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)

The hematopoietic and stromal cell-specific properties of the cells involved in gamma irradiation leukemogenesis in vitro were defined. Cocultivation of clonal factor-dependent (FD), interleukin 3 (IL-3)-dependent cell lines 32D cl 3 or B6SUtA, or dual IL-3-/granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent cell lines FDC-P1 or bg/bg d64 was carried out with clonal stromal cell lines D2XRII, GB1/6, +/+ 2.4, or Sld3. FD cell lines were added to control or 5000-cGy-irradiated plateau phase monolayer cultures of each stromal cell line, and parameters of stem cell engraftment and malignant transformation in vitro were quantitated. Cobblestone island formation by FD cells, cumulative production of nonadherent hematopoietic cells, and evolution of tumorigenic factor-independent (FI) subclonal lines were quantitated over 5-8 weeks. There was no detectable evolution of FI sublines with 32D cl 3, B6SUtA, or bg/bg d64 cells cocultivated with control or irradiated Sld3 stromal cells. IL-3-dependent cell lines 32D cl 3 or B6SUtA formed small 10- to 49-cell cobblestone "clusters" at low frequency on control or irradiated D2XRII, showed limited proliferation for less than 1 week, and showed no detectable evolution of FI cell lines. Subclones of 32D cl 3 derived by transfection and expression of recombinant oncogenes v-sis, or c-myc, or the epidermal growth factor receptor remained factor dependent and did not transform to factor independence after cocultivation with irradiated stromal cell lines. In contrast, cell line bg/bg d64, and each of seven subclonal lines of FDC-P1, including subclones selected for growth in GM-CSF, formed abundant cobblestone island colonies of greater than or equal to 50 cells on irradiated D2XRII stromal cells, produced non-adherent cells over 5-8 weeks, and showed evolution of tumorigenic FI subclonal lines. The data provide evidence for stable biological differences in both the hematopoietic and stromal cell components of the in vitro model of gamma irradiation leukemogenesis.
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PMID:Hematopoietic stem cell- and marrow stromal cell-specific requirements for gamma irradiation leukemogenesis in vitro. 218 23

Previous studies suggested that the potent immunosuppressive activities of transforming growth factor-beta (TGF-beta) were mediated in part through the inhibition of IL-2-dependent S-phase progression and mitosis of activated T cells. To further investigate the mechanism of T cell growth inhibition by TGF-beta, two constitutively activated murine T cell clones were employed as defined model systems for the growth factor-dependent phase of T cell proliferation. The Th cell line, HT-2, proliferated in response to either IL-2 or IL-4, whereas the cytotoxic T cell line, CT6, exhibited strict dependence on IL-2 for growth stimulation. In both cell lines, picomolar concentrations of TGF-beta inhibited S-phase progression stimulated by IL-2 or IL-4. TGF-beta pretreatment decreased the expression of high affinity IL-2R on HT-2 cells, but not on CT6 cells. In contrast, IL-2-stimulated transferrin receptor expression was markedly inhibited by TGF-beta in both T cell lines. Analyses of growth factor-dependent specific mRNA accumulation revealed that TGF-beta exerted selective inhibitory effects on gene expression in HT-2 and CT6 cells. TGF-beta significantly reduced early (1 to 2 h) increases in c-myc mRNA levels stimulated by IL-2 or IL-4 in both cell lines. In HT-2 cells, TGF-beta pretreatment also inhibited the early increase in granulocyte-macrophage CSF mRNA stimulated by IL-2 or IL-4. The inhibition of c-myc and granulocyte-macrophage cyte-macrophage CSF gene expression by TGF-beta was explained, at least in part, by suppression of the growth factor-dependent transcriptional activation of these genes. These studies suggest that inhibition of c-myc gene transcription may play a fundamental role in the antiproliferative effect of TGF-beta on IL-2- or IL-4-stimulated T cells.
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PMID:Regulatory effects of transforming growth factor-beta on IL-2- and IL-4-dependent T cell-cycle progression. 240 83

We report that highly purified human platelet factor 4 (PF4) inhibits human megakaryocytopoiesis in vitro. At greater than or equal to 25 micrograms/ml, PF4 inhibited megakaryocyte colony formation approximately 80% in unstimulated cultures, and approximately 58% in cultures containing recombinant human IL 3 and granulocyte-macrophage colony-stimulating factor. Because PF4 (25 micrograms/ml) had no effect on either myeloid or erythroid colony formation lineage specificity of this effect was suggested. A synthetic COOH-terminal PF4 peptide of 24, but not 13 residues, also inhibited megakaryocyte colony formation, whereas a synthetic 18-residue beta-thromboglobulin (beta-TG) peptide and native beta-TG had no such effect when assayed at similar concentrations. The mechanism of PF4-mediated inhibition was investigated. First, we enumerated total cell number, and examined cell maturation in control colonies (n = 200) and colonies (n = 100) that arose in PF4-containing cultures. Total cells per colony did not differ dramatically in the two groups (6.1 +/- 3.0 vs. 4.2 +/- 1.6, respectively), but the numbers of mature large cells per colony was significantly decreased in the presence of PF4 when compared with controls (1.6 +/- 1.5 vs. 3.9 +/- 2.3; P less than 0.001). Second, by using the human leukemia cell line HEL as a model for primitive megakaryocytic cells, we studied the effect of PF4 on cell doubling time, on the expression of both growth-regulated (H3, p53, c-myc,and c-myb), and non-growth-regulated (beta 2-microglobulin) genes. At high concentrations of native PF4 (50 micrograms/ml), no effect on cell doubling time, or H3 or p53 expression was discerned. In contrast, c-myc and c-myb were both upregulated. These results suggested the PF4 inhibited colony formation by impeding cell maturation, as opposed to cell proliferation, perhaps by inducing expression of c-myc and c-myb. The ability of PF4 to inhibit a normal cell maturation function was then tested. Megakaryocytes were incubated in synthetic PF4, or beta-TG peptides for 18 h and effect on Factor V steady-state mRNA levels was determined in 600 individual cells by in situ hybridization. beta-TG peptide had no effect on FV mRNA levels, whereas a approximately 60% decrease in expression of Factor V mRNA was found in megakaryocytes exposed to greater than or equal 100 ng/ml synthetic COOH-terminal PF4 peptide. Accordingly, PF4 modulates megakaryocyte maturation in vitro, and may function as a negative autocrine regulator of human megakaryocytopoiesis.
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PMID:Inhibition of human megakaryocytopoiesis in vitro by platelet factor 4 (PF4) and a synthetic COOH-terminal PF4 peptide. 252 11

Quiescent T cells can be induced to express many genes by mitogen or antigen stimulation. The messenger RNAs of some of these genes undergo relatively rapid degradation compared to messenger RNAs from constitutively expressed genes. A T cell activation pathway that specifically regulates the stability of messenger RNAs for the lymphokines interleukin-2, interferon-gamma, tumor necrosis factor-alpha, and granulocyte-macrophage colony-stimulating factor is induced by stimulation of the CD28 surface molecule. This pathway does not directly affect the steady-state messenger RNA level, transcription, or messenger RNA half-life of other T cell activation genes, including c-myc, c-fos, IL-2 receptor, and the 4F2HC surface antigen. These data show that stimuli received at the cell surface can alter gene expression by inducing specific changes in messenger RNA degradation.
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PMID:Regulation of lymphokine messenger RNA stability by a surface-mediated T cell activation pathway. 254 May 28

The addition of interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) to hormone-dependent cells induces tyrosine phosphorylation of Janus protein kinase 2 (Jak2) and activates its in vitro kinase activity. To explore the role of Jak2 in IL-3/GM-CSF-mediated signal transduction, we constructed a CD16/CD7/Jak2 (CD16/Jak2) fusion gene containing the external domain of CD16 and the entire Jak2 molecule and expressed this fusion protein using a recombinant vaccinia virus. The clustering of CD16/Jak2 fusion protein by cross-linking with an anti-CD16 antibody induced autophosphorylation of the fusion protein but did not induce the phosphorylation of either the endogenous Jak2 or the beta chain. Cross-linking of CD16/Jak2 stimulates the tyrosine phosphorylation of a large group of proteins that are also phosphorylated after the addition of IL-3 or GM-CSF and include proteins of 145, 97, 67, 52, and 42 kDa. Closer analysis demonstrated that the CD16/Jak2 phosphorylates Shc, a 52-kDa protein, and the 145-kDa protein associated tightly with Shc, as well as mitogen-associated protein kinase (pp42). Electrophoretic mobility shift assays demonstrate that CD16/Jak2 activates the ability of signal transduction and activation of transcription (STAT) proteins to bind to an interferon-gamma-activated sequence oligonucleotide in a manner similar to that seen after IL-3 treatment. Cross-linking of the CD16/Jak2 protein stimulated increases in c-fos and junB similar to IL-3 but did not cause major changes in the levels of the c-myc message, which normally increases after IL-3 treatment. Thus, a transmembrane CD16/Jak2 fusion is capable of activating protein phosphorylation and mRNA transcription in a manner similar but not identical to hematopoietic growth factors.
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PMID:Signal transduction by a CD16/CD7/Jak2 fusion protein. 754 2

Steel factor (SLF) synergizes with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3) to stimulate proliferation of human factor-dependent cell line, MO7e. To elucidate molecular mechanisms underlying this synergism, induction of immediate-early genes was studied. Treatment of MO7e cells with SLF, GM-CSF, and IL-3 induced/enhanced expression of c-fos, junB, egr-1, and c-myc genes. SLF treatment of MO7e cells led to higher expression of c-fos, junB, and egr-1 genes than did treatment with GM-CSF or IL-3. However, GM-CSF and IL-3 had more prolonged effects on enhancement of the c-myc gene than SLF. Using optimal dosages for cell proliferation, induction of c-fos and junB was greater than additive with SLF plus GM-CSF or IL-3, as compared with each factor alone. Using suboptimal amounts of SLF with optimal GM-CSF or IL-3, induction of c-fos, junB, egr-1, and c-myc genes was greater than additive. De novo protein synthesis was not required for greater induction of these immediate-early genes by the combination of SLF plus GM-CSF. Based on nuclear run-on and actinomycin D experiments, the data suggest that the synergistic effects of SLF plus GM-CSF on the induction of immediate-early genes may be mediated in part at the level of transcription and mRNA stabilization for c-fos, at the level of mRNA stabilization for junB, and at the level of transcription for egr-1.
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PMID:Involvement of immediate-early gene expression in the synergistic effects of steel factor in combination with granulocyte-macrophage colony-stimulating factor or interleukin-3 on proliferation of a human factor-dependent cell line. 767 61

The ability of the receptor for the hematopoietic cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) to function in non-hematopoietic cells is unknown. NIH3T3 fibroblasts were transfected with cDNAs encoding the alpha and beta subunit of the human GM-CSF receptor and a series of stable transformants were isolated that bound GM-CSF with either low (KD = 860 - > 1000 pM) or high affinity (KD = 20-80 pM). Low affinity receptors were not functional. However, the reconstituted high affinity receptors were found to be capable of activating a number of signal transduction pathways, including tyrosine kinase activity, phosphorylation of Raf-1, and the transient induction of c-fos and c-myc mRNAs. The activation of protein tyrosine phosphorylation by GM-CSF in NIH3T3 cells was rapid (< 1 min) and transient (peaking at 5-20 min) and resulted in the phosphorylation of proteins of estimated molecular weights of 42, 44, 52/53 and 58-60 kDa. Some of these proteins co-migrated with proteins from myeloid cells that were phosphorylated on tyrosine residues in response to GM-CSF. In particular, p42 and p44 were identified as mitogen-activated protein kinases (MAP kinases), and the phosphorylation on tyrosine residues of p42 and p44 MAP kinases occurred at the same time as the phosphorylation of Raf-1. However, despite evidence for activation of many mitogenic signal transduction molecules, GM-CSF did not induce significant proliferation of transfected NIH3T3 cells. These results suggest that murine fibroblasts contain signal transducing molecules that can effectively interact with the human GM-CSF receptor, and that are sufficient to activate at least some of the same signal transduction pathways this receptor activates in myeloid cells, including activation of one or more tyrosine kinase(s). However, the level of activation of signal transduction is either below a threshold of necessary activity or at least one mitogenic signal necessary for proliferation is missing.
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PMID:The human granulocyte-macrophage colony-stimulating factor receptor is capable of initiating signal transduction in NIH3T3 cells. 768 77

Deletion analysis of the beta subunit of the human granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor previously defined two cytoplasmic regions required for distinct signaling. The membrane-proximal region is responsible for induction of c-myc and pim-1, and is indispensable for GM-CSF-dependent proliferation of mouse BaF3 transfectants. The distal region is required for activation of Ras, Raf-1, MAP kinase and p70 S6 kinase as well as induction of c-fos and c-jun, but is dispensable for GM-CSF-dependent proliferation of transfectants under normal culture conditions containing serum. Here we show that signals induced by the distal region of the beta subunit are also required for proliferation. GM-CSF supported proliferation of BaF3 transfectants expressing the normal beta subunit, even in serum-free medium. However, in the absence of seru, GM-CSF did not support proliferation of BaF3 transfectants that have the beta deletion mutants lacking the distal region. Serum-induced activation of Ras, phosphorylation of MAP kinase and expression of c-fos in parental BaF3 cells and antisense oligonucleotide against c-raf blocked DNA synthesis of BaF3 cells. These results indicate that proliferation of BaF3 cells requires signals induced by the proximal as well as the distal region of the beta subunit of the GM-CSF receptor, and that serum alleviates the requirement of signals induced by the distal region.
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PMID:Serum alleviates the requirement of the granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced Ras activation for proliferation of BaF3 cells. 792 37

Interleukin-5 (IL-5) regulates the production and function of B cells, eosinophils, and basophils. The IL-5 receptor (IL-5R) consists of two distinct membrane proteins, alpha and beta. The alpha chain (IL-5R alpha) is specific to IL-5. The beta chain is the common beta chain (beta c) of receptors for IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF). The cytoplasmic domains of both alpha and beta chains are essential for signal transduction. In this study, we generated cDNAs of IL-5R alpha having various mutations in their cytoplasmic domains and examined the function of these mutants by expressing them in IL-3-dependent FDC-P1 cells. The membrane-proximal proline-rich sequence of the cytoplasmic domain of IL-5R alpha, which is conserved among the alpha chains of IL-5R, IL-3R, and GM-CSF receptor (GM-CSFR), was found to be essential for the IL-5-induced proliferative response, expression of nuclear proto-oncogenes such as c-jun, c-fos, and c-myc, and tyrosine phosphorylation of cellular proteins including JAK2 protein-tyrosine kinase. In addition, analysis using chimeric receptors which consist of the extracellular domain of IL-5R alpha and the cytoplasmic domain of beta c suggested that dimerization of the cytoplasmic domain of beta c may be an important step in activating the IL-5R complex and transducing intracellular growth signals.
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PMID:A critical cytoplasmic domain of the interleukin-5 (IL-5) receptor alpha chain and its function in IL-5-mediated growth signal transduction. 762 58

Interleukin (IL)-3, granulocyte-macrophage colony-stimulating factor, and IL-5 receptors (IL-3R, GMR, and IL-5R) are composed of the alpha chain specific to each and the common beta chain, and both the alpha and beta subunits are members of the cytokine receptor superfamily. We previously showed that the high-affinity human GMR reconstituted by cotransfecting the alpha and beta chain cDNA clones transduces signals in response to hGM-CSF to activate transcription of c-fos, c-jun, and c-myc proto-oncogenes in mouse proB cell line BA/F3 or in mouse fibroblast NIH3T3 cells. These results indicated that molecules, such as tyrosine kinase, unique to hematopoietic cells are not essential to transduce signals. In this study, the function of the alpha subunit of GMR was compared with those of IL-3R and IL-5R by cotransfecting human cDNAs encoding the alpha subunit of IL-3R or IL-5R and the common beta subunit into BA/F3 or NIH3T3 cells. We found that the reconstituted human IL-3R, in response to hIL-3, transduced signals to activate transcription of c-fos promoter and induced DNA synthesis in both types of cells in a manner similar to hGMR. Likewise, hIL-5 activates c-fos promoter in transfected NIH3T3 cells expressing hIL-5R. These results indicated that the alpha subunits of IL-3R and IL-5R have properties similar to those of the GMR alpha subunit. In contrast, transfected human IL-4 receptor (hIL-4R) cDNA, which weakly activated c-fos promoter and induced DNA synthesis in BA/F3 cells, failed to elicit these activities in NIH3T3 cells in response to hIL-4.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of early response genes and cell proliferation by human interleukin-3, granulocyte-macrophage colony-stimulating factor, and interleukin-5 receptors: comparison with human interleukin-4 receptor signaling. 808 68

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