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)

Hepatocyte growth factor and its receptor (the product of the c-met protooncogene) are believed to be necessary for the normal growth and development of many tissues and organs. This ligand/receptor system controls essential cellular responses such as cell proliferation and motility as well as morphogenesis and differentiation. HGF mRNA is expressed primarily in mesenchymal but not in epithelial cells while its receptor is predominately expressed in epithelial cells. This pattern of HGF and HGFR gene expression in combination with the unique biological effects of HGF on its target cells has led to the postulate that HGF is one of the long-sought mediators conveying cross-talk between the epithelial and stromal compartments of a given tissue. The expression of HGF and HGFR genes are unregulated in several types of human cancer; therefore, understanding the control mechanisms governing HGF and HGFR gene expression is of great clinical interest. Toward this goal, we have analyzed the effects of various physiological agents such as cytokines and hormones on the expression of HGF and the HGFR in a multitude of cell types in vitro. Moreover, we have cloned and analyzed the HGF promoter and its 5'-flanking region to uncover the basis for its inducible and cell-type specific expression at the transcriptional level. Our results indicate that HGF and HGFR gene expression is inducible and their expression is orchestrated in stromal and epithelial cells, respectively, by extracellular signals derived from steroid hormones as well as cytokines such as IL-1, IL-6, and TNF alpha.
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PMID:Regulation of HGF and HGFR gene expression. 852

Epidermal growth factor is a potential mitogen for many different human tumours. Its effect is mediated via a bispecific receptor (EGFR), the expression of which correlates well with invasive disease. We investigated the modulation of EGFR by cytokines produced following bacillus Calmette Guerin (BCG)-immunotherapy. Our data demonstrate the IFN gamma, TNF alpha and IL-1 alpha can decrease the expression of EGFR on some bladder tumour cell lines. IFN gamma reduced EGFR expression on two of eight cell lines (RT4, SD). However, IL-1 and TNF did not share this activity. When cells were treated with a combination of all three cytokines, EGFR was decreased on three cell lines (RT4, RT112, SD) and furthermore, the change in the receptor expression was even more marked. Treatment with phorbol ester (thereby activating protein kinase C) resulted in rapid disappearance of the receptor from the cell surface. Interestingly, the decrease of EGFR expression did not require protein synthesis. Although the cytokines studied could down modulate EGFR, this only occurred on three out of eight cell lines; therefore, it is unlikely that the suppression of proliferative activity caused by cytokine-induced decrease of EGFR expression is central to the antitumour action of BCG therapy, but in a proportion of tumours this mechanism may be involved.
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PMID:Cytokine modulation of epidermal growth factor receptor expression on bladder cancer cells is not a major contributor to the antitumour activity of cytokines. 856 66

Neutral endopeptidase (NEP; EC 3.4.24.11) is a type-2 cell-surface metalloproteinase known by a variety of eponyms, including enkephalinase, common acute lymphoblastic leukemia antigen (CALLA), and CD10. Identified substrates are largely neural or humoral oligopeptide agonists, and the enzyme functions to terminate signaling by degrading the ligand, analogous to the acetylcholine/acetylcholinesterase system. Targeted disruption of the NEP locus in mice results in enhanced lethality to endotoxin shock with a pronounced gene-dosage effect. The site(s) of action appears downstream from release of TNF and IL-1, as NEP-deficient animals demonstrate increased sensitivity to these mediators as well. This unexpected finding indicates an important protective role for NEP in septic shock.
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PMID:Neutral endopeptidase modulates septic shock. 860 28

JNK/SAPKs are identified as new members of the MAPK family; they phosphorylate c-Jun protein in response to several cellular stimuli including ultraviolet irradiation, TNF and osmotic shock. We have identified a protein kinase, MUK, as an activator of the JNK-pathway, whose kinase domain shows significant homology to MAPKKK-related proteins such as c-Raf and MEKK. The over-expression of MUK or MEK kinase (MEKK) in NIH3T3 or COS1 cells results in the activation of JNK1 and the accumulation of a hyper-phosphorylated form of c-Jun. While MEKK also activates the ERK pathway, MUK is a rather selective activator of the JNK pathway. On the other hand, c-Raf activates the JNK pathway only slightly despite its remarkable ability to activate the ERK pathway. Even though we originally identified MUK as a MAPKKK-related protein kinase, a greater similarity to mixed lineage kinase (MLK) is found not only in the catalytic domain but also in the 'leucine-zipper'-like motifs located at the C-terminal side of the catalytic domain. The structural divergence between MUK and MEKK reveals the multiplicity of signaling pathways that activate JNK/SAPKs.
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PMID:Activation of the JNK pathway by distantly related protein kinases, MEKK and MUK. 863 21

Acute HIV-1 infection of H9 and C8166 cultures has been shown to be suppressed by certain flavonoids, and evidence for inhibition of HIV-1 protease, integrase, and reverse transcriptase by flavonoids also exists. The present aim was to determine whether flavonoids inhibit HIV-1 activation in models of latent infection. By screening flavonoids from six different classes, three structurally related compounds (chrysin, acacetin, and apigenin) were identified that inhibited HIV expression in TNF-alpha-treated OM-10.1 cultures. The three compounds had favorable potencies against HIV activation in relation to their growth inhibitory effects (therapeutic index 5-10). Chrysin also inhibited HIV expression in response to PMA in OM-10.1 cells, in ACH-2 cells stimulated with either TNF-alpha or PMA, and in 8E5 cultures. Furthermore, return to viral latency in OM-10.1 cells previously exposed to TNF-alpha occurred over a shorter time interval when chrysin was added. The inhibition of HIV activation was not dependent on preincubation with flavonoids relative to TNF, and was characterized by a lack of HIV RNA accumulation by Northern analysis. Gel-shift experiments revealed that NF-kappa B activation after TNF-alpha treatment was not inhibited by these agents, suggesting that some other critical factor(s) needed for viral transcription was being affected. These findings indicate that flavonoids inhibit HIV-1 activation via a novel mechanism, and that these agents are potential candidates for therapeutic strategies aimed at maintaining a cellular state of HIV-1 latency.
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PMID:Inhibition of HIV activation in latently infected cells by flavonoid compounds. 882 17

Bacterial superantigen such as staphylococcal enterotoxin B (SEB) induced strong ICAM-1 expression in organ-cultured human keratinocytes. Other superantigens (SEA, SEC1, SEC2) but not mite antigen (Dermatophagoides) also induced ICAM-1 expression both at protein and mRNA level. In contrast to ICAM-1, vascular endothelial cell expression of VCAM-1 was only demonstrated at mRNA level following ICAM-1 expression in keratinocytes. Patterns of cytokine expression in keratinocytes were variable. TNF alpha was strongly expressed in keratinocytes both at protein and mRNA level, while IL1 beta and IL1 alpha were only demonstrated at mRNA level. These results clearly demonstrated that bacterial superantigen could induce cell adhesion molecule expression in keratinocytes through the induction of various cytokines and play an important role in the induction of refractory eczematous lesions in atopic dermatitis.
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PMID:Superantigen-induced cytokine expression in organ-cultured human skin. 886 30

The aim of this study was to evaluate the effect of acute human corticotropin (ACTH)-releasing hormone (CRH) administration (100 micrograms, as i.v. bolus) on tumor necrosis factor-alpha (TNF alpha) levels in the inferior petrosal sinuses and in the peripheral blood of 7 patients with Cushing's disease subjected to diagnostic inferior petrosal sinus sampling. Blood samples for ACTH, beta-endorphin (beta-EPH) and TNF alpha were collected from inferior petrosal sinuses and periphery simultaneously. In addition, TNF alpha concentrations were measured after CRH administration (10 nmol/l, 100 nmol/l and 1 mumol/l) in culture medium from primary cultures obtained in 3 of 7 patients. At baseline, plasma ACTH and beta-EPH levels were significantly higher in the inferior petrosal sinus ipsilateral to the ACTH-secreting adenoma than in the contralateral one and in the periphery (p < 0.001) whereas no significant difference was found as far as serum TNF alpha levels were concerned. CRH administration caused a significant increase of ACTH (p < 0.001), beta-EPH (p < 0.01) and TNF alpha (p < 0.01) levels greater in the ipsilateral inferior petrosal sinus than in the contralateral one and in the periphery. In addition, CRH increased ACTH, beta-EPH and TNF alpha levels in the culture medium of three ACTH-secreting tumors at the doses of 100 nmol/l and 1 mumol/l (greater than 300, 200 and 110% of baseline pretreatment incubation levels, respectively). These data suggest that CRH may increase TNF alpha concentrations in the inferior petrosal sinus ipsilateral to the ACTH-secreting adenoma and in the peripheral blood as well. In addition, it stimulated TNF alpha release both in vivo and in vitro. These findings suggest the possibility that an imbalanced intrapituitary TNF alpha production can be detected in ACTH-secreting adenomas.
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PMID:Tumor necrosis factor-alpha increases after corticotropin-releasing hormone administration in Cushing's disease. In vivo and in vitro studies. 893 Sep 39

This study compares the ability of LFA-3 (CD58) and B7-1 (CD80) ligands to provide costimulatory signals for superantigen (SAg)-stimulated CD8+ and CD4+ T cells. We show that B7-1 and LFA-3 costimulation activate CD8+ T cells to proliferation, cytokine production (IL-2, TNF, and IFN-gamma), and cytotoxicity. A long-lasting proliferative response was observed after combined DR/B7-1/LFA-3 costimulation. Detailed analysis of SEA-activated CD8+ T cells revealed that maximal production of IFN-gamma was seen in LFA-3-costimulated cells, while production of IL-2 was mainly induced after B7-1 costimulation. A fivefold increase in the IFN-gamma production was observed when activated CD8+ T cells were costimulated with Chinese hamster ovary (CHO)-DR/LFA-3 cells compared with the secretion induced by CHO-DR/B7-1. In contrast, SEA-treated CD4+ T cells costimulated with B7-1 or LFA-3 gave rise to a similar production of IFN-gamma, suggesting a preferential function for the CD2/LFA-3 pathway in the regulation of IFN-gamma in CD8+ T cells. Moreover, the generation of CTL was supported similarly by B7-1 and LFA-3 costimulation, but not by CHO-DR cells. We conclude that ligation of the CD28 and CD2 receptors mediate distinct effect on CD8+ and CD4+ T cell effector functions.
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PMID:The role of B7-1 and LFA-3 in costimulation of CD8+ T cells. 899 78

IL-1-activated chondrocytes express a large number of genes which contribute to cartilage degradation. The signaling pathways activated in response to IL-1 in these cells are not well-defined. We examined the effects of IL-1 and other stimuli on the mitogen activated protein kinase (MAPK) pathways in rabbit articular chondrocytes. We demonstrate that IL-1 activates three MAPKs, ERK, JNK and p38, in a time and dose-dependent manner. Activation is maximal by 15 minutes and returns to baseline levels by 1 hour. Maximal activation of ERK and p38 occurs with 1 ng/ml IL-1 whereas activation of JNK requires 10-fold higher levels. In contrast to IL-1, the PKC activator, PDBu preferentially activates ERK while TNF alpha preferentially activates JNK. LPS and TGF beta fail to stimulate any of the kinases examined. These results suggest that activation of the various MAPK pathways is important in the response of chondrocytes to IL-1, cytokines and growth factors.
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PMID:The effects of IL-1 on mitogen-activated protein kinases in rabbit articular chondrocytes. 901 64

TNF induces cytotoxicity in human tumor cells through a receptor-mediated process with unknown signaling characteristics. Evidence suggests that overexpression of transmembrane growth factor receptors with intrinsic tyrosine kinase activity may suppress the antiproliferative or cytotoxic activity of TNF, suggesting antagonism between these two signaling pathways in tumor cells. To investigate TNF cytotoxic signal transduction, ME-180 cervical carcinoma cell variants were isolated that expressed complete cytotoxic sensitivity (ME-180S) or resistance (ME-180R) to TNF but identical levels of p55 TNF receptor expression. ME-180R cells expressed threefold higher EGFR than the ME-180S cell line and TNF treatment stimulated EGFR tyrosine phosphorylation only in resistant cells. Activation of tyrosine phosphorylation in ME-180R cells was TNF concentration dependent and maximally stimulated (three- to-five-fold) after 10-15 minutes of treatment. Other tyrosine phosphoproteins were not affected by TNF incubation demonstrating specific TNF-stimulated tyrosine phosphomodulation of EGFR. Pretreatment with the tyrosine kinase inhibitor tryphostin before incubation with TNF resulted in partial reversal of TNF cytotoxic resistance in ME-180R cells and enhanced TNF responsiveness in ME-180S cells, suggesting a "protective" role for tyrosine phosphorylation in TNF-induced cytotoxicity. Together these results demonstrate that TNF-mediated tyrosine phosphorylation is differentially regulated in sensitive and resistant tumor cells and may play a critical role in the cytotoxic signaling process through differential expression or regulation of tyrosine protein kinases and phosphatases.
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PMID:Activation of epidermal growth factor receptor tyrosine phosphorylation by tumor necrosis factor correlates with loss of cytotoxic activity. 916 24


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