UNIPROT:P04141 - FACTA Search

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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Colony-stimulating factor (CSF-1) purified from L-cell-conditioned medium is a haemopoietic growth factor that specifically stimulates the proliferation and differentiation of mononuclear phagocytes. Using radioactively labelled CSF-1 [( 125I]CSF-1), the presence of specific CSF-1 receptor has been identified in the cells of the mononuclear phagocytic series and their precursors only. To determine the fate of [125I]CSF-1 bound to peritoneal exudate macrophages (PEM) at 37 degrees C, we have examined the distribution of radioactivity as a function of time by quantitative electron microscopic autoradiography. At 0 degrees C, we have localized the initial step in the binding of [125I]CSF-1 to the plasma membrane and its invaginations of the mouse PEM. Approximately 16% of the macrophages were not labelled at this time point. When the temperature was raised to 37 degrees C, the labelled CSF-1 was internalized progressively by the cells in a time-dependent fashion. The proportion of grains associated with the phagolysosome compartment increased progressively, reaching a plateau by 40 min after warming up, while the relative areas of the surface membrane and its invaginations decreased in invaginated membrane. At 37 degrees C, incubation with unlabelled CSF-1 resulted in a "down-regulation' of the subsequent [125I]CSF-1-binding activity by PEM in a time- and dose-dependent fashion. The restoration of CSF-1-binding activity after CSF-1 induced down-regulation was inhibited by cycloheximide, a potent protein synthesis inhibitor. These data provide direct evidence that at 37 degrees C, saturable binding of CSF-1 to PEM is followed by internalization and cellular degradation of the ligand and possibly its receptor by phagolysosomes.
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PMID:Receptor-mediated binding and internalization of colony-stimulating factor (CSF-1) by mouse peritoneal exudate macrophages. 609 1

In this study we have examined the expression and modulation of the human granulocyte colony-stimulating factor (G-CSF) receptor (R) in immature and differentiated myeloid cells using a 125I labelled human G-CSF analogue (TG50). Equilibrium binding data revealed a single affinity class of receptor on all cell types expressing G-CSFR (KD 235-606 pM) with neutrophils expressing 2883 +/- 672 Rs/cell. Rapid internalization of surface receptor-bound ligand at 37 degrees C was detected in both immature cells (U937) and neutrophils with > 70% of specifically bound ligand internalized within 5 min. Concentration-response data showed that the level of occupancy of neutrophil G-CSFRs by ligand at 37 degrees C was approximately 5-fold greater than predicted by equilibrium binding data and correlated closely with concentration-response data for biological activity. Re-expression of G-CSFRs following down-regulation by internalization was not detected. Down-regulation of the neutrophil G-CSFR by several agents including granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor (TNF), lipopolysaccharide (LPS), f-met-leu-phe (fMLP), phorbol ester (TPA) and C5a was observed at 37 degrees C but not at 4 degrees C. In contrast, G-CSFRs on immature myeloid cells were significantly down-regulated by TPA only. Differentiation of myeloid leukaemic cell line HL-60 with DMSO, a frequently used model of granulocytic differentiation, was associated with a significant reduction in G-CSFR expression (11 +/- 5% of control) whereas treatment with retinoic acid led to increased G-CSFR expression (161 +/- 3%).
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PMID:Expression and dynamic modulation of the human granulocyte colony-stimulating factor receptor in immature and differentiated myeloid cells. 750 64

Development of small molecular mimics of larger polypeptide ligands is an important approach to pharmacophore design. One strategy for the development of such mimics is analysis of alternative ligands that bind to the same site as the native ligand. These allow examination of the structural and chemical constraints for binding within the setting of diverse backbone geometries. The use of antireceptor antibodies as alternative ligands has allowed the development of biologically active peptides in several ligand-receptor systems. This technology has been applied to the study of interactions between human granulocyte-macrophage colony-stimulating factor (GM-CSF) and its receptor (GM-CSFR). GM-CSF is one of a family of signal-transducing cytokines and growth factors characterized by a four-helix bundle core structure. The GM-CSFR is comprised of an alpha-chain (GM-CSFR alpha) specific for GM-CSF, and a beta-chain (beta c) shared with the interleukin-3 and interleukin-5 receptors. At least two sites on GM-CSF have been implicated in the GM-CSF-GM-CSFR alpha/beta c ternary complex. In studies summarized here, synthetic peptide analogs of GM-CSF sequences were designed and used to map neutralizing epitopes. One neutralizing epitope corresponded to the A helix of GM-CSF, and a synthetic analog displayed biological activity as a GM-CSF antagonist in vitro, suggesting interaction with the GM-CSFR alpha/beta c complex. A second peptide comprising the B and C helices was recognized by monoclonal neutralizing antibodies and similarly displayed antagonist activity. Recombinant antibody (rAb) technology was also employed. An expression library of rAbs from mice immunized with neutralizing anti-GM-CSF antibodies was developed and screened with a neutralizing anti-GM-CSF monoclonal antibody. One clone which displayed receptor binding activity exhibited structural similarity with epitopes on GM-CSF previously implicated as interaction sites with the neutralizing monoclonal antibody. A synthetic peptide analog of the rAb inhibited GM-CSF bioactivity. Critical contact residues were predicted on the basis of structural similarity of the rAb peptide and GM-CSF. These studies indicate the feasibility of using rAbs in bioactive peptide design, providing lead compounds and information regarding contact residues for drug design.
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PMID:Granulocyte-macrophage colony-stimulating factor mimicry and receptor interactions. 753 25

The present study was designed to reexamine the interaction of granulocyte-macrophage colony-stimulating factor (GM-CSF) with endothelial cells (EC) and to investigate the expression of CSF receptor chains in these cells. In agreement with previous data, GM-CSF induced directional migration and, to a lesser degree, proliferation of human umbilical vein EC. When compared to basic fibroblast growth factor, GM-CSF was comparable in terms of chemotactic activity and was substantially less active in terms of proliferation. Binding studies confirmed the presence of receptors for GM-CSF (GM-CSFR) on EC. The expression of the beta chain common to the GM-CSFR, IL-3 receptor, and IL-5 receptor, as well as of the individual alpha chains, was studied by Northern analysis and/or reverse transcription and polymerase chain reaction. EC expressed high levels of the common beta chain transcripts. Expression of the alpha(GM) and alpha(IL-5) chain mRNA was minimal or absent in normal EC, though the transformed ECV304 endothelial cell line had substantial amounts of alpha(GM) chain mRNA. Unexpectedly, EC expressed alpha(IL-3) chain transcripts. IL-3 induced migration of EC across polycarbonate filters, whereas IL-5 was inactive.
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PMID:Differential expression of the common beta and specific alpha chains of the receptors for GM-CSF, IL-3, and IL-5 in endothelial cells. 768 96

Inflammatory bowel disease (IBD) is characterized by T-cell activation and mucosal influx of inflammatory cells partly mediated by increased local release of cytokines and chemokines. Increased levels of activated platelets are reported in IBD. Activated platelets induce endothelial cells in vitro to secrete several cytokines and growth factors and to express adhesion molecules. This study investigates the expression of interleukin-1 (IL-1), IL-8 and granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors on circulating platelets from patients with IBD and healthy controls and assesses the in vitro effect of various concentrations of IL-1 beta, IL-8 and GM-CSF on platelet activation in healthy controls. Flow cytometry was performed to quantify the percentage of platelets binding phycoerythrin (PE) labeled recombinant human IL-1 beta, IL-8 and GM-CSF. Platelet activation was assessed using fluorochrome labeled anti-GMP-140, an activation-dependent antigen. Results are expressed as percentage cytokine receptor expressing platelets (median and interquartile range IQR). Platelets from patients with IBD expressed significantly more cytokine receptors compared to healthy controls: IL-1R [8.7% (5.5-18.2) vs 3.1% (2.4-4.8), p < 0.05], IL-8R [22.5% (18.1-27.9) vs 8% (4.5-9.2), p < 0.001)], GM-CSFR [25.9% (16.1-39.2) vs 3.9% (2.7-3.9), p < 0.001]. The percentage of activated platelets was significantly increased after in vitro stimulation with IL-1 beta, IL-8 and GM-CSF. We conclude that cytokines and chemokines modulate platelet activation through specific, functional receptors which are upregulated in IBD.
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PMID:[Thrombocytes express functional cytokine receptors in patients with Crohn disease and ulcerative colitis]. 776 8

The multipotent hematopoietic precursor line A4GMV#2, derived by infection of FDCP-mix cells with a retroviral vector expressing the granulocyte-macrophage colony-stimulating factor (CSF) gene, proliferates continuously in interleukin 3 and presents the unique advantage of synchronous granulocyte and macrophage differentiation upon interleukin 3 withdrawal. Using this system, we showed previously that the mRNAs for lineage-specific receptors (granulocyte-CSF receptors, CSF-1 receptors, and Erythropoietin receptors) and ligands (granulocyte-CSF and CSF-1) are up-regulated during myeloid maturation. Here we address the specific question of the regulation of the expression of CSF-1 and its receptor and of their relevance to macrophage differentiation. Both genes were transcribed with equal efficiency in undifferentiated and differentiating cells. CSF-1 mRNA was detected in undifferentiated cells and increased slightly in the early phases of differentiation. CSF-1 receptor mRNA, absent in undifferentiated cells, accumulated early in differentiation (24 h) and remained constant thereafter. The production of both proteins, detected later during the differentiation of A4GMV#2 cells and of bone marrow-derived myeloid precursors, was therefore controlled at the posttranscriptional level. CSF-1 was produced by cells of the macrophage lineage and accumulated in mature phagocytes. A neutralizing anti-CSF-1 serum selectively impaired macrophage differentiation of A4GMV#2 cells and, most significantly, of primary myeloid precursors. These data indicate that CSF-1 and its receptor interact productively during differentiation and that the resulting autocrine stimulation selectively promotes macrophage maturation.
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PMID:Coordinate expression of the lineage-specific growth factor colony-stimulating factor (CSF)-1 and its receptor selectively promotes macrophage maturation during differentiation of multipotential progenitor cells. 784 13

A superfamily of growth factor and cytokine receptors has recently been identified, which is characterized by four spatially conserved cysteine residues and a tryptophan-serine motif (WSXWS) in the extracellular domain and proline-rich cytoplasmic domain. The high-affinity human granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor, hGM-CSFR, consists of two subunits, alpha (hGM-CSFR alpha), which is required for ligand binding, and beta (hGM-CSFR beta), which is required for signal transduction. Both the alpha and beta subunits are members of the cytokine receptor superfamily. In this study, we analyzed mutations in the conserved amino acids of the alpha subunit to determine their function in signal transduction, as assayed by tyrosine phosphorylation and proliferation. Disruption of either of the conserved disulfide bonds in the extracellular domain abolishes low-affinity binding but not binding to a preformed heterodimeric complex with the beta-chain. Cells expressing receptors with mutations in cysteines 2 or 3 grew as well as cells expressing wild-type receptors in human GM-CSF (hGM-CSF) and phosphorylated the same proteins on tyrosine residues, although the level of phosphorylation may be attenuated; cysteine 3 appears to be required for generation of the true high-affinity binding site. The WSXWS motif and the cytoplasmic domain are required for function of the human GM-CSF receptor, as stable cell lines expressing receptors with these mutations were unable to proliferate continuously in hGM-CSF. Surprisingly, no function for the conserved proline-rich region of the cytoplasmic domain could be ascertained from these studies; cells expressing these receptors were indistinguishable from wild-type in both binding and functional assays.
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PMID:Conserved amino acids in the human granulocyte-macrophage colony-stimulating factor receptor-binding subunit essential for tyrosine phosphorylation and proliferation. 789 25

Acute myelogenous leukemia (AML) cells express CD23 surface antigen after in vitro treatment with various cytokines, including interleukin-4 (IL-4) and interferon gamma. Subsequent ligation of CD23 by specific monoclonal antibody (MoAb) induces substantial morphologic and functional modifications in these cells. In the present study, we investigated the role of CD23 in the proliferation and the maturation of leukemic cells from AML patients or the U937 cell line. CD23+ cell treatment with CD23 MoAb inhibited the proliferation of leukemic cells. This correlated with their terminal differentiation after 7 to 9 days incubation because they (1) definitively lost their growth capacity; (2) adhered to culture flasks and became monocyte/macrophage-like; and (3) expressed mature monocyte markers including nonspecific esterases. Intracellular mechanism of this antitumoral effect was then analyzed in U937 cells. Induction of high-density surface CD23 expression by IL-4 or granulocyte-macrophage colony-stimulating factor coincided with a transient decrease of U937 cell proliferation. CD23 ligation during this low-proliferative phase induced a rapid activation of L-arginine-dependent pathway and the intracellular accumulation of cyclic guanosine monophosphate and cyclic adenosine monophosphate (cAMP). Induction of these early messengers was followed by the activation of nuclear factor-kB transcription factor and the modulation of proto-oncogene expression by U937 cells. Whereas U937 cell treatment with IL-4 decreased c-fos/c-jun expression, CD23 MoAb reinduced c-fos/c-jun and promoted the expression of cell maturation-associated proto-oncogenes junB and c-fms, during the first 24 hours. Both IL-4 and CD23 MoAb downregulated the expression of c-myb. CD23 ligation also induced the production of TNF alpha by U937 cells. Inhibitors of cAMP and nitric oxide reversed CD23-mediated modification in U937 cells. These data evidence the ability of CD23 surface antigen to mediate terminal differentiation of early leukemic myelomonocytic cells.
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PMID:Growth arrest and terminal differentiation of leukemic myelomonocytic cells induced through ligation of surface CD23 antigen. 794 82

Colony-stimulating factor-1 (CSF-1) is a cytokine required for proliferation, differentiation, activity, and survival of cells of the mononuclear phagocytic system. The growth factor is synthesized as a soluble, matrix, or membrane associated molecule. The specific functions of these forms are not clear. However, some data suggest a dependence of the development of various populations of tissue macrophages on the locally expressed and presented cytokine. Deficiency in CSF-1, as is the case in the murine mutant strain op/op, results in low numbers of macrophages and monocytes and, most striking, leads to osteopetrosis due to a virtual absence of osteoclasts. Using the op/op mutation as a model, CSF-1 was established as one of the growth factors for osteoclasts. The expression of CSF-1 receptors, encoded by the proto-oncogene c-fms, by osteoclast precursors and osteoclasts, suggested an effect of this cytokine not only during osteoclast formation but also on the mature cells. In fact, CSF-1 was shown to inhibit the resorbing activity, to stimulate migration, and to support survival of isolated osteoclasts in vitro. By these actions on cells of the osteoclast lineage, CSF-1 induces recruitment of new osteoclasts, leading to a net increase of bone resorption, and might govern the spatial distribution of resorption sites within the bone. During these processes, locally expressed and presented forms of the growth factor may play a crucial role, as will be discussed in this article.
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PMID:Role of colony-stimulating factor-1 in bone metabolism. 796 66

A full length clone of murine fms-like tyrosine kinase 3 [flt3, also known as fetal liver kinase 2 (flk2)] was constructed from sequences obtained from a brain complementary DNA (cDNA) library and from cDNA prepared from the cell line Tikaut. In the absence of a ligand to study the function of Flt3, a chimeric molecule was constructed comprising the extracellular domain of murine c-Fms and the transmembrane and cytoplasmic domains of Flt3. A plasmid encoding the chimeric receptor was cotransfected along with a plasmid conferring neomycin resistance into FDC-P1 cells that do not normally express c-fms or flt3 and require granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin 3 for growth. Two types of clones were obtained following selection in GM-CSF and G418. Two of seven clones had the capacity for M-CSF-dependent colony formation in semisolid medium, indicating that the cytoplasmic domain of Flt3 can transduce a proliferative signal. From the remaining clones, M-CSF-dependent clonogenic cells could be selected by prior bulk liquid culture in M-CSF. It has been shown previously that the GM-CSF-dependent proliferative capacity is strongly inhibited by M-CSF in FDC-P1 cells engineered to express full length c-fms. This phenomenon was also observed with FD/fms-flt3 cells that were clonogenic in M-CSF. Stimulation of FD/fms or FD/fms-flt3 cells in liquid culture by M-CSF caused differentiation of a small proportion of cells along the myelomonocytic pathway which was enhanced by the combination of M-CSF and GM-CSF.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Fms-like tyrosine kinase 3 catalytic domain can transduce a proliferative signal in FDC-P1 cells that is qualitatively similar to the signal delivered by c-Fms. 804 61

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