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)

In the presence of hemopoietic cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), mast cell growth factor (MGF; also known as steel factor, stem cell factor, and c-kit ligand) has proven to be a potent hemopoietic regulator in vitro. In these studies, we examined the in vivo effects of MGF in combination with GM-CSF or GM-CSF plus IL-3. Effects were based on the ability of these cytokines to stimulate recovery from radiation-induced hemopoietic aplasia. Female B6D2F1 mice were exposed to a sublethal 7.75-Gy dose of 60Co radiation followed by subcutaneous administration of either saline, recombinant murine (rm) MGF (100 micrograms/kg/day), rmGM-CSF (100 micrograms/kg/day), rmIL-3 (100 micrograms/kg/day), or combinations of these cytokines on days 1-17 postirradiation. Recoveries of bone marrow and splenic spleen colony-forming units (CFU-s), granulocyte macrophage colony-forming cells (GM-CFC), and peripheral white blood cells (WBC), red blood cells (RBC) and platelets (PLT) were determined on days 14 and 17 during the postirradiation recovery period. MGF administered in combination with GM-CSF or in combination with GM-CSF plus IL-3 either produced no greater response than GM-CSF alone or down-regulated the GM-CSF-induced recovery. These results sharply contrasted results of in vitro studies evaluating the effects of these cytokines on induction of GM-CFC colony formation from bone marrow cells obtained from normal or irradiated B6D2F1 mice, in which MGF synergized with GM-CSF or GM-CSF plus IL-3 to increase both GM-CFC colony numbers and colony size. These studies demonstrate a dichotomy between MGF-induced effects in vivo and in vitro and emphasize that caution should be taken in attempting to predict cytokine interactions in vivo in hemopoietically injured animals based on in vitro cytokine effects.
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PMID:Mast cell growth factor (C-kit ligand) in combination with granulocyte-macrophage colony-stimulating factor and interleukin-3: in vivo hemopoietic effects in irradiated mice compared to in vitro effects. 752 Jul 25

In order to clarify the role of haematopoietic stem and progenitor cells in bone-marrow toxicity induced by 1,3-butadiene, we examined the effects of its primary metabolite, 3,4-epoxybutene, on the cytokine response of these cells from C57B1/6 mice. Pretreatment with epoxybutene in vitro suppressed recombinant interleukin-3-stimulated colony formation in haematopoietic stem and progenitor cells, had no effect on colony formation with recombinant granulocyte/macrophage-colony stimulating factor or recombinant granulocyte-colony stimulating factor alone, and completely blocked the synergism of recombinant c-kit ligand and granulocyte/macrophage colony stimulating factor. Butadiene-induced leukaemogenesis, macrocytic anaemia and thymic atrophy are reminiscent of the conditions observed in mice bearing mutations at the W or Sl loci, which are deficient in the c-kit receptor and c-kit ligand, respectively. Epoxybutene did not suppress colony formation in cells from W/Wv and Sl/Sld mice, consistent with the absence of the population of haematopoietic stem and progenitor cells that is susceptible to butadiene in those genetically deficient strains. These findings indicate that the pathological conditions observed after either exposure to butadiene or W or Sl mutations are due to a functional defect in a subpopulation of primitive haematopoietic stem and progenitor cells that plays a major role in the pathogenesis of both T-cell leukaemia/lymphoma and anaemia in the mouse.
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PMID:Toxicity of 1,3-butadiene to bone marrow mimics haematopoietic defects observed in mice bearing white spotted or steel mutations. 752 Aug 86

We assessed the expression of the adhesion molecules leukocyte function antigen-1 (LFA-1, CD11a), intercellular adhesion molecule-1 (ICAM-1, CD54), homing-associated cell adhesion molecule (H-CAM, CD44), and c-kit (stem cell factor receptor) on the CD34+ progenitor population from the leukapheresis products of 23 patients (LP CD34+). For blood stem cell collection granulocyte colony-stimulating factor (G-CSF) or interleukin-3/granulocyte-macrophage colony-stimulating factor (IL-3/GM-CSF) was administered after cytotoxic chemotherapy. Furthermore, bone marrow- and blood-derived CD34+ progenitor cells from 6 normal volunteers (BM and PB CD34+) were analyzed. LFA-1 expression was higher on PB CD34+ (88.2 +/- 2.5%, mean +/- SEM) than on BM CD34+ (75.3 +/- 4.3%). Following cytokine administration, LFA-1 was expressed on only 59.7 +/- 3.7% of LP CD34+ at a low fluorescence intensity, suggesting that down-regulation of LFA-1 may facilitate the egress of cells from the bone marrow and prolong their circulation. In contrast, ICAM-1 was weakly positive on CD34+ cells from all sources. CD44 was expressed on the vast majority of CD34+ cells (> 95%) in all samples studied. The highest proportion of CD34+ cells costaining for c-kit was found in normal bone marrow (32.2 +/- 3.3%). In normal peripheral blood and after cytokine mobilization, fewer of the CD34+ cells weakly expressed c-kit (< 15%). The low percentage and level of c-kit expression may indicate that the majority of cytokine-mobilized CD34+ cells are lineage-committed progenitor cells, as reflected by the coexpression pattern for CD38, HLA-DR, and CD33.
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PMID:Expression of adhesion molecules and c-kit on CD34+ hematopoietic progenitor cells: comparison of cytokine-mobilized blood stem cells with normal bone marrow and peripheral blood. 752 8

A study of gene expression of GM-CSF, IL-3, c-kit ligand, and IL-1 by bone marrow stromal cells of mice who were treated with an LD50 cytosine arabinoside (Ara-C) dose was carried out. It was shown previously that this dose causes extensive hematopoietic damage which is followed by regeneration in surviving mice. Using PCR, we demonstrated GM-CSF and IL-1 expression by adherent cells taken from marrow fibroblast layers following Ara-C-induced hematopoietic damage and during marrow regeneration, while expression in control layers was not detected. The IL-3 gene was not expressed either by layers of Ara-C-treated mice or by controls, probably due to the absence of T-lymphocytes in 2-4 week old cultures. The c-kit ligand gene was expressed by layers during marrow regeneration and by control layers, but was absent during the stage of hematopoietic damage. In parallel, in vitro cytokine production was evaluated. While IL-3 and GM-CSF were not present in the conditioned medium of marrow fibroblast layers either from Ara-C-treated mice or controls, IL-1 was found in low concentrations in cultures from Ara-C-treated animals. We conclude that GM-CSF, c-kit ligand and IL-1 have important roles in sustaining marrow regeneration following extensive damage. The role of IL-3 in marrow regeneration cannot be assessed in fibroblast layers of 2-4 week incubation where T-lymphocytes are generally absent.
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PMID:Cytokine and growth factor gene expression by bone marrow stroma of mice with damaged hematopoiesis and during regeneration. 752 95

We recently reported that interleukin-3, Steel factor, and erythropoietin all induce the tyrosine phosphorylation of Shc and its association with Grb2 in hemopoietic cell lines. We have now further characterized the proteins that become associated with Shc following stimulation with these cytokines and found that, in response to all three, the tyrosine-phosphorylated form of Shc binds to common 145- and 52-kDa proteins which also become tyrosine phosphorylated in response to these growth factors. The 145-kDa protein, which appears, from antiphosphotyrosine blots of two-dimensional O'Farrell gels, to exist in four different phosphorylation states following cytokine stimulation (with isoelectric points ranging from 7.2 to 7.8), does not appear to be immunologically related to the beta subunit of the interleukin-3 receptor, c-Kit, BCR, ABL, JAK1, JAK2, Sos1, eps15, or insulin receptor substrate 1 protein. Silver-stained sodium dodecyl sulfate gels indicate that the association of the 145-kDa protein with Shc occurs only after cytokine stimulation and that it can bind to the tyrosine-phosphorylated form of Shc in its non-tyrosine-phosphorylated state. The latter finding, in conjunction with the observations that p145 does not bind, in vitro, to the Src homology 2 (SH2) domain of Shc, that it is not present in anti-Grb2 immunoprecipitates, and that a phosphopeptide which blocks the binding of Shc to the SH2 domain of Grb2 also blocks the binding of Shc to p145, suggests that p145 contains an SH2 domain and competes with Grb2 for the same tyrosine-phosphorylated site on Shc. This implicates p145 as a potential regulator of Ras activity and, perhaps, of other as yet unidentified functions of Shc.
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PMID:Multiple cytokines stimulate the binding of a common 145-kilodalton protein to Shc at the Grb2 recognition site of Shc. 752 59

Multiple cycles of high-dose chemotherapy can be hematologically supported by repeated administration of peripheral blood progenitors obtained after mobilization using cytokine alone or in combination with chemotherapy. We have explored the quality of such cells and their potential to undergo ex vivo expansion. Twenty-five leukapheresis samples from 19 patients who had received extensive prior chemotherapy for stage IV breast cancer were subjected to CD34+ cell selection using immunoaffinity columns of immunomagnetic bead separation. Cells were cultured in suspension in the presence of c-kit ligand, interleukin-3, interleukin-6, erythropoietin, and granulocyte colony-stimulating factor. Ten experiments were performed using weekly exchange of media and cytokines (Delta assay). Median myeloid and erythroid progenitors expanded 15-fold at 7 days (range, 7 to 43), 40-fold at 14 days (range, 18 to 470), 46-fold at 21 days (range, 0 to 118), and 21-fold at 28 days (range, 0 to 61). In a system using gas-permeable bags without exchange of media or cytokine, median progenitors expanded 13-fold at 7 days (range, 7 to 36), 14-fold at 10 days (range, 4 to 61), 14-fold at 12 days (range, 3 to 46), and 10-fold at 14 days (range, 1 to 35). Progenitor expansion less than 10-fold occurred in 8% of experiments at day 7, in 17% at day 10, in 43% at day 12, and in 50% at day 14. When autologous plasma, autologous plasma processed (removal of cryoprecipitate, centrifugation, then filtration), or human serum were substituted for 20% fetal calf serum, the ratio of progenitor expansion at 7 days relative to 20% fetal calf serum for 10% human serum, 20% human serum, and 1% autologous plasma processed was 1.01 (range, 0.62 to 1.33), 0.88 (range, 0.61 to 1.20), and 0.96 (range, 0.55 to 1.64), respectively. These findings support the feasibility of ex vivo expansion in a system free of nonhuman proteins of CD34(+)-derived progenitors obtained from the peripheral blood of patients who have received prior chemotherapy.
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PMID:Optimization of conditions for ex vivo expansion of CD34+ cells from patients with stage IV breast cancer. 752 42

The expression of c-kit ligand and interleukin 6 (IL-6) genes in mouse bone marrow-derived stromal cell lines was examined using quantitative polymerase chain reaction (PCR) analysis based on the design of an internal DNA control. The stromal cells studied included the 14F1.1 endothelial-adipocytes that support long-term hemopoiesis and two additional cell lines (MBA-1, MBA-13) which do not have this function. All the cell lines expressed c-kit ligand gene constitutively, and this expression was not increased by lectins. On the other hand, the expression of the IL-6 gene was markedly induced in all the lines by lipopolysaccharide (LPS) and by phorbol 12-myristate 13 acetate (PMA). The constitutive expression of c-kit ligand in 14F1.1 cells was the lowest among the three cell lines studied and could be increased by stimulation with IL-4. Thus, we observed some quantitative differences among the cell lines in their expression of cytokine genes. However, the unique capacity of 14F1.1 cells to support in vitro hemopoiesis cannot thus far be explained solely on the basis of the ability of these cells to secrete cytokines which are not produced by other stromal cell lines. c-kit ligand may be necessary, but its presence alone is not sufficient for 14F1.1 cells to support prolonged hemopoiesis.
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PMID:Expression of the c-kit ligand and interleukin 6 genes in mouse bone marrow stromal cell lines. 752 93

Stem cell factor (CSF), also called c-kit ligand (KL) or mast cell growth factor (MGF) is a peptide growth factor/cytokine with broad activities, especially on hematopoiesis. Its physiological role is best understood through the naturally occurring steel and W mutations in the mouse. This cytokine has recently been made available because of molecular cloning and its expression in recombinant form SCF is produced by a variety of cells, especially fibroblast, and interacts with target cells in each of the hematopoietic lineages to stimulate proliferation and differentiation. It has been found that SCF is important for the survival, proliferation and differentiation of mast cells and that it influences all stages of their development. SCF activity is not restricted to hematopoiesis, as it plays an important role in the development of germ cells and melanocytes as well. Preclinical studies show that SCF can protect against lethal irradiation, elicit multilineage responses in peripheral blood and bone marrow cellularity and increase circulating peripheral blood progenitor cells in a dose-dependent manner. Recombinant human SCF has major clinical potential through its synergy with other factors, especially G-CSF, to enhance mobilization of stem cells in peripheral blood.
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PMID:[Stem cell factor]. 752 11

The supernatant of homogenized human placental tissues at early and late stages of pregnancy were found to contain 40-100 pg of stem cell factor (SCF)/mg of total protein by enzyme linked immunosorbent assay. When the SCF mRNA expression was examined by reverse transcriptase-polymerase chain reaction (RT-PCR), the secretory type and membrane-bound type SCF mRNA were detected in the human placental tissues in the early stages of pregnancy and in a human placental cell line;tPA30-1 cells. However, the secretory type SCF mRNA was predominant and membrane-bound type SCF mRNA was absent or very weak in the term placental tissues. When the distribution of SCF mRNA and c-kit mRNA in the placental tissues was examined by in situ hybridization, SCF mRNA was detected in the cytotrophoblast, the intermediate trophoblastic cell column and the stromal cells, while c-kit mRNA was detected in the cytotrophoblast and the intermediate trophoblastic cell column. Both c-kit and SCF mRNA were absent or very weak in the syncytiotrophoblasts. The supernatant of primary cultured cytotrophoblasts and tPA30-1 cells were found to contain SCF. In cytotrophoblasts in the early stage of pregnancy cultured in the presence of recombinant human secretory type SCF, DNA synthesis was increased depending on the SCF concentration. These findings indicate that SCF is a cytokine which promotes the growth of placental cells by the autocrine and paracrine mechanism.
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PMID:Localization of stem cell factor (SCF) and c-kit mRNA in human placental tissue and biological effects of SCF on DNA synthesis in primary cultured cytotrophoblasts. 752 21

Retroviral gene transfer into human myeloid precursor cells allows introduction of marker genes as well as genes conferring resistance to chemotherapeutic drugs. We transduced a human mutant dihydrofolate reductase (DHFR) cDNA into CD34 antigen-positive peripheral blood cells from patients with breast or ovarian cancer obtained after treatment with chemotherapy and granulocyte colony-stimulating factor (G-CSF). This mutant DHFR has been shown to confer resistance to methotrexate (MTX) in murine bone marrow. We established a transduction protocol that permitted ex vivo expansion and selection of transduced early progenitor cells. The number of progenitor cells from transduced CD34-positive cells increased 50-fold after cytokine prestimulation with interleukin-1 (IL-1), c-kit ligand (KL; stem cell factor), and IL-3 and 2 weeks in liquid culture. Transduced colony-forming unit-granulocyte-macrophage (CFU-GM), assayed directly after the transduction procedure, were protected completely against 2 x 10(-8) mol/L MTX, a concentration that significantly reduced the CFU-GM detected in the control population. Gene transfer of the mutant DHFR led to a twofold selective advantage for a pre-CFU population after exposure to MTX in liquid culture (P < .001). Polybrene, in contrast with protamine, significantly inhibited the expansion of progenitors. The presence of proviral DNA was monitored by polymerase chain reaction (PCR) and was detected in greater than 80% of CFU-GM and ex vivo expanded pre-CFU. We have demonstrated that human hematopoietic precursor cells can be expanded extensively after retroviral gene transfer. The same population of early progenitors can be selected ex vivo with low-dose MTX. As long-term expression of transduced genes in human hematopoietic cells remains a problem in vivo, these results may have implications for future clinical trials, especially for the introduction of nonselectable genes.
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PMID:Ex vivo expansion and selection of human CD34+ peripheral blood progenitor cells after introduction of a mutated dihydrofolate reductase cDNA via retroviral gene transfer. 752 65


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