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

Bone marrow from each of two inbred mouse strains, C57BL/6J and DBA/2J, was highly enriched for stem cells using flow cytometry and was divided into two stem cell subpopulations using the mitochondrial dye rhodamine 123 (Rh-123). The Rh-123lo population was determined to be more primitive than Rh-123hi based on the expression of stem cell markers such as the c-kit protooncogene (stem cell factor receptor) and the Ly-6A/E stem cell antigen (Sca-1) as well as the lack of in vitro colony-forming ability. Compared to DBA/2J mice, marrow from the C57BL/6J strain consistently showed a higher proportion of "very primitive" (Rh-123lo) cells, suggesting that the sizes of functionally distinct stem cell subpopulations are maintained under precise genetic control. Marrow from both strains exposed to the cytotoxic drug 5-fluorouracil showed a dramatic increase in the proportion of Rh-123lo cells within 2 days as repopulation began. Marrow subpopulations returned to pretreatment proportions by the eighth day in DBA/2J mice but not until 14 days in C57BL/6J mice. This intrinsic difference in 5-fluorouracil recovery time was attributed to an increase rate of stem cell cycling in DBA/2J relative to C57BL/6J mice. When stem cell factor was injected into a C57BL/6J<-->DBA/2J allophenic mouse, blood cell chimerism shifted markedly but transiently toward the DBA/2J genotype, suggesting that the DBA/2J target population, because of an inherent kinetic advantage, was able to respond faster to the cytokine. A model is proposed that is based on these and our earlier observations to explain this strain-specific stem cell behavior and offer new insights into the genetic control of stem cell cycling and population dynamics.
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PMID:Genetic control of murine hematopoietic stem cell pool sizes and cycling kinetics. 128 Aug 31

The gene product of the murine Steel (Sl) locus encodes an early-acting hematopoietic growth factor that is a ligand for the c-kit protooncogene. Several cDNAs for the Sl gene product, known as mast cell growth factor (MGF), stem cell factor (SCF), or kit ligand (KL), have recently been isolated, and both soluble and membrane-associated versions have been shown to be biologically active. The potential for therapeutic usage of recombinant MGF (rMGF) indicated a need for determining the biodistribution and elimination parameters of this cytokine. Pharmacokinetic studies demonstrated that radiolabeled rMGF had a distribution half-life of 2 min and an elimination half-life of 2.1 h in wild-type mice following iv injection, during which a striking localization of labeled rMGF in the lungs was noted. When administered by subcutaneous injection the elimination half-life was prolonged to 8.4 h. The primary sites of rMGF elimination appeared to be the kidneys and the liver. Pharmacokinetic analysis of labeled rMGF in mutant Sl/Sld mice, which are mast cell deficient, demonstrated similar distribution and elimination half-lives compared to wild-type mice (1.4 min and 1.8 h, respectively). In addition, the biodistribution pattern of the labeled rMGF in Sl/Sld mice was similar to that observed in wild-type mice, including the striking localization to the lungs. Binding of radiolabeled rMGF to lungs in vivo subsequent to iv injection was completely inhibited by excess unlabeled rMGF. Interestingly, mice that received an iv injection of the higher doses of rMGF (15 micrograms) demonstrated profound respiratory distress and hypotension within minutes of administration. Histologic analysis of lungs from such mice revealed extensive mast cell degranulation, which was associated with vasodilatation and pronounced hyperemia of virtually all pulmonary vessels. The respiratory distress in normal mice was probably a consequence of mast cell degranulation induced by rMGF since similar findings were not observed in Sl/Sld mice injected with identical concentrations of rMGF.
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PMID:Pharmacokinetic parameters of recombinant mast cell growth factor (rMGF). 128 75

Cytokine regulation of prethymic T-lymphoid progenitor-cell proliferation and/or differentiation has not been well-defined, although much is known of cytokine regulation of hemopoietic stem- and progenitor-cell development. Here we use a recently identified hemopoietic growth factor, stem-cell factor (SCF) (a form of the c-kit ligand), and a transplant model of thymocyte regeneration to assess the effect of SCF on the in vivo generation of prethymic, thymocyte progenitor-cell activity. We show that recombinant rat SCF (rrSCF164) administered to weanling rats selectively induces an increase in thymocyte progenitor activity in the spleens of treated rats as compared to rats treated with vehicle, polyethylene glycol (PEG)-conjugated rat albumin, or recombinant human granulocyte colony-stimulating factor (rhG-CSF). These data demonstrate that administration of SCF in vivo affects extrathymic-origin thymocyte regenerating cells and may influence, directly or indirectly, early prethymic stages of T-cell lymphopoiesis in addition to its known effect on early stages of myelopoiesis and erythropoiesis.
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PMID:Rat stem-cell factor induces splenocytes capable of regenerating the thymus. 128 80

Products of the ras gene family, termed p21ras, are GTP-binding proteins that have been implicated in signal transduction via receptors encoding tyrosine kinase domains. Recent findings have defined a superfamily of hemopoietin receptors that includes receptors for a number of interleukins and colony-stimulating factors. The intracellular portions of these receptors show only restricted homologies, have no tyrosine kinase domain, and provide no clues to the mode of signal transduction. However, in most cases the factors stimulate tyrosine phosphorylation. We demonstrate here that ligand-induced activation of the interleukin (IL)-2, IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor receptors resulted in activation of p21ras in various hemopoietic cell lines. The only cytokine tested that binds to a hemopoietin receptor and that did not activate p21ras was IL-4. Activation of p21ras was also observed in response to Steel factor, which stimulates the endogenous tyrosine kinase activity of the c-kit receptor, as well as with phorbol esters, which activate protein kinase C. Experiments with protein kinase inhibitors implicated tyrosine kinase activity, but not protein kinase C activity, as the upstream signal in p21ras activation via these growth factor receptors. Attempts to demonstrate tyrosine phosphorylation of the p21ras GTPase-activating protein (GAP) were negative, suggesting that phosphorylation of GAP may not be the major mechanism for regulation of p21ras activity by tyrosine kinases.
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PMID:p21ras activation via hemopoietin receptors and c-kit requires tyrosine kinase activity but not tyrosine phosphorylation of p21ras GTPase-activating protein. 137 79

Human mast cell growth factor (MGF, a c-kit ligand) and colony stimulating factors (Epo, GM-CSF, G-CSF, IL-3) were assessed in the absence or presence of serum for stimulation in semi-solid medium of single CD34 , CD34 HLA-DR+, or CD34 HLA-DR+CD33- cells sorted per microtiter well. The % of wells containing CFU-GM and erythroid containing (BFU-E and CFU-GEMM) colonies increased in proportion to the number of cytokines added. In the presence of serum, 1, to 4 cytokine combinations resulted in respective increases in cloning efficiencies of 10 to 21.0, 19.5 to 31.5, 35.8 to 42.9, and 46.3 to 60.0%. MGF had little effect by itself, but did act in combination with CSFs to enhance numbers and size of the colonies from isolated single cells. High cloning efficiencies were also obtained in the absence of serum when multiple cytokines were used. The results demonstrate that MGF and CSFs can act directly on the proliferation of single hematopoietic progenitor cells in the absence of accessory cells and serum.
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PMID:Influence of combinations of cytokines on proliferation of isolated single cell-sorted human bone marrow hematopoietic progenitor cells in the absence and presence of serum. 137 67

It is now established that the subclasses of mast cells (MC) that reside in mucosal and serosal environments can be distinguished from one another in terms of their expression of specific secretory granule-localized proteases and proteoglycans. Further, the hematopoietic- and connective tissue-derived cytokines that regulate expression of the genes that encode these constituents of the granule can now be identified using recently developed gene-specific probes and recombinant cytokines. When bone marrow-derived MC (BMMC) were developed with recombinant interleukin 3 (rIL-3) and maintained with this cytokine in the absence or presence of recombinant c-kit ligand (rKL), they remained safranin-, produced almost no 35S-labeled heparin proteoglycans, and contained greater levels of mouse MC protease (MMCP) -5 mRNA and mast cell carboxypeptidase A (MC-CPA) mRNA than MMCP-6 mRNA. They did not contain MMCP-4 or -2 mRNA, genes expressed late in the differentiation of progenitor cells into serosal and mucosal MCs, respectively. In contrast, BMMC developed with rKL alone or by sequential culture in medium containing rIL-3 followed by rKL expressed high levels of MMCP-4 and -6 mRNA, as well as the transcripts that encode MMCP-5 and MC-CPA. Although rKL-developed BMMC were safranin+ and produced substantial amounts of 35S-labeled heparin proteoglycans, they contained only minimal amounts of histamine and MC-CPA enzymatic activity relative to serosal MC. These are the first studies to characterize the transcriptional granule phenotype of a population of BMMC derived using any recombinant cytokine, to demonstrate a dissociation between histochemical staining and granule maturation, and to demonstrate antagonistic regulation of late expressed protease genes by a cytokine.
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PMID:Differential expression of secretory granule proteases in mouse mast cells exposed to interleukin 3 and c-kit ligand. 137 40

An evaluation of the effectiveness of a genetically engineered recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF)/interleukin 3 (IL-3) fusion protein (FP) as a means of delivering cytokine combinations to megakaryocyte (MK) progenitor cells was performed, utilizing a serum-depleted clonal assay system and a long-term bone marrow culture system. The effects of the FP, alone and in combination with a variety of other cytokines, on the primitive MK progenitor cell, the megakaryocyte burst-forming unit (BFU-MK), and the more differentiated megakaryocyte colony-forming unit (CFU-MK) were assessed. Subpopulations of bone marrow cells (CD34+ DR- for BFU-MK and CD34+ DR+ for CFU-MK) served as sources of these two classes of MK progenitor cells. The FP was equivalent to a combination of optimal concentrations of GM-CSF and IL-3 in promoting both the number and size of BFU-MK-derived colonies. The GM-CSF/IL-3 combination, however, promoted the formation of far greater CFU-MK-derived colonies than did the FP alone. The size of MK colonies formed in the presence of the FP or GM-CSF/IL-3 was similar. The ability of the FP to stimulate BFU-MK- but not CFU-MK-derived colony formation was also further augmented by the addition of interleukin 1 alpha (IL-1 alpha). The addition of c-kit ligand (KL) increased both FP-stimulated CFU-MK- and BFU-MK-derived colony numbers but only BFU-MK-derived colony size. In addition, the FP alone sustained long-term megakaryocytopoiesis in vitro to a level equivalent to that of the GM-CSF/IL-3 combination and was superior in this regard to either GM-CSF or IL-3 alone. These data indicate that FP is capable of supporting various stages of human megakaryocytopoiesis. We conclude that such genetically engineered molecules as the FP may prove to be effective means of pharmacologically delivering the biological effects of specific cytokine combinations.
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PMID:Recombinant GM-CSF/IL-3 fusion protein: its effect on in vitro human megakaryocytopoiesis. 137 90

A mouse antihuman monoclonal IgG2a antibody, termed stem cell receptor-1 (SR-1), specific for a determinant of the c-kit ligand receptor (KR), was used as an immunologic probe to analyze KR expression by human bone marrow hematopoietic progenitor cells. Monoclonal antibodies to CD34 and HLA-DR were used in a multicolor staining protocol in conjunction with SR-1 to further define the phenotypes of various classes of hematopoietic progenitor cells. Expression of KR (SR-1+) on hematopoietic progenitor cells identified subpopulations of cells expressing CD34 (CD34+). While one-half of the CD34- and HLA-DR-expressing cells (CD34+ HLA-DR+) expressed the KR (SR-1+), one-third of the CD34+ cells that lacked HLA-DR expression (CD34+ HLA-DR-) were SR-1+. The CD34+ HLA-DR+ SR-1+ cell population contained the vast majority of the more differentiated progenitor cells, including the colony-forming unit (CFU) granulocyte-macrophage; burst-forming unit-erythrocyte; CFU-granulocyte, erythrocyte, macrophage, megakaryocyte; and the CFU-megakaryocyte. The overall progenitor cell cloning efficiency of this subpopulation was greater than 31%. By contrast, the CD34+ HLA-DR- SR-1+ cell population contained fewer of these more differentiated progenitor cells but exclusively contained the more primitive progenitor cells, the BFU-megakaryocyte, high proliferative potential-colony-forming cell, and long-term bone marrow culture-initiating cell. The overall progenitor cell cloning efficiency of this subpopulation was greater than 7%. Both the CD34+ HLA-DR- and CD34+ HLA-DR+ cell subpopulations lacking KR expression contained few assayable hematopoietic progenitor cells. Long-term bone marrow cultures initiated with CD34+ HLA-DR- SR-1+ but not CD34+ HLA-DR- SR-1- cells, which were repeatedly supplemented with c-kit ligand (KL) and interleukin-3, generated assayable progenitor cells of at least 2 lineages for 10 weeks. These experiments demonstrate the expression of the KR throughout the hierarchy of human hematopoietic progenitor cell development. We conclude from our data that the KL and KR play a pivotal role in cytokine regulation of both the primitive and more differentiated human hematopoietic progenitor cells.
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PMID:Further phenotypic characterization and isolation of human hematopoietic progenitor cells using a monoclonal antibody to the c-kit receptor. 137 42

The "stromal" or adherent cells of long-term murine Dexter explant bone marrow cultures provide the best in vitro model of the bone marrow microenvironment. Colony-stimulating factor-1 (CSF-1) is produced constitutively by these cells and is easily detected, but most investigators have not found constitutive production of the other hemolymphopoietic cytokines. We have previously reported the detection of granulocyte-macrophage-CSF (GM-CSF) in murine stromal cultures and its induction by the lectin Pokeweed mitogen. The present studies analyzing stromal cytokine messenger RNA (mRNA) production by standard Northern blot analysis show constitutive production of mRNAs for CSF-1, GM-CSF, granulocyte-CSF (G-CSF), c-kit ligand (KL), and interleukin-6 (IL-6), but not IL-3, IL-4, or IL-5 by 3-week irradiated or nonirradiated murine Dexter stromal cells. Exposure of stromal cells to Pokeweed mitogen or IL-1 16 hours before RNA harvest induces the messages for GM-CSF, G-CSF, KL, and IL-6, but not IL-3, IL-4, IL-5, or CSF-1. Polymerase chain reaction amplification of cDNA made with reverse transcriptase from stromal RNA using two separate sets of IL-3-specific primers shows the presence of IL-3 message in irradiated stromal cells, which is only detectable with this more sensitive technique. The factor-dependent cell lines FDC-P1 and 32D are supported by the stromal cells without the addition of exogenous growth factors, demonstrating a cytokine activity in these cultures that is inhibited by the addition of anti-IL-3 or anti-GM-CSF antibodies. These data indicate that murine Dexter stromal cells constitutively produce CSF-1, GM-CSF, G-CSF, IL-6, KL, and IL-3. This growth factor production could explain the support of granulocyte, macrophage, and megakaryocyte production and stem cell maintenance in Dexter-type long-term murine bone marrow cultures.
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PMID:Biologic significance of constitutive and subliminal growth factor production by bone marrow stroma. 137 43

The growth of a panel of eight different human glioblastoma cell lines was examined in a human tumor cloning assay in agar, a tritiated thymidine uptake assay, and by counting cell numbers, in cultures performed in the absence or presence of increasing concentrations (1 to 100 ng/ml) of recombinant human stem cell factor (SCF). Growth of 7 of 8 cell lines was not significantly and reproducibly affected by recombinant human SCF. However, growth of the CRL 1620 cell line could be stimulated up to 5-fold by the cytokine. In contrast to the other cell lines investigated, CRL 1620 expressed the c-kit protooncogene assessed on the mRNA and protein level. Furthermore, SCF-induced proliferation of CRL 1620 cells was sensitive to the tyrosine kinase inhibitor erbstatin. Our data suggest that SCF can be operative in growth modulation of malignant cells outside the hematopoietic system, and this finding should be further studied for its possible clinical implications.
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PMID:Recombinant human stem cell factor stimulates growth of a human glioblastoma cell line expressing c-kit protooncogene. 137 70


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