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)

Steel factor (SF), the ligand for the c-kit, also called kit ligand, stem cell factor, or mast cell growth factor, was evaluated on colony formation alone or in combination with other cytokines, from purified human hematopoietic CD34+ cells in low density cell culture. SF alone had a slight effect on granulocyte (G) and macrophage (M) colony formation. It synergized with other cytokines on colony formation from colony-forming unit-granulocyte, erythroid, macrophage, megakaryocyte (CFU-GEMM), erythroid and granulocyte-macrophage (CFU-GM) progenitors. However, combination of SF with lineage-specific factors, such as erythropoietin (Epo) or/and granulocyte colony-stimulating factor (G-CSF) was not sufficient for the proliferation of multipotential progenitors (CFU-GEMM). These multipotential progenitors required the presence of multi-lineage factors, such as interleukin 3 (IL3) or granulocytic-macrophage CSF(GM-CSF) for their development.
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PMID:Co-stimulatory effects of steel factor, the c-kit ligand, on purified human hematopoietic progenitors in low cell density culture. 768 20

A number of cytokines have been shown to have stimulatory activity on multipotent haematopoietic precursors. These include kit ligand (KL), interleukins (IL) 1, 3 and 6 and granulocyte macrophage-colony stimulating factor (GM-CSF). Using reverse transcriptase/polymerase chain reaction method (RT/PCR) we have examined the expression of these cytokines, the c-kit and IL-6 receptors, in long-term bone marrow culture (LTC) adherent layer cells in human bone marrow hypoplasia syndromes. Disorders studied include Fanconi's anaemia (FA, n = 16), idiopathic aplastic anaemia (AA, n = 11), Seckel's syndrome (n = 2), dyskeratosis congenita (n = 2), Shwachman-Diamond syndrome (n = 1), thrombocytopenia with absent radii syndrome (n = 1), acquired amegakaryocytosis (n = 1), paroxysmal nocturnal haemoglobinuria (n = 1) and acquired agranulocytosis (n = 1). IL-6 and GM-CSF expression appeared reduced in most patients with FA, suggesting that impaired production of these cytokines may contribute to the bone marrow failure seen in most patients with FA. In contrast, abundant IL-6 and GM-CSF expression were seen in most patients with AA when compared with the FA group and controls; these may be mediators of a stromal response in this disorder. No obvious differences were seen between the different patients' groups and controls in expression of the other cytokines or cytokine receptors studied.
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PMID:The expression of cytokine and cytokine receptor genes in long-term bone marrow culture in congenital and acquired bone marrow hypoplasias. 751 72

The proto-oncogene c-kit is allelic with the white spotting locus (W) on mouse chromosome 5 and it encodes a transmembrane protein tyrosine kinase which belongs to the platelet-derived growth factor and macrophage-colony stimulating factor (CSF-1) receptor subfamily. In an effort to study the function of the c-kit receptor, specifically the physiological mechanism of controlling the signal induced by the ligand, the effect and mechanism of down-regulation of the c-kit receptor by the kit ligand (KL) was investigated in mast cells. Following preincubation with KL, the capacity of mast cells to bind kit antibody was reduced and binding of radiolabeled KL to mast cells decreased with similar kinetics, suggesting that KL stimulates the loss of c-kit receptor from the cell surface. After binding to the c-kit receptor, KL was rapidly internalized, and degradation of the receptor was accelerated. The c-kit receptor was transmodulated by the protein kinase C activator 12-O-tetradecanoylphorbol-13-acetate (TPA) and by the calcium ionophore ionomycin. TPA- and ionomycin-induced down-regulation of the c-kit receptor was accompanied by release of the extracellular domain of the receptor, presumably by proteolytic cleavage near the transmembrane domain. Release of the extracellular domain of the c-kit receptor occurred also in untreated cells but at a slow rate. In addition, ionomycin induced shedding of the intact c-kit receptor. In mast cells depleted of protein kinase C, the c-kit receptor remained sensitive to down-regulation induced by KL and ionomycin, but not by treatment with TPA. Therefore, the down-regulation of the c-kit receptor induced by KL, activated protein kinase C, and an increased level of intracellular calcium is mediated through independent mechanisms.
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PMID:Mechanism of kit ligand, phorbol ester, and calcium-induced down-regulation of c-kit receptors in mast cells. 768 52

W/Wv and S1/S1d mice with macrocytic anemias are a potential model for human inherited pure red cell anemia, called Diamond-Blackfan anemia (DBA). The W mutation involves the gene for c-kit, and the S1 mutation the gene for the kit ligand, called mast cell growth factor, steel factor, or stem cell factor. Since many children with DBA respond to treatment with corticosteroids, we administered steroids to these genetically anemic mice, to determine whether they might provide a model for the human disease. There was no improvement in the murine anemia, consistent with other evidence suggesting that mutations in kit or steel may not be involved in Diamond-Blackfan anemia.
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PMID:Lack of effect of corticosteroids in W/Wv and S1/S1d mice: these strains are not a model for steroid-responsive Diamond-Blackfan anemia. 768 5

The recently identified ligand for c-kit, a protooncogene encoded by the W locus in mice, is a member of the tyrosine kinase receptor family with growth factor activity for mouse mast cells. Mature human mast cells regularly develop from agranular precursors in cord blood in long-term cocultures of cord blood and murine fibroblasts. Since the c-kit ligand is a product of murine fibroblasts, we examined the growth effect of recombinant human c-kit ligand (stem cell factor), of recombinant murine c-kit ligand (mast cell growth factor), and of a partially purified fraction derived from mouse fibroblast culture supernatant on the mast cell lineage of humans by electron microscopy in 8-week cultures of cord blood cells. We found that immature mast cells which developed in cultures containing the recombinant ligand for c-kit of human or murine origin as well as the naturally occurring c-kit ligand in 3T3 fibroblast supernatants were identical. Thus, each of these sources of the c-kit ligand exerted identical effects on the ontogeny of human mast cells as they develop from their agranular precursors in cord blood. Full maturity of factor-supported mast cells did not occur.
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PMID:Human and murine recombinant c-kit ligands support the development of human mast cells from umbilical cord blood cells: ultrastructural identification. 768 96

Previous studies in vivo and in vitro show that KIT kinase promotes normal melanocyte development and growth. However, the role of the KIT proto-oncogene in neoplastic melanocytes is not certain. We therefore examined KIT expression and function in human melanomas. Our results show that KIT mRNA was expressed in 12 of 28 melanoma cell lines (approximately 40%), mainly in those originating from pigmented tumors. Surprisingly, activation of KIT with mast cell growth factor (MGF) in melanoma cells produced biological responses opposite to those elicited in normal melanocytes. MGF inhibited rather than stimulated the growth of metastatic melanoma cell lines. The opposite effects may be due to aberrant signal transduction by KIT in melanoma cells in response to MGF. The in vitro inhibition of melanoma cells by MGF suggests that growth in vivo of this tumor is not promoted by KIT kinase activation, but rather that transformed melanocytes might regress when MGF is expressed in their immediate environment.
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PMID:KIT ligand (mast cell growth factor) inhibits the growth of KIT-expressing melanoma cells. 768 62

Natural killer (NK) cells are large granular lymphocytes thought to be important in the host's early immune response to viral infection and malignant transformation. NK cells proliferate and display enhanced cytotoxic activity in response to the T cell growth factor, interleukin 2 (IL-2). Stem cell factor or steel factor (SF) is the ligand for the c-kit receptor, and when combined with other hematopoietic growth factors, SF synergistically promotes the proliferation and differentiation of bone marrow stem cells. In the present study we show the c-kit receptor to be uniquely expressed on a subset of resting human NK cells (CD56bright) which constitutively expresses both the high affinity IL-2 receptor (IL-2R) and the intermediate affinity IL-2R. Other lymphocyte populations, including CD56dim NK cells, did not appear to express the c-kit receptor. Within the CD56bright NK cell subset, SF alone had no obvious effect on proliferation or cytotoxic activity. SF was shown to significantly augment the proliferative effect of IL-2, and caused a marked shift in the dose-response curve at IL-2 concentrations that selectively saturate the high affinity IL-2R. The potentiating effect of SF on NK cell proliferation was dependent on IL-2 binding to the high affinity IL-2R, and was blocked by a monoclonal antibody directed against the c-kit receptor. SF did not enhance proliferation at higher IL-2 concentrations that saturate the intermediate affinity IL-2R, nor did SF enhance IL-2-induced cytotoxic activity. Together, these data indicate that SF and IL-2 act synergistically to directly augment the proliferative capacity of a unique human NK cell subset constitutively expressing the high affinity IL-2R and the c-kit receptor. The implications of these findings on NK cell development and the host's early immune response to pathogen invasion are discussed.
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PMID:Expression of a functional c-kit receptor on a subset of natural killer cells. 768 85

We have analyzed c-kit expression by hematopoietic progenitors from normal and 5-fluorouracil (5-FU)-treated mice by staining with monoclonal anti-c-kit antibody ACK-4. Marrow cells that were enriched for progenitors by a combination of metrizamide density separation and negative immunomagnetic selection with lineage-specific monoclonal antibodies (MoAbs) were separated into three populations based on the level of c-kit expression, c-kit(high), c-kit(low), and c-kit-. The majority of colony-forming cells from normal mice were in c-kit(high) population, whereas most of the progenitors from 5-FU-treated mice were in the c-kit(low) population. Optimal colony formation from c-kit(low) cells from 5-FU-treated mice required the interactions of at least two factors among interleukin-3 (IL-3), IL-11 and steel factor (SF) whereas colony formation from c-kit(high) cells of normal mice was supported well by IL-3 alone. Blast cells that were derived from 5-day culture of c-kit(low) post 5-FU cells were c-kit(high). These observations suggest that the primitive hematopoietic progenitors in cell cycle dormancy are c-kit(low) whereas actively cell cycling maturer progenitors are c-kit(high). Mature cells, with the exception of mast cells, derived from secondary culture of the c-kit(high) blast cells expressed little, if any, c-kit. These results are consistent with a model in which c-kit expression progresses from low levels on primitive, dormant multipotent progenitors to high levels on later, actively cycling progenitors, and finally, decreases to very low or undetectable levels on most mature blood cells, with the exception of mast cells.
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PMID:Stage-specific expression of c-kit protein by murine hematopoietic progenitors. 769 Dec 57

W and Steel mutant mice exhibit similar developmental defects in melanogenesis, haematopoiesis, and gametogenesis. Consistent with the cell autonomous and microenvironmental nature of W and Sl mutations, respectively, W encodes the c-kit receptor tyrosine kinase while Steel encodes the Kit ligand. Both c-kit and Steel are expressed in various cells in which no corresponding mutant phenotype has yet been demonstrated. In the adult ovary, certain stromal-derived cells (theca and interstitial), as well as oocytes, express c-kit, while granulosa cells express Steel. We show here that the cessation of oocyte growth, at the transition of the follicle to the antral stage, is associated with the cessation of Steel expression in the cumulus granulosa cells in the vicinity of the oocyte. These observations suggest a role for the Kit signaling pathway in oocyte growth or in meiotic arrest. In addition, the cyclic secretion of luteinizing hormone immediately and dramatically results in elevated Steel expression in mural granulosa cells and decreased levels of c-kit transcripts in stromal-derived cells. This influence of the estrous reproductive cycle on c-kit/Steel expression suggests that the Kit signaling pathway, in addition to its previously described role in primordial germ cell development, is involved in follicular development in the adult female.
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PMID:Dynamic changes in ovarian c-kit and Steel expression during the estrous reproductive cycle. 769 Dec 75

In both murine and human systems the c-kit ligand, also known as mast cell growth factor (MGF), acts synergistically with several colony stimulating factors, including the granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 3 (IL-3), in stimulating the proliferation and differentiation of different types of hematopoietic progenitors. In addition, MGF is also known to enhance the effects of GM-CSF and IL-3 on the in vitro proliferative activity of myeloid leukemic cells. MGF synergizes with a number of other cytokines such as GM-CSF, IL-3, IL-2, IL-4, IL-6 and IL-9 in sustaining the proliferation of growth factor dependent M-07e cells. In order to explore the molecular basis of this synergistic activity and to elucidate the regulatory mechanisms of c-kit expression, we investigated the effects of GM-CSF, IL-3 and MGF on c-kit mRNA and protein levels in M-07e cells. GM-CSF, unlike MGF and IL-3, induced a transient but significant increase of c-kit mRNA levels. Moreover, following MGF and GM-CSF treatment, c-kit protein expression in M-07e cells decreased, whereas all the other cytokines tested are unable to modulate c-kit protein. These data together with the results of protein turnover analysis suggest that MGF and GM-CSF regulate c-kit expression at the post-transcriptional level. In addition, the finding that IL-3 has no detectable effect on c-kit expression raises the possibility that GM-CSF-induced c-kit regulation is not mediated by the common signal transducing element: the beta subunit of the IL-3/GM-CSF receptor complex.
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PMID:Regulation of c-kit expression in human myeloid cells. 769 27


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