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)

Interferon-gamma-induced tryptophan metabolism of human macrophages was compared to ten human neoplastic cell lines of various tissue origin and to normal dermal human fibroblasts. Tryptophan and metabolites were determined in supernatants of cultures, after incubation for 48 h, by high-performance liquid chromatography with ultraviolet and fluorescence detection. With the exception of two cell lines (Hep G 2, hepatoma and CaCo 2, colon adenocarcinoma) in all of the ten other cells and cell lines tryptophan degradation was induced by interferon-gamma. Five of these ten formed only kynurenine (SK-N-SH, neuroblastoma; T 24, J 82, bladder carcinoma; A 431, epidermoid carcinoma; normal dermal fibroblasts), three formed kynurenine and anthranilic acid (U 138 MG, glioblastoma; SK-HEP-1, hepatoma; A 549, lung carcinoma). Only one line, A 498 (kidney carcinoma) showed the same pattern of metabolites as macrophages (kynurenine, anthranilic acid and 3-hydroxyanthranilic acid). Interferon-gamma regulated only the activity of indoleamine 2,3-dioxygenase. All other enzyme activities detected were independent of interferon-gamma, as shown by the capacity of the cells to metabolize L-kynurenine or N-formyl-L-kynurenine. Increasing the extracellular L-tryptophan concentration resulted in a marked induction of tryptophan degradation by macrophages. Contrarily, a significant decrease of the tryptophan degrading activity was observed when the extracellular L-tryptophan concentration was increased 2-fold with SK-N-SH, T 24 and J 82, 4-fold with A 431 and A 549 and 10-fold with U 138 MG and SK-HEP-1. The activity was unaffected by extracellular L-tryptophan with dermal fibroblasts and A 498. Though interferon-gamma was the most potent inducer of tryptophan metabolism, interferon-alpha and/or -beta showed small but distinct action on some of the cells. In all cells which reacted to interferon-gamma by enhanced expression of class I and/or class II major histocompatibility complex antigens tryptophan degradation was also inducible. These results demonstrate that induction of indoleamine 2,3-dioxygenase is a common feature of interferon-gamma action, that the extent of this induction is influenced by extracellular L-tryptophan concentrations and that indoleamine 2,3-dioxygenase is the only enzyme in the formation of 3-hydroxyanthranilic acid from tryptophan which is regulated by interferon-gamma.
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PMID:Characteristics of interferon induced tryptophan metabolism in human cells in vitro. 250 Sep 76

Many cell types display two classes of epidermal growth factor receptor (EGFR) as judged from EGF binding studies; i.e., a major class of low affinity EGFR and a minor class of high affinity EGFR. We have studied their respective contribution to the cascade of events elicited by EGF in human A431 carcinoma cells, using anti-EGFR mAb 2E9. This antibody specifically blocks EGF binding to low affinity EGFR, without activating receptors in intact cells, and thus enables us to study the effects of exclusive EGF binding to high affinity EGFR. We show that blocking of low affinity EGFR by mAb 2E9 has almost no effect on the activation of the receptor protein-tyrosine kinase by EGF, suggesting that EGFR kinase activation occurs exclusively through the subclass of high affinity EGFR (5-10%). In addition, we provide evidence that high affinity EGFR exists both in monomeric and dimeric forms, and that cross-phosphorylation of low affinity EGFR by high affinity EGFR may take place in dimers of both receptor types. We demonstrate that the following early cellular response to EGF are also unimpaired in the presence of mAb 2E9: (a) inositol phosphate production, (b) release of Ca2+ from intracellular stores, (c) rise in intracellular pH, (d) phosphorylation of EGF on threonine residue 654, (e) induction of c-fos gene expression, and (f) alteration in cell morphology. As possible nonspecific side effects, we observed that the EGF induced Ca2+ influx and fluid-phase pinocytosis were inhibited in A431 cells in the presence of mAb 2E9. We conclude, therefore, that the activation of the EGFR signal transduction cascade can occur completely through exclusive binding of EGF to the subclass of high affinity EGFR.
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PMID:Signal transduction by epidermal growth factor occurs through the subclass of high affinity receptors. 255 48

We have investigated the biological function of an unidentified human growth factor, the ligand of the putative HER2 receptor, by characterizing the signalling properties of its receptor. HER2 (or c-erbB-2), the human homolog of the rat neu proto-oncogene, encodes a transmembrane glycoprotein of the tyrosine kinase family that appears to play an important role in human breast carcinoma. Since a potential ligand for HER2 has not yet been identified, it has been difficult to analyze the biochemical properties and biological function of this cell surface protein. For this reason, we replaced the HER2 extracellular domain with the closely related ligand binding domain sequences of the epidermal growth factor (EGF) receptor, and examined the ligand-induced biological signalling potential of this chimeric HER1-2 protein. This HER1-2 receptor is targetted to the cell surface of transfected NIH 3T3 cells, forms high and low affinity binding sites, and generates normal mitogenic and cell transforming signals upon interaction with EGF or TGF alpha. The constitutive activation of wild-type HER2 in transfected NIH 3T3 cells suggests the possibility that these cells synthesize the as yet unidentified HER2 ligand and activate HER2 by an autocrine mechanism.
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PMID:HER2 cytoplasmic domain generates normal mitogenic and transforming signals in a chimeric receptor. 256 8

The effects of epidermal growth factor (EGF) on membrane potential were investigated in suspensions of the following three cell types endowed with a large complement of specific receptors: EGFR-T17 (a clone of mouse NIH-3T3 fibroblasts overexpressing EGF receptors); A431 and KB (two human carcinoma lines). In all these lines EGF induced a rapid and marked hyperpolarization constituted by an initial peak (in all three cell lines) and a subsequent sustained plateau phase, concomitant with the well-known increase of [Ca2+]i. The time course and phorbol ester inhibitability of the membrane potential effects were the same as for the [Ca2+]i response. Experiments with Na+-free and chloride-free media excluded a major role of the latter ions in the EGF-induced hyperpolarization. In contrast, experiments with high K+ media, with the monovalent cation ionophore gramicidin and with Ca2+-free media together with either a Ca2+ ionophore (ionomycin, in A431 and EGFR-T17), or an agonist (bradykinin, in A431) addressed to a receptor coupled to phosphoinositide hydrolysis, were consistent with the involvement of Ca2+-activated K+ channels. The EGF-induced hyperpolarization was completely blocked by the K+ channel blocker, quinidine, and unaffected by a variety of other drugs. Patch clamping of individual EGFR-T17 cells confirmed the initial hyperpolarization (from approximately -30 mV, the resting potential, to -60, -80 mV) was due to activation of an outward current. This initial hyperpolarization was followed by fluctuations (period approximately 1 min) persisting as long as the cells could be analyzed. Thus, the changes of membrane potential appear to be not only novel members of the group of early events triggered by EGF in target cells but also long-lasting effects of the growth factor, which continue for unexpectedly long periods of time after EGF application.
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PMID:The effect of epidermal growth factor on membrane potential. Rapid hyperpolarization followed by persistent fluctuations. 278 95

Functional characterization of oncogene products that induce cellular transformation has progressed rapidly in recent years. However, less is known about the mechanism(s) by which the transformed cells may escape destruction by host immune defenses and form tumors. A recently described oncogene that has an important association with aggressive human breast carcinoma is "HER2," for human epidermal growth factor receptor 2. The oncogene has also been called NGL and human c-erbB-2 (ERBB2). In this paper we show that amplification of HER2 oncogene expression can induce resistance of NIH 3T3 cells to the cytotoxic effects of recombinant tumor necrosis factor alpha (rTNF-alpha) or macrophages. Resistance is accompanied by an increased dissociation constant for rTNF-alpha binding to high-affinity receptors on the HER2-transformed NIH 3T3 cells. The resistance phenotype is independent of transformation since NIH 3T3 cells transformed by the activated human homologue of the Harvey-ras oncogene (HRAS) retain high-affinity binding sites for rTNF-alpha as well as sensitivity to its cytotoxic effects. These results suggest that HER2 may potentiate tumorigenesis by inducing tumor cell resistance to host defense mechanisms.
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PMID:Amplified expression of the HER2/ERBB2 oncogene induces resistance to tumor necrosis factor alpha in NIH 3T3 cells. 289 23

The human monoblast leukemia line U937 is growth inhibited and induced to express various characteristics of mature monocytes by lymphokines (LK) and other cytokines. Previous experiments have shown that interferon-gamma (IFN-gamma) is responsible for some but not all of the differentiation-inducing effects on U937. To determine the variety and specificity of activity, the following factors were studied: phytohemagglutinin-induced LK that contained IFN-gamma (100 units/ml); purified IFN-gamma; human colony-stimulating factor 1 (CSF-1); and conditioned medium(a) (CM) from the human bladder carcinoma cell line 5637 and the hepatoma cell line SK-HEP. LK preparations contained no colony-stimulating activity, whereas CM from 5637 and SK-HEP both contained granulocyte-macrophage CSF (3000 to 4000 units/ml) but no IFN activity. IFN-gamma is the major immunoglobulin G Fc receptor-inducing species within lymphokine, since anti-interferon-gamma antibody inhibited most of this activity. Other sources of Fc receptor-inducing activity were CM from SK-HEP and 5637 cell lines. Human CSF-1 when tested up to 800 units/ml was inactive for Fc receptor induction. LK induced the chemotactic peptide receptor, but this induction was due to factors other than IFN-gamma as anti-IFN-gamma antibody did not inhibit the induction, and purified IFN-gamma at a dose equivalent to that found in LK (100 units/ml) had no activity in the assay. SK-HEP and 5637 CM had strong chemotactic peptide receptor-inducing activity, but human CSF-1 was inactive up to 800 units/ml. Peroxide production after stimulation with phorbol myristic acid could be induced by LK, LK with anti-IFN-gamma antibody, 5637, and SK-HEP treatment. IFN-gamma (100 units/ml) and CSF-1 (800 units/ml) were ineffective. Peroxide production was induced by IFN-gamma at concentrations above 1000 units/ml. The inducibility of several enzymatic activities was determined as additional measures of maturation. N-Acetylglucuronidase was induced, for example, by LK, IFN-gamma, 5637 CM, and phorbol myristic acid. Alkaline phosphatase was induced by LK, IFN-gamma, dexamethasone, and phorbol myristic acid. 1,25-Dihydroxycholecalciferol was also examined and could induce most of the maturational markers examined. The results demonstrate that non-IFN cytokines from several sources have profound differentiation-inducing effects on monoblast leukemia cells in a pattern different from that of IFN-gamma.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Distinct activities of interferon-gamma, lymphokine and cytokine differentiation-inducing factors acting on the human monoblastic leukemia cell line U937. 298 Nov 61

A combination of retinoic acid (RA) and human recombinant DNA-derived interferon-gamma (Hu-IFN-gamma) was tested with respect to the growth inhibitory action on several human mammary carcinoma cell lines (ZR-75.1, 734-B, MCF-7, and BT-20), a human lung carcinoma cell line (CCL-185), and a human laryngeal carcinoma cell line (HEP-2). The mammary carcinoma cell lines were all sensitive to Hu-IFN-gamma, and 2 of them (ZR-75.1 and 734-B) were also affected by RA. The combination of both substances led to a pronounced synergistic amplification of growth inhibition in ZR-75.1 and 734-B cells. RA also increased the antiproliferative activity of Hu-IFN-gamma in the RA-resistant BT-20 cells and to a less pronounced degree in MCF-7 cells. In contrast to these findings, no synergistic effects were observed between Hu-IFN-gamma and RA in CCL-185 and HEP-2 cells. Human recombinant DNA-derived interferon-alpha 2 amplified the action of RA only in BT-20 cells, but it did not act synergistically with RA in the other cell lines tested.
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PMID:Synergistic antiproliferative effect of human recombinant interferons and retinoic acid in cultured breast cancer cells. 309 46

Effects of human recombinant-DNA derived interferon-gamma and -alpha 2 on the adhesion of cultured breast cancer cells (BT-20, ZR-75.1, MCF-7, 734-B and Hs-578-T), larynx carcinoma cells (HEP-2), epidermoid carcinoma cells (KB), lung carcinoma cells (CCL 185), and ovarian carcinoma cells (1847) to the surface of cell culture plastic dishes were studied. Layered cells were detached after a 3-day treatment with interferon either by trypsin-EDTA, trypsin, protease or cooling to 4 degrees C. Treatment with interferon-gamma (500 unit/ml) significantly increased the incubation time for trypsin-EDTA, EDTA and at 4 degrees C necessary to bring cells into suspension for the 4 cell lines BT-20, ZR-75.1, MCF-7 and HEP-2. Interferon-alpha 2 was not able to induce a similar effect. Reattachment of interferon-gamma treated ZR-75.1 cells was not increased after harvesting by trypsinization or EDTA action. Decreased adhesion of cultured cells is associated with transformation and the effects of interferon-gamma may be explained by reinforced normal phenotype. Interferon-gamma induced adhesion was not associated with other interferon effects especially the anti-proliferative activity or modulation of surface antigens.
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PMID:Human interferon-gamma increases adhesion of cultured carcinoma cells to the substratum. 311 53

Amplification of the neu (or c-erbB-2 or HER) oncogene is relatively frequent in human breast carcinomas. We have raised a polyclonal rabbit serum in order to detect the neu protein product in tissue sections of tumors. This serum specifically reacted with a 185 kilodaltons neu protein in SKBR-3 cells, a mammary carcinoma cell line with amplified neu. Immunohistochemistry on paraffin-embedded sections of tumors in which the neu gene was amplified showed distinct membrane staining of groups of tumor cells. Sections of tumors with normal copy numbers of neu were negative. Lymph node metastases from tumors positive for neu overexpression also showed the membrane staining pattern, whereas lymph node metastases from tumors negative for neu staining never did. Neu amplification is thus associated with neu protein overproduction in tumors and lymph node metastases, and a routine antibody staining technique can discriminate a high level of neu protein expression from levels commonly present in tumors with normal neu copy numbers.
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PMID:Immunohistochemical detection of the neu protein in tissue sections of human breast tumors with amplified neu DNA. 328 95

The human hepatoma cell PLC/PRF/5 contains cloned genomes of hepatitis B virus, one of which was transfected to mouse cells (LTK-) or to human carcinoma cells (HeLa). Expression of the viral surface proteins was measured using monoclonal antibodies. The large protein with the pre-S1 domain was best expressed in HeLa cells and least in LTK- cells. In vivo growth of parental hepatoma cells or transfected HeLa cells increased expression of large, and decreased expression of small protein. Secretion of large protein required an excess of small protein. The secreted HBsAg from transfected HeLa cells contained filaments. Since the virus contains a defined proportion of all three proteins, a special regulatory situation is necessary for maturation of its envelope and its secretion in vivo.
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PMID:Cell-type dependent expression and secretion of hepatitis B virus pre-S1 surface antigen. 331 59


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