Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The alpha subunit of the receptor for human granulocyte-macrophage colony-stimulating factor (GM-CSF) is a glycoprotein containing 11 potential N-glycosylation sites in the extracellular domain. We examined the role of N-glycosylation on alpha subunit membrane localization and function. Tunicamycin, an N-glycosylation inhibitor, markedly inhibited GM-CSF binding, GM-CSF-induced deoxyglucose uptake, and protein tyrosine phosphorylation in HL-60(eos) cells but did not affect cell surface expression of the alpha subunit as detected by an anti-alpha subunit monoclonal antibody. In COS cells expressing the alpha subunit and treated with tunicamycin, N-unglycosylated alpha subunit was expressed and transported to the cell surface but was not capable of binding GM-CSF. High affinity binding in COS cells expressing both alpha and beta subunits was also blocked by tunicamycin treatment. These studies indicate that N-linked oligosaccharides are essential for alpha subunit ligand binding and signaling by the human GM-CSF receptor.
 ...
PMID:N-glycosylation of the human granulocyte-macrophage colony-stimulating factor receptor alpha subunit is essential for ligand binding and signal transduction. 759 77

Interleukin-3 (IL-3) regulates growth and differentiation of multipotential as well as lineage-committed progenitor cells. The human IL-3 receptor (IL-3R) consists of the alpha and common beta (beta c) subunits. The alpha subunit (IL-3R alpha) is specific for IL-3 and binds IL-3 with low affinity. In contrast, the beta c subunit does not bind any cytokine by itself, but forms a high-affinity receptor with IL-3R alpha. As the same beta c subunit also forms high-affinity receptors for IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) with the respective cytokine-specific alpha subunit, the expression of the alpha subunits is responsible for specificity of cytokines. To examine the expression of IL-3R alpha, we have developed a monoclonal antibody (MoAb), N3A. N3A specifically bound to cells expressing IL-3R alpha and immunoprecipitated a 75 Kd glycoprotein, which became 43 Kd on N-glycosidase digestion. N3A and an anti-beta c antibody, CRS1, were used in double color fluorescence-activated cell sorter (FACS) staining with several lineage markers to see the IL-3R expression pattern in peripheral blood (PB), cord blood (CB), and bone marrow (BM) cells. Both IL-3R subunits were expressed on myeloid cell lineages (CD13+, CD14+, CD15Lo, or CD33+). To further study the IL-3R expression on hematopoietic progenitor cells, the CD34+ populations were isolated from both BM and CB cells. Those populations showed positive staining profiles with the N3A MoAb and were weakly stained with the CRS1 MoAb. Furthermore, anti c-kit antibody staining of the CD34+ fraction from CB, but not from BM, showed two intensities and the IL-3R alpha expression seemed to be higher in a fraction of low c-kit expression. Because IL-1, IL-6, G-CSF, stem cell factor (SCF), interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha are known to enhance IL-3-dependent colony formation, we have examined whether this enhancement could be correlated with upregulation of the IL-3R expression. Incubation of CD34+ cells with TNF-alpha for 2 days significantly increased the level of beta c and G-CSF increased the number of cells with high level expression of alpha, while other factors did not affect the IL-3R expression. Thus, different cytokines appear to have different mechanisms for enhancement of IL-3-dependent proliferation.
 ...
PMID:Expression and factor-dependent modulation of the interleukin-3 receptor subunits on human hematopoietic cells. 768 90

A new culture and quantitation system has been established for growth of megakaryocyte-lineage cells from human progenitor cells. CD34+ progenitor cells were enriched from umbilical cord blood using an avidin-biotin immunoadsorption process. These cells were preincubated in bulk liquid culture for 3 to 4 days in the presence of the growth factors interleukin-3 (IL-3) and IL-6. The cells were then washed and seeded at 5000 cells/well in 96-well plates that contained a variety of test samples. The plates were incubated for 7 days, and the cells were then washed, transferred to ELISA plates, and fixed. Megakaryocyte growth was determined by an ELISA for the platelet glycoprotein (GP) IIb/IIIa, an abundant membrane protein found on cells committed to the megakaryocyte lineage. The growth factor IL-3 was found to produce a very strong signal in this assay. The addition of granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, stem cell factor (SCF), or leukemia inhibitory factor (LIF) to low levels of IL-3 also stimulated megakaryocyte growth, as measured by IIb/IIIa expression. Plasma from patients with aplastic anemia was also stimulatory in this assay, and showed marked synergy with IL-3. This progenitor cell culture system, due to its judicious use of progenitor cells and an automated, 96-well quantitation method, allows for screening large numbers of test samples and multiple combinations and concentrations of growth factors.
 ...
PMID:A new culture and quantitation system for megakaryocyte growth using cord blood CD34+ cells and the GPIIb/IIIa marker. 769 35

The human neutrophil lactoferrin (Lf), a cationic iron-binding glycoprotein, has an inhibitor role on granulocyte macrophage colony-stimulating factor (GM-CSF) production via interleukin-1 (IL-1). The nuclear localization of Lf suggests that it may be involved in the transcriptional regulation of GM-CSF gene expression. To explore this possibility, the effect of Lf on GM-CSF gene expression was investigated in various cell lines and in primary cultures of fibroblasts. Down-regulation of GM-CSF mRNA level was observed in Lf-transfected embryonic fibroblasts induced to produce GM-CSF by IL-1 beta. In 5637 cell-line and in embryonic fibroblasts, co-transfection experiments, in which an Lf expression vector was used together with a vector carrying a reporter gene linked to the GM-CSF promoter, revealed that Lf reduces the activity of the GM-CSF promoter. This effect is marked in IL-1 beta-stimulated cells. These findings suggest that Lf plays a negative role in GM-CSF expression at the transcriptional level, perhaps through the mediation of IL-1 beta.
 ...
PMID:Lactoferrin down-modulates the activity of the granulocyte macrophage colony-stimulating factor promoter in interleukin-1 beta-stimulated cells. 774 78

Human CD38 is a surface glycoprotein expressed by different immuno-competent cells such as immature and activated lymphocytes, plasma cells and natural killer cells. It has recently been reported that the CD38 molecule exerts adenosine diphosphate ribosyl cyclase activity and is associated with distinct transmembrane signaling molecules. This study reports that ligation of CD38 by specific monoclonal antibodies (mAb) induces multiple cytokine mRNA expression in cultured peripheral blood mononuclear cells (PBMC). The mRNA for tumor necrosis factor-alpha, interleukin (IL)-1 beta, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-12 were always detected, whereas interferon-gamma and IL-10 mRNA expression were seen in most, but not all PBMC cultures. Low levels of IL-2, IL-4 and IL-5 mRNA were also found. The key observation of this work is that CD38 ligation in PBMC induces a large spectrum of cytokines, many of which overlap with those induced via CD3 activation. The main differences between CD38 and CD3 activation are the low to undetectable levels of IL-2 mRNA, and the sustained IL-1 beta and IL-6 mRNA accumulation found in PBMC cultures following treatment with anti-CD38 mAb. Furthermore, PBMC proliferation was not found to be a prerequisite for CD38-mediated cytokine induction. Together, these results suggest that human CD38 activates a signaling pathway which leads to the induction of a discrete array of cytokines, and that this pathway only partially overlaps with that controlled by T cell receptor CD3.
 ...
PMID:CD38 ligation induces discrete cytokine mRNA expression in human cultured lymphocytes. 777 53

Inoculation of plasmid vectors encoding a viral protein into muscle tissue was shown to result in expression of the transantigen and, consequently, an antiviral immune response. Here, we show that coinoculation of a plasmid expressing the glycoprotein of rabies virus with plasmids encoding mouse cytokines modulated the immune response to the viral protein. Coinoculation with a vector expressing mouse granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced the B and T helper cell activity to rabies virus, while coinoculation with a plasmid expressing interferon-gamma (IFN gamma) resulted in a decrease of the immune response to the viral antigen.
 ...
PMID:Manipulation of the immune response to a plasmid-encoded viral antigen by coinoculation with plasmids expressing cytokines. 789 69

Resolution of inflammation involves removal of recruited neutrophils from inflamed sites via a noninflammatory mechanism, possibly involving neutrophil apoptosis and engulfment/phagocytosis by macrophages. In this study, we describe the reduction in surface expression (> 90%) of the neutrophil molecule Fc gamma RIII (CD16) during in vitro culture at 37 degrees C, which was found to be temporally associated with the appearance of neutrophils with apoptotic morphology during in vitro culture and inhibitable by granulocyte-macrophage colony-stimulating factor (GM-CSF), which postpones apoptosis in the neutrophil. By using dual fluorescence analysis, CD16 "low" expressing neutrophils showed reduced staining with the DNA-binding dye propidium iodide, suggesting that CD16 low expressing neutrophils were apoptotic. Separation of CD16 "high" and CD16 "low" expressing neutrophils by fluorescence-activated cell sorting revealed that morphologically apoptotic cells exhibited the CD16 low phenotype. We did not observe similar marked changes in expression of other neutrophil surface molecules (including other phosphatidylinositol (PI)-linked molecules), indicating that generalized loss of surface molecules does not occur during apoptosis. We believe this to be the first reported cell type-specific membrane alteration in a surface glycoprotein associated with apoptosis, suggesting that the program of cell death in the neutrophil, in addition to morphologic and nuclear changes, includes alterations in expression of surface receptors.
 ...
PMID:Neutrophil apoptosis is associated with a reduction in CD16 (Fc gamma RIII) expression. 802 53

Developing erythroid cells require the glycoprotein hormone, erythropoietin (EPO) as an activator of the rapid proliferation of early proerythroblasts (colony forming units-erythroid [CFU-e]), and subsequently as an activator of late erythroid gene expression. Activation of these growth and differentiation events proceeds from the binding of EPO at its transmembrane receptor (Class I cytokine receptor), to the engagement of a complex set of signaling pathways. Studies of reconstituted activities of the cloned EPO receptor in transfected hematopoietic cell lines have served well in identifying receptor domains and downstream mediators involved in proliferative signaling. Extracellular domains have been defined which contribute to ligand binding, receptor processing and transport, and possible dimerization. Cytosolic regions have been delineated which mediate induced mitogenesis, early gene transcription, activated protein tyrosine phosphorylation, down modulation of EPO- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced proliferation, and direct association with PI3- and JAK-2 kinases. These newly defined properties begin to align the EPO receptor mechanistically with growth factor receptors (GFR) which encode, or likewise associate with, regulated protein tyrosine kinases including the Class II cytokine receptors for interferons alpha/beta and gamma. An improved understanding of factors which mediate EPO-induced late erythroid gene activation also is emerging. These factors and pathways may be distinct from those associated with EPO-induced proliferation and may involve induced increases in cellular Ca++, cAMP and arachidonic acid, as well as the modulation of GATA-1, and/or SCL. Attributes of model systems used in studies of the role of EPO in late erythroid differentiation also are considered.
 ...
PMID:Signal transduction in the erythropoietin receptor system. 824 49

An adult T cell leukemia cell line, HIL-3, constitutively secretes a factor which induces the phenotypical and functional eosinophilic differentiation of a human eosinophilic leukemia cell line, EoL-1. Biochemical characteristics of the factor, termed eosinophilic leukemia cell differentiation factor (ELDF), were examined. ELDF was precipitated by 35 to 65% saturated ammonium sulfate from the culture supernatants of HIL-3 cells (HIL-3 sup). ELDF was eluted in a peak corresponding to a molecular weight of 30 to 40 kd by gel filtration. Isoelectric focusing in the Rotofor showed that ELDF had isoelectric points of 5 to 6. ELDF was trypsin-sensitive and stable to heat treatment at 65 degrees C for 30 minutes but labile at 80 degrees C or pH lower than 3. Half of the activity adhered to lentil-lectin but not to Con-A, indicating that a part of ELDF is glycoprotein with an N-linked carbohydrate moiety, which did not seem to be essential for ELDF activity. The biochemical characteristics of ELDF and blocking experiments using cytokine-specific neutralizing antibodies suggest that ELDF is different from gamma-interferon (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-5 (IL-5) and interleukin-2 (IL-2), which may exist in HIL-3 sup, and that ELDF may be a previously unrecognized leukemia differentiation factor.
 ...
PMID:Characterization of an eosinophilic leukemia cell differentiation factor (ELDF) produced by a human T cell leukemia cell line, HIL-3. 850 May 76

The alpha subunit of the human interleukin-3 receptor (IL-3R alpha) is a 70-kD glycoprotein member of the hematopoietin receptor superfamily. This protein associates with a beta subunit common to the receptors for IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) to form a high-affinity receptor for IL-3. To identify regions of IL-3R alpha critical for ligand binding and receptor function, cDNAs encoding mutant receptors were generated and expressed in COS cells along with the beta subunit. Mutant receptors lacking almost the entire cytoplasmic domain of IL-3R alpha [IL-3R alpha(CD)] or carrying a substitution of trp for leu in the membrane proximal leu-ser-x-trp-ser (LSXWS) box bound 125I-IL-3 with nearly the same affinity as wild-type IL-3R alpha. In contrast, a mutant lacking the entire "LSXWS" motif failed to bind 125I-IL-3 with high affinity despite showing surface expression. In addition, hybrid receptors composed of the first 104 amino acids (aa) of IL-3R alpha joined to aa 118 through 400 of the alpha subunit of the GM-CSF receptor (GM-R alpha) [IL-3R alpha/GM-R alpha] or the first 118 aa of GM-R alpha joined to aa 104 through 378 of IL-3R alpha [GM-R alpha/IL-3R alpha] failed to bind 125I-IL-3 in the presence of the beta subunit. A third hybrid receptor composed of the first 281 residues of IL-3R alpha fused to residues 306 through 379 of GM-R alpha [IL-3R alpha/GM-R alpha-DS] also failed to bind 125I-IL-3 in the presence of the beta subunit but, in contrast to the IL-3R alpha/GM-R alpha hybrid, demonstrated weak surface expression. Mutant receptors lacking the N-terminal 30 aa and the N-terminal 9 aa also did not bind 125I-IL-3 with high affinity, although both were expressed on the cell surface. These data suggest that although the cytoplasmic domain and the leucine residue of the "LSXWS" box are not critical for ligand binding or beta-subunit association, the "LSXWS" motif and amino-terminal sequences are important for these functions.
 ...
PMID:Mutational analysis of the alpha subunit of the human interleukin-3 receptor. 854 32


<< Previous 1 2 3 4 5 6 7 8 Next >>