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Query: UNIPROT:P06889 (Mol)
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A conserved DNA sequence element, termed cytokine 1 (CK-1), is found in the promoter regions of many hemopoietic growth factor (HGF) genes. Mutational analyses and modification interference experiments show that this sequence specifically binds a nuclear transcription factor, NF-GMa, which is a protein with a molecular mass of 43 kilodaltons. It interacts with different affinities with the CK-1-like sequence from a number of HGF genes, including granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte (G)-CSF, interleukin 3 (IL-3), and IL-5. We show here that the level of NF-GMa binding is induced in embryonic fibroblasts by tumor necrosis factor-alpha (TNF-alpha) treatment and that the CK-1 sequence from the G-CSF gene is a TNF-alpha-responsive enhancer in these cells. The NF-GMa protein is distinct from another TNF-alpha-responsive transcription factor, NF-kappa B, by several criteria. Firstly, several NF-kappa B-binding sites, although having sequence similarity with the CK-1 sequence, cannot compete efficiently for NF-GMa binding to CK-1. Secondly, the CK-1 sequence from both G-CSF and GM-CSF does not respond to phorbol ester treatment as would an NF-kappa B-binding element. These results demonstrate that NF-GMa is a novel transcription factor inducible by TNF-alpha and binds to a common element in HGF gene promoters.
Mol Cell Biol 1990 Jun
PMID:A novel tumor necrosis factor-responsive transcription factor which recognizes a regulatory element in hemopoietic growth factor genes. 234 64

It is unknown whether local resident cells of the upper airway are able to regulate the number and function of phagocytic cells by the secretion of cytokines. We undertook to determine if tracheal epithelial cells (TEC) produce the potent cytokine granulocyte/macrophage colony-stimulating factor (GM-CSF) and how TEC-derived GM-CSF might be regulated. Conditioned media (TEC-CM) from 7- to 21-day-old primary cultures of rat TEC contained material with bioactivity similar to GM-CSF. This bioactivity was increased in conditioned medium from lipopolysaccharide (LPS)-treated (1 microgram/ml) TEC. Molecular characterization of bioactivity revealed a molecular weight of 27 to 44 kD by gel-filtration high performance liquid chromatography (HPLC), and elution at 44 to 50% acetonitrile by reverse-phase HPLC, similar to that of authentic GM-CSF. The biologic activity of TEC-CM was completely blocked by a goat polyclonal anti-GM-CSF antibody. With in situ hybridization using a murine GM-CSF cDNA probe, more than 95% of the adherent TEC population expressed GM-CSF transcripts, and the number of transcripts was significantly increased by LPS (1 microgram/ml, 48 h). TEC appear to produce a cytokine that is functionally, biochemically, and antigenically indistinguishable from GM-CSF. The ability of TEC to produce GM-CSF suggests that these cells may play a role in modulating the inflammatory response in the airway.
Am J Respir Cell Mol Biol 1990 Jan
PMID:Rat tracheal epithelial cells produce granulocyte/macrophage colony-stimulating factor. 240 73

Granulocyte (G) and granulocyte-macrophage (GM) colony-stimulating factors (CSF) are necessary for proliferation and differentiation of myeloid hematopoietic cells. Fibroblasts stimulated by tumor necrosis factor alpha (TNF alpha) and several other agents are a rich source of these CSF. The GM-CSF synthesized by these cells had the same molecular weight and glycosylation pattern as that produced by activated T lymphocytes, as shown by [35S]methionine labeling studies. Northern (RNA) blot analysis showed that the fibroblasts had trace levels of G- and GM-CSF mRNA. Both G- and GM-CSF mRNA concentrations coordinately increased after exposure of the cells to TNF alpha (greater than or equal to 5 ng/ml), 12-O-tetradecanoylphorbol 13-acetate (TPA) (greater than or equal to 5 x 10(-10) M), or cycloheximide (20 micrograms/ml). Both TNF alpha and TPA increased levels of G- and GM-CSF mRNA in the absence of new protein synthesis. Transcriptional run-on studies demonstrated that fibroblasts constitutively transcribed GM-CSF, and transcription was enhanced 3.0-fold by TNF alpha and 2.5-fold by TPA and was unchanged by cycloheximide. The stability of G- and GM-CSF transcripts was determined after exposure of the cells to actinomycin D; the half-lives of G- and GM-CSF mRNA in unstimulated cells were less than 0.25 h and were increased 2- to 16-fold in cells cultured with TNF, TPA, or cycloheximide. In summary, both transcriptional and posttranscriptional signals acted coordinately to modulate the levels of G- and GM-CSF mRNAs in fibroblasts.
Mol Cell Biol 1988 Aug
PMID:Transcriptional and posttranscriptional modulation of myeloid colony-stimulating factor expression by tumor necrosis factor and other agents. 246 77

The turnover of the colony-stimulating factor 1 receptor (CSF-1R), the c-fms proto-oncogene product, is accelerated by ligand binding or by activators of protein kinase C (PKC), such as the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). The mechanisms of ligand- and TPA-induced downmodulation were shown to differ by the following criteria. First, in cells in which PKC was downmodulated, CSF-1R reexpressed at the cell surface remained sensitive to ligand but was refractory to TPA-induced degradation. Second, a kinase-defective receptor containing a methionine-for-lysine substitution at amino acid 616 at its ATP-binding site failed to undergo ligand-induced downmodulation but remained responsive to TPA. Following CSF-1 stimulation, no intermediates of receptor degradation could be immunoprecipitated with polyvalent antisera to CSF-1R. In contrast, TPA induced specific proteolytic cleavage of the receptor near its transmembrane segment, resulting in the release of the extracellular ligand-binding domain from the cell and the generation of an intracellular fragment containing the kinase domain. Two-dimensional phosphopeptide mapping demonstrated no new sites of phosphorylation in response to TPA in either the residual intact receptor or the intracellular proteolytic fragment. Therefore, PKC appears not to trigger downmodulation by directly phosphorylating the receptor but, rather, activates a protease which recognizes CSF-1R as a substrate.
Mol Cell Biol 1989 Jul
PMID:Ligand and protein kinase C downmodulate the colony-stimulating factor 1 receptor by independent mechanisms. 252 80

A retroviral vector encoding the receptor for human colony-stimulating factor-1 (CSF-1) was introduced into murine myeloid FDC-P1 cells which require interleukin-3 (IL-3) for their proliferation and survival in culture. Cells expressing the CSF-1 receptor (CSF-1R), selected by fluorescence-activated cell sorting in the continued presence of murine IL-3, formed colonies in semisolid medium and were able to proliferate continuously in liquid cultures containing human recombinant CSF-1. Thus, although they do not synthesize endogenous murine CSF-1R, FDC-P1 cells express the downstream components of the CSF-1 mitogenic pathway necessary for its signal-response coupling. After receptor transduction, slowly proliferating factor-independent variants that produced neither CSF-1 nor growth factors able to support the proliferation of parental FDC-P1 cells also arose. When the human CSF-1R was expressed in FDC-P1 cells under the control of an inducible metallothionein promoter, the frequencies of both CSF-1-responsive and factor-independent variants increased after heavy-metal treatment. In addition, a monoclonal antibody to human CSF-1R arrested colony formation by both the CSF-1-dependent and factor-independent cells but did not affect their growth in response to IL-3. Therefore, the induction of both the CSF-1-dependent and factor-independent phenotypes depended on expression of the transduced human CSF-1R.
Mol Cell Biol 1989 Sep
PMID:Transduction of human colony-stimulating factor-1 (CSF-1) receptor into interleukin-3-dependent mouse myeloid cells induces both CSF-1-dependent and factor-independent growth. 252 88

A system has been established for analyzing the functions of the c-fms/macrophage colony-stimulating factor (M-CSF) receptor gene product in hematopoietic growth and differentiation. The murine c-fms gene was introduced into the factor-dependent murine hematopoietic cell line FDC-P1 by retroviral infection, and conversion to M-CSF-dependent growth was assayed in agar cultures. Expression of the c-fms gene in FDC-P1 cells, which normally do not express this gene, resulted in the conversion of resultant FD(c-fms) cells to M-CSF-dependent growth. Stimulation of FD(c-fms) cells by M-CSF led to the formation of colonies of altered morphology and produced reversible morphological changes suggestive of myeloid differentiation. M-CSF also induced expression of mature myeloid surface marker proteins in the FD(c-fms) cells. Neither multi-CSF nor granulocyte-macrophage CSF induced similar phenotypic changes but remained able to stimulate the proliferation of undifferentiated FD(c-fms) cells. These results indicate that the c-fms gene was expressed functionally in FDC-P1 cells and transmitted signals for growth. Also, the interaction of M-CSF with the c-fms gene product generated an additional signal for myeloid differentiation but did not irreversibly commit FD(c-fms) cells to terminal differentiation. This system can be used for molecular analysis of the growth- and differentiation-promoting activities of the c-fms proto-oncogene.
Mol Cell Biol 1989 Nov
PMID:Induction of macrophage colony-stimulating factor-dependent growth and differentiation after introduction of the murine c-fms gene into FDC-P1 cells. 253 2

Human granulocyte-macrophage colony stimulating factor (hGM-CSF) is an important regulator of growth and differentiation for mononuclear and polymorphonuclear phagocytes. Here we report the crystallization and preliminary X-ray studies of Escherichia coli-expressed hGM-CSF. The crystals are orthorhombic, with the space group P212121, and have unit cell dimensions a = 46.62 A, b = 58.73 A and c = 126.42 A. Recombinant hGM-CSF crystals diffract X-rays to 2.4 A resolution and are thus suitable for X-ray structural studies.
J Mol Biol 1989 Feb 20
PMID:Crystallization and preliminary X-ray studies of recombinant human granulocyte-macrophage colony stimulating factor. 264 13

Tissue eosinophilia has been reported to occur in pulmonary fibrosis, a disease characterized by chronic inflammation and lung fibroblast proliferation. We have examined the in vitro interaction of these two cell types by determining the in vitro survival of human peripheral blood eosinophils co-cultured with human lung fibroblasts. Survival of eosinophils cultured alone was 10% at day 3 and less than 1% at day 7. In contrast, survival of eosinophils that had been co-cultured with fibroblasts was 98, 90, 73, and 69% at days 3, 7, 10, and 14, respectively. Fibroblast-conditioned medium (CM) elicited a similar result in a dose-dependent fashion. Survival of eosinophils cultured with CM which had been preincubated with a monoclonal-neutralizing antibody to human GM-CSF was inhibited in a dose-dependent manner. Human recombinant-derived GM-CSF supported eosinophil survival in the dose-dependent fashion. Survival at day 7 of eosinophils treated with one single dose of GM-CSF (10 U/ml) was 64%. The effect of fibroblast-CM on eosinophils likely represents true survival since eosinophil proliferation as determined by [3H]thymidine incorporation did not occur. We also report that freshly isolated eosinophils had normal ultrastructural, scanning and transmission electron microscopy characteristics, and were normodense. In contrast, eosinophils co-cultured for 7 days with fibroblasts acquired irregular shapes and became hypodense and partially degranulated. Thus, our results indicate that human lung fibroblast-derived GM-CSF mediates the in vitro survival of human eosinophils.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1989 Oct
PMID:Human lung fibroblast-derived granulocyte-macrophage colony stimulating factor (GM-CSF) mediates eosinophil survival in vitro. 269 15

The murine IL-4 and IL-5 genes encode hemopoietic growth factors involved in the stimulation, proliferation, and differentiation of cells of the T lymphocyte, B lymphocyte, and granulocyte lineages. We have mapped the Il-4 and Il-5 loci representing the structural genes for IL-4 and IL-5, respectively, to mouse chromosome 11 using Chinese hamster x mouse and rat x mouse somatic cell hybrids. Physical linkage studies of the IL-4 and IL-5 genes by pulsed field gel electrophoresis have shown that they are closely linked, being 110-180 kb apart. Since the Il-5 locus maps to the interface of bands A5 and B1 in the same location as the genes for IL-3 and GM-CSF, this places these three cytokine genes, as well as the IL-4 gene, within a region of about 5000-10,000 kb. The present physical linkage studies indicate that the IL-4 and IL-5 genes are a minimum of 600 kb apart from the closely linked IL-3 and GM-CSF genes. The gene clustering, together with similarities in gene structure, regulation, and biological function, raises the possibility that the four genes may be part of a distantly related cytokine gene family.
Somat Cell Mol Genet 1989 Mar
PMID:The IL-4 and IL-5 genes are closely linked and are part of a cytokine gene cluster on mouse chromosome 11. 278 91

Protein synthesis, antigen synthesis, and cell membrane permeability were analyzed after inoculating human diploid fibroblasts with control or cytotoxic CSF, herpes simplex virus type 1 (HSV 1), poliovirus 3, or Clostridium difficile toxin. Whereas protein synthesis and membrane permeability were affected by the viruses, and virus antigens detectable by pooled human serum were synthesized, the bacterial toxin and cytotoxic CSF did not induce any new proteins or antigens, although the cytotoxic CSF reduced cellular protein synthesis levels and caused an increase in the permeability of the cell membranes. The effect of the cytotoxic CSF in cell culture resembles that of a toxin rather than a replicating virus.
Exp Mol Pathol 1985 Jun
PMID:A comparison of the effects of cytotoxic cerebrospinal fluid on cell cultures with other cytopathogenic agents. 298 25


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