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)

In the CAST, blood leukocytes are prestimulated with the cytokine IL-3 and exposed to allergen(s). Mainly basophiles react by synthesizing sulfidoleukotrienes (sLT), namely LTC4 and its metabolites LTD4 and LTE4. They are detected by ELISA technique. 66 patients with suspected allergy to hymenoptera venoms were evaluated. Allergic reactions comprised all severity grades (I-IV ref. H. L. Mueller). The workup included skin tests (up to 1 microgram/ml, Pharmacia), measurement of specific serum IgE with RAST-CAP (Pharmacia), and CAST with three concentrations of bee (Apis mellifera) and wasp (Vespula spec.) venom (Aquagen ALK). A control group of 13 nonallergic, RAST-CAP negative individuals was established. CAST demonstrated pronounced variations of individual s-LT synthesis in patients and controls. The use of elevated cut-offs improved the results, while the use of three allergen concentrations did not increase reliability. Diagnostic accuracy of CAST was evaluated by comparison with skin tests as the "gold standard". With bee venom and a cut-off at 3 standard deviations, a sensitivity and specificity of 73%/71% was obtained. Wasp venom showed better results at 2 standard deviations, with a sensitivity and specificity of 68%/100%. CAST results were not influenced by the severity of the allergic reaction nor by the time lapse since the sting had occurred. In conclusion, CAST is a valuable test in insect sting allergy. However, established methods such as skin tests and RAST-CAP achieve better results. CAST should therefore be considered a supplementary method in cases where established methods fail. It remains to be shown whether CAST can be used as a parameter for monitoring patients who have undergone immunotherapy.
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PMID:[Cellular antigen stimulation test (CAST)--applicability in the diagnosis of insect toxin allergies]. 903 29

Bone marrow (BM) stromal cells are required for normal hematopoiesis. A number of soluble factors secreted by these cells that mediate hematopoiesis have been characterized. However, the mechanism of hematopoiesis cannot be explained solely by these known factors, and the existence of other, still unknown stromal factors has been postulated. We showed that hepatocyte growth factor (HGF) is one such cytokine produced by human BM stromal cells. BM stromal cells were shown to constitutively produce HGF and also to express the c-MET/HGF receptor. The production of HGF was enhanced by addition of heparin and phorbol ester. Dexamethasone and tumor growth factor-beta (TGF-beta) inhibited the production of HGF. Interleukin-1 alpha (IL-1 alpha) tumor necrosis factor-alpha (TNF-alpha), and N6,2'-o-dibutyryl-adenosine-3':5'-cyclic monophosphate (dbc-AMP) showed no obvious influence on HGF production. Western blot analysis of HGF derived from BM stromal cells showed two bands at 85 and 28 kD corresponding to native and variant HGF, respectively. Addition of recombinant HGF significantly promoted the formation of burst-forming unit-erythroid (BFU-E) and colony-forming unit-granulocyte erythroid macrophage (CFU-GEM) by BM mononuclear cells in the presence of erythropoietin and granulocyte-macrophage colony-stimulating factor (GM-CSF), but the formation of CFU-GM was not modified. However, HGF had no effects on colony formation by purified CD34+ cells. Within BM mononuclear cells, c-MET was expressed on a proportion of cells (CD34-, CD33+, CD13+, CD14+, and CD15+), but was not found on CD34+ cells. We conclude that HGF is constitutively produced by BM stromal cells and that it enhances hematopoiesis. In addition, expression of c-MET on the stromal cells suggests the presence of an autocrine mechanism, operating through HGF, among stromal cells.
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PMID:Hepatocyte growth factor is constitutively produced by human bone marrow stromal cells and indirectly promotes hematopoiesis. 905 37

Vascular endothelial growth factor (VEGF) is a multifunctional cytokine involved in angiogenesis, inflammation, and wound healing. It is secreted by a variety of tumor cell lines, including hematopoietic lines. Therefore, we investigated expression of VEGF and its receptors on fresh leukemic blasts. VEGF-specific transcripts were detected by polymerase chain reaction (PCR) in 20 of 28 patients with de novo acute myeloid leukemia (AML) and in 3 of 5 patients with secondary AML. Using immunocytochemistry, we found VEGF protein in 2 leukemic cell lines and in 8 AML patients, in concordance with PCR results. Supernatants of fresh leukemic cells from 24 AML patients contained significantly more VEGF than supernatants from bone marrow cells of 9 normal donors or of CD34-enriched cells from 3 normal volunteer donors as determined by an enzyme-linked immunosorbent assay. VEGF possesses two high-affinity receptors, KDR and FLT1. Using a sensitive nested PCR assay, we detected expression of FLT1 in 10 of 20 patients with de novo AML and 3 of 5 patients with secondary AML. KDR was expressed in 4 of 22 patients with de novo AML and 1 of 4 with secondary AML. To study possible paracrine growth stimulation of AML blasts, endothelial cells from human umbilical cords were incubated with increasing concentrations of VEGF. A dose-dependent increase of granulocyte-macrophage colony-stimulating factor secretion from endothelial cells was identified.
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PMID:Vascular endothelial growth factor, a possible paracrine growth factor in human acute myeloid leukemia. 905 6

The effects of FLT3/FLK-2 ligand (FL) and KIT ligand (KL) on in vitro expansion of hematopoietic stem cells were studied using lineage-negative (Lin-)Sca-1-positive (Sca-1+) c-kit-positive (c-kit+) marrow cells from 5-fluorouracil (5-FU)-treated mice. As single agents, neither FL nor KL could effectively support the proliferation of enriched cells in suspension culture. However, in combination with interleukin-11 (IL-11), both FL and KL enhanced the production of nucleated cells and progenitors. The kinetics of stimulation by FL was different from that by KL in that the maximal expansion by FL of the nucleated cell and progenitor pools required a longer incubation than with KL. We then tested the reconstituting abilities of cells cultured for 1, 2, and 3 weeks by transplanting the expanded Ly5.1 cells together with "compromised" marrow cells into lethally irradiated Ly5.2 mice. Cells that had been expanded with either cytokine combination were able to maintain the reconstituting ability of the original cells. Only cells that had been incubated with KL and IL-11 for 21 days had less reconstituting ability than fresh marrow cells. These results indicate that there can be significant expansion of progenitors in vitro without compromising the reconstituting ability of stem cells. Addition of IL-3 to permissive cytokine combinations significantly reduced the ability of cultured cells to reconstitute the hematopoiesis of irradiated hosts. These observations should provide a basis for a rational approach to designing cytokine combinations for in vitro expansion of hematopoietic stem cells.
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PMID:In vitro expansion of hematopoietic progenitors and maintenance of stem cells: comparison between FLT3/FLK-2 ligand and KIT ligand. 905 11

The granulocyte-macrophage colony-stimulating factor (GM-CSF) analog E21R induces apoptosis of hemopoietic cells. We examined the GM-CSF receptor subunit requirements and the signaling molecules involved. Using Jurkat T cells transfected with the GM-CSF receptor we found that both receptor subunits were necessary for E21R-induced apoptosis. Specifically, the 16 membrane-proximal residues of the alpha subunit were sufficient for apoptosis. This sequence could be replaced by the corresponding sequence from the interleukin-2 receptor common gamma subunit, identifying this as a conserved cytokine motif necessary for E21R-induced apoptosis. Cells expressing the alpha subunit and truncated betac mutants showed that the 96 membrane-proximal residues of betac were sufficient for apoptosis. E21R, in contrast to GM-CSF, did not alter tyrosine phosphorylation of betac, suggesting that receptor-associated tyrosine kinases were not activated. Consistent with this, E21R decreased the mitogen-activated protein kinase ERK (extracellular signal-regulated kinase). E21R-induced apoptosis was independent of Fas/APO-1 (CD95) and required interleukin-1beta-converting enzyme (ICE)-like proteases. In contrast, Bcl-2, which protects cells from growth factor deprivation-induced cell death, did not prevent this apoptosis. These findings demonstrate the GM-CSF receptor and ICE-like protease requirements for E21R-induced apoptosis.
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PMID:The apoptosis-inducing granulocyte-macrophage colony-stimulating factor (GM-CSF) analog E21R functions through specific regions of the heterodimeric GM-CSF receptor and requires interleukin-1beta-converting enzyme-like proteases. 909 24

The early response to inflammation is characterized by the synthesis of a variety of proteins under cytokine and glucocorticoid control. During episodes of infection or inflammation, a secretory phospholipase A2 (sPLA2) appears in the circulation along with a variety of acute-phase proteins (APP), suggesting possible common regulatory elements amongst sPLA2 and APP. Using the human hepatoma line, HepG2, regulation of sPLA2 expression was examined in relation to synthesis of HP and ACH. The patterns of induction of sPLA2, HP and ACH were distinct for each of IL- 1, tumour necrosis factor (TNF) and IL-6, oncostatin M, IL-11 and leukaemia inhibitory factor. Dexamethasone had an enhancing effect on IL-6-induced expression of HP and ACH, but inhibited sPLA2 expression by 50%. Both 8-bromo-cAMP and dibutyryl cAMP increased sPLA2 expression (48.8-fold and 64.2-fold, respectively), whereas KT5720, an inhibitor of protein kinase A, down-regulated cytokine-induced sPLA2 synthesis by 51%. These data show that a panel of cytokines induced varying patterns of up-regulation of sPLA2, ACH and HP. Although dexamethasone potentiated IL-6-induced APP expression in HepG2 cells, it suppressed sPLA2 expression in a dose-dependent manner. In several respects, sPLA2 regulation is similar to that of HP and ACH, but a notable difference is the reciprocal effect of glucocorticoids on sPLA2 expression compared with that of ACH and HP.
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PMID:Coordinate expression of group II phospholipase A2 and the acute-phase proteins haptoglobin (HP) and alpha1-anti-chymotrypsin (ACH) by HepG2 cells. 909 27

The transcription factors Elk-1 and SAP-1 bind together with serum response factor to the serum response element present in the c-fos promoter and mediate increased gene expression. The ERK, JNK, and p38 groups of mitogen-activated protein (MAP) kinases phosphorylate and activate Elk-1 in response to a variety of extracellular stimuli. In contrast, SAP-1 is activated by ERK and p38 MAP kinases but not by JNK. The proinflammatory cytokine interleukin-1 (IL-1) activates JNK and p38 MAP kinases and induces the transcriptional activity of Elk-1 and SAP-1. These effects of IL-1 appear to be mediated by Rho family GTPases. To examine the relative roles of the JNK and p38 MAP kinase pathways, we examined the effects of IL-1 on CHO and NIH 3T3 cells. Studies of NIH 3T3 cells demonstrated that both the JNK and p38 MAP kinases are required for IL-1-stimulated Elk-1 transcriptional activity, while only p38 MAP kinase contributes to IL-1-induced activation of SAP-1. In contrast, studies of CHO cells demonstrated that JNK (but not the p38 MAP kinase) is required for IL-1-stimulated Elk-1-dependent gene expression and that neither JNK nor p38 MAP kinase is required for IL-1 signaling to SAP-1. We conclude that (i) distinct MAP kinase signal transduction pathways mediate IL-1 signaling to ternary complex transcription factors (TCFs) in different cell types and (ii) individual TCFs show different responses to the JNK and p38 signaling pathways. The differential utilization of TCF proteins and MAP kinase signaling pathways represents a potential mechanism for the determination of cell-type-specific responses to extracellular stimuli.
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PMID:Role of p38 and JNK mitogen-activated protein kinases in the activation of ternary complex factors. 911 5

Ascorbic acid (ascorbate or vitamin C) has been shown to suppress the induction of HIV in latently infected T lymphocytic cells following stimulation with a tumor promoter (PMA) and inflammatory cytokine (TNF-alpha). To assess whether this inhibition was mediated via modulation of the cellular transcription factor, NF-kappa B, we carried out gel shift analysis on nuclear extracts prepared under different conditions of cell stimulation in the presence or absence of ascorbate, N-acetylcysteine (NAC), or zidovudine (AZT). Pretreatment of ACH-2 T cells by NAC followed by stimulation with PMA, TNF-alpha, or hydrogen peroxide (H2O2) resulted in strong suppression of NF-kappa B activation. In contrast, neither ascorbate nor AZT affected NF-kappa B activity under all three induction conditions in the ACH-2 cell line. Ascorbate and AZT also had no effect on NF-kappa B activation following TNF-alpha- or PMA-induced stimulation of U1 promonocytic cells. These results suggest that the molecular mechanism of HIV inhibition by ascorbate is not mediated via NF-kappa B inhibition, unlike that seen with other antioxidants.
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PMID:NF-kappa B-independent suppression of HIV expression by ascorbic acid. 911 10

IL-6 is a multifunctional cytokine involved in hemopoiesis, immune regulation, inflammation, neural development, and infection. IL-6 belongs to a family of related cytokines that includes leukemia inhibitory factor, oncostatin M, IL-11, ciliary neurotropic factor, and cardiotropin-1, all of which initiate signaling through a receptor-associated gp130. IL-6 induces homodimerization of gp130 and activates the Jak/STAT pathway of signal transduction. In addition, IL-6 stimulates the mitogen-activated protein kinases designated ERK (extracellular signal-regulated kinase)-1 and -2. Activation of ERK-1 and -2 may involve the Src homology-2 containing proteins Shc and Grb2. Here we provide evidence that Shc could function as signaling molecules for IL-6 in DeFew-IL-6R/gp130 cells, a human B lymphoma cell line engineered to express high levels of both the IL-6R (p80) and the gp130 subunit. IL-6 was shown to promote the rapid tyrosine phosphorylation of gp130, Jak2, and Shc proteins. Moreover, Shc associated both in vivo and in vitro with phosphorylated gp130 through the Shc-Src homology-2 domain. We also report that Shc bound to activated Jak2 by using the Shc amino terminal phosphotyrosine interaction domain. Following IL-6 stimulation, Shc physically associated with Grb2. Thus, the data point to Shc proteins as a functional link between the Jak2 and Ras pathways of IL-6 signal transduction.
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PMID:Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase. 912 68

The stress-activated protein/c-Jun N-terminal kinases (SAPK/JNK) have been shown to be activated by pro-inflammatory cytokines, as well as physical and chemical stresses. We now show that a variety of hematopoietic growth factors, including Steel locus factor (SLF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-3 (IL-3), all of which promote the growth and survival of various lineages of hematopoietic cells, activate the stress-activated protein kinases in the factor-dependent cell line MC/9. These hematopoietic growth factors activated both 46- and 55-kD isoforms of both SAPK gamma and SAPK alpha. Furthermore, we demonstrate that SAPK activation correlated with the phosphorylation of SAPK/ERK kinase-1 (SEK1) after treatment with SLF or GM-CSF. Interestingly, IL-4, a cytokine with distinctive and important effects on the immune system, was the exception among the hematopoietic growth factors we examined in failing to induce activation of SAPK gamma, SAPK alpha, or SEK1. These findings show that activation of SAPK is involved, not only in responses to stresses, but also in signaling by growth factors that regulate the normal development and function of cells of the immune system.
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PMID:Activation of the stress-activated protein kinases by multiple hematopoietic growth factors with the exception of interleukin-4. 912 10


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