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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mast cells have been implicated in a wide variety of biological responses, but identifying the nature and importance of the mast cell's specific contributions to these reactions has been difficult. W/Wv mice have mutations affecting the c-kit tyrosine kinase receptor which is encoded at the W locus and which is necessary for normal mast cell development. In W/Wv mice, the cells which ordinarily give rise to normal mast cell populations do not adequately respond to a major migration, survival, proliferation and maturation factor expressed in the microenvironments where mast cells ordinarily develop: the c-kit receptor ligand, SCF. As a result, W/Wv mice virtually lack tissue mast cells. However, adoptive transfer to W/Wv mice of immature mast cells derived in vitro from the bone marrow cells of the congenic normal (+/+) mice selectively repairs the mast cell deficiency of the W/Wv recipients. These "mast cell knock-in" mice can be used to analyze the expression of biological responses in tissues which differ only because they do or do not contain populations of mast cells. This approach permits identification and quantification of the specific contributions of the mast cell to biological responses expressed in the skin, gastrointestinal tract and other anatomical sites, and also greatly facilitates analysis of the mechanisms by which mast cells influence these responses.
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PMID:Analyzing mast cell development and function using mice carrying mutations at W/c-kit or Sl/MGF (SCF) loci. 128 Sep 35

To identify cytokines required for proliferation of murine pre-B cells, we established a pre-B cell clone MH11 (B220+ MB-1+ sIgM-) on a stromal cell line ST2 from day 13 fetal liver. The growth of MH11 is dependent on ST2. Another stromal cell line PA6, non-secretor of IL-7, could not support MH11 unless IL-7 was added. We investigated the effect of cytokines on proliferation of MH11 with or without stromal cells. IL-7 had a stimulatory effect on proliferation of MH11, but IL-7 alone could not support MH11 growth without ST2. Recombinant stem cell factor (rSCF) also had a positive effect on MH11. rSCF and rIL-7, when added together, could maintain the growth of MH11 in the absence of stromal cells. Moreover, the growth of MH11 on ST2 was inhibited almost completely by anti-c-kit monoclonal antibody (mAb). These results demonstrate that direct SCF/c-kit interaction is involved in the stimulation of pre-B cells.
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PMID:Establishment of a murine pre-B cell clone dependent on interleukin-7 and stem cell factor. 128 57

Previously, we have shown that conditioned medium from a subpopulation of human marrow stromal cells (CFU-RF) contain an activity able to stimulate the growth of macroscopic epo-dependent erythroid colonies. The ligand for the product of the c-kit proto-oncogene (also known as stem cell factor or SCF), among other activities, has been reported to have similar effects on erythroid colony growth. We have also presented data showing that SCF together with phytohemagglutinin-stimulated leukocyte conditioned medium can stimulate erythroid colony growth in the presence of antibodies to erythropoietin. Using the human SCF cDNA probe (K. Zsebo, Amgen Inc.) we now show that cells derived from CFU-RF colonies express SCF but not c-kit. Human umbilical vein endothelial cells were also found to express SCF and this expression was increased by addition of monocyte supernatant, IL-1 beta or thrombin. Cells of the human erythroleukemia cell line HEL were found to express c-kit but not SCF. Neither c-kit nor SCF mRNA were detected in phytohemagglutinin-stimulated lymphocytes. Together, these data support the view that the behaviour of proliferating erythroid stem cells in the marrow, which may express c-kit, could be regulated by membrane-bound SCF present on surrounding stromal cells.
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PMID:Expression of stem cell factor and c-kit mRNA in cultured endothelial cells, monocytes and cloned human bone marrow stromal cells (CFU-RF). 137 91

We describe the effect of soluble c-kit ligand (stem cell factor, SCF) on highly purified CD34-positive hemopoietic progenitors from human umbilical cord blood. Progenitor cells were purified from cord blood mononuclear cells by immune rosetting with lineage specific antibodies and subsequent sorting of the rosette-negative population for CD34(BI3C5)-positive cells. This procedure enriched greater than 100-fold for colony forming cells (CFC). Using optimal concentrations of colony-stimulating factors (CSF) without added SCF approximately 2.5% of cells formed colonies. SCF also had CSF activity on this population, up to 0.5% of cells forming small colonies in response to SCF alone. In contrast, the addition of SCF to optimal concentrations of the other growth factors produced a greater than 10-fold increase in colony number. However, the most notable effect was an approximately 100-fold increase in the number of cells in each colony. Equally striking was the very high proportion (50-80%) of mixed colonies (CFU-MIX). These findings suggest the progenitor cell pool in cord blood is skewed towards very early cells. However, when day 14 colonies formed in response to SCF and other factors were assessed for their re-cloning potential they did not contain significant numbers of CFC, implying that SCF did not support the self-renewal of these CD34 positive cord blood progenitor cells. These findings support a role for SCF as an enhancing factor for hemopoietic progenitor cells but it does not promote self-renewal in these populations.
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PMID:The effect of recombinant stem cell factor (SCF) on purified CD34-positive human umbilical cord blood progenitor cells. 137 77

The high levels of hematopoietic growth factors required for in vitro and in vivo activity raise questions as to their role in normal hematopoietic maintenance. We hypothesize that the use of combinations of cytokines to stimulate hematopoietic progenitors might allow individual factors to exert their influence at lower, more physiologically relevant concentrations. Growth factor combinations were assessed by their ability to stimulate both total colonies and high proliferative potential colony-forming cells (HPP-CFC), an early murine hematopoietic progenitor, in double-layer agar cultures. Very-low-level combinations of colony-stimulating factor (CSF)-1, granulocyte CSF (G-CSF), granulocyte-macrophage CSF (GM-CSF), interleukin (IL)-1 alpha, and IL-3 had little or no clonogenic capacity. Plateau levels of rr stem cell factor (rrSCF), a c-kit ligand, used alone also had negligible clonogenic capacity, but when combined with the low-level combination of the other five factors produced total colony and HPP-CFC growth approaching that produced by all factors at plateau levels. Delayed addition experiments suggest that this effect may represent sequential activity of SCF and the other factors. We propose a model of the normal hematopoietic microenvironment in which SCF at locally high concentration on the stromal cell surface "anchors" the hematopoietic stem cell's response to multiple other cytokines at physiologically relevant levels.
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PMID:Stem cell factor induction of in vitro murine hematopoietic colony formation by "subliminal" cytokine combinations: the role of "anchor factors". 137 85

Mutation at S1 or W loci are characterized by lacks of pigmentation, gametogenesis and hematopoiesis. Stem cell factor and its receptor, which is encoded by c-kit proto-oncogene, play an important role in the survival and proliferation of these primitive cells. Primordial germ cell is maintained and expanded on cells transfected with membrane-bound SCF gene. Pigmentation of mouse embryo is influenced by administration of monoclonal antibody for c-kit product, ACK 2, because of inhibition of melanoblast migration to epidermal tissue. Moreover, hematopoietic progenitors are considered to be maintained and expanded in liquid culture in the presence of SCF and other growth factors. All of these primitive cells express c-kit product and the direct action of SCF is expected. However, two types of SCF, soluble form and membrane-bound form, exist and the physiological significance of these forms in vivo remain unsolved.
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PMID:[Stem cell factor/c-kit interaction in primordial germ cell, melanoblast and hematopoietic progenitors]. 138 68

Mutant mice of mi/mi genotype are osteopetrotic and deficient in tissue mast cells due to a defect in osteoclasts and mast cells. In an effort to further understand the mechanisms behind why mi/mi mouse-derived cultured mast cells (mi/mi-CMC) responded to interleukin-3 (IL-3), but not to the proliferative stimuli presented by fibroblasts, mi/mi-CMC and congenic normal (+/+) mouse-derived CMC (+/+-CMC), both of which expressed the phenotypic characteristics of immature mast cells, were cocultured with Swiss albino/3T3 fibroblasts in a medium containing IL-3. In the in vitro CMC/fibroblast coculture, mi/mi-CMC did not acquire the phenotypes of connective tissue-type mast cells (CTMC), while +/+-CMC did. In addition, attachment of mi/mi-CMC to the fibroblasts was found to be significantly lower than that of +/+-CMC. Because the interaction of c-kit product with its ligand (stem cell factor [SCF]) is known to play an important role not only in proliferation and differentiation of mast cells but also in attachment of CMC to fibroblasts, the expression and function of c-kit were investigated in mi/mi-CMC and +/+-CMC. Recombinant rat SCF (rrSCF164) induced a dose-dependent proliferation of +/+-CMC. Also, rrSCF164 induced +/+-CMC to acquire the phenotypes of CTMC in the medium containing IL-3. By contrast, rrSCF164 did not stimulate the proliferation of mi/mi-CMC nor induce a phenotypic change of the cells from immature mast cells to mature, CTMC-like mast cells. Immunoblotting with antiphosphotyrosine antibody showed that rrSCF164 induced considerable tyrosine phosphorylation of 145- to 165-Kd protein, the product of c-kit, in +/+-CMC, whereas tyrosine phosphorylation of the protein was barely detectable in mi/mi-CMC. Northern blot and flow cytometry analyses showed that mi/mi-CMC expressed much less c-kit at both protein and message levels than +/+-CMC. Further, mi/mi-CMC were found to differ from +/+-CMC in the expression of mouse mast cell protease-6 (MMCP-6) and MMCP-2 messenger RNA transcripts. These results suggest that the gene product of the mi locus may be important in regulating the expression of gene products such as c-kit, and that mast cell deficiency of mi/mi mice appears to be due, at least in part, to impaired signaling through the c-kit receptor because of the low c-kit expression.
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PMID:Low c-kit expression of cultured mast cells of mi/mi genotype may be involved in their defective responses to fibroblasts that express the ligand for c-kit. 138 28

The effects of recombinant rat stem cell factor (SCF/c-kit ligand) on murine megakaryocytopoiesis were studied using partially purified bone marrow cells derived from normal and 5-fluorouracil (5-FU)-treated mice in a serum-free culture system. SCF alone did not support the formation of megakaryocyte (M) and granulocyte-macrophage-megakaryocyte (GMM) colonies. However, the addition of SCF to cultures containing interleukin-3 (IL-3) resulted in a significant increase in the number of M and GMM colonies formed by bone marrow cells from normal mice, whereas IL-6 augmented only M colony growth. The stimulatory effect of SCF was approximately three to four times as high as that of IL-6 on the primitive progenitors capable of megakaryocytic-lineage expression derived from 5-FU-treated mice. In addition, SCF, but not IL-6, significantly increased the number of constituent cells in the individual M colonies supported by IL-3. On the other hand, SCF did not exert any effect on the size and DNA content of megakaryocytes in IL-3-dependent M and GMM colonies, whereas IL-6 enhanced the maturation of megakaryocytes. These results suggest that SCF stimulates the proliferative process in megakaryocytic progenitors and that the main activity of IL-6 is the promotion of megakaryocyte maturation.
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PMID:Stem cell factor enhances proliferation, but not maturation, of murine megakaryocytic progenitors in serum-free culture. 138 2

The effects of the c-kit ligand (stem cell factor [SCF]) on the development of a highly enriched population of granulocyte-macrophage colony-forming cells (GM-CFC) were assessed. In soft agar assays, both in serum-containing and in serum-deprived cultures, SCF promoted the formation of colonies that contained predominantly granulocytic cells with some blast cells also present. The size of these colonies was far smaller than observed in the presence of interleukin-3 (IL-3). In serum-deprived conditions, no colonies were formed in the presence of macrophage colony-stimulating factor (M-CSF), but when M-CSF was combined with SCF, a marked change was noted in that large colonies were produced containing predominantly macrophages. When GM-CFC were cultured in the presence of IL-3 and SCF, colonies were formed that contained blast cells, granulocytes, and macrophages. A synergistic interaction was also seen using a combination of G-CSF plus SCF in either serum-containing or serum-deprived cultures. The addition of SCF to colony-forming assays markedly reduced the concentration of IL-3 or G-CSF required for optimal levels of colony formation. Furthermore, SCF was capable of promoting the survival of GM-CFC for several days, after which large colonies containing mature cells were formed upon the addition of a secondary growth factor such as G-CSF or IL-3. Thus, SCF can directly act on highly enriched committed progenitor cells in serum-deprived conditions to promote survival, proliferation, and development.
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PMID:Stem cell factor directly stimulates the development of enriched granulocyte-macrophage colony-forming cells and promotes the effects of other colony-stimulating factors. 138 98

Mice carrying mutations at the W (Dominant white spotting) and Sl (Steel) loci develop abnormalities in three independent systems: neural crest-derived melanocytes, primordial germ cells and haematopoietic stem cells. Consequently, homozygotes of viable mutant alleles have white coats and are sterile and severely anaemic. Tissue recombination studies predict that the W gene is expressed cell autonomously, whereas the product of the Sl locus affects the microenvironment in which the stem cells migrate, proliferate and differentiate. The W locus encodes the protoncogene c-kit, a member of the tyrosine kinase receptor family. The haematopoietic growth factor SCF (stem cell factor) has been identified as the product of the Sl locus and a ligand for c-kit. Here, we report that SCF is expressed during embryogenesis in cells associated with both the migratory pathways and homing sites of melanoblasts, germ cells and haematopoietic stem cells. Both SCF and c-kit are also expressed in a variety of other tissues, including the brain and spinal cord, suggesting that the receptor-ligand system has additional roles in embryogenesis.
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PMID:Embryonic expression of a haematopoietic growth factor encoded by the Sl locus and the ligand for c-kit. 169 34


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