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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rapid transcriptional induction of genes in response to gamma interferon (IFN-gamma) is mediated by the IFN-gamma activation site (GAS) and its cognate protein, the IFN-gamma activation factor (GAF). We describe a GAS-associated, differentiation-induced factor (DIF) as a potential molecular link between the activities of IFN-gamma and of growth and differentiation factors. DIF DNA binding was activated by colony-stimulating factor 1 in murine macrophages and also during tetradecanoyl phorbol acetate-induced differentiation or IFN-gamma treatment in myeloid U937 cells. IFN-gamma activation of DIF decreased significantly upon monocytic differentiation. DIF binding to DNA was inhibited by antiphosphotyrosine antibodies and could be induced by treatment of U937 cells with vanadate. Unlike GAF, DIF-DNA complexes did not contain the 91-kDa protein (p91) from ISGF-3. DIF bound with high affinity to GAS from the promoters of the IFP 53/tryptophanyl-tRNA synthetase and Fc gamma RI genes, intermediate affinity to the Ly6A/E GAS, and low affinity to the guanylate-binding protein GAS. DIF may belong to a family of cytokine- or growth factor-induced factors binding with variable affinities to GAS-related elements: the interleukin-6-responsive acute-phase response factor associated with GAS from different IFN-inducible promoters but with a different preference of binding compared with DIF. The sis-inducible element of the c-fos promoter bound GAF but not DIF. However, the sis-inducible element could be changed by point mutation to compete for GAF and DIF binding. Our data show DIF to be a novel DNA-binding protein which is activated in response to differentiating signals. Moreover, they suggest that a family of cytokine- or growth factor-regulated proteins integrates and coordinates the responses to cytokines and to growth and differentiation factors by binding to GAS-related elements.
Mol Cell Biol 1994 Feb
PMID:A factor induced by differentiation signals in cells of the macrophage lineage binds to the gamma interferon activation site. 750 5

Oncogenic activation of the macrophage colony stimulating factor (M-CSF) receptor (c-Fms) requires mutation or truncation of the carboxyl terminus and specific amino acid substitutions in or near the fourth immunoglobulin (Ig)-like loop in the extracellular domain. Using a murine c-Fms system, we investigated the effect of C-terminal truncation, substitutions at amino acids 301 and 374 in the fourth Ig-like loop of the extracellular domain, or the combined mutations on individual steps in receptor activation. The mutations at amino acids 301 and 374 were necessary, but not sufficient, for receptor dimerization in the absence of M-CSF. Only receptors with a truncated C-terminus as well as the extracellular domain mutations dimerized efficiently in the absence of M-CSF, suggesting that the C-terminus of c-Fms also regulates receptor oligomerization. Truncation of the C-terminus alone did not cause receptor dimerization and did not activate the kinase enzymatic activity. Thus, truncation of the C-terminus did not activate receptor monomers in cis. Receptors with both a truncated C-terminus and the extracellular domain mutations underwent ligand-independent aggregation, transphosphorylation, and phosphorylation of cellular proteins, followed by rapid internalization and degradation. These results suggest that M-CSF binding to c-Fms initiates activation by inducing conformational changes in both the cytoplasmic C-terminal domain and the fourth Ig-like loop of the extracellular domain, leading to the formation of stable receptor dimers.
Mol Biol Cell 1994 Jan
PMID:The effect of activating mutations on dimerization, tyrosine phosphorylation and internalization of the macrophage colony stimulating factor receptor. 751 58

Fms, the macrophage colony-stimulating factor (M-CSF) receptor, is normally expressed in myeloid cells and initiates signals for both growth and development along the monocyte/macrophage lineage. We have examined Fms signal transduction pathways in the murine myeloid progenitor cell line FDC-P1. M-CSF stimulation of FDC-P1 cells expressing exogenous Fms resulted in tyrosine phosphorylation of a variety of cellular proteins in addition to Fms. M-CSF stimulation also resulted in Fms association with two of these tyrosine-phosphorylated proteins, one of which was identified as the 55-kDa Shc, which is shown in other systems to be involved in growth stimulation, and the other was a previously uncharacterized 150-kDa protein (p150). Fms also formed complexes with Grb2 and Sos1, and neither contained phosphotyrosine. Whereas both Grb2 and Sos1 complexed with Fms only after M-CSF stimulation, the amount of Sos1 complexed with Grb2 was not M-CSF dependent. Shc coimmunoprecipitated Sos1, Grb2, and tyrosine-phosphorylated p150, while Grb2 immunoprecipitates contained mainly phosphorylated p150, Fms, Shc, and Sos1. Shc interacted with tyrosine-phosphorylated p150 via its SH2 domain, and the Grb2 SH2 domain likewise bound tyrosine-phosphorylated Fms and p150. Analysis of Fms mutated at each of four tyrosine autophosphorylation sites indicated that none of these sites dramatically affected p150 phosphorylation or its association with Shc and Grb2. M-CSF stimulation of fibroblast cell lines expressing exogenous murine Fms did not phosphorylate p150, and this protein was not detected either in cell lysates or in Grb2 or Shc immunoprecipitates. The p150 protein is not related to known signal transduction molecules and may be myeloid cell specific. These results suggest that M-CSF stimulation of myeloid cells could activate Ras through the nucleotide exchange factor Sos1 by Grb2 binding to either Fms, Shc, or p150 and that Fms signal transduction in myeloid cells differs from that in fibroblasts.
Mol Cell Biol 1994 Sep
PMID:Shc, Grb2, Sos1, and a 150-kilodalton tyrosine-phosphorylated protein form complexes with Fms in hematopoietic cells. 752 May 23

Nitric oxide (NO) modulates the activity of a number of cell types, but little is known about its possible role in bone metabolism. In the present study we demonstrate that freshly isolated murine osteoblasts and an osteoblastic cell line express NO-synthase mRNA and release NO when stimulated with IL-1 or LPS, thus confirming the results of some recent reports using human and rat osteoblast-like cells. Synergistic effects were found between IL-1 and LPS or TNF. Enzyme induction was blocked by dexamethasone and IL-4. 1,25-dihydroxyvitamin D3 did not modify basal NO synthesis, but it markedly increased the cytokine-induced NO release. M-CSF, GM-CSF, IL-3, LIF, PTH, estradiol and calcitonin did not show significant effects on NO synthesis. NOS induction was blocked by various tyrosine-kinase inhibitors, geldanamycin and herbimycin A being the most potent. These results suggest that endogenous NO might participate in the regulation of bone remodeling at the local level, and may mediate some effects of vitamin D on bone. NO has recently been reported to inhibit osteoclastic bone resorption. The release of NO induced by bone-stimulating factors such as IL-1 may represent a protective mechanism helping to avoid excess resorption and preserve bone integrity in inflammatory conditions.
Mol Cell Endocrinol 1995 Jan
PMID:Mechanisms controlling nitric oxide synthesis in osteoblasts. 754 Sep 93

The presentation and recognition of foreign antigen is the critical initial event in the development of local immunity. In the lung, antigen-presenting cell activity is largely attributable to pulmonary dendritic cells (DC) that are distributed along the airways and throughout the pulmonary interstitium in close proximity to overlying alveolar epithelial cells. To test the hypothesis that DC immunostimulatory activity might be locally regulated by overlying alveolar epithelial cells, we evaluated the ability of rat type II alveolar epithelial cells to influence the capacity of purified rat pulmonary DC to stimulate T-cell proliferation in an allogeneic, mixed leukocyte reaction. We found that alveolar epithelial cells greatly enhanced the ability of dendritic cells to induce T-cell proliferation. This effect on DC immunostimulatory activity was mediated by a soluble factor preferentially secreted from the basolateral epithelial cell surface. Alveolar epithelial cultures were found to express mRNA for granulocyte macrophage colony-stimulating factor (GM-CSF), and blocking antibodies against GM-CSF partially neutralized the effect of epithelial cell-conditioned media on DC stimulatory activity, indicating that the effect was due at least in part to alveolar epithelial cell-derived GM-CSF. Through the polar secretion of GM-CSF, alveolar epithelial cells may play an important role in creating distinct immunologic environments within the lung.
Am J Respir Cell Mol Biol 1995 Oct
PMID:Regulation of rat pulmonary dendritic cell immunostimulatory activity by alveolar epithelial cell-derived granulocyte macrophage colony-stimulating factor. 754 72

Several studies have demonstrated that bronchial epithelial cells are capable of synthesizing proinflammatory cytokines that may influence eosinophil and neutrophil activity. We have cultured human bronchial epithelial cells to confluence, as explant cultures, and investigated the effect of conditioned medium from these cells on (1) the chemotaxis of eosinophils and neutrophils and (2) the adherence of these cells to cultured human endothelial cells. Analysis of cytokines, namely interleukin-1 beta (IL-1 beta), interleukin-8 (IL-8), tumor necrosis factor alpha (TNF alpha), granulocyte/macrophage colony-stimulating factor (GM-CSF), and RANTES, which are thought to be involved in these processes, demonstrated that all these cytokines were synthesized and released constitutively from the bronchial epithelial cell cultures. Conditioned medium obtained after 24 h of incubation significantly increased the chemotaxis of eosinophils and neutrophils, from median values of 4.0 cells/per high power field (hpf) (range, 3.0 to 7.0) and 17 cells/hpf (range, 13.0 to 25.0), respectively, for medium 199, to median values of 11.0 cells/hpf (range, 9 to 12; P = 0.005) and 30 cells/hpf (range, 19 to 33; p = 0.01). Whereas anti-GM-CSF and anti-IL-8 neutralizing monoclonal antibodies significantly attenuated the conditioned medium-induced chemotaxis of eosinophils and neutrophils, anti-RANTES neutralizing antibody significantly attenuated the chemotaxis of only eosinophils. Conditioned medium also significantly increased the percentage of eosinophils and neutrophils adhering to endothelial cells in a dose-dependent manner. Both anti-human TNF alpha and anti-human IL-1 beta neutralizing antibodies significantly attenuated the conditioned medium-induced adherence of eosinophils and neutrophils to the endothelial cells and were found to have an additive effect when studied together. Similarly, treatment of endothelial cells with either anti-ICAM-1 or anti-E-selectin, for 1 h before co-culture with eosinophils and neutrophils, significantly attenuated the conditioned medium-induced adherence of both eosinophils and neutrophils to endothelial cells. Treatment of endothelial cells with anti-VCAM-1 attenuated the adherence of eosinophils but not neutrophils. These results suggest that human bronchial epithelial cells, through their ability to generate proinflammatory mediators, are likely to play a role in the pathogenesis of airway disease by influencing chemotaxis and adherence of eosinophils and neutrophils.
Am J Respir Cell Mol Biol 1995 Dec
PMID:The effect of conditioned medium from cultured human bronchial epithelial cells on eosinophil and neutrophil chemotaxis and adherence in vitro. 757 11

Interleukin 3 (IL-3) or granulocyte macrophage colony-stimulating factor (GM-CSF) activates c-fos, c-jun, and c-myc genes and proliferation in both hematopoietic and nonhematopoietic cells. Using a series of deletion mutants of the beta subunit of human GM-CSF receptor (hGMR) and inhibitors of tyrosine kinase, two distinct signaling pathways, one for activation of c-fos and c-jun genes, and the other for cell proliferation and activation of c-myc gene have been elucidated. In contrast to wealth of information on the pathway leading to activation of c-fos/c-jun genes, knowledge of the latter is scanty. To clarify the mechanisms of activation of c-myc gene by cytokines, we established a transient transfection assay in mouse proB cell line BA/F3 cells expressing hGMR. Analyses of hGMR beta subunit mutants revealed two cytoplasmic regions involved in activation of the c-myc promoter, one is essential and the other is dispensable but enhances the activity. These regions are located at the membrane proximal and the distal regions covering amino acid positions 455-544 and 544-589, respectively. Characterization of cis-acting regulatory elements of the c-myc gene showed that the region containing the P2 promoter initiation site is sufficient to mediate the response to mIL-3 or hGM-CSF. Electrophoretic mobility shift assay using an oligonucleotide corresponding to the distal putative E2F binding site revealed that p107/E2F complex, the negative regulator of E2F, decreased, and free E2F increased after mIL-3 stimulation. These results support the thesis that mIL-3 or hGM-CSF regulates the c-myc promoter by altering composition of the E2F complexes at E2F binding site.
Mol Biol Cell 1995 Jun
PMID:Characterization of cis-regulatory elements of the c-myc promoter responding to human GM-CSF or mouse interleukin 3 in mouse proB cell line BA/F3 cells expressing the human GM-CSF receptor. 757 83

hM-CSF was reported to have biological activity only in a dimeric form. Using oligonucleotide-directed mutagenesis of hM-CSF (1-149aa) cDNA, we have substituted Ser31 for Cys31 which forms intermolecular disulfide bond in native hM-CSF. The mutant hM-CSF cDNA was expressed in insect BmN cells using baculovirus as a vector under the control of polyhedrin promoter. Biological activity analysis and radioligand receptor assay both showed that there was little difference between the mutant hM-CSF and the native dimeric hM-CSF. These results strongly support that the biologically active human M-CSF in its monomeric form can be expressed in recombinant baculovirus infected insect cells.
Biochem Mol Biol Int 1995 Apr
PMID:Human macrophage colony stimulating factor (HM-CSF) expressed in baculovirus infected insect cells is biologically active in its monomeric form. 762 28

In the present study, we have constructed a subtraction cDNA library to identify novel genes induced by IFN-gamma in GM-CSF-derived bone marrow macrophage (m phi). M theta were treated with 50 U/ml IFN-gamma for 40, 70 and 140 min to induce expression of early genes regulated by IFN-gamma, and the M phi were pooled. Poly(A)+RNA was prepared from both unactivated and IFN-gamma-stimulated m theta, and cDNA libraries were constructed in lambda ZAP. Genes expressed in common by both m theta populations were removed by subtraction using biotin-avidin precipitation of hybrid complexes. Further selection was performed by differential screening using cDNA prepared from mRNA of unactivated m phi as a probe, followed by colony hybridization to remove sister clones. Of 17 clones from which sequence information was obtained, two appeared to be identical with the murine genes, C10 (clone GM2B1) and Mac-2 (clone GM2C4) and an additional two clones had high similarity to human cDNAs encoding proteins of unknown function. cDNAs containing sequences which did not match published sequences were used to probe Northern blots prepared from both unstimulated and IFN-gamma-activated GM-CSF- and CSF-1-derived m phi. Five clones (GM1A2, GM1B4, GM1F2, GM2A12 and GM2B8) showed enhanced transcript levels following IFN-gamma treatment of GM-CSF-derived m phi, but demonstrated high constitutive transcript levels in CSF-l-derived m phi. In addition, C10 transcripts were constitutively expressed by GM-CSF-derived m phi, but not by CSF-1-derived m phi, even after activation by IFN-gamma. These data suggest that much of the functional heterogeneity of GM-CSF- and CSF-1-derived m phi resides in the differential expression of early genes specifically induced by IFN-gamma.
Mol Immunol 1995 Jul
PMID:Differential expression of novel genes by bone marrow-derived macrophage populations. 765 99

Human macrophage colony-stimulating factor (hM-CSF) expressed in the silkworm larvae was monomeric. The nature of the interaction of iodinated monomeric M-CSF with murine bone marrow derived macrophage (BMM) was studied. On incubation with 2 nM [125I]M-CSF at 4 degrees C, approximately 90% of the maximal binding occurred within 15 min with a plateau around 1hr which then gradually declined. Scatchard plot analysis showed that the Kd for the monomeric M-CSF is 5.3 x 10(-10) M and the number of binding sites per cell is 4 x 10(4). Competition experiment indicated that cellular binding of the iodinated monomeric rhM-CSF was almost as effective as the native M-CSF. The results show that the interchain disulfide bond of M-CSF is not essential for the natural folding of active M-CSF.
Biochem Mol Biol Int 1995 Feb
PMID:Interaction of silkworm larvae expressed monomeric hM-CSF with its receptor on murine bone marrow derived macrophage. 766 89


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