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)

Retrovirally mediated introduction of a cDNA encoding a placenta-derived low-affinity receptor for human granulocyte-macrophage colony-stimulating factor (GM-CSF) into murine FDC-P1 hemopoietic cells allowed these cells to proliferate when stimulated by human GM-CSF. The expressed human receptors on cloned lines were of low affinity (Kd = 4-6 nM), were internalized, and did not interact with endogenous GM-CSF receptors. Concentrations of human GM-CSF of 6.5-13 nM were required to stimulate 50% maximal colony formation versus a concentration of murine GM-CSF of 6 pM; this difference is comparable with the difference in relative affinities of the human and murine receptors for their respective ligands. If maintained in murine GM-CSF, cells able to bind or respond to human GM-CSF were rapidly lost due to transcriptional inactivation of the inserted cDNA. The observations indicate that low-affinity receptors for human GM-CSF can deliver a proliferative signal in appropriate cells and that the signaling mechanisms are not species-specific.
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PMID:Low-affinity placenta-derived receptors for human granulocyte-macrophage colony-stimulating factor can deliver a proliferative signal to murine hemopoietic cells. 216 53

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

The mechanisms responsible for regulating the growth and differentiation of pluripotent stem cells involve the complex interaction of a series of specific and nonspecific growth factors and signals. In this report, colony-stimulating factor (CSF)-dependent clonal cell lines, recombinant and/or purified CSFs, and clonal assays were used to investigate the mechanism of interleukin 4 (IL-4)-induced modulation of CSF-dependent cell growth. IL-4 inhibits in a dose-dependent fashion either the interleukin 3 (IL-3)- or granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced growth of the myelomonocytic progenitor cell line, FDC-P1. This inhibitory effect of IL-4- on IL-3- or GM-CSF-induced cell growth was verified using normal bone marrow cells. Our data supports the hypothesis that IL-4 is acting directly on the progenitor cell and not indirectly through the action of accessory cells. Further, because the inhibitory effect of IL-4 is selective and does not affect all CSF-dependent cell lines, other factors, including the maturational state or the lineage of the cell may be important in dictating an effect, if any, mediated by IL-4.
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PMID:The dual regulatory role of interleukin 4 is mediated through a direct effect on the target cell. 220 58

We have recently described a system that supports the development of continuously growing and tumorigenic cell lines after infection of individual multilineage hematopoietic colonies with Abelson murine leukemia virus (A-MuLV). We now provide definitive evidence that these transformed lines express features characteristic of mast cells. Although these lines have been maintained in some cases for more than a year in the absence of exogenous growth factors other than those present in fetal calf serum, colony formation could consistently after 2 months, and variably after 5 months, be shown to be increased several fold when pokeweed mitogen-stimulated spleen cell conditioned medium (CM) was added to the cultures. CM from the A-MuLV-transformed lines was then tested for its ability to stimulate hematopoietic colony formation by cells from both fetal and adult tissues. Four of four randomly selected cell lines produced factors that were active on erythropoietic, granulopoietic, and in some cases pluripotent progenitors. Removal of viral particles from the CM from one of the lines (27d1) by either heat inactivation or high-speed centrifugation did not alter the colony-stimulating activity detected. When CM from 27d1 cells was tested for its ability to stimulate the proliferation of interleukin 3 (IL3) granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent FDC-P1 cells, a positive result was obtained. This stimulatory activity was not reduced in the presence of neutralizing anti-IL 3 immunoglobulin (Ig), suggesting that the activity detected was GM-CSF and not IL 3. This was confirmed by the lack of expression of the IL 3 gene in 27d1 cells as determined by Northern analysis of 27d1 cell RNA. Furthermore, S1 analysis of mRNA from 27d1 cells as well as two other lines indicated that the GM-CSF gene in all three was transcriptionally active. Taken together, these data suggest that A-MuLV transformation of normal mast cells or their precursors under certain conditions commonly activates the production of GM-CSF.
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PMID:Production of granulocyte-macrophage colony-stimulating factor by Abelson virus-induced tumorigenic mast cell lines. 349 Feb 85

A retrovirus encoding polyoma middle T antigen has been used to infect a murine hemopoietic cell line (FDC-P1) dependent on either granulocyte-macrophage colony-stimulating factor (GM-CSF) or multipotential colony-stimulating factor (Multi-CSF). A number of cell lines have been established on the basis of their initial ability to proliferate in the absence of added colony-stimulating factor (CSF). The transformed lines display one of three patterns of growth in vitro: those able to grow fully autonomously; those whose proliferation depends on cell density; and those displaying dependence on added CSF regardless cell density. This latter class of cells are reminiscent of the majority of primary myeloid leukemic cells. Unlike parental FDC-P1 cells, all three classes of transformed cells are leukemogenic in syngeneic mice; moreover, they produce variable amounts of GM-CSF which we believe underlies their neoplastic behavior.
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PMID:The in vitro behavior of hemopoietic cells transformed by polyoma middle T antigen parallels that of primary human myeloid leukemic cells. 350 72

We have combined retroviral expression cloning with random mutagenesis to identify two activating point mutations in the common signal-transducing subunit (h beta c) of the receptors for human granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3 and IL-5 by virtue of their ability to confer factor independence on the haemopoietic cell line, FDC-P1. One mutation (V449E) is located within the transmembrane domain and, by analogy with a similar mutation in the neu oncogene, may act by inducing dimerization of h beta c. The other mutation (I374N) lies in the extracellular, membrane-proximal portion of h beta c. Neither of these mutants, nor a previously described mutant of h beta c (FI delta, which has a small duplication in the extracellular region), was capable of inducing factor independence in CTLL-2 cells, while only V449E could induce factor independence in BAF-B03 cells. These results imply that the extracellular and transmembrane mutations act by different mechanisms. Furthermore, they imply that the mutants, and hence also wild-type h beta c, interact with cell type-specific signalling molecules. Models are presented which illustrate how these mutations may act and predict some of the characteristics of the putative receptor-associated signalling molecules.
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PMID:Activating point mutations in the common beta subunit of the human GM-CSF, IL-3 and IL-5 receptors suggest the involvement of beta subunit dimerization and cell type-specific molecules in signalling. 755 69

Cells of the murine interleukin-3 (IL-3) or granulocyte-macrophage colony-stimulating factor (GM-CSF) factor-dependent line, FDC-P1, express the tyrosine kinase receptor, c-kit. The ligand for c-kit, steel factor (SLF), encoded by the steel (Sl) locus, is produced as both membrane-bound and soluble forms by fibroblastoid cells. Fibroblasts derived from normal (+/+) WCB6F1 mice are known to produce both forms of SLF and were able to support FDC-P1 cells in a contact-dependent manner in the presence of neutralizing anti-GM-CSF antiserum. In contrast, Sl/Sld mutant fibroblasts, which produce only a soluble form of SLF, were incapable of supporting FDC-P1 cells in the presence of GM-CSF antiserum. These results suggested that FDC-P1 cells were being supported on fibroblast layers by membrane-bound SLF. Attempts to grow FDC-P1 cells in high levels of soluble recombinant SLF to mimic the SLF-dependent response seen in co-culture experiments showed that cells which had been previously grown in GM-CSF or IL-3 were minimally responsive to SLF at concentrations up to 100 ng/mL. Although these cultures were not supported by SLF alone, the cells showed synergistic proliferative responses to SLF combined with suboptimal levels of GM-CSF or IL-3. FDC-P1 cells could, however, be adapted to grow in SLF alone by gradual substitution of SLF for GM-CSF over a period of 3 weeks. These cells showed 5.6- to 8.4-fold and 2.5-fold higher levels of c-kit mRNA than cells grown in GM-CSF or IL-3, respectively. Downregulation of surface c-kit protein was also seen in FDC-P1 cells grown in GM-CSF or IL-3 compared with cells grown in SLF. Although FDC-P1 cells propagated in SLF were more responsive to SLF, they were still able to proliferate as well in GM-CSF and IL-3 as the cells originally grown in the latter factors. Thus, functional downregulation of c-kit by GM-CSF and IL-3 was unidirectional.
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PMID:Responses of the murine myeloid cell line FDC-P1 to soluble and membrane-bound forms of steel factor (SLF). 768

Mechanisms of helper virus-induced growth factor-independence were examined in FDC-P1 cells and FDC-P1 cells expressing the erythropoietin receptor (FDER cells). Retroviral mutagenesis of FDC-P1 cells led to factor-independent (FI) colonies from which cell lines could readily be established; whereas control cells exhibited at least 20 to 40-fold lower rates of factor-independence. From 44 independent experiments using either FDC-P1 or FDER cells, 205 autonomous cell lines were obtained. Sixteen colonies displayed a novel ("satellite-inducing") appearance in agar and produced up to 4.1 x 10(5) U/mL granulocyte-macrophage colony-stimulating factor (GM-CSF) (some with altered GM-CSF transcript sizes) and/or interleukin-3 (IL-3). Retroviral mutagenesis of FDER cells increased the repertoire of autocrine growth factors now responsible for stimulating autocrine proliferation: 3% of FI cell lines produced erythropoietin (Epo) (0.5 U/mL). Unexpectedly, in every autonomous FDC-P1 cell line, reverse transcriptase-PCR demonstrated expression of a growth factor normally required for proliferation. Thus, a profound selection for cells able to produce growth factors as the mechanism for achieving autonomous proliferation was documented. The ectopic expression of a receptor lacking a cognate ligand ("orphan") followed by retroviral mutagenesis and selection for autocrine mutants may offer an effective method for identifying new ligands.
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PMID:The cytokine receptor repertoire specifies autocrine growth factor production in factor-dependent cells. 772 Aug 17

Cocultivation of cells from the gamma-irradiated D2XRII murine bone marrow stromal cell line with an interleukin-3/granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent hematopoietic progenitor cell line FDC-P1JL26 stimulates the emergence of factor-independent hematopoietic cell sublines. Several lines of evidence suggested that M-CSF or a protein antigenically related to M-CSF, termed leukemogenic stromal factor (LSF), that was expressed by D2XRII cells may have played a role in the emergence of the factor-independent sublines. In an effort to isolate a factor antigenically related to M-CSF, molecular clones were isolated from a D2XRII cDNA library that hybridized to a mouse M-CSF genetic probe. Two of these molecular clones, designated 60.8.2 and 6452, contained an 885-bp deletion in the M-CSF coding region. Such a cDNA clone has not been previously described in the mouse, but a cDNA clone homologous to it has been isolated from a human pancreatic tumor cell line, MIA-PaCa-2. Three transcripts (4.8, 3.4, and 1.8 kb) were detected that hybridized to an oligonucleotide probe that was specific to RNA transcripts containing the 60.8.2 deletion. The level of the 1.8-kb transcript was not detectably induced by ionizing irradiation; however, the levels of the 4.8-kb and 3.4-kb transcripts and two other M-CSF transcripts of sizes to 4.4 kb and 2.3 kb showed a 1.4- to 2.2-fold increase after gamma irradiation. Reverse transcription-polymerase chain reaction showed that the deletion-specific transcript(s) was detected in multiple mouse bone marrow stromal cell lines and in normal mouse tissues. The present studies establish the existence of an increased spectrum of murine M-CSF transcripts in bone marrow stromal cells and other tissues. This complexity of transcripts along with their increased accumulation after irradiation provides additional evidence for a role of proteins encoded by M-CSF transcripts in the response of bone marrow stromal cells to ionizing irradiation.
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PMID:Cloning and expression of unique murine macrophage colony-stimulating factor transcripts. 778 Jan 34

The proliferation of normal hematopoietic cells is strictly factor dependent, while leukemic cell lines and primary leukemic cells are frequently factor independent. Although autocrine growth stimulation of human leukemias is occasionally observed in vitro, it is possible that mutations of signal-transduction or cell-cycle control genes may also be important in the development of factor independence. We have previously shown that the proto-oncogene Raf-1, a 70-kd serine/threonine protein kinase, is rapidly phosphorylated and activated by hematopoietic growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and Steel factor and is likely to be an important intermediate in mitogenic signal transduction pathways in hematopoietic cells. In an effort to better understand the possible role of abnormal signal transduction in the development of factor independence, we compared the state of phosphorylation and associated kinase activity of Raf-1 between a series of factor-dependent human and murine-myeloid normal cells or cell lines and a series of factor-independent myeloid cell lines. In factor-dependent myeloid cells (normal neutrophils; monocytes; and the cell lines MO7, 32Dc13, and FDC-P1), Raf-1 phosphorylation and associated kinase activity was strictly regulated by the supply of growth factor. In contrast, each of eight factor-independent leukemic cell lines examined, HL-60, KG-1, K562, U937, JOSK-S, JOSK-M, JOSK-K, and JOSK-I, expressed hyperphosphorylated Raf-1 with increased Raf-1 associated kinase activity in the absence of growth factor addition. To further explore the relationship of Raf-1 to factor-independent growth, factor-independent sublines were derived from two factor-dependent cell lines, MO7 and FDC-P1, by culture in CSF-deprived medium. Also, several factor-independent sublines were derived by transfection of a cDNA encoding p210BCR/ABL into three different cell lines: MO7, 32Dc13, and FDC-P1. In each case, the new sublines expressed constitutively hyperphosphorylated and activated Raf-1. The correlation of hyperphosphorylation of Raf-1 with factor independence was also observed with primary acute myeloblastic leukemia cells. The rate of "spontaneous" proliferation of primary acute myeloblastic leukemia (AML) cells in vitro correlated with the extent of Raf-1 phosphorylation. These results suggest that the evolution of myeloid leukemic cells to factor independence is associated with phosphorylation and activation of Raf-1, implicating Raf-1 and signal transduction pathways which activate RAf-1 in this process.
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PMID:Factor independence of human myeloid leukemia cell lines is associated with increased phosphorylation of the proto-oncogene Raf-1. 792 78

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