Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human malarial parasite Plasmodium vivax invades erythrocytes by binding to a cell surface protein identified as the Duffy blood group antigen. The molecular properties of the Duffy antigen, which was recently cloned, are very similar to those of a chemokine binding protein known as the human erythrocyte chemokine receptor. This has led to the suggestion that these two molecules are the same protein. To further investigate the suspected double identity of the Duffy antigen we have transfected it into a human erythroleukemic cell line, K562. Cells stably expressing the Duffy antigen were isolated and used to characterize the protein. K562 cells transfected with the Duffy antigen displayed specific 125I-melanoma growth-stimulating activity (MGSA) binding while mock transfected cells did not. Comparison of 125I-MGSA binding to the Duffy antigen and the human erythrocyte chemokine receptor showed that the specific 125I-MGSA binding to both proteins was displaced by excess unlabeled MGSA, interleukin-8, RANTES, monocyte chemotactic peptide-1, and platelet factor 4, but not by macrophage inflammatory protein-1 alpha or -1 beta. Scatchard analysis of competition binding studies with these unlabeled chemokines revealed high affinity binding to the Duffy antigen with KD binding values of 24 +/- 4.9, 20 +/- 4.7, 41.9 +/- 12.8, and 33.9 +/- 7 nM for MGSA, interleukin-8, RANTES, and monocyte chemotactic peptide-1, respectively. A monoclonal antibody, Fy6, to the Duffy antigen inhibited 125I-MGSA binding to K562 cells expressing the Duffy antigen. Cell membranes from K562 cells permanently expressing the Duffy antigen were chemically cross-linked with 125I-MGSA. SDS-polyacrylamide gel electrophoresis analysis of the cross-linked products showed covalent incorporation of radiolabeled MGSA into a protein of molecular mass 47 kDa, and cross-linking was inhibited in the presence of unlabeled MGSA. These studies provide evidence that the Duffy blood group antigen is the same protein as the human erythrocyte chemokine receptor.
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PMID:Expression of the Duffy antigen in K562 cells. Evidence that it is the human erythrocyte chemokine receptor. 813 97

Monocyte chemotactic and activating factor (MCAF) is an important mediator of monocyte recruitment to sites of chronic inflammation and neoplasia. In the present study, we determined whether MCAF can also enhance the activation of tumoricidal capacity of monocytes. Human monocytes incubated with MCAF and subthreshold concentrations of lipopolysaccharide (LPS) exhibited synergistic tumoricidal activity against allogeneic A375 melanoma cells, irrespective of their metastatic potential. The sequence of MCAF and LPS treatment was crucial. Monocytes treated first with MCAF for 4 h and then with LPS for 18 h were highly cytotoxic to the melanoma cells, whereas monocytes first treated with LPS and then with MCAF were not. Treatment of monocytes with MCAF and LPS also significantly increased production of tumor necrosis factor. These data suggest that like interferon-gamma, MCAF can prime human monocytes to respond to LPS. Interleukin-8, a chemokine for neutrophils, did not enhance the monocytes' LPS-triggered tumoricidal response. Collectively, these data show that MCAF can influence the recruitment and tumoricidal activation of blood monocytes. Therefore, MCAF may be an important mediator of tumor regression.
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PMID:Synergism between human recombinant monocyte chemotactic and activating factor and lipopolysaccharide for activation of antitumor properties in human blood monocytes. 826 May 37

The solution structure of melanoma growth stimulating activity (MGSA) has been investigated using proton NMR spectroscopy. Sequential resonance assignments have been carried out, and elements of secondary structure have been identified on the basis of NOE, coupling constant, chemical shift, and amide proton exchange data. Long-range NOEs have established that MGSA is a dimer in solution. The secondary structure and dimer interface of MGSA appear to be similar to those found previously for the homologous chemokine interleukin-8 [Clore et al. (1990) Biochemistry 29, 1689-1696]. The MGSA monomer contains a three stranded anti-parallel beta-sheet arranged in a 'Greek-key' conformation, and a C-terminal alpha-helix (residues 58-69).
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PMID:1H assignment and secondary structure determination of human melanoma growth stimulating activity (MGSA) by NMR spectroscopy. 839 4

Macrophage inflammatory protein (MIP)-2, MIP-1 alpha, and MIP-1 beta all belong to the newly recognized "chemokine" superfamily of structurally related, activation-inducible cytokines with inflammatory and growth regulatory activities. We report the isolation and sequencing of genomic clones for murine MIP-2 and murine MIP-1 beta, and analyze their regulatory sequences in comparison with each other and with several other members of the chemokine family. The murine (mu)MIP-2 genomic clone displays the canonical four exon/three intron structure typical of other genes in the chemokine alpha subfamily (e.g., IL-8). Potential cis regulatory elements in the proximal promoter region were highly conserved between muMIP-2 and its three most closely related human homologs: human (hu)GRO-alpha, huGRO-beta, and huGRO-gamma. A mouse macrophage cell line, RAW 264.7, was transfected with a growth hormone reporter construct driven by a proximal fragment of the muMIP-2 5' promoter, and nested deletion mutant analysis localized the LPS responsive element to a region that contains a conserved NF kappa B consensus motif and lies 51 to 70 bp 5' from the transcription start site. In contrast to that of MIP-2, the muMIP-1 beta genomic clone exhibited the three exon/two intron structure characteristic of the chemokine beta family members (e.g., MCP-1). A comparison of the promoters for muMIP-1 beta and muMIP-1 alpha reveals a conserved CK-1 element, but transient expression studies in RAW 264.7 macrophages with proximal fragments of either the muMIP-1 beta or the muMIP-1 alpha 5' promoter fused to a human growth hormone reporter gene link LPS-inducibility in both to promoter segments near to, but not identical with, the consensus CK-1 sequence. Proximal 5' promoter fragments cloned from both the MIP-1 alpha and MIP-1 beta genes unexpectedly conferred constitutive expression on the fused reporter gene sequences in macrophage-like cells, but initial 5' deletion analysis did not link this responsiveness to known sequence motifs. The muMIP-1 beta promoter, but not the muMIP-1 alpha promoter, was constitutively active in B16 mouse melanoma cells, and both promoters were active in the myelomonocytic cell line WEHI 3B(A)d-, the muMIP-1 alpha promoter being three times stronger.
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PMID:Genomic cloning and promoter analysis of macrophage inflammatory protein (MIP)-2, MIP-1 alpha, and MIP-1 beta, members of the chemokine superfamily of proinflammatory cytokines. 849 1

Melanoma growth stimulatory activity (MGSA)/growth regulated (GRO) and interleukin-8 (IL-8) are highly related chemokines that have a causal role in melanoma progression. Expression of these chemokines is similar in that both require the NF-kappa B element and additional regions such as the CAAT/enhancer binding protein (C/EBP) element of the IL-8 promoter. The constitutive and cytokine IL-1-induced promoter activity of the chemokine MGSA/GRO alpha in normal retinal pigment epithelial and the Hs294T melanoma cells is partially regulated through the NF-kappa B element, which binds both NF-kappa B p50 and RelA (NF-kappa B p65) homodimers and heterodimers. Mutational analysis of the MGSA/GRO alpha promoter reveals that, in addition to the NF-kappa B element, the immediate upstream region (IUR) is necessary for basal expression in retinal pigment epithelial and Hs294T cells. Gel mobility shift and UV cross-linking analyses demonstrate that several constitutive DNA binding proteins interact with the IUR. Although this region has sequence similarity to the several transcription factor elements including C/EBP, the IUR includes sequences that have no similarity to previously identified enhancer regions. Furthermore, RelA transactivates through either the NF-kappa B element or the IUR, suggesting a putative interaction between NF-kappa B and this novel complex.
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PMID:Constitutive and cytokine-induced expression of the melanoma growth stimulatory activity/GRO alpha gene requires both NF-kappa B and novel constitutive factors. 853 Apr 98

The chemokine GRO alpha is an autocrine growth factor for melanoma cells. Although GRO alpha has been identified as a high affinity ligand for the IL-8 receptor beta (IL-8R beta) in recombinant systems, the receptor mediating its action in melanoma cells has been a matter of debate. Here, we show by reverse transcription and PCR expression of IL-8R beta, mRNA transcripts in different melanoma cell lines and in normal human melanocytes. To characterize the role of the IL-8R beta in melanoma cells, antiserum was raised in rabbits against a fusion protein containing the NH2-terminal portion of the receptor. Its specificity was shown by flow cytometry with IL-8R beta-transfected HL60 cells. A specific epitope could be mapped with IL-8R beta mutants to the peptide sequence between ASP-4 and ASP-14 of this receptor. Binding studies with [125I]GRO alpha in IL-8R beta transfectants indicated ligand antagonistic properties of this Ab. Expression of IL-8R beta protein at the cell surface of various melanoma cell lines could be shown by flow cytometry with F(ab')2 fragments of the IL-8R beta antiserum. Moreover, anti-IL-8R beta Ab partially blocked specific binding of [125I]GRO alpha in various melanoma cell lines. Addition of F(ab')2 fragments of the IL-8R beta antiserum or of neutralizing anti-GRO alpha mAb to different melanoma cell lines identified this GRO alpha-IL-8R beta interaction as a major component required for serum-independent melanoma cell growth.
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PMID:Expression and growth-promoting function of the IL-8 receptor beta in human melanoma cells. 855 89

To investigate which members of the recently discovered family of chemotactic cytokines (chemokines) are important in leukocyte recruitment to a bacterial inflammation site, four different chemokines in the effluent of peritoneal dialysis patients suffering from acute bacterial peritonitis were measured. The presence of two neutrophil-attracting chemokines, interleukin-8 and human melanoma growth-stimulating activity (huGRO alpha), and two monocyte-attracting members of the chemokine superfamily, monocyte chemotactic protein-1 (MCP-1) and regulated on activation normal T cell expressed and secreted (RANTES), was investigated in patient effluents just before, during, and after a peritonitis episode. This was studied in seven peritonitis effluents of five patients by using chemokine-specific enzyme-linked immunosorbent assays. Cell populations in the dialysates were differentiated on cytocentrifuge preparations. The contribution of the detected chemokines to neutrophilic and monocytic cell influxes in the inflamed peritoneal cavity was analyzed by correlating concentrations of chemokines to the relevant cell numbers present in the dialysates of these patients. The detection of the neutrophil-attracting chemokine interleukin-8 during peritonitis was in accordance with other studies. Moreover, a second neutrophil chemoattractant, huGRO alpha, was identified in vivo. Both were elevated during inflammation (P < 0.02) and contributed significantly to the neutrophilic cell influx (P < 0.05). One of the monocyte-attracting chemokines, RANTES, could not be detected in any of the effluents, whereas the other, MCP-1, was significantly elevated during peritonitis (P < 0.02). In contrast to the other chemokines measured, MCP-1 concentration was relatively high in steady-state peritoneal dialysates. An absolute correlation between dialysate MCP-1 concentration and the number of macrophages in these effluents was absent. However, in a 48-well chemotaxis assay, monocyte migration toward peritonitis, as well as steady-state patient dialysates, could be blocked with antibodies to MCP-1. It was concluded, therefore, that MCP-1 is the most important monocyte chemoattractant in peritoneal dialysis steady-state and peritonitis patients; whereas, besides interleukin-8, huGRO alpha was identified as a major neutrophil-attracting chemokine in the peritonitis situation.
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PMID:Identification of the major chemokines that regulate cell influxes in peritoneal dialysis patients. 895 28

IL-8 is expressed by activated and neoplastic astrocytes and enhances the survival of hippocampal neurons in vitro. Since mRNA encoding chemokine receptors have been demonstrated in brain, the expression of chemokine receptors by specific cell types in anatomic regions of the central nervous system (CNS) was investigated. Archival tissues from various regions of the CNS were stained with specific mAbs to the Duffy Ag/receptor for chemokines, a promiscuous receptor that binds selected chemokines; the specific receptor for IL-8 (CXCR1); and the receptor (CXCR2) shared by IL-8 and melanoma growth stimulatory activity. The Duffy Ag/receptor for chemokines was expressed exclusively by Purkinje cells in the cerebellum. Chemokine binding and radioligand cross-linking confirmed the presence of a high affinity, promiscuous chemokine receptor in the cerebellum. Although CXCR1 was not expressed in the CNS, CXCR2 was expressed at high levels by subsets of projection neurons in diverse regions of the brain and spinal cord, including the hippocampus, dentate nucleus, pontine nuclei, locus coeruleus, and paraventricular nucleus, and in the anterior horn, interomediolateral cell column, and Clarke's column of the spinal cord. Fibers that express CXCR2 included those in the superior cerebellar peduncle and the substantia gelatinosa. Immunohistochemical analysis of the involved brain tissues from patients with Alzheimer's disease revealed expression of CXCR2 in the neuritic portion of plaques surrounding deposits of amyloid. These data suggest that chemokines may play a role in reactive processes in normal neuronal function and neurodegenerative disorders.
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PMID:Expression of chemokine receptors by subsets of neurons in the central nervous system. 905 25

Melanoma growth stimulatory activity (MGSA/GROalpha) is a 73 amino acid peptide sharing sequence characteristics with the alpha-chemokine superfamily. MGSA/GROalpha is produced by diverse melanoma cell lines and reported to act as an autocrine growth factor for the cells. We tested the binding of MGSA/GROalpha to melanoma cell lines, Hs 294T and RPMI7951, and found that these cells could bind to MGSA/GROalpha but not to interleukin-8. Recently, we defined a novel hexapeptide, antileukinate, which is a potent inhibitor of binding of alpha-chemokines to their receptors on neutrophils. When antileukinate was added to melanoma cells, it inhibited the binding of MGSA/ GROalpha. The growth of cells from both melanoma cell lines was suppressed completely in the presence of 100 microM peptide. The cell growth inhibition was reversed by the removal of the peptide from the culture media or by the addition of the excess amount of MGSA/GROalpha. The viability of Hs 294T cells in the presence of 100 microM peptide was > 92%. These findings suggest that MGSA/GROalpha is an essential autostimulatory growth factor for melanoma cells and antileukinate inhibits their growth by preventing MGSA/GROalpha from binding to its receptors.
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PMID:A synthetic peptide inhibitor for alpha-chemokines inhibits the growth of melanoma cell lines. 916 87

The expression of the CXC chemokine MGSA is often deregulated during viral infection, chronic inflammation, and melanoma tumor progression. In Hs294T melanoma cells, the increased constitutive expression of MGSA is due to increased gene transcription. Moreover, nuclear extracts from unstimulated Hs294T cells contain 19-fold more immunoreactive NF-kappaB p65 than that observed in normal retinal pigment epithelial (ARPE) cells. This increase in NF-kappaB p65 correlates with increased NF-kappaB DNA binding activity in Hs294T nuclear extracts. After stimulation with interleukin 1, Western and electrophoretic mobility shift assay analysis indicate that in both cell types, additional activated NF-kappaB p65 is translocated to the nucleus. However, the rate of postinduction repression of NF-kappaB DNA binding is delayed in Hs294T melanoma cells compared to ARPE cells. Western analysis of whole-cell lysates from both Hs294T and ARPE cells indicates that protein levels of the inhibitor of NF-kappaB, I-kappaB alpha, are 3-fold lower in Hs294T cells. The decrease in I-kappaB alpha cannot be attributed to alterations in the transcription or translation of I-kappaB alpha. Rather, the posttranslational processing has been altered. In Hs294T cells, the half-life of the I-kappaB alpha protein is 45 min, compared to 120 min in ARPE cells. These results indicate that in Hs294T melanoma cells the equilibrium between I-kappaB alpha degradation and resynthesis has been altered, leading to constitutive nuclear translocation and activation of NF-kappaB. Similar mechanisms could also operate in other tumorigenic processes, as well as in viral and chronic inflammatory disorders, to produce high constitutive and unregulated chemokine expression.
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PMID:Enhanced degradation of I-kappaB alpha contributes to endogenous activation of NF-kappaB in Hs294T melanoma cells. 923 Feb 19


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