presence of the STK receptor did not significantly alter the expression of the IFN-gamma receptor, STAT1 phosphorylation, or the up-regulation of IFN response factor-1 expression following IFN-gamma stimulation. However, nuclear translocation of NF-kappaB following stimulation of RAW cells with IFN-gamma and LPS was reduced in the presence of the MSP/STK signaling pathway. These results suggest that the negative regulation of macrophage responses by MSP/STK occurs at least in part via inhibition of costimulatory signals, resulting in NF-kappaB activation, that cooperate with IFN-gamma to promote activation.
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PMID:Negative regulation of macrophage activation in response to IFN-gamma and lipopolysaccharide by the STK/RON receptor tyrosine kinase. 1058 55

CD34(+) cells are nonpermissive to infection by HIV strains X4 and R5, despite the fact that many CD34(+) cells express high levels of the viral receptor protein CD4 and the coreceptor CXCR4 on their surface. In these cells, the co-receptor CCR5 protein, which, like CXCR4, is a chemokine receptor, is detected mainly intracellularly. We hypothesized that CD34(+) cells secrete CCR5-binding chemokines and that these factors interfere with HIV R5 interactions with these cells, possibly by binding CCR5 or by inducing its internalization. We found that human CD34(+) cells and CD34(+)KIT(+) cells, which are enriched in myeloid progenitor cells, expressed and secreted the CCR5 ligands RANTES, MIP-1alpha, and MIP-1beta and that IFN-gamma stimulated expression of these chemokines. In contrast, SDF-1, a CXCR4 ligand, was not detectable in the CD34(+)KIT(+) cells, even by RT-PCR. Conditioned media from CD34(+) cell culture significantly protected the T lymphocyte cell line PB-1 from infection by R5 but not X4 strains of HIV. Interestingly, the secretion of endogenous chemokines decreased with the maturation of CD34(+) cells, although ex vivo, expanded megakaryoblasts still secreted a significant amount of RANTES. Synthesis of CCR5-binding chemokines by human CD34(+) cells and megakaryoblasts therefore largely determines the susceptibility of these cells to infection by R5 HIV strains. We postulate that therapeutic agents that induce the endogenous synthesis of chemokines in human hematopoietic cells may protect these cells from HIV infection.
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PMID:Bone marrow CD34(+) cells and megakaryoblasts secrete beta-chemokines that block infection of hematopoietic cells by M-tropic R5 HIV. 1060 28

Previous studies have shown that activation of the RON receptor tyrosine kinase inhibits inducible NO production in murine peritoneal macrophages. The purpose of this study is to determine whether inflammatory mediators such as LPS, IFN-gamma, and TNF-alpha regulate RON expression. Western blot analysis showed that RON expression is reduced in peritoneal macrophages collected from mice injected with a low dose of LPS. The inhibition was seen as early as 8 h after LPS challenge. Experiments in vitro also demonstrated that the levels of the RON mRNA and protein are diminished in cultured peritoneal macrophages following LPS stimulation. TNF-alpha plus IFN-gamma abrogated macrophage RON expression, although individual cytokines had no significant effect. Because LPS and TNF-alpha plus IFN-gamma induce NO production, we reasoned that NO might be involved in the RON inhibition. Two NO donors, S-nitroglutathione (GSNO) and (+/-)-S-nitroso-N-acetylpenicillamine (SNAP), directly inhibited macrophage RON expression when added to the cell cultures. Blocking NO production by NO inhibitors like TGF-beta prevented the LPS-mediated inhibitory effect. In Raw264.7 cells transiently transfected with a report vector, GSNO or SNAP inhibited the luciferase activities driven by the RON gene promoter. Moreover, GSNO or SNAP inhibited the macrophage-stimulating protein-induced RON phosphorylation and macrophage migration. We concluded from these data that RON expression in macrophages is regulated during inflammation. LPS and TNF-alpha plus IFN-gamma are capable of down-regulating RON expression through induction of NO production. The inhibitory effect of NO is mediated by suppression of the RON gene promoter activities.
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PMID:Regulation of the RON receptor tyrosine kinase expression in macrophages: blocking the RON gene transcription by endotoxin-induced nitric oxide. 1072 42

The role of nitric oxide (NO) and adherent spleen cells in systemic immunosuppression developing in animals carrying malignant glioma isografts was analyzed. Rats harboring a subcutaneous glioma isograft for 3 weeks were immunized with glioma cells genetically engineered to express IFN-gamma. One week later spleen cells were tested for immune responsiveness in vitro. A decreased cytotoxic activity of NK-cells and T-cells compared to tumor-free animals immunized in parallel was shown. Spleen cell proliferative responses to tumor cells, SEA, and anti-CD3 were all significantly suppressed, as was the production of IFN-gamma and IL-10. Plastic adherent spleen cells from tumor-bearing rats suppressed the SEA-induced proliferative response and the production of IFN-gamma and IL-10 by nonadherent spleen cells from tumor-free rats. A major part of this suppression appears to be dependent on the production of NO because suppression was efficiently counteracted in vitro by the NO-synthase inhibitor N-nitro-l-arginine methyl ester. Moreover, a significantly increased level of nitrite in culture supernatants correlated with the observed suppression. We conclude that the systemic immunosuppression associated with growing gliomas is in part mediated by mechanisms dependent on NO overproduction in adherent spleen cells.
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PMID:Nitric-oxide-dependent systemic immunosuppression in animals with progressively growing malignant gliomas. 1075 3

Expression of SH2 domain-containing leukocyte-specific phosphoprotein of 76 kDa (SLP-76), a hematopoietic cell-specific adapter protein, is required to couple Syk family tyrosine kinase activation to downstream mediators such as phospholipase C (PLC)-gamma following TCR, platelet collagen receptor and mast cell Fc epsilon R stimulation. In addition to T cells, mast cells and platelets, SLP-76 is expressed in monocytes and macrophages. To determine the role of SLP-76 in Fc gamma R-stimulated signaling pathways in macrophages, we examined cultured bone marrow-derived macrophages (BMM) from SLP-76(-/-) and wild-type mice. In this study, we show that Fc gamma R cross-linking rapidly induces tyrosine phosphorylation of SLP-76 in wild-type BMM. Surprisingly, however, BMM from SLP-76(-/-) mice activate ERK2 and phosphorylate PLC-gamma 2 following Fc gamma R ligation. Furthermore, SLP-76(-/-) BMM display normal Fc gamma R-dependent phagocytic function and reactive oxygen intermediate production. SLP-76(-/-) and SLP-76(+/+) BMM secrete comparable levels of IL-12 in response to lipopolysaccharide and IFN-gamma. To examine macrophage function in vivo, SLP-76(-/-) mice were challenged i.v. with Listeria monocytogenes. SLP-76(-/-) mice survive and efficiently contain the acute phase of infection similar to wild-type mice but exhibit a stable chronic infection attributed to the lack of mature T cells. These data show that, although SLP-76 is required to couple Syk family PTK activity to downstream mediators and effector functions in Fc gamma R-induced pathways in some cell types, activation of Fc gamma R-dependent pathways occurs independently of SLP-76 in BM
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PMID:In vitro and in vivo macrophage function can occur independently of SLP-76. 1083 16

Our previous studies have shown that the enzymatic activities of Neu-1, an endogenous sialidase encoded in the murine MHC, are involved in promoting IL-4 synthesis by naive CD4(+)T cells. Our present studies have characterized responsible sialoconjugate targets of Neu-1 and questioned possible biochemical mechanisms responsible for their regulatory influences on IL-4 gene expression. These studies determined that treatment of T cells with the naturally occurring ganglioside GM3 inhibited the production of IL-4 without affecting the production of IL-2. An analysis of IL-4-primed CD4(+)T cells further demonstrated that GM3 treatment specifically inhibited the restimulated production of IL-4, IL-5 and IL-13, without inhibiting the production of IL-2 and IFN-gamma. The inhibitory effects of GM3 could be overcome by treatment with thapsigargin or ionomycin, suggesting ganglioside regulation occurs upstream of activation-induced calcium mobilization. GM3 treatment attenuated the level of calcium influx following CD3epsilon crosslinking, and CD4(+)T cells from Neu-1-deficient B10.SM strain mice (neu-1(a)and IL-4-deficient) expressed reduced levels of intracellular calcium following activation. Our results indicate that activities by membrane gangliosides can influence the cytokine programs in CD4(+)T cells, possibly through the modulation of calcium responses induced by T cell activation.
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PMID:Ganglioside control over IL-4 priming and cytokine production in activated T cells. 1088 Feb 42


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