Gene/Protein Disease Symptom Drug Enzyme Compound
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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)

Presented are the steps in creating a recombinant DNA molecule, examples of recombinant drug products, a description of DNA fingerprinting methods for diagnosing diseases, a discussion of the patenting of recombinant drugs, and a look to the future of this revolutionary biotechnology. Constructing a recombinant DNA molecule involves cutting the DNA into fragments with restriction endonucleases and rejoining the fragments in novel arrangements with ligase. Propagating the molecule in a microorganism, or cloning, is necessary to increase the number of gene copies to facilitate detection of the gene of interest and to produce the protein it encodes. Recombinant DNA drug products have been developed that represent the communicator, structural, and modifier classes of proteins. Recombinant communicator proteins include interferons alfa-2a and alfa-2b and granulocyte-macrophage colony-stimulating factor (immune system modulators); epidermal growth factor and erythropoietin (tissue repair promoters); and human insulin, growth hormone, and atrial peptide (metabolism modulators). Recombinant structural proteins include hepatitis B virus vaccine and CD4 protein, and recombinant modifier proteins include tissue plasminogen activator and superoxide dismutase (agents that split or splice organic molecules). In the future, gene defects associated with genetic diseases will be unraveled, leading to the production of new therapeutic agents designed to counteract or actually reverse those defects. Recombinant protein drugs will be further tailored to enhance their activity and specificity. These advances are so novel and momentous that patent protection has been extended not only to recombinant drugs but to the recombinant microorganisms in which they are manufactured. In cloning genes, investigators directly use the protein designs that occur naturally. Basic research will soon lead to the engineering of novel proteins with specified functions.
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PMID:Drug products of recombinant DNA technology. 267 63

A number of recombinant cytokines believed to regulate normal hematopoiesis are now being used in cancer treatment protocols to reduce the myelosuppressive toxicity of intensive chemoradiotherapy regimens. It is widely assumed that such cytokines are relatively specific for hematopoietic cells, although some cell lines derived from a variety of non-hematopoietic human tumors can respond to some of these factors. However, relatively little is known about their ability to stimulate (or inhibit) the proliferation of freshly isolated normal or malignant non-hematopoietic cells. We have used a serum-free culture medium that selectively supports the growth of human breast epithelial cells (HBEC) obtained directly from normal or malignant tissue samples to evaluate potential stimulatory or inhibitory effects of eight cytokines: granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, Steel factor, interleukin-2, interleukin-3, interleukin-6, transforming growth factor-beta and macrophage inflammatory protein-1 alpha, on these cells cultured both in the presence of epidermal growth factor, a potent stimulator of HBEC growth, and in its absence. HBEC growth was assessed after 7 and 14 days using the tetrazolium-dye reduction assay. Potential effects on the well studied MCF-7 breast cancer cell line, cultured under the same conditions, were also investigated. None of the cytokines (which were tested over a wide range of concentrations) had any modulating effect on the growth of normal or malignant HBEC under the conditions used with the exception of transforming growth factor-beta, which was consistently and significantly inhibitory.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lack of effect of hematopoietic growth factors on human breast epithelial cell growth in serum-free primary culture. 751 1

The upstream regulatory region of the c-fos promoter contains two growth factor-regulated promoter elements: the serum response element, which binds a ternary complex comprising serum response factor (SRF) and a ternary complex factor (TCF); and the sis-inducible element (SIE) which binds STAT transcription factors. We used transient transfection of c-fos promoter mutants in NIH 3T3 cells to assess the contributions of these elements to activation by different extracellular stimuli. Colony-stimulating factor-1, platelet-derived growth factor and epidermal growth factor activate the c-fos promoter via cooperation of the SIE and the SRE; however, mutants that can bind SRF but not STATs or TCF remain inducible by whole serum. Activation by the SIE is context-dependent: interferons activate STAT DNA binding activity and transcription of SIE reporter genes, but not the c-fos promoter, which requires an additional ras-dependent signal. SRE activation by receptor tyrosine kinases requires TCF binding, and can be mediated by the TCF Elk-1. In contrast, SRE activation following activation of heterotrimeric G proteins by lysophosphatidic acid or aluminium fluoride ion requires SRF but is independent of TCF binding. These results suggest that heterotrimeric G proteins activate a signalling pathway distinct from those that activate the STATs and the TCFs, that controls SRF activity.
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PMID:Differential activation of c-fos promoter elements by serum, lysophosphatidic acid, G proteins and polypeptide growth factors. 758 32

The product of the c-raf-1 proto-oncogene, Raf-1, is known to encode a 74-kDa ubiquitously expressed cytoplasmic serine/threonine kinase. Various growth factors such as epidermal growth factor, acidic fibroblast growth factor, platelet-derived growth factor, insulin, granulocyte-macrophage colony-stimulating factor, interleukin (IL)-2, IL-3 and erythropoietin have been shown to induce phosphorylation of Raf-1, thereby activating Raf-1 kinase. Raf-1 is, thus, believed to play a role in coupling growth factor receptors to proliferation. We have examined the role of Raf-1 in the mitogenic response of human peripheral blood-derived IL-2 receptor expressing T cells to human recombinant IL-2 employing c-raf antisense (AS) oligodeoxyribonucleotide. Uptake studies of oligonucleotides indicated that incorporation of oligomers was maximal at 4 h and oligodeoxynucleotides remained stable in these cells for up to 24 h. Treatment of T cells with the AS oligodeoxyribonucleotide in intracellular duplex formation followed by efficient translation blockade of c-raf-1. In contrast, sense (S) and nonsense (NS) oligodeoxynucleotides failed to form intracellular duplexes and did not interfere with translation of c-raf-1, suggesting specific elimination of c-raf-1 by the AS oligomer. Proliferation of T cells ([3H]thymidine incorporation) following exposure to IL-2 was substantially reduced when the c-raf-1 AS oligodeoxyribonucleotide was added to cultures, while the mitogenic response to this factor remained almost unaffected in the presence of S and NS oligodeoxyribonucleotides.
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PMID:The mitogenic response of T cells to interleukin-2 requires Raf-1. 825 28

A naturally occurring receptor-level antagonist of interleukin-1 (IRAP or IL-1 ra) has recently been cloned. To determine what stimuli might regulate this inhibitor, cytokines were tested for their effects on the steady-state level of IRAP mRNA in phorbol ester-differentiated U937 cells. The cytokines tested fell into one of three groups: (a) inducers: granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-4, (b) weak inducers (< 2-fold stimulation): [IL-1 alpha, IL-1 beta, and transforming growth factor-beta (TGF-beta)] and (c) cytokines with no effect: (IL-2, platelet-derived growth factor, acidic fibroblast growth factor, basic fibroblast growth factor, epidermal growth factor, granulocyte colony-stimulating factor, IL-3, IL-5, IL-6, interferon-gamma, multi-colony stimulating factor, tumor necrosis factor-alpha and IRAP itself. One hundred U/ml of either GM-CSF or IL-4 was the dose inducing peak IRAP mRNA expression; that peak expression occurred 12 h after addition of cytokine. GM-CSF induced a 34 +/- 15-fold increase in IRAP mRNA, and IL-4 induced a 15 +/- 6-fold increase. In the same RNA samples, GM-CSF increased IL-1 beta mRNA 5.9 +/- 1.7-fold, but IL-4 decreased IL-1 beta mRNA to half that of control levels (0.45 +/- 0.17). Thus, a single stimulus (IL-4) decreased the expression of an agonist (IL-1) while it increased the expression of an antagonist (IRAP). When U937 cells were treated with both IL-4 and GM-CSF, the level of IRAP mRNA induced was additive, suggesting that the cytokines acted differently to increase IRAP mRNA levels. The level of IL-1 mRNA in cells treated with both IL-4 and GM-CSF was intermediate. Dexamethasone and cycloheximide inhibited all mRNA increases and did not reverse IL-4-induced decreases in IL-1 mRNA. These studies have identified two cytokines which induce IRAP in the monocytic cells studied, and have partially characterized the differential regulation of IL-1 and its antagonist, IRAP.
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PMID:Cytokine regulation of the interleukin-1 receptor antagonist protein in U937 cells. 841 85

Blastocysts were flushed from CD1 mice and were cultured in plastic or laminin-coated plates as an in vitro model of implantation. The purified cytokines epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) markedly stimulated 3H-thymidine incorporation; but recombinant murine granulocyte-macrophage colony-stimulating factor (GM-CSF), which might be produced by alloantigen-stimulated T cells at the feto-maternal interface, had no growth-stimulating effect. Indeed, higher nonphysiological concentrations of GM-CSF manifested a toxic inhibition. Surprisingly, a purified nonrecombinant murine GM-CSF preparation induced proliferation of both blastocyst and ectoplacental cone trophoblast whereas recombinant murine (and human) GM-CSF had no effect, indicating that the growth stimulation may have been due to a contaminant. Decidual supernatants prepared on Days 5.5-6.5 of pregnancy from mice with high abortion rates (DBA/2-mated CBA/J) had no toxic or stimulating effect on blastocyst trophoblast outgrowth compared to similarly prepared supernatants from low-abortion-rate DBA/2-mated C3H/HeJ mice. These data suggest that it is not GM-CSF that is crucial for the trophoblast proliferation that determines the success of pregnancy.
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PMID:Effects of decidual cell supernatants and lymphokines on murine trophoblast growth in vitro. 848 59

The ability to culture human thymic epithelial cells has greatly facilitated studies of direct cell-cell interaction between thymic epithelial cells and T lymphocytes in vitro, as well as cytokine production and regulation of cytokine production. In vitro, human thymic epithelial cells bind to T lymphocytes via two adhesion pathways: CD2-lymphocyte function-associated antigen-3 and lymphocyte function-associated antigen-1-intercellular adhesion molecule-1. Cultured human thymic epithelial cells produce interleukins-1 alpha, -1 beta, -3, -6 and -8, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, leukemia inhibitory factor and transforming growth factor-alpha. Production of thymic epithelial cell-derived cytokines is regulated by both adhesion molecules (lymphocyte function-associated antigen-3) and soluble factors via both autocrine (interleukin-1 alpha, transforming growth factor-alpha) and paracrine (interleukin-4, interferon-gamma) pathways. Transforming growth factor-alpha and epidermal growth factor regulate various cytokine mRNA at a post-transcriptional level by increasing cytokine mRNA stability.
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PMID:Human thymic epithelial cells: adhesion molecules and cytokine production. 851 15

Prostate tumor cells preferentially metastasize to bony sites and lymph nodes at a frequency in excess of that which would be predicted by random tumor cell dissemination. In order to determine whether chemoattractants in these organs promote organ-specific metastasis, we utilized human cell lines derived from and/or related to these organs as sources of potential chemoattractants. Secretory proteins derived from the cell lines MG-63 (osteosarcoma), SK-ES-1 (Ewing's sarcoma), and KG-1 (leukemia) stimulated chemomigration of the TSU-pr1 prostate tumor cells in a dose-dependent manner in Boyden chambers. In addition, secretory proteins from a human prostatic stromal cell line (hPS) and from the TSU-Pr1 prostate tumor cell line were also able to stimulate chemomigration of the TSU-pr1 cells through Boyden chambers. Since lymph nodes and bony sites represent organs of hematopoietic/lymphoid proliferation and activation, we undertook identification of specific cytokines present at these sites which may promote the chemomigration of prostate tumor cells. In this context, the cytokines interleukin-1 alpha, interleukin-2, interleukin-6, tumor necrosis factor-beta, transforming growth factor-beta, interferon alpha 2-a, and granulocyte-macrophage colony-stimulating factor did not stimulate chemomigration of the TSU-pr1 prostate tumor cell line. In contrast, the cytokine epidermal growth factor (EGF) stimulated chemomigration of the TSU-pr1 prostate tumor cells through the Boyden chambers in a dose-dependent manner. Western blot analysis of secretory proteins from the cell lines KG-1, SK-ES-1, MG-63, hPS, and TSU-pr1 identified EGF-immunoreactive proteins in all cases. In addition, EGF immunoreactivity was localized to the stroma of the human prostate, the osteogenic stroma of pelvic medullary bone, and the stroma within the capsule and trabeculae of pelvic lymph nodes. Hence, these results demonstrate that the cytokine EGF promotes the chemomigration of the TSU-pr1 prostate tumor cell line, and that EGF within the stroma of pelvic lymph nodes and medullary bone may act as a chemoattractant for prostate tumor cells, thereby facilitating the preferential formation of metastatic foci within these organs.
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PMID:Epidermal growth factor (EGF) promotes chemomigration of a human prostate tumor cell line, and EGF immunoreactive proteins are present at sites of metastasis in the stroma of lymph nodes and medullary bone. 854 75

We have examined basal and lipopolysaccharide (LPS)-induced release of epidermal growth factor (EGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), growth-regulated peptide alpha (GRO alpha), leukaemia inhibitory factor (LIF), macrophage inflammatory protein-1a (MIP-1 alpha) and platelet-derived growth factor-AB (PDGF-AB) in peripheral blood mononuclear cells (PBMC) from 20 persons with either high (n = 10) or low (n = 10) levels of high-density lipoprotein (HDL). PBMC were incubated with 100 ng LPS/ml for up to 160 h, and showed a significantly higher release of the chemokines GRO alpha (P = 0.04) and MIP-1 alpha (P < 0.01) in persons with high HDL, whereas levels of GM-CSF were similar. Levels of EGF, LIF and PDGF-AB were always low, and remained unaltered during 160 h of incubation. These findings indicate that PBMC from persons with high or low levels of HDL have different functional properties, of importance in cell recruitment and activation.
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PMID:LPS-induced release of EGF, GM-CSF, GRO alpha, LIF, MIP-1 alpha and PDGF-AB in PBMC from persons with high or low levels of HDL lipoprotein. 858 Mar 73

We demonstrate the constitutive expression of interleukin 6 (IL-6), IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha) and epidermal growth factor receptor (EGFR) in normal kidney cells, and in the majority of renal oncocytomas, papillary and non-papillary renal cell carcinomas (RCCs) by reverse transcriptase polymerase chain reaction (RT-PCR) technique. No expression of IL-6 and TGF-alpha and variable expression of GM-CSF, IL-8, EGF and EGFR was seen in chromophobe RCCs. The lack of expression of IL-6 and TGF-alpha might be correlated with the growth pattern, poor vascularity and low malignancy of chromophobe RCCs.
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PMID:Lack of interleukin 6 (IL-6) and transforming growth factor alpha (TGF-alpha) expression in chromophobe renal cell carcinomas. 982 Jan 73


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