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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)

Nonhematopoietic malignant cells may express receptors for hematopoietic growth factors and respond to these peptides. The aim of the present study was to investigate whether small cell lung cancer (SCLC) cells may be stimulated to proliferate by hematopoietic growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), which are currently used in clinical trials in combination with cytotoxic chemotherapy. We studied two SCLC cell lines, H69 and N417. The effects of GM-CSF and IL-3 were evaluated by studying clonal growth, 3H-thymidine incorporation, BUDR/DNA bivariate flow cytometry, c-myc and N-myc oncogene expression, and myeloid surface markers. Our experiments show that both GM-CSF and IL-3 can increase 3H-thymidine incorporation and cloning efficiency and reduce DNA synthesis time of H69 and, to a lesser extent, N417 cells, supporting the hypothesis that hematopoietic growth factors can stimulate the growth of some malignant nonhematopoietic cells in vitro. Further in vitro and in vivo studies are needed to determine whether clinical trials applying these factors for bone marrow recovery after chemotherapy of solid tumors may be hazardous by potentially stimulating growth of remaining tumor tissue.
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PMID:Effects of granulocyte-macrophage colony-stimulating factor and interleukin-3 on small cell lung cancer cells. 818 6

Delineating the molecular basis for agonist-induced destabilization of mRNA of G-protein-linked receptors that contributes to receptor down-regulation is fundamental to our understanding of long-term regulation of receptors by agonist. Previously we identified a prominent, M(r) 35,000 cytosolic RNA-binding protein that (i) binds selectively to beta 1 and beta 2-adrenergic receptor mRNAs, both of which undergo agonist-induced down-regulation; (ii) does not bind either to alpha 1b-adrenergic receptor mRNA, which does not undergo agonist-induced down-regulation, or to beta-globin mRNA; (iii) displays binding to beta 2-adrenergic receptor mRNA that is selectively competed by poly(U) RNA, but not poly(A),-(C), or -(G) RNA; and (iv) its abundance varies inversely with the level of receptor mRNA, being induced by agonists that down-regulate receptor mRNA (Port, J. D., Huang, L.-y., and Malbon (1992) J. Biol. Chem. 267, 24103-24108). We demonstrate here that the binding of beta-adrenergic receptor mRNA by this protein, termed beta-ARB protein, is sensitive to competition by AU-rich domains of the 3'-untranslated regions of c-fos, c-myc, and human granulocyte-macrophage colony-stimulating factor. Using the AU-rich 3'-untranslated regions of wild-type adenovirus IVa2 mRNA and variants with defined mutations in the AUUUApentamer, AU-rich, and U-rich domains, we were able to define sequences critical to the binding of the beta 2-receptor mRNA by the beta-ARB protein. Recognition of beta-ARB protein requires not only an AUUUA destabilization pentamer, but also a flanking U-rich domain(s). Using radiolabeled 3'-untranslated regions of short-lived mRNA, we were able to identify this same M(r) 35,000 cytosolic RNA-binding protein(s), beta-ARB protein, as selective for beta 2-adrenergic receptor mRNA.
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PMID:The M(r) 35,000 beta-adrenergic receptor mRNA-binding protein induced by agonists requires both an AUUUA pentamer and U-rich domains for RNA recognition. 824 13

The degradation of some proto-oncogene and lymphokine mRNAs is controlled in part by an AU-rich element (ARE) in the 3' untranslated region. It was shown previously (G. Brewer, Mol. Cell. Biol. 11:2460-2466, 1991) that two polypeptides (37 and 40 kDa) copurified with fractions of a 130,000 x g postribosomal supernatant (S130) from K562 cells that selectively accelerated degradation of c-myc mRNA in a cell-free decay system. These polypeptides bound specifically to the c-myc and granulocyte-macrophage colony-stimulating factor 3' UTRs, suggesting they are in part responsible for selective mRNA degradation. In the present work, we have purified the RNA-binding component of this mRNA degradation activity, which we refer to as AUF1. Using antisera specific for these polypeptides, we demonstrate that the 37- and 40-kDa polypeptides are immunologically cross-reactive and that both polypeptides are phosphorylated and can be found in a complex(s) with other polypeptides. Immunologically related polypeptides are found in both the nucleus and the cytoplasm. The antibodies were also used to clone a cDNA for the 37-kDa polypeptide. This cDNA contains an open reading frame predicted to produce a protein with several features, including two RNA recognition motifs and domains that potentially mediate protein-protein interactions. These results provide further support for a role of this protein in mediating ARE-directed mRNA degradation.
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PMID:Purification, characterization, and cDNA cloning of an AU-rich element RNA-binding protein, AUF1. 824 82

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 proB 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 NIH3T3 cells, but its ability to transduce signals in fibroblasts remained unanswered. In the present study, we further characterized signal transduction by the reconstituted hGM-CSFR both in NIH3T3 cells and BA/F3 cells. We found that the reconstituted hGM-CSFR transduces signals in NIH3T3 fibroblasts and BA/F3 cells in response to human GM-CSF to activate transcription of c-fos, c-jun and c-myc protooncogenes. hGM-CSF also induces protein tyrosine phosphorylation and DNA synthesis in both cell types. The ability of hGM-CSFR to transduce signals was affected by inhibitors of tyrosine kinase. These results indicated that the hGM-CSFR is functional in fibroblasts, that signal transduction via the hGM-CSFR in fibroblasts involves tyrosine kinase(s) and that association of hGM-CSFR with factor(s) specific to hematopoietic cell lineage is not essential to transduce growth promoting signals.
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PMID:Reconstitution of functional human GM-CSF receptor in mouse NIH3T3 fibroblasts and BA/F3 proB cells. 836 Dec 10

The human granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor is composed of an alpha subunit which binds GM-CSF and a beta subunit which allows for high affinity binding. To investigate the role of the short cytoplasmic tail (54 amino acids) of the alpha receptor in mediating signal transduction and in controlling cell growth, we placed a stop codon after the alpha receptor transmembrane domain and expressed this receptor in murine Ba/F3 cells. Unlike the complete alpha subunit, this shortened receptor was unable to stimulate protein phosphorylation or mediate entry into the cell cycle. By comparing Ba/F3 cells expressing the alpha and beta receptors with those expressing the alpha or the terminated alpha receptor, we have been able to correlate specific GM-CSF-induced events with cell cycle commitment. We find that cell growth is correlated with prolonged increases in the cell levels of c-myc, pim-1, and cyclin D2 mRNAs, but not with changes in either immediate early genes or mitogen-activated protein kinase phosphorylation. This suggests that additional signal transduction pathways not mediated by known phosphoproteins are activated by GM-CSF. Since the beta receptor is shared by human interleukins 3 and 5, our data suggest that the specificity of response to GM-CSF is mediated in part by the short cytoplasmic tail of the alpha receptor subunit.
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PMID:A critical role for the cytoplasmic domain of the granulocyte-macrophage colony-stimulating factor alpha receptor in mediating cell growth. 837 36

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

Hematopoietic growth factors may be useful in improving the clinical effectiveness of arabinofuranosylcytosine (ara-C). In vitro studies have indicated that interleukin 3(IL-3) and, to a lesser extent, granulocyte-macrophage colony-stimulating factor (GM-CSF), but not G-CSF or M-CSF, may be capable of specifically augmenting the ability of ara-C to kill leukemic myeloid cells by pharmacological and cytokinetic mechanisms including increase of intracellular ara-CTP/dCTP pool ratios and enhanced ara-C DNA incorporation in leukemic blast cells, decrease of IC 90 of ara-C for leukemic colony-forming cells (CFC) as compared with normal CFC growth, and recruitment of quiescent leukemic cells into the cell cycle. In contrast, the combination of ara-C with M-CSF or with the leukemia inhibitory factor (LIF) appears to be useful in overcoming the block in differentiation of leukemic blast, while the effects of GM-CSF and IL-3 on ara-C-induced differentiation appear limited. The combined treatment of human myeloid leukemia cells by ara-C and LIF is associated with down-regulation of c-myc gene expression, transcriptional activation of jun/fos gene expression, and features of functional differentiation (e.g., the capability to reduce nitroblue tetrazolium, to express lysozyme, or to display differentiation-related surface receptors including C3bi and the c-fms protein). On the basis of these in vitro studies first clinical trials are underway that are examining the efficacy of ara-C combinations with these molecules for the treatment of myeloid disorders.
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PMID:Modulation of cytotoxicity and differentiation-inducing potential of arabinofuranosylcytosine in myeloid leukemia cells by hematopoietic cytokines. 846 21

The AMEX method of fixation permitted the serial study of c-myc expression in bone-marrow (BM) biopsies obtained from 6 patients with acute myelogenous leukaemia (AML) and one with myelodysplastic syndrome (MDS) during therapy with various cytotoxic and bioactive agents. BM cytotoxic therapy and therapy with bioactive agents was capable of altering c-myc expression in vivo. While cytotoxic therapy was generally associated with a fall in myc expression, it did not produce a dramatic effect on myc expression. Recombinant human granulocyte-macrophage colony-stimulating factor (RhGM-CSF) can increase and retinoic acid/alpha-interferon can decrease c-myc expression in myeloid cells in vivo.
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PMID:The serial study of c-myc expression in bone marrow biopsy specimens during treatment for acute myelogenous leukaemia. 851 28

The interleukin-2 (IL-2) receptor (IL-2R) consists of three distinct subunits (alpha, beta, and gamma c) and regulates proliferation of T lymphocytes. Intracellular signalling results from ligand-mediated heterodimerization of the cytoplasmic domains of the beta and gamma c chains. To identify the residues of gamma c critical to this process, mutations were introduced into the cytoplasmic domain, and the effects on signalling were analyzed in the IL-2-dependent T-cell line CTLL2 and T-helper clone D10, using chimeric IL-2R chains that bind and are activated by granulocyte-macrophage colony-stimulating factor. Whereas previous studies of fibroblasts and transformed T cells have suggested that signalling by gamma c requires both membrane-proximal and C-terminal subdomains, our results for IL-2-dependent T cells demonstrate that the membrane-proximal 52 amino acids are sufficient to mediate a normal proliferative response, including induction of the proto-oncogenes c-myc and c-fos. Although gamma c is phosphorylated on tyrosine upon receptor activation and could potentially interact with downstream molecules containing SH2 domains, cytoplasmic tyrosine residues were dispensable for mitogenic signalling. However, deletion of a membrane-proximal region conserved among other cytokine receptors (cytoplasmic residues 5 to 37) or an adjacent region unique to gamma c (residues 40 to 52) abrogated functional interaction of the receptor chain with the tyrosine kinase Jak3. This correlated with a loss of all signalling events analyzed, including phosphorylation of the IL-2R beta-associated kinase Jak1, expression of c-myc and c-fos, and induction of the proliferative response. Thus, it appears in T cells that Jak3 is a critical mediator of mitogenic signaling by the gamma c chain.
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PMID:A membrane-proximal region of the interleukin-2 receptor gamma c chain sufficient for Jak kinase activation and induction of proliferation in T cells. 852 10

Herbimycin A, a benzoquinonoid ansamycin antibiotic, reduces intracellular phosphorylation by some protein tyrosine kinases and inhibits the proliferation of malignant cells which express high tyrosine kinase activity. Herbimycin A inhibited the proliferation of human monoblastic leukemia U937 cells, but this inhibition was abrogated by the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF). On the other hand, a derivative of herbimycin A, 19-allylaminoherbimycin A, inhibited the proliferation of such cells without interference by the addition of GM-CSF. Phosphorylation of MAP kinase and c-myc expression induced by GM-CSF in U937 cells were inhibited by both herbimycin A and 19-allylaminoherbimycin A. The time courses of growth inhibition showed that the growth-inhibitory activity of herbimycin A in U937 cells was initially potent, but gradually decreased in the presence of GM-CSF. Thiol compounds, glutathione (GSH) and 2-mercaptoethanol, abrogated the inhibition of the growth of U937 cells by herbimycin A, but not by 19-allylaminoherbimycin A, like GM-CSF. Intracellular GSH content in U937 cells was increased by treatment with GM-CSF, and decreased with herbimycin A, but returned to the control level with the addition of GM-CSF to herbimycin A. In thin-layer chromatography, after in vitro incubation with herbimycin A and GSH, nothing could be detected at the position of intact herbimycin A, while 19-allylaminoherbimycin A was stably detected. These findings suggest that changes in the intracellular concentration of GSH play a role in the abrogation of the inhibition of U937 cell growth by herbimycin A. In the presence of GSH, 19-allylaminoherbimycin A inhibited the proliferation of U937 cells and Philadelphia chromosome-positive K562 cells more effectively than herbimycin A. Since GSH plays a role in detoxicating several anticancer drugs, 19-allylaminoherbimycin A may have therapeutic advantages over herbimycin A against some types of leukemia.
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PMID:19-Allylaminoherbimycin A, an analog of herbimycin A that is stable against treatment with thiol compounds or granulocyte-macrophage colony-stimulating factor in human leukemia cells. 854 53


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