UMLS:C0025202 - FACTA Search

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Query: UMLS:C0025202 (melanoma)
69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of the chemokine MGSA/GRO is upregulated as melanocytes progress to melanoma cells. We demonstrate that constitutive and cytokine induced MGSA/GRO alpha expression requires multiple DNA regulatory regions between positions -143 to -62. We have previously shown that the NF-kappa B element at -83 to -65 is essential for basal and cytokine induced MGSA/GRO alpha promoter activity in the Hs294T melanoma and normal retinal pigment epithelial (RPE) cells, respectively. Here, we have determined that the Sp1 binding element located approximately 42 base pairs upstream from the NF-kappa B element binds Sp1 and Sp3 constitutively and this element is necessary for basal MGSA/GRO alpha promoter activity. We demonstrate that the high mobility group proteins HMGI(Y) recognize the AT-rich motif nested within the NF-kappa B element in the MGSA/GRO alpha promoter. Loss of either NF-kappa B or HMGI(Y) complex binding by selected point mutations in the NF-kappa B element results in decreased basal and cytokine induced MGSA/GRO alpha promoter activity. Thus, these results indicate that transcriptional regulation of the chemokine MGSA/GRO alpha requires at least three transcription factors: Sp1, NF-kappa B and HMGI(Y).
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PMID:HMGI(Y) and Sp1 in addition to NF-kappa B regulate transcription of the MGSA/GRO alpha gene. 747 86

Chemokines/intercrines are structurally and functionally related cytokines that induce specific actions on the immune system and are released in response to infection, inflammation, and trauma. These pathological processes are frequently accompanied with food intake suppression. In the present study, the action of chemokines/intercrines on the regulation of feeding was investigated using the intracerebroventricular microinfusion of chemokine/intercrine-alpha subfamily members [interleukin-8 (IL-8); growth-related cytokine/melanoma growth-stimulating activity (GRO-alpha/MGSA); platelet factor-4 (PF-4); beta-thromboglobulin (beta-TG); and interferon-inducible protein-10 (IP-10)] and beta-subfamily members [monocyte chemotactic protein-1/monocyte chemotactic and activating factor (MCP-1/MCAF); regulated upon activation normal T-cell expressed and presumably secreted (RANTES); macrophage inflammatory protein-1 alpha (MIP-1 alpha); and macrophage inflammatory protein-1 beta (MIP-1 beta)]. The doses administered were 1.0, 20, and 100 ng/rat of the chemokine/intercrine. The intracerebroventricular administration of three members of the alpha-subfamily (IL-8, PF-4, and IP-10) and two members of the beta-subfamily (MCP-1/MCAF and RANTES) decreased the short-term (2-h) food intake. These effective chemokines/intercrines, however, were significantly less potent than IL-1 beta in decreasing feeding. The results support the hypothesis that only a subset of immunomodulators released during pathological processes may participate in the regulation of feeding with different potencies.
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PMID:Chemokines/intercrines and central regulation of feeding. 751 92

The erythrocyte chemokine receptor is a cell surface protein that binds a wide array of chemokines including interleukin-8 (IL-8), melanoma growth stimulating activity (MGSA), monocyte chemotactic protein-1 (MCP-1), and RANTES (Regulated on Activation, Normal T Expressed and Secreted). This protein has also been identified as the Duffy blood group antigen, a cell surface receptor for the malarial parasite Plasmodium vivax. In the present study, we have identified a chemokine receptor-like binding protein in a human erythroleukemic cell line (HEL), which, based on its molecular properties, may be related to the erythrocyte chemokine receptor. Saturation binding studies with 125I-IL-8 revealed a single class of IL-8 binding sites in HEL cells with a KD of 7.4 +/- 1.9 nM and a receptor density of 12,818 +/- 965 binding sites/cell. In competition studies unlabeled IL-8 MGSA, MCP-1, and RANTES were fully able to inhibit the binding of 125I-IL-8 to HEL cells. Chemical cross-linking with radiolabeled IL-8 resulted in a cross-linked species of 60 kDa in membranes from HEL cells. The labeling was specific since it was inhibited by pre-incubation with 1 microM unlabeled IL-8 or MGSA. A monoclonal antibody (Fy6) to the human erythrocyte Duffy blood group antigen/chemokine receptor blocked the binding of IL-8 and other chemokines to the HEL cell chemokine receptor-like binding protein. Cell membranes from HEL cells and from erythrocyte ghosts were subjected to SDS-PAGE and analyzed by Western blotting with anti-Fy6. The antibody bound to a molecule with a molecular mass of 50 kDa in HEL cell membranes and 40 kDa in erythrocyte ghosts. Northern blot analysis of mRNA revealed that the HEL chemokine-binding protein hybridized to a cDNA probe to the Duffy antigen/chemokine receptor.
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PMID:Identification and characterization of a promiscuous chemokine-binding protein in a human erythroleukemic cell line. 751

1H NMR has been used to investigate the structural properties of RANTES, a protein from the C-C branch of the chemotactic cytokine family that has a strong chemoattractive effect on monocytes, lymphocytes, and eosinophils. Titration of pH from 5.0 to 2.5 indicates that RANTES is extensively aggregated in solution above pH 4.0. At pH 3.7 the protein is mostly dimeric, although this species does dissociate to the monomer with a Kd of 35 microM. NMR data have been acquired and resonance assignments made for the dimeric species. Structures of the dimer have been generated by distance geometry and simulated annealing calculations that utilized 1956 intramolecular distance restraints, 120 intermolecular distance restraints, 164 dihedral angle restraints, and 68 restraints enforcing 34 hydrogen bonds (17.0 restraints per residue). The structure is well-defined (average root mean square deviation from the average structure of 0.38 +/- 0.06 and 0.53 +/- 0.12 A for backbone heavy atoms of residues 4-66 of the monomer and dimer, respectively). Each monomer consists of a C-terminal alpha-helix packing against a three-stranded antiparallel beta-sheet and two short N-terminal beta-strands; dimerization occurs between the N-terminal regions of each monomer. This quaternary structure is very different from that of the C-X-C chemokines such as interleukin-8 and melanoma growth stimulatory activity but similar to that found for the C-C chemokine macrophage inflammatory factor 1 beta. Distinct structural differences between RANTES and other chemokines at both the tertiary and quaternary level are discussed with regard to the distinct biological functions of the C-C and C-X-C members of this protein family.
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PMID:Proton NMR assignments and solution conformation of RANTES, a chemokine of the C-C type. 753 88

Ultraviolet radiation can induce the transcription and release of cytokines from keratinocytes (KC's). These cytokines have the potential to modulate local and systemic immunologic responses. In this paper we report that northern blotting showed that human KC and KC lines expressed a 1.2-1.4 kb transcript for the chemokine and melanoma growth-stimulatory protein, GRO-alpha and that ultraviolet B radiation (UVB) could upregulate the expression of GRO-alpha mRNA and protein in the KC line A431. The GRO-alpha gene response to UVB was maximal at 48h post-irradiation with 70 J/m2. Reverse transcription-polymerase chain reaction (RT-PCR) revealed a 4.5-fold increase in GRO-alpha mRNA over basal levels (p < 0.001). GRO-alpha protein was measured in the culture media by enzyme-linked immunosorbent assay (ELISA). Media from unirradiated cultures contained 1166 +/- 83 pg/ml GRO-alpha protein. After UVB, a time-dependent increase in GRO-alpha protein was seen in the culture media from 6-48h. At 48h post-irradiation the GRO-alpha protein content was 27583 +/- 678 pg/ml, or 23 times the basal level. This protein release could be inhibited by 70% when the cells were pre-incubated with 10 micrograms/ml interleukin-1 receptor antagonist (IL-1RA). We also show that another potent leukocyte chemoattractant, Interleukin-8 (IL-8), was induced in A431 cells by UVB. This induction of IL-8 mRNA began as early as 3h post-irradiation, when it reached twice basal levels (p < 0.05) and reached 4.5-fold basal levels at 48h post-irradiation (p < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin-8 and melanoma growth-stimulating activity (GRO) are induced by ultraviolet B radiation in human keratinocyte cell lines. 755 61

The Duffy antigen (DARC) is a promiscuous chemokine receptor that also binds Plasmodium vivax. DARC belongs to a family of heptahelical chemokine receptors that includes specific (IL-8RA) and shared (IL-8RB) IL-8 receptors. Ligand binding specificity of IL-8 receptors was localized to the amino-terminal extracellular (E1) domain. To determine the basis for promiscuous chemokine binding by DARC, a chimeric receptor composed of the E1 domain of DARC and hydrophobic helices and loops from IL-8RB (DARCe1/IL-8RB) was constructed. Scatchard analysis of stable transfectants demonstrated that the DARCe1/IL-8RB chimeric receptor bound IL-8 and melanoma growth stimulating activity (MGSA) with KD values almost identical to the native receptors. The hybrid receptor also bound RANTES, MCP-1, and MGSA-E6A (which binds DARC, but not IL-8RB), but not MIP-1 alpha, similarly to DARC. Ligand binding to DARC transfectants was unaltered by anti-Fy3, but inhibited by Fy6, which binds an epitope in the E1 domain. The epitope recognized by Fy3 was localized to the third extracellular loop by analysis of insect cells expressing chimeric receptors composed of complementary portions of DARC and IL-8RB. These findings implicate the E1 domain of DARC in multispecific chemokine binding.
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PMID:The promiscuous chemokine binding profile of the Duffy antigen/receptor for chemokines is primarily localized to sequences in the amino-terminal domain. 759 30

We have previously characterized the stably transfected, clonally selected human placental cell line, 3ASubE P-3, which overexpresses the type B interleukin-8 receptor (IL-8RB) and responds to the chemokine melanoma growth stimulatory activity (MGSA) with enhanced phosphorylation of this receptor. In work described here, we demonstrate that the MGSA-enhanced phosphorylation of this receptor is mediated via a process involving pertussis toxin-sensitive G proteins. Furthermore, treatment of the 3ASubE P-3 cells with either 12-O-tetradecanoylphorbol 13-acetate (TPA) or 1,2-dioctanoyl-sn-glycerol (diC8), two different activators of protein kinase C (PKC), results in a concentration-dependent increase in the phosphorylation of the IL-8RB. Inhibition of PKC, by treatment with staurosporin (50 nM for 2 h), or down-regulation of PKC, by prolonged treatment with TPA (400 nM for 40 h) suppresses the TPA-enhanced receptor phosphorylation, but has no effect on the MGSA-enhanced receptor phosphorylation. These data suggest that the isoforms of PKC that are sensitive to these manipulations may not play a role in mediating the MGSA-enhanced phosphorylation of the IL-8RB. TPA treatment also results in a time-dependent decrease in 125I-MGSA binding to the 3ASubE P-3 cells. A 30-min treatment with 400 nM TPA results in approximately a 50% decrease in binding, whereas a 2-h treatment essentially eliminates specific binding of 125I-MGSA to these cells. The TPA-induced decrease in 125I-MGSA binding is accompanied by enhanced degradation of the IL-8RB, as indicated by Western blot analysis and pulse-chase experiments, suggesting a potential role for PKC as a negative regulator of the IL-8RB. MGSA treatment (50 nM for 2 h) also stimulates receptor degradation in the 3ASubE P-3 cells, indicating that this receptor is down-regulated in response to prolonged exposure to its ligand. In similar studies conducted on the promonocytic cell line, U937, MGSA treatment of the U937 cells resulted in receptor phosphorylation, whereas PKC activation failed to significantly modulate the phosphorylation state of the IL-8RB. Treatment of the U937 cells with MGSA, TPA, or diC8 resulted in a loss of receptor protein present in these cell types. These data imply that MGSA signaling through the IL-8RB is similar in both the non-hematopoietic and hematopoietic cell types, whereas activation of PKC by TPA or diC8 elicits different responses in these two distinct cell types.
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PMID:Activation of protein kinase C enhances the phosphorylation of the type B interleukin-8 receptor and stimulates its degradation in non-hematopoietic cells. 773 78

Expression of mRNA for the neutrophil (PMN) chemokine, KC, in rat models of lung injury suggests a role for this chemokine in pulmonary inflammation. We addressed this hypothesis at the protein level by functionally characterizing recombinant rat KC (rKC) in vitro and in vivo. In vitro, rKC induced PMN chemotaxis and increased the expression of CD11b/CD18 on PMNs. Recombinant KC also induced a respiratory burst (quantitated by flow cytometry) in rat PMNs, similar to that caused by its human structural homologue, gro/melanoma growth-stimulating activity, on human PMNs, but less than that caused by IL-8 on human PMNs. Intratracheal instillation of rKC induced dose-dependent PMN influx into airspaces (average PMNs in bronchoalveolar lavage: vehicle = 1.5%, n = 4; rKC (1 microgram) = 11.5%, n = 2; rKC (10 micrograms) = 77.3%, n = 2). A neutralizing anti-KC Ab reduced the chemotactic activity of rat bronchoalveolar lavage fluid collected after the intratracheal administration of LPS (48.3 +/- 8% of control, n = 4). Anti-KC neutralizing Ab markedly inhibited PMN accumulation (71 +/- 6%) within the lungs in response to an intratracheal challenge of LPS. We conclude that rat KC is a major but not exclusive mediator of PMN activation and recruitment during LPS-induced pulmonary inflammation.
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PMID:Functional characterization of the rat chemokine KC and its importance in neutrophil recruitment in a rat model of pulmonary inflammation. 799 53

IFN-gamma and LPS have both been shown to stimulate enhanced chemoattractant cytokine gene expression in mononuclear phagocytes. In this report, IFN-gamma was found to suppress LPS-induced chemokine mRNA expression in a cell type- and gene-specific fashion. Expression of JE (monocyte chemoattractant protein-1) and KC (GRO/melanoma growth-stimulating activity) mRNA in macrophages stimulated with LPS was markedly suppressed by IFN-gamma in a dose- and time-dependent fashion. LPS-induced IP-10 mRNA was unaffected by IFN-gamma under identical experimental conditions. This effect was cell type-specific because JE and KC mRNA expression in LPS-stimulated murine endothelial cells, TNF-alpha-stimulated endothelial cells, and NIH-3T3 cells were unaffected by IFN-gamma. The IFN-gamma-mediated suppression of LPS-stimulated KC mRNA expression was independent of protein synthesis and mediated at the transcriptional level. These observations indicate that IFN-gamma may function as a negative regulatory signal for the expression of some proinflammatory cytokines in macrophages. The cell type-dependent differential behavior of individual members of the chemokine family may be an important determinant of the cellular composition and outcome of an inflammatory response.
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PMID:IFN-gamma selectively inhibits lipopolysaccharide-inducible JE/monocyte chemoattractant protein-1 and KC/GRO/melanoma growth-stimulating activity gene expression in mouse peritoneal macrophages. 805 20

The solution structure of melanoma growth stimulating activity (MGSA), a dimeric chemokine consisting of 73 residues per monomer, has been determined using two-dimensional homonuclear and three-dimensional heteronuclear NMR spectroscopy. Structure calculations were carried out using a hybrid distance geometry-simulated annealing approach with the programs DGII and X-PLOR. The structure is based on a total of 2362 experimental restraints, comprising 2150 NOE-derived distance restraints (2076 unambiguous intrasubunit restraints, 60 unambiguous intersubunit restraints, and 14 ambiguous restraints with potential contributions from both intra- and intersubunit NOEs), 84 distance restraints for 42 backbone hydrogen bonds, and 128 torsion angle restraints. The ambiguous distance restraints were treated using a target function which accounts for both intra- and intermolecular contributions to the NOE intensity. A total of 25 structures were calculated, with the backbone (N, C alpha, C) atomic r.m.s. distribution about the mean coordinates for residues 8 to 69 being 0.44(+/- 0.10) A for the dimer and 0.34(+/- 0.07) A for the individual monomers. The N- and C-terminal residues (1 to 7 and 70 to 73, respectively) are disordered. The overall structure of the MGSA dimer is similar to that reported previously for the NMR and X-ray structures of interleukin-8 (IL-8), and consists of a six-stranded antiparallel beta-sheet packed against two C-terminal antiparallel alpha-helices. A best fit superposition of the NMR structure of MGSA on the X-ray and NMR structures of IL-8 yields backbone atomic r.m.s. differences of 0.99 and 1.28 A, respectively for individual monomers, and 1.08 and 1.82 A, respectively for the dimers (using MGSA residues 8 to 14 and 19 to 69). In general, the MGSA structure resembles the IL-8 X-ray structure more than it does the IL-8 NMR structure. At the tertiary (monomer) level the two main differences between the MGSA solution structure and IL-8 NMR structure involve the loops between residues 14 to 19 and between residues 30 to 38. At the quaternary (dimer) level the difference results from differing angles between the beta-strands which form the dimer interface, and is manifest as a different interhelical separation (distance of closest approach between the two helices is 15.3 A in the IL-8 NMR structure and 11.7 (+/- 0.4) A in the MGSA structure).
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PMID:The solution structure of melanoma growth stimulating activity. 808 46

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