UNIPROT:P10721 - FACTA Search

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

In this study we review our present understanding of the effect of stem cell factor (SCF) on the in vitro growth of hemopoietic progenitors from patients with acquired severe aplastic anemia (SAA). We have run three separate sets of experiments. First, we have tested the expression of receptor mRNAs for granulocyte-macrophage colony stimulating factor/interleukin 3 (GM-CSF/IL-3) and for c-kit protein on bone marrow (BM) cells from SAA patients. Molecular analysis revealed the presence of normal transcripts for alpha and beta chains of GM-CSF/IL-3 receptor and for c-kit protein by Northern blot analysis. Second, we have tested the in vitro response to SCF of BM cells derived from 11 SAA patients: SCF induced a significant enhancement of erythroid burst forming unit (BFU-E) growth (8 to 29, p = 0.01) and allowed the formation of granulocyte/erythroid/macrophage/megakaryocyte (GEMM) colonies which were not scored in baseline culture conditions (0 to 8, p = 0.01). Granulocyte-macrophage colony forming unit (CFU-GM) growth was also enhanced (4 to 20, p = 0.3). This was true for patients both at diagnosis and after antilymphocyte globulin (ALG) treatment. We concluded that SCF can promote the in vitro growth of hemopoietic progenitors in patients with acquired SAA. Third, we have tested the response to SCF of peripheral blood (PB) hemopoietic progenitors collected from patients receiving in vivo long-term treatment with granulocyte CSF (G-CSF). When PB cells were plated directly in the presence of GM-CSF there was no colony formation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vitro effect of stem cell factor on colony growth from acquired severe aplastic anemia. 769 24

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

Sorted fractions from mouse bone marrow containing highly purified hemopoietic stem and progenitor cells were studied for the expression of growth factor receptors. With the use of rhodamine 123 WGA+, 15-1.1-, low density cells were separated into quiescent pluripotent stem cells and committed progenitor cells. RNA was extracted and cDNA was prepared by reverse transcription. Using primers specific for growth factor receptors, the cDNA of each sorted fraction was amplified by polymerase chain reaction (PCR). The quiescent rhodamine 123 dull stem cell fraction was found to express the interleukin 3 (IL-3) receptor beta unit and c-kit, but not the granulocyte-macrophage colony stimulating factor (GM-CSF) receptor beta unit nor flk-2. The rhodamine 123 bright fraction with activated stem cells and mostly committed progenitor cells similarly expressed the IL-3-R beta, and c-kit. However, this fraction also expressed flk-2 and GM-CSF-R beta. Since the expression of c-kit in the stem cell fraction does not correspond with the poor response to the kit-ligand stem cell factor (SCF) by these cells, we further analyzed the fractions with respect to their binding of biotinylated SCF. The SCF-binding cells were found to be all rhodamine 123 bright. This indicates that the expression of c-kit is not sufficient to yield a functional receptor for SCF; c-kit probably needs a partner molecule to form a functional high-affinity binding site for SCF. Similar to the beta unit of the GM-CSF receptor, this partner is then not expressed in the stem cell fraction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The expression of cytokine receptors by purified hemopoietic stem cells. 769 28

The c-kit ligand or stem cell factor (SCF) and the c-kit ligand receptor (KR) are thought to play pivotal roles in the regulation of human hematopoiesis. When added to interleukin 3 (IL-3) and/or granulocyte-macrophage colony stimulating factor (GM-CSF), SCF has an especially profound effect on the in vitro proliferation of several classes of primitive hematopoietic progenitor cells including the burst forming unit megakaryocyte (BFU-MK), the high proliferative potential colony forming cell (HPP-CFC) and the long-term bone marrow culture-initiating cell (LTBMC-IC). These primitive hematopoietic progenitor cells are present in a CD34+HLA-DR- fraction of marrow which has in vivo marrow populating ability and thereby resembles the pluripotent hematopoietic stem cell. Furthermore, the CD34+HLA-DR- marrow subpopulation which expresses KR contains virtually all of the marrow BFU-MK, HPP-CFC and LTBMC-IC, indicating that the human stem cell is KR positive. The addition of SCF, IL-3 and GM-CSF to suspension cultures initiated with CD34+HLA-DR- cells results in an exponential expansion of the numbers of hematopoietic progenitor cells. Large numbers of such progenitor cells generated ex vivo may be useful as transfusion products for the treatment of chemotherapy induced cytopenias. The therapeutic potential of the in vivo administration of SCF has also been evaluated in a phase I trial of recombinant methionyl SCF. SCF administration led to an increase in both differentiated and primitive hematopoietic progenitor cells within the marrow. Such studies suggest that in vivo SCF administration may be useful for improving the quality of bone marrow grafts to be used either for autologous or allogeneic bone marrow transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The in vitro and in vivo effects of stem cell factor on human hematopoiesis. 769 31

Cell kinetic studies of acute myeloid leukemia (AML) have provided evidence for the presence of nonproliferating cells. Hemopoietic growth factors (GF) can regulate proliferation of leukemic cells, furnishing new possibilities for recruiting quiescent cells into the cycle and overcoming cytokinetic resistance in AML. To assess the role of the novel identified cytokine, mast cell growth factor (MGF), in enhancing cytosine arabinoside (Ara-C) cytotoxicity, we have primed AML blasts with MGF and then exposed these cells to the S phase specific agent Ara-C. Other growth factors such as PIXY, interleukin 3 (IL-3), granulocyte-macrophage colony stimulating factor (GM-CSF) and granulocyte CSF (G-CSF) and the combination of MGF plus PIXY were also tested. Cytokinetic changes and clonogenic growth of leukemic colony forming unit (CFU-L) cells in methylcellulose were used to detect proliferative and cytotoxic effects on AML blasts. Expression of MGF receptor, the c-kit protein, was also measured by flow cytometry. We report in this preliminary study that MGF is able to increase proliferation in 75% of the samples studied and enhance Ara-C cytotoxicity in some of these cases. When MGF proliferative activity was compared with other GFs, individual cases showed heterogeneity in response, although the combination of MGF plus PIXY was always the most effective.
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PMID:Effects of mast cell growth factor on Ara-C mediated acute myeloid leukemia cell killing. 769 32

Seven patients received cancer chemotherapy with high-dose cyclophosphamide (HD-CTX) associated with either recombinant human granulocyte colony-stimulating factor (rhG-CSF), rh interleukin-3 (rhIL-3), rh granulocyte-macrophage CSF (rhGM-CSF) plus rh erythropoietin (rhEpo), rhIL-3 plus rhGM-CSF, or rhIL-3 plus rhG-CSF. In the steady-state blood samples (before HD-CTX), megakaryocyte burst-forming units (BFU-Meg) and megakaryocyte colony-forming units (CFU-Meg) were virtually undetectable (< or = 1/mL BFU-Meg and CFU-Meg, range 0 to 1) by assaying unfractionated leukocytes. In contrast, in the recovery-phase blood samples (after HD-CTX), BFU-Meg and CFU-Meg increased several hundred-fold over steady-state values. This occurred regardless of the in vivo growth factors used and in parallel with increases in mixed, erythroid, and myeloid progenitors. In vitro, recovery-phase BFU-Meg and CFU-Meg responded to the novel GM-CSF/IL-3 fusion protein PIXY321 similarly as to optimal concentrations of rhIL-3 and rhGM-CSF. However, these progenitors differed from those in the steady state because BFU-Meg had faster duplication time and CFU-Meg prevailed numerically (CFU-Meg to BFU-Meg ratio 3.4 [recovery] vs. 0.52 [steady state]). Furthermore, soluble c-kit ligand/rh stem cell factor (rhSCF), in vitro in combination with rhIL-3 and rhGM-CSF or PIXY321, increased the size but not the number of colonies derived from recovery-phase BFU-Meg and CFU-Meg. These quantitative and qualitative changes occurring in circulating megakaryocyte progenitors contribute to the understanding of the rapid platelet recovery that occurs when peripheral blood hematopoietic progenitors elicited by HD-CTX and growth factor(s) are transplanted into patients treated with myeloablative chemoradiotherapy.
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PMID:Increase in peripheral blood megakaryocyte progenitors following cancer therapy with high-dose cyclophosphamide and hematopoietic growth factors. 769 40

In this paper we attempt to improve upon the methods of hematopoietic stem cell expansion. We evaluate the effects of recombinant human stem cell factor (SCF or c-kit ligand) alone and also in combination with recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 3 (IL-3), on cell proliferation and differentiation in human long term bone marrow cultures (LTBMC). Weekly addition of 5 ng/ml of SCF with 25% serum containing media resulted in increased recovery of total nonadherent cells, granulocyte-macrophage colony forming units (CFU-GM), and burst-forming units erythroid (BFU-E) at week 1, but the number of bone marrow (BM) progenitor cells fell below the level of untreated control cultures at weeks 3 (BFU-E) and 4 (CFU-GM). At week 8, when the cultures were terminated, the CFU-GM recovery was markedly reduced in flasks supplemented with SCF compared with the controls (p < 0.002). Moreover, SCF treatment induced the early disappearance of BFU-E. When LTBMC were supplemented with the combination of SCF plus GM-CSF (100 U/ml) and IL-3 (5 ng/ml), synergistic activity of the CSFs was observed at week 1. The number of BM colony forming cells (CFC) rapidly declined below the level of growth factor-free controls, leading to the early exhaustion of the culture when SCF was combined with GM-CSF. By comparison, GM-CSF and IL-3 alone induced a statistically significant increase above the controls (no growth factor) in the number of nonadherent cell colonies of CFU-GM and BFU-E. Analysis of adherent layer cells from cultures supplemented with SCF showed increased cellularity, no adipogenesis, and early disappearance of myeloid progenitors while the percentage of CFU-GM in S phase, assessed by cytosine arabinoside (Ara-C) suicide assay, was 9.2 +/- 5% SD versus 27.7 +/- 10% SD in control (no growth factor) samples (p < 0.01). SCF increased the number of fibroblast colony forming units (CFU-F) and also showed a synergistic activity (9.6-fold increase) when combined with IL-3. These findings suggest that SCF, GM-CSF and IL-3 exert their activity on different cell populations within the hematopoietic system. Further investigations are needed to optimize the use of SCF in supporting hematopoiesis.
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PMID:Effect of stem cell factor (c-kit ligand), granulocyte-macrophage colony stimulating factor and interleukin 3 on hematopoietic progenitors in human long-term bone marrow cultures. 769 21

Maintenance of the progenitor cells responsible for hematopoiesis has generally been accomplished using a feeder layer of stromal cells in stationary culture. Here, we compared the expansion of the total cell and progenitor cell populations using low-density mononuclear cells (LDMCs) obtained from human bone marrow in static culture (T-flasks) and in different cell culture bioreactors designed for the scale-up of mammalian cells. Static cultures were performed without the presence of a previously established stromal cell layer. Expansion of marrow in all cases was accomplished through the use of added cytokines such as IL-3, GM-CSF, and c-kit ligand. The results for the total cell expansion in static culture ranged from 4.4- to 32-fold. The cell number increase was affected by such factors as patient to patient variability, freeze-thawing, and the combination of cytokines used. Due to widespread use and the small amount of marrow needed, static cultures were used as a basis for comparison with other expansion systems. The cell culture systems used to evaluate the scale-up of marrow cultures included suspension, microcarrier, airlift, and hollow fiber bioreactors. Using identical media, cytokines, and feed schedules, LDMCs in the suspension bioreactor expanded to a value of 1.6 compared to a normalized value of 1.0 for static cultures for the two runs investigated. Expansion results for microcarrier cultures averaged 0.75 when compared to static cultures. A cell number increase in the airlift bioreactor resulted in an expansion which was 0.70 of the control static culture. Granulocyte-macrophage and erythroid progenitor assay data were also evaluated for the suspension, microcarrier, and airlift bioreactors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expansion and differentiation of human hematopoietic cells from static cultures through small-scale bioreactors. 776 89

Basophils and mast cells represent important effector cells in allergic inflammation. Furthermore, these cell types are suggested to play a role in the pathogenesis of other forms of chronic inflammation and in the maintenance of tissue homeostasis. Recent studies provided new information on the morphology, development, distribution and effector function of the histamine-containing cells. Particularly the identification of new surface membrane molecules such as CD40 ligand on basophils or c-kit on mast cells, and of new triggering agents and modulators of mediator release such as IL-3, IL-5, GM-CSF and nerve growth factor (for basophils) or c-kit ligand (for mast cells) allows a better understanding of the regulation of these cell types. The regulating cytokines are produced by lymphocytes and tissue cells. On the same time, membrane proteins and soluble mediators of basophils and mast cells regulate tissue and immune functions. Thus, basophils and mast cells are not only effectors but also regulators of inflammation. It is, therefore, tempting to speculate that both cell types play an important role as mediator cells between the unspecific effector level and the specific antigen-recognizing cells of the host immune defense system. This review is mostly restricted to the human system.
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PMID:[Human basophilic granulocytes and mast cells: mediators between allergic inflammation and the specific immune system]. 792 73

The supernatant (CM) of long-term bone marrow culture (LTBMC) contains colony promoting activity (CPA) which does not have granulocyte-macrophage (GM) colony-stimulating activity but which enhances GM-colony formation in the presence of CSF. CPA is different from IL-1, IL-3 and GM, G-, and M-CSF. Since CPA-containing LTBMC-CM always contains a substantial level of IL-6, CPA was thought to be similar to IL-6. In the present study, we found that LTBMC with a particular batch of horse serum produced IL-6 without a corresponding production of CPA. Addition of IL-6 to GM-colony assay system in the presence of GM-CSF did not enhance the colony formation. LTBMC-CM did not stimulate proliferation nor differentiation of mast cell progenitors. Anti-IL-6 antibodies suppressed IL-6 activity, but not CPA. These results indicate that CPA is a novel factor distinct from IL-1, IL-3, G-, M-, GM-CSF, IL-6 and SCF (c-kit ligand).
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PMID:Colony promoting activity (CPA) is a novel factor distinct from IL-6. 821 51

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