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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)

In this paper we report on the structure and expression of the genes encoding the alpha and beta chains of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor in human leukemia. The alpha chain gene is highly polymorphic in normal individuals and no evidence for rearrangement within this locus was found in 47 hemopoietic, nine non-hemopoietic malignancies and five human cell lines. Using the polymerase chain reaction the gene for the alpha chain was shown to be expressed in 18/18 primary myeloid as well as 8/8 primary lymphoid leukemias analysed. To investigate the integrity of the mRNA, polymerase chain reactions (PCR) using a combination of oligonucleotides spanning the entire coding region of the alpha chain were performed. Normal sized fragments were generated with all combinations of oligonucleotides from all but one leukemia. One chronic lymphoid leukemia displayed an apparent alteration at the 3' end of the 3' untranslated region of the alpha chain mRNA. No polymorphisms were detected in the beta chain gene which was also not rearranged in any of the samples analysed. The beta chain mRNA was expressed in 17/18 primary myeloid and 7/8 primary lymphoid leukemias and in those leukemias there was no evidence for any lesions in the mRNA, as judged by PCR fragment size. Thus gross structural lesions in the genes encoding the GM-CSF receptor alpha and beta chains appear to be infrequent in hemopoietic neoplasms.
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PMID:Structure and expression of the GM-CSF receptor alpha and beta chain genes in human leukemia. 841 81

To identify domains in hematopoietic growth factor receptors that are important for signal transduction, a hybrid receptor (GMER) was constructed by splicing the DNA of the entire extracellular and transmembrane domains of the human granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor alpha 2 subunit (GMR) to the cytoplasmic domain of the murine erythropoietin receptor (mEpoR). The hybrid receptor was introduced into the interleukin-3 factor-dependent murine hematopoietic cell line Ba/F3. Cells that expressed high receptor numbers were selected by cell sorting using phycoerythrin-labeled human GM-CSF. Immunoprecipitation of GMER from Ba/F3 cells showed a band with an Mr of 105,000 daltons. Human GM-CSF binding to Ba/F3 cells that expressed GMER showed a kd of 3.0 nmol/L and 475 binding sites/cell, while the same cells that expressed GMR had 300 sites/cell and a kd of 3.5 nmol/L. The proliferative response to GM-CSF of Ba/F3 cells that expressed GMER showed 1/2 maximal cell growth (as measured by 3H-thymidine incorporation) at a GM-CSF concentration of 2.5 x 10(-8) mol/L. When cultured in human GM-CSF, Ba/F3-GMER cells expressed cell surface glycophorin. Similar results were obtained with Ba/F3 cells transfected with the mEpoR and cultured in erythropoietin. Expression of GMR plus the human GM-CSF receptor beta chain in the same cell line also resulted in human GM-CSF stimulated proliferation; however, cell surface glycophorin was not detected. These data show that a low-affinity GM-CSF/Epo hybrid receptor can promote GM-CSF-dependent proliferation and can induce the expression of glycophorin, an erythroid-specific protein.
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PMID:A low-affinity human granulocyte-macrophage colony-stimulating factor/murine erythropoietin hybrid receptor functions in murine cell lines. 842 55

Granulocyte-macrophage colony-stimulating factor (GM-CSF) plays a critical role in growth and differentiation of myeloid cells. We previously reconstituted high-affinity human GM-CSF receptor (hGM-CSFR) in a pro-B cell line, BA/F3, by cotransfecting alpha- and beta-chain cDNA clones and showed that the reconstituted receptor could transduce growth-promoting signals. The high-affinity hGM-CSFR was also reconstituted in mouse NIH 3T3 cells, but its ability to transduce signals in fibroblasts remained undetermined. In the present study, we further characterized signal transduction by the reconstituted hGM-CSFR in both NIH 3T3 cells and BA/F3 cells. We found that the reconstituted hGM-CSFR transduces signals in NIH 3T3 fibroblasts and BA/F3 cells in response to hGM-CSF to activate transcription of the c-fos, c-jun, and c-myc proto-oncogenes. hGM-CSF also induces protein tyrosine phosphorylation and DNA synthesis in both cell types. These results indicated that hGM-CSFR is functional in fibroblasts, that signal transduction via hGM-CSFR in fibroblasts involves tyrosine kinase(s), and that association of hGM-CSFR with a factor(s) specific to hematopoietic cell lineage is not essential to transduce growth-promoting signals.
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PMID:Reconstituted human granulocyte-macrophage colony-stimulating factor receptor transduces growth-promoting signals in mouse NIH 3T3 cells: comparison with signalling in BA/F3 pro-B cells. 844 89

Tumor metastasis is the primary cause of death for cancer patients. The metastatic cascade requires successful tumor cell invasion into and through vascular and parenchymal barriers. We have shown that autocrine motility factor (AMF, autotaxin) and the insulin-like growth factors (IGFs) induce tumor-cell migration. Since granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to prime neutrophils for chemotaxis, we have therefore studied the influence of GM-CSF upon tumor cells and report that GM-CSF stimulates migration of these cells in a dose-dependent fashion. The ED50 for A2058 human melanoma cell line chemotaxis to GM-CSF is approx. 60 pM. The motile response to GM-CSF was additive to that of IGF-I and AMF, both of which are potent attractants for tumor cells. Pre-treatment of cells for 2 hr with non-toxic concentrations of pertussis toxin (PT) or amiloride resulted in a 50% inhibition of chemotaxis to GM-CSF. Therefore, GM-CSF, through PT- and amiloride-sensitive signal pathways, is a potent attractant for melanoma cells, the response to which is additive to that of other attractants. The presence of the GM-CSF receptor in A2058 melanoma cells was indicated by Northern-blot analysis which identified message transcripts of 2.1 and 3.0 kb. These data emphasize the versatility of the melanoma cell migration response to an array of cytokines, including GM-CSF.
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PMID:Granulocyte-macrophage colony-stimulating factor induces human melanoma-cell migration. 847 54

We have used two in vitro models to identify genes whose expression may serve as markers of lineage commitment during the development of hematopoietic stem cells. One system involves the development in vitro of blastocyst-derived embryonic stem cells into embryoid bodies. The second involves culturing of day 3.5 blastocysts in vitro under conditions that support their development into yolk saclike cysts. In both cases, hematopoietic cells arise in a manner that closely mimics the normal process occurring in the yolk sac of the early mouse embryo. We have focused our analysis on the expression of mRNAs for 15 hematopoietic growth factor receptor genes and other genes expressed in a hematopoietic lineage-specific manner. Although some growth factor receptor genes are apparently expressed constitutively during in vitro development, there are several classes of genes that undergo a highly consistent pattern of induction in both model systems. Genes induced early include those encoding the shared beta subunits of the interleukin-3 (IL-3), IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors; those induced at intermediate times include the c-fms, G-CSF receptor, and CD34 genes; and a gene induced late during in vitro development is the IL-7 receptor gene. The defined temporal order for the expression of these genes suggests that they may be useful as markers for multiple stages in the development of different hematopoietic cell lineages during embryogenesis.
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PMID:Hematopoietic growth factor receptor genes as markers of lineage commitment during in vitro development of hematopoietic cells. 794 55

Two distinct components, alpha and beta chains, which compose the high affinity receptor for human granulocyte-macrophage colony-stimulating factor (GM-CSF) do not contain any catalytic domains of known enzymes. However, in mouse lymphoid cell lines transfected with cDNAs of the both chains, GM-CSF triggers tyrosine phosphorylation of several cellular proteins and allows continuous proliferation. To elucidate whether the high affinity receptor functions in nonhematopoietic cells, we have reconstituted human GM-CSF receptor in mouse NIH3T3 fibroblasts. In NIH3T3 clones, in which the high affinity receptor is reconstituted, human GM-CSF has triggered rapid tyrosine phosphorylation of cellular proteins, transfected beta chain, and another protein of 40-45 kDa. Moreover, human GM-CSF stimulated DNA synthesis and induced morphological transformation. These observations indicate that coordinately expressed alpha and beta chains of human GM-CSF receptor activates intrinsic protein-tyrosine kinases by the stimulation with human GM-CSF and that the activated protein-tyrosine kinases phosphorylate tyrosine residues of an intrinsic 40-45-kDa protein and the transfected beta chain in NIH3T3 cells. Activation of the protein-tyrosine kinases is likely to have biological functions to induce DNA synthesis and morphological transformation of mouse fibroblasts.
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PMID:Coordinate expression of the alpha and beta chains of human granulocyte-macrophage colony-stimulating factor receptor confers ligand-induced morphological transformation in mouse fibroblasts. 851 1

Cytokines transduce their signals through specific receptors. Receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3, and IL-5 share the common signal transducing subunit (beta c), whereas the alpha subunits function as specific ligand binding components. In this study we prepared specific mouse monoclonal antibodies against human GM-CSF receptor-alpha subunit (hGMR alpha) by immunizing mice with Ba/F3 cells transfected with hGMR alpha complementary DNA. Using these anti-hGMR alpha antibodies in combination with antibodies against IL-3 receptor-alpha (IL-3R alpha), beta c subunits, and c-kit, we examined expression patterns and modulation of these receptor subunits on several human hematopoietic cells, including CD34+ cells and leukemic cell lines. GMR alpha and IL-3R alpha were expressed on GM-CSF- and IL-3-responsive cell lines, such as TF-1 and UT-7, whereas the expression levels were much lower on UT-7E, a GM-CSF- and IL-3-unresponsive subline of UT-7. The GMR alpha subunit was expressed only on mature granulocytes and monocytes, and IL-3R alpha was expressed on monocytes but not on mature granulocytes, and none of these subunits were expressed on lymphocytes. For CD34+ cells, GMR alpha was expressed more abundantly on CD34+ CD33high cells than on CD34+ CD33low cells, whereas IL-3R alpha was expressed more abundantly on CD34+ CD33low cells than on CD34+ CD33high and CD34+ CD33neg cells. Slight but significant expression of the beta c subunit was detected on CD34+ cells. Expression of not only GMR alpha and IL-3R alpha subunits but also c-kit was specifically downregulated by 48-hour incubation with their respective ligands. Receptor transmodulation between GM-CSF, IL-3, and stem cell factor (or kit ligand) was not detected on CD34+ cells in 48-hour cultures. We also detected upregulation of these alpha subunits by IL-1 alpha and interferon-gamma on leukemic cell lines. Our study showed expression levels for each receptor subunit--including GMR, IL-3R, and c-kit on human bone marrow and peripheral blood cells and leukemic cell lines--and revealed differential regulation of the expression of the receptor subunits.
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PMID:Differential expression of granulocyte-macrophage colony-stimulating factor and IL-3 receptor subunits on human CD34+ cells and leukemic cell lines. 854 66

The high-affinity and functional granulocyte-macrophage colony-stimulating factor receptor (GMR) is composed of two distinct subunits, alpha and beta; and the cytoplasmic domain of the beta subunit is essential to transduce growth-promoting signals. In contrast to the beta subunit, the role of the alpha subunit is not well characterized. We examined the requirement of the cytoplasmic domain of the alpha subunit and its functional region by deletion analyses. We demonstrated that the cytoplasmic domain of the alpha subunit, especially 29 amino acids residues near the transmembrane domain, was absolutely required for various signaling events including activation of immediate early genes, induction of tyrosine phosphorylation of cellular proteins, and cell growth. We further analyzed the role of the cytoplasmic domain of each subunit by constructing chimeric subunits, designated alpha/beta and beta/alpha, by exchanging cytoplasmic domains of the alpha and beta subunits of human (h) GMR. Reconstituted high-affinity chimeric hGMRs, hGMR(alpha/beta,beta/alpha) and hGMR(alpha/beta,beta), transduced signals at levels similar to the wild type hGMR(alpha,beta) in Ba/F3 cells and in NIH3T3 cells. These observations indicate that the original configuration between the extracellular and the cytoplasmic domains of the hGMR(alpha,beta) subunits is not required and that hGMR(alpha/beta,beta) transduced signals through the cytoplasmic domain of the beta subunit in an oligomeric form, without involvement of the cytoplasmic domain of the alpha subunit. Therefore human granulocyte-macrophage colony-stimulating factor signals are mainly transduced through the beta subunit, and the cytoplasmic domain of the alpha subunit is likely to activate the beta subunit in the normal hGMR.
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PMID:Roles of the cytoplasmic domains of the alpha and beta subunits of human granulocyte-macrophage colony-stimulating factor receptor. 854 67

Recently, many genes encoding the members of the cytokine receptor superfamily (CRSF), which have common structural features, have been characterized. Analyses on the structures of the genes encoding the alpha subunits of human IL-3 (hIL-3R alpha) and granulocyte-macrophage colony-stimulating factor receptors (hGMR alpha) revealed that they have the structural features common to all members of the CRSF (i.e., conservation of the intron phase pattern as "1-2-1-0-1" rule in the fibronectin type III domains located in extracellular segments of type I cytokine receptor subunits. This finding led us to propose a possible model for gene evolution for the CRSF. We pointed out that the CRSF genes derived from a putative common ancestral gene. In addition to these common features, we found an additional intron that is unique to the IL-3R alpha and the GMR alpha genes. This additional intron suggests that the IL-3R alpha and the GMR alpha genes evolved closely in the evolution process of the CRSF genes. This evidence and results of recent studies on the evolution of mammalian X chromosome make it tempting to speculate that a putative common ancestral gene of the subfamily including IL-3R alpha, GMR alpha, and IL-5R alpha emerged in an autosome at least before the divergence of marsupials and eutherian mammals, early in the 200 million-year history of mammals.
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PMID:Gene structures of the alpha subunits of human IL-3 and granulocyte-macrophage colony-stimulating factor receptors: comparison with the cytokine receptor superfamily. 854 68

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.
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PMID:Mutational analysis of the alpha subunit of the human interleukin-3 receptor. 854 32


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