Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

T-cell activation results in the production of multiple lymphokines. Efficient lymphokine gene expression appears to require both T-cell antigen receptor (TCR) signal transduction and an uncharacterized second or costimulatory signal. CD28 is a T-cell differentiation antigen that can generate intracellular signals that synergize with those of the TCR to increase T-cell activation and interleukin-2 (IL-2) gene expression. In these studies, we have examined the effect of CD28 signal transduction on granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 3 (IL-3), and gamma interferon (IFN-gamma) promoter activity. Stimulation of CD28 in the presence of TCR-like signals increases the activity of the GM-CSF, IL-3, and IFN-gamma promoters by three- to sixfold. As previously demonstrated for the IL-2 promoter, the IL-3 and GM-CSF promoters contain distinct elements of similar sequence which specifically bind a CD28-induced nuclear complex. Mutation of the CD28 response elements in the IL-3 and GM-CSF promoters abrogates the CD28-induced activity without affecting phorbol ester- and calcium ionophore-induced activity. UV cross-linking indicates that the CD28-induced nuclear complex contains polypeptides of approximately 35, 36, and 44 kDa. These studies indicate that the TCR and CD28-regulated signal transduction pathways coordinately regulate the transcription of several lymphokines and that the influence of CD28 signals on transcription is mediated by a common complex.
Mol Cell Biol 1992 Oct
PMID:Regulation of T-cell lymphokine gene transcription by the accessory molecule CD28. 132 52

Recombinant human granulocyte-macrophage colony-stimulating factor (rhuGM-CSF) and recombinant canine granulocyte colony-stimulating factor (rcG-CSF) were administered to normal dogs, and effect on monocyte number and function was evaluated. rhuGM-CSF, administered for 14 days, induced a 2.5-fold increase in monocyte counts on day 3. Leukocytes increased two-fold after 1 day. Counts peaked on day 11, then declined, approaching pretreatment counts by day 15. On day 7, in vivo monocyte cytostasis activity was significantly enhanced, and declined on day 14. rcG-CSF induced a 4.5-fold increase in monocyte counts on day 3. Leukocyte counts increased three-fold after 1 day. Increased counts were maintained for 69 days, at which time treatment was discontinued. There was no effect of rcG-CSF on in vivo monocyte cytostasis activity on days 7 and 14.
Mol Biother 1992 Mar
PMID:Effect of colony-stimulating factors on number and function of circulating monocytes in normal dogs. 137 83

The human monocyte chemoattractant protein (MCP)-1 encoded by the JE gene belongs to a family of low molecular weight secretory cytokines with monocyte-stimulating activity. JE transcripts are constitutively synthesized by normal and leukemic monocytes, as well as mesenchymal cells, including fibroblasts, vascular endothelial cells, and smooth muscle cells. Expression of MCP-1/JE is increased severalfold upon exposure of cells to recombinant human granulocyte-macrophage colony-stimulating factor but is down-regulated when cells are treated with lipopolysaccharide (LPS). Given the proinflammatory properties of MCP-1/JE, we have examined the modulatory effects of various antiinflammatory agents, including indomethacin, dexamethasone, cyclosporin A, and interleukin-4, on levels of MCP-1/JE transcripts either constitutively or inducibly expressed by human peripheral blood monocytes. Whereas indomethacin had no detectable effect on synthesis of MCP-1/JE transcripts and interleukin-4 treatment resulted in only a modest increase in steady state JE mRNA levels, exposure of monocytes to dexamethasone (DXS) led to a significant (2.5-10-fold) down-regulation of MCP-1/JE transcript levels. Studies examining the mechanism of down-regulation of JE mRNA by DXS indicated that DXS was acting transcriptionally and posttranscriptionally, by reducing the transcriptional rate of the MCP-1/JE gene and by destabilizing JE mRNA, a process requiring de novo RNA and protein synthesis. Although cyclosporin A by itself had no effect on synthesis of JE transcripts, it apparently relieved LPS-mediated down-regulation of JE transcript levels, by interfering with the destabilizing effect of LPS on JE mRNA. These results may provide new information regarding the action of antiinflammatory agents on synthesis of endogenous proinflammatory cytokines.
Mol Pharmacol 1992 Jul
PMID:Effect of antiinflammatory agents on synthesis of MCP-1/JE transcripts by human blood monocytes. 138 39

Plasma lactoferrin content was measured before and after therapy with recombinant granulocyte-macrophage colony-stimulating factor in five patients with aplastic anaemia, six with myelodysplasia, and three with prolonged, severe, chemotherapy-induced neutropenia. Before therapy plasma lactoferrin content was uniformly low. However, patients with aplastic anemia and those with chemotherapy-induced neutropenia had a normal lactoferrin:neutrophil ratio. The low levels of plasma lactoferrin thus reflected the low granulocyte mass. On the other hand, patients with myelodysplasia also had reduced lactoferrin:neutrophil ratios, suggesting qualitative/quantitative abnormalities of neutrophil lactoferrin production. After treatment with granulocyte-macrophage colony-stimulating factor, plasma lactoferrin levels increased in patients with aplastic anemia and in those with chemotherapy-induced neutropenia who showed a neutrophil response to treatment. In these patients, the lactoferrin:neutrophil ratio became elevated, suggesting increased synthesis/release of lactoferrin from neutrophils. However, patients with myelodysplasia continued to show depressed lactoferrin:neutrophil ratios, even when there had been an increase in granulocyte count, suggesting persistent abnormalities of neutrophil lactoferrin production/release. The implications of these findings for treatment of neutropenic patients with granulocyte-macrophage colony-stimulating factors are discussed.
Mol Biother 1992 Jun
PMID:Plasma lactoferrin content in neutropenic patients: effects of treatment with recombinant granulocyte-macrophage colony-stimulating factor. 151 94

The crystal structure of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) has been determined at 2.8 A resolution using multiple isomorphous replacement techniques. There are two molecules in the crystallographic asymmetric unit, which are related by an approximate non-crystallographic 2-fold axis. The overall structure is highly compact and globular with a predominantly hydrophobic core. The main structural feature of rhGM-CSF is a four alpha-helix bundle, which represents approximately 42% of the structure. The helices are arranged in a left-handed antiparallel bundle with two overhand connections. Within the connections is a two-stranded antiparallel beta-sheet. The tertiary structure of rhGM-CSF has a topology similar to that of porcine growth factor and interferon-beta. Most of the proposed critical regions for receptor binding are located on a continuous surface at one end of the molecule that includes the C terminus.
J Mol Biol 1992 Apr 20
PMID:Three-dimensional structure of recombinant human granulocyte-macrophage colony-stimulating factor. 156 68

We examined the effects of various hemopoietins on c-kit mRNA and protein expression. Interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor, and erythropoietin, but not IL-4, down-regulated levels of c-kit mRNA expressed by mast cells and stem cell progenitors. The effect of IL-3 was dominant and independent of cell growth or viability and was paralleled by reduced expression in c-kit protein. These observations indicate that regulation of c-kit expression is closely interlinked with the molecular mechanisms triggered by erythropoietin, IL-3, and granulocyte-macrophage colony-stimulating factor.
Mol Cell Biol 1991 May
PMID:Modulation of c-kit mRNA and protein by hemopoietic growth factors. 170 97

Colony-stimulating factor-1 (CSF-1) has been primarily characterized as a hematopoietic growth factor required for the proliferation and differentiation of monocytic cells. Recent immunohistological observations have shown that this growth factor is also synthesized by the glandular epithelial cells of the pregnant human endometrium and by first trimester human trophoblasts. In the present study endometrial glands were purified from nonpregnant human endometria collected through the menstrual cycle and examined for CSF-1 mRNA expression. The two major mRNAs (4.0 and 3.0 kilobases in length) detected in midproliferative and midsecretory phases differed in the size of the exon 6 and coded, respectively, for a secreted and a cell surface form of CSF-1. The 3.0-kilobase transcript represented a novel CSF-1 mRNA species that was molecularly cloned and sequenced. These data raise the possibility that CSF-1 may be involved in both distant and cell to cell regulatory pathways of cell proliferation and differentiation in the human endometrium.
Mol Endocrinol 1991 Dec
PMID:Expression of colony-stimulating factor-1 (CSF-1) messenger RNA in human endometrial glands during the menstrual cycle: molecular cloning of a novel transcript that predicts a cell surface form of CSF-1. 179 39

Cultured human bronchial epithelial cells constitutively produce granulocyte/macrophage colony-stimulating factor (GM-CSF). An upregulation of the synthesis and release of GM-CSF from those cells might contribute to the persistence of infiltration and local activation of inflammatory cells in some inflammatory diseases of the airways, such as asthma. Increased levels of immunoreactive and biologically active interleukin-1 (IL-1) have been identified in the airway secretions of asthmatic patients, together with an increase in GM-CSF contents. As IL-1 is known to upregulate GM-CSF production in many cell populations, in this study we investigated the ability of IL-1 to bind to specific receptors on bronchial epithelial cells and promote GM-CSF synthesis and release. Bronchial epithelial cells possessed specific single-class surface receptors for recombinant IL-1. The addition of exogenous IL-1 led to a dose-dependent increase in the accumulation of GM-CSF mRNA and release of immunoreactive GM-CSF to the culture medium. Release of IL-1 in the bronchial mucosa during allergic and nonallergic responses may lead to enhanced GM-CSF synthesis and release by epithelial cells, thus promoting airway inflammation.
Am J Respir Cell Mol Biol 1991 Jun
PMID:Interleukin-1 binds to specific receptors on human bronchial epithelial cells and upregulates granulocyte/macrophage colony-stimulating factor synthesis and release. 182 52

An AU-rich sequence present within the 3' untranslated region has been shown to mark some short-lived mRNAs for rapid degradation. We demonstrate by label transfer and gel shift experiments that a 32-kDa polypeptide, present in nuclear extracts, specifically interacts with the AU-rich domains present within the 3' untranslated region of human granulocyte-macrophage colony-stimulating factor, c-fos, and c-myc mRNAs and a similar domain downstream of the poly(A) addition site of the adenovirus IVa2 mRNA. Competition experiments and partial protease analysis indicated that the same polypeptide interacts with all four RNAs. A single AUUUA sequence in a U-rich context was sufficient to signal binding of the 32-kDa polypeptide. Insertion of three copies of this minimal recognition site led to markedly reduced accumulation of beta-globin RNA, while the same insert carrying a series of U-to-G changes had little effect on RNA levels. Steady-state levels of beta-globin-specific nuclear RNA, including incompletely processed RNA, and cytoplasmic mRNA were reduced. Cytoplasmic mRNA containing the AU-rich recognition sites for the 32-kDa polypeptide exhibited a half-life shorter than that of mRNA with a mutated insert. We suggest that binding of the 32-kDa polypeptide may be involved in the regulation of mRNA half-life.
Mol Cell Biol 1991 Jun
PMID:A 32-kilodalton protein binds to AU-rich domains in the 3' untranslated regions of rapidly degraded mRNAs. 190 42

Previously we have described the derivation of three distinct classes of leukemic cell clones from a single in vivo-passaged myelomonocytic leukemia, WEHI-274, that arose in a mouse infected with the Abelson leukemia virus/Moloney leukemia virus complex (K. B. Leslie and J. W. Schrader, Mol. Cell. Biol. 9:2414-2423, 1989). The three classes of cell clones were characterized by distinct patterns of growth in vitro, the production of cytokines, and the presence of cytokine gene rearrangements. However, all three classes of WEHI-274 clones bore a common rearrangement of the c-myb gene, suggesting that all were derived from the one ancestral cell and that at least three distinct and independent autostimulatory events were involved in the progression of a single myeloid leukemic disease. In this article, we demonstrate that the autocrine growth factor production by the WEHI-274 leukemic clones resulted from cytokine gene activations mediated by the insertion of an intracisternal A-type particle (IAP) sequence 5' to the interleukin-3 (IL-3) gene, in the case of the class I clone, or 5' to the gene for granulocyte-macrophage colony-stimulating factor (GM-CSF), in the case of the class II clones. IAPs are defective murine retroviruses encoded by endogenous genetic elements which may undergo transpositions and act as endogenous mutagens. The functional IL-3 and GM-CSF mRNAs were generated by mechanisms in which the splice donor apparatus of the IAP sequence has been used in IAP gag-to-IL-3 or -GM-CSF splicing events.
Mol Cell Biol 1991 Nov
PMID:Intracisternal A-type particle-mediated activations of cytokine genes in a murine myelomonocytic leukemia: generation of functional cytokine mRNAs by retroviral splicing events. 192 64


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