Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The c-kit proto-oncogene encodes the receptor for a novel hemopoietic cytokine, termed stem cell factor (SCF) or mast cell growth factor (MGF) according to its stimulating spectrum. The human receptor for SCF/MGF is expressed in a subset of normal bone marrow progenitor cells, in leukemic myeloid cells, and in mast cells. In the present study, the effects of recombinant human growth regulators (IL-1 through -9, granulocyte-macrophage/granulocyte/macrophage-CSF, IFN, and TNF) on c-kit proto-oncogene product expression were analyzed by indirect immunofluorescence, by using the anti-SCF/MGFR mAb YB5.B8, and Northern blot analyses, by using a c-kit oligonucleotide probe. Of all cytokines tested, IL-4 was found to down-regulate expression of YB5.B8 Ag in the human mast cell line HMC-1 (maximum inhibition, 51.05 +/- 16.36% mean fluorescence intensity of control; p less than 0.02), as well as in primary leukemic myeloid cells. IL-4 was also found to down-regulate expression of YB5.B8 Ag in normal enriched bone marrow progenitor cells. The effects of IL-4 on expression of YB8.B8 Ag in myeloid/mast cell progenitors was dose and time dependent (maximum effects observed on days 2 and/or 4, by using 50 U/ml of rIL-4) and could be neutralized by using anti-IL-4 mAb. Moreover, IL-4 was found to down-regulate expression of c-kit mRNA in leukemic myeloid cells as well as in HMC-1 cells. Together, these observations identify IL-4 as a regulator of c-kit proto-oncogene product expression in the human system. The effects of IL-4 on human hemopoietic progenitor cells and mast cells may be mediated in part through regulation of SCF/MGFR expression.
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PMID:IL-4 regulates c-kit proto-oncogene product expression in human mast and myeloid progenitor cells. 172 42

Tumor necrosis factor alpha (TNF alpha), as a modulator of hematopoiesis, interacts with many growth factor receptors, such as interleukin-3, granulocyte-macrophage colony-stimulating factor (CSF), and granulocyte-CSF receptors. Here, we studied the interactions between TNF alpha and the stem cell factor (SCF) receptor, c-kit, in normal CD34+ hematopoietic progenitors and their leukemic counterpart, ie, acute myeloid leukemic (AML) CD34+ cells coexpressing c-kit antigen. The results showed that (1) incubation of normal bone marrow mononuclear cells with 200 U/mL rhTNF alpha for 20 hours induced a diminution of 31.2% +/- 5.2% of CD34+ cells coexpressing c-kit; (2) the same decrease was observed using purified CD34+ cells and, furthermore, their proliferative response to SCF was inhibited by 31.5% +/- 7.3% after exposure to TNF alpha; (3) similar experiments performed on CD34+ c-kit+ AML cells from 11 patients gave comparable results. Further analysis at the mRNA level indicated that TNF alpha decreased c-kit mRNA transcripts. Moreover, using monoclonal antibodies against the two types of TNF alpha receptors, p75 and p55, we showed that the downregulation of c-kit proto-oncogene product by TNF alpha, on normal and leukemic CD34+ cells, was exclusively mediated by the TNF alpha p55 receptor. Therefore, we conclude that TNF alpha acts as a downregulator of the SCF receptor expression.
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PMID:Tumor necrosis factor alpha (TNF alpha) downregulates c-kit proto-oncogene product expression in normal and acute myeloid leukemia CD34+ cells via p55 TNF alpha receptors. 752 32

TNF-alpha is a pleiotropic cytokine with stimulatory as well as inhibitory effects on hematopoiesis. We have previously demonstrated that TNF-alpha directly inhibits CSF-induced proliferation of primitive murine lineage-negative bone marrow progenitors (Lin-) and stem cell antigen-1 hematopoietic progenitors through the 75-kDa TNF receptor (TNF-R2), whereas TNF-alpha-induced inhibition of more committed Lin- progenitors is mediated through the 55-kDa TNF-R (TNF-R1), indicating a differential role of the two TNF-Rs in hematopoiesis. Numerous studies have demonstrated the ability of stem cell factor (SCF), a key regulator of hematopoiesis signaling through c-kit, to synergize with other hematopoietic growth factors, but little is known about cytokines capable of inhibiting hematopoiesis induced by SCF. While TNF-alpha has been demonstrated to enhance SCF-induced proliferation of myeloid leukemia blasts, the present report demonstrates that TNF-alpha, by signaling through TNF-R2, inhibits SCF-induced proliferation of normal murine Lin- and stem cell antigen-1 hematopoietic progenitors. SCF-stimulated proliferation of the hematopoietic cell line FDC-P1 was also potently inhibited by TNF-alpha and was accompanied by down-regulation of c-kit cell surface expression as well as c-kit mRNA levels. Finally, treatment of the FDC-P1 cell line with TNF-alpha resulted in increased levels of the tumor suppressor p53 mRNA, suggesting another mechanism by which hematopoietic effects of TNF-alpha may be mediated.
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PMID:Inhibition of stem cell factor-induced proliferation of primitive murine hematopoietic progenitor cells signaled through the 75-kilodalton tumor necrosis factor receptor. Regulation of c-kit and p53 expression. 753 12

We have investigated the stimulative effects of mast cell growth factor (MGF) in primary acute myeloid leukemia (AML) in vitro. MGF stimulated DNA synthesis of purified leukemic blasts in eight out of 10 cases and colony formation in four cases in serum-free (SF) culture. MGF synergized with interleukin-3 (IL-3; four out of 10 cases), granulocyte-macrophage colony-stimulating factor (GM-CSF; three out of 10 cases), granulocyte colony-stimulating factor (G-CSF; six out of 10 cases), macrophage colony-stimulating factor (M-CSF; one out of 10 cases) and erythropoietin (EPO; one out of 10 cases) when added to culture in combination. Synergistic effects of MGF in combination with other CSFs were also seen in the colony assay. Antibodies against GM-CSF, M-CSF, G-CSF, and IL-6 did not inhibit the MGF response, suggesting that the stimulative effect of MGF was not mediated through autocrine release of those cytokines. Cell recovery data in liquid cultures that contained MGF, IL-3, or MGF + IL-3, indicated that both MGF and IL-3 augmented the maintenance of clonogenic cells as compared to nonsupplemented cultures, but the effect of the combination of IL-3 + MGF did not show synergy. In contrast, activation of DNA synthesis by MGF was abrogated in the presence of tumor necrosis factor (TNF; four out of 10 cases) and interleukin-4 (IL-4; two out of 10 cases). Fluorescence-activated cell sorting (FACS) analysis with anti c-kit antibodies revealed MGF receptor expression in eight out of nine cases, often in a subpopulation of the cells. Scatchard analysis of MGF receptors in two cases indicated the presence of 1460 and 41,500 (mean) binding sites, respectively, of high affinity (Kd 40-160 pmol/l). The MGF dose-response curve in the presence of IL-3 or GM-CSF resulted in a higher plateau of DNA synthesis, however no shift in the dose response was apparent. The respective reciprocal dose response relations to GM-CSF, IL-3, or G-CSF were similarly elevated when MGF was added. MGF did not alter IL-3 and GM-CSF receptor expression, nor did IL-3, GM-CSF, G-CSF, TNF, or IL-4 influence MGF binding to AML cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of mast cell growth factor on acute myeloid leukemia cells in vitro: effects of combinations with other cytokines. 768 Apr 1

Several cytokines have been identified that support the development of dendritic cells from murine and human precursor populations, most notably GM-CSF, TNF alpha, and IL-4. We have been interested in human bone marrow as a source of defined CD34+ progenitors to generate large numbers of autologous dendritic cells for use as adjuvants in immune based therapy. In serum-replete conditions with c-kit-ligand, GM-CSF, and TNF alpha, dendritic cells constitute approximately 10-15% of the myeloid progeny (equivalent to approximately 1.7 x 10(6) dendritic cells per single ml of starting bone marrow); and they develop together with granulocytic intermediates and monocytes in the same cultures. CD14- dendritic cells share expression of class II MHC and costimulatory ligands with CD14+ monocyte progeny, but only the CD14- HLA-DR+ dendritic cells are highly stimulatory of resting unprimed T cells. We have further identified a novel colony that develops in the presence of GM-CSF and TNF alpha alongside typical CFU-GM, which is comprised of dendritic cells mixed with < or = 15% monocytes (CFU-DC/mono). c-kit-ligand recruits and expands early progenitors responsive to the dendritic cell-differentiating effects of GM-CSF and TNF alpha, effecting a 100- to 1000-fold greater expansion of CFU-DC/mono by 14d and 21d respectively than does the combination of GM-CSF and TNF alpha without c-kit-ligand.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Progenitor recruitment and in vitro expansion of immunostimulatory dendritic cells from human CD34+ bone marrow cells by c-kit-ligand, GM-CSF, and TNF alpha. 852 47

There is considerable evidence to suggest that polypeptide growth factors from either the oviduct or the endometrium can control preimplantation development of the mammalian embryo. These act directly through receptors expressed on the embryo. In addition, embryos also produce growth factors. The reverse transcriptase-polymerase chain reaction (RT-PCR) was used to determine the pattern of expression of mRNAs encoding several growth factor ligand and receptor genes throughout preimplantation development of cryopreserved human embryos. Transcripts encoding the receptor for c-fms, the receptor for colony-stimulating factor-1 (CSF-1), and c-kit (the receptor for stem cell factor [SCF]) were expressed throughout preimplantation development. Other growth factor ligand and receptor transcripts were expressed in a stage-specific manner: these included receptors for interleukin (IL)-6 (IL-6R), leukemia inhibitory factor (LIFR), tumor necrosis factor alpha (TNF alpha) (TNFRp80 and TNFRp60), and gp130. The transcripts for gp130 and the ligand SCF showed stage-specific splice variants. Blastocysts expressed a novel cDNA encoding gp130, which predicts a truncated form lacking the intracellular signaling domain. No expression of mRNAs encoding LIF, CSF-1, or the cloned receptor for platelet-activating factor was seen in any embryonic stage studied. We have shown that RT-PCR provides a sensitive and powerful method for identifying transcripts encoding growth factors and their receptors in single human embryos. The method is economical, allowing the expression pattern of many genes to be determined from a single embryo. These data are important in defining which cytokines may be involved in regulating human preimplantation development and when they may act.
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PMID:Stage-specific expression of cytokine and receptor messenger ribonucleic acids in human preimplantation embryos. 854 94

The increased reactivity of mast cells during allergic airway inflammation has been linked to several aspects of pulmonary disease. A primary inducer of mast cell differentiation, proliferation, and activation has been identified as c-kit ligand or stem cell factor (SCF). In the present study, we used an established murine model of allergic eosinophilic airway inflammation to examine the role of SCF during an Ag-specific airway response. Initial data demonstrates increased SCF protein production at 8 h postchallenge in both lungs and serum of allergen-challenged, but not vehicle-challenged, mice. The immunolocalization of SCF in Ag-challenged lungs suggested that macrophage populations were the primary source of SCF, while epithelial cell regions also stained positive. Intense immunohistochemical staining of macrophages in bronchoalveolar lavage samples recovered from Ag-sensitized mice indicate that these cells may be a significant source of SCF in the lungs. Alveolar macrophages from the airways of normal mice stimulated with either TNF (0.1-10 ng/ml) or IL-4 (10 ng/ml) produced significant levels of SCF. Furthermore, neutralization studies demonstrated that the inhibition of airway SCF during allergen challenge significantly decreased eosinophil, but not neutrophil, infiltration throughout the response. Furthermore, when mice were treated with anti-SCF Ab, histamine levels were significantly reduced at 8 h postchallenge, the time of significant SCF production. Together, these data indicate that the production of SCF during Ag-induced lung inflammation by alveolar macrophages can play a significant role in the subsequent recruitment of eosinophils, possibly via mast cell activation and degranulation.
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PMID:Stem cell factor (c-kit ligand) influences eosinophil recruitment and histamine levels in allergic airway inflammation. 862 35

The expression of cytokine receptors by a variety of solid tumour tissues was examined, using an immunofluorescence procedure optimized for sensitivity. Several cytokines generally considered as relevant only to the immune and haematopoietic systems were shown to be expressed by solid tumours. For example, breast carcinoma frequently expressed both chains of the IL-3 receptor, the beta chain of the IL-2 receptor, the TNF type two receptor, the signal-transducing chain CD130, and c-kit. The broad expression of cytokine receptors suggests that the receptor profile of individual tumours should be determined before the application of therapy that involves the administration of cytokines.
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PMID:Cytokine receptor expression by solid tumours. 872 78

The murine cell line SR-4987 was originated in our laboratory from adherent cells of a long term bone marrow culture. SR-4987 cells do not express p21-ras and c-fms products on membrane whereas secrete M-CSF, evidence a fibroblast-like morphology and are vimentine positive. This line shows a very poor "in vitro" agar clonogenicity which is not modulated by the addition of different cytokines and growth factors (M-CSF, GM-CSF, G-CSF, IL-3, IL-7, alpha-TNF, PDGF, and EGF). On the contrary, a dramatic increase in clonogenicity is observed in the presence of bFGF. The RT-PCR investigation evidences the mRNA encoding for bFGF, IL-7, GM-CSF, and SCF (c-kit ligand). The analysis of CD antigen expression on SR-4987 cell membrane indicates a phenotype (CD5+, CD44+, 45R(B220)+, sIg+, 5'-nucleotidase+) that is consistent with a B cell feature. Our observations suggest that exogenous bFGF might represent an appropriate stimulus for inducing the SR-4987 cells proliferation also in the absence of cell-substrate anchorage. Further, they indicate that SR-4987 cells could represent a particular differentiation stage in which characters of "stromal cell" and "B cell" are coexpressed in agreement with the hypothesis of a common stromal-hematopoietic differentiation.
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PMID:Expression of B cell markers on SR-4987 cells derived from murine bone marrow stroma. 919 33

Human dendritic cells can be generated from bone marrow CD34+ progenitors in the presence of GM-CSF and TNF alpha. The addition of a factor like c-kit-ligand optimizes the expansion of dendritic cells, as well as the other myeloid progeny grown under the same conditions, and facilitates their identification and characterization. In contrast to cord blood, where dendritic cells account for the majority of the class II MHC positive myeloid progeny, bone marrow CD34(+)-derived dendritic cells are less frequent than macrophages. When mature macrophages are depleted from days 5-6 cultures, terminally differentiated CD14+ HLA-DR dendritic cells as well as non-monocyte/macrophage CD14+ HLA-DR+ cells can be distinguished. The latter are post-CFU, bipotential, intermediate precursors that can terminally differentiate into either dendritic cells or macrophages depending on subsequent cytokine exposure. Human CD34+ progenitors isolated from bone marrow, as well as cord and peripheral blood, include CFU-DC that give rise to pure dendritic cell colonies in the combined presence of GM-CSF and TNF alpha. The different sources of CD34+ progenitors are not equivalent, however, with respect to frequency of CFU-DC growth. Cord blood is relatively enriched for dendritic cell progenitors. The developmental relationship of CFU-DC and CFU-GM, to the early developing dendritic cells and the bipotential intermediates observed in suspension culture, is not yet established.
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PMID:Growth and differentiation of human dendritic cells from CD34+ progenitors. 928 31


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