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)

Stem cell factor (SCF) is an essential hematopoietic cytokine that interacts with other cytokines to preserve the viability of hematopoietic stem and progenitor cells, to influence their entry into the cell cycle and to facilitate their proliferation and differentiation. SCF on its own cannot drive noncycling hematopoietic progenitor cells into the cell cycle but does prevent their apoptotic death. SCF when combined with other cytokines increases the cloning efficacy of hematopoietic progenitor cells from all lineages. SCF also stimulates the growth of CD34+ leukemic progenitor cells from most patients with acute myeloid leukemia (AML). The mRNA expression of the SCF receptor c-kit has been shown to be significantly increased in all fresh AML blast cells compared with normal controls (healthy volunteers), in particular CD34+ cells. Two inhibitory cytokines, transforming growth factor-beta and interleukin-4, decreased c-kit expression, whereas tumor necrosis factor-alpha increased c-kit expression, but chemotherapeutic drugs showed no effect on c-kit expression, but chemotherapeutic drugs showed no effect on c-kit expression in AML cells. Apoptosis has been shown to be directly related to a high complete remission rate in AML patients following induction therapy. Since SCF has been shown to stimulate the proliferation of mainly CD34+ AML cells, we have investigated whether the poor response of patients with CD34+ myeloid leukemia cells to chemotherapy could be due to SCF-induced resistance to apoptosis. The effect of SCF on the apoptosis induced by chemotherapeutic drugs commonly used in the treatment of AML - cytarabine, daunorubicin and carboplatin - was examined in human CD34+ myeloid leukemia cells in serum-free cultures. SCF significantly reduced the induced apoptosis by more than 50% in all CD34+ human leukemia cells treated by any of the three chemotherapeutic drugs. Antibodies blocking c-kit reversed the significant inhibitory effect of SCF on chemotherapy-induced apoptosis, confirming the role of SCF in the resistance to chemotherapy-induced apoptosis in CD34+ human leukemia. These results suggest that the poor response of patients with CD34+ leukemia cells could be at least partially due to less chemotherapy-induced apoptosis resulting from protection by SCF as an adjuvant mechanism for drug resistance in myeloid leukemia. We conclude that an antisense strategy to block c-kit expression in AML blast cells may prove valuable for decreasing the chemoresistance of AML patients. The abrogation of leukemic resistance to apoptotic death through anti-SCF/c-pit expression combined with chemotherapy offers potential for designing novel therapeutic approaches for refractory AML patients.
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PMID:Stem cell factor as a survival and growth factor in human normal and malignant hematopoiesis. 867 52

Bone marrow microvascular endothelial cells (BMEC) are a functional component of the bone marrow stroma and have been shown to release hematopoietic regulatory factors as well as to selectively adhere and support the proliferation and differentiation of CD34+ hematopoietic progenitors. An early passage of these cells was immortalized by transfection with a vector (pSVT) encoding the large T antigen of SV40. The transformed cell line (CDC/CU.BMEC-1) expresses the SV40 transcript, retains the primary cell expression of Ulex europeaus and vWF/ FVIII, and incorporates acetylated low-density lipoprotein. In addition, BMEC-1 mirrors the phenotype of the primary cells with only a few exceptions. Both cell populations express the cellular adhesion molecules ICAM-1 and PECAM and also VCAM-1 and ELAM-1 after upregulation by tumor necrosis factor-alpha. The fibronectin receptor, hyaluronate receptor, collagen receptor, integrins VLA-alpha 3, VLA-alpha 4, and beta 4, endoglin, collagen IV, CD58, and CD61 are also expressed. The only differences are that BMEC-1 expresses higher levels of ICAM-1, CD58, CD34, CD36, and c-kit than the primary cells. The supernatants of primary cell and BMEC-1 contain stem cell factor, interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-1 alpha, IL-11, and G-CSF. The functional significance of these hematopoietic cytokines was demonstrated in transwell cultures. Both cell populations supported the expansion of progeny from CD34+ cell-enriched cord blood mononuclear cells suspended in the upper chamber. These characteristics, plus the fact that BMEC-1 can be maintained independently of exogenous growth factors and exhibit contact inhibition, indicate that this cell line can be used to further define the role of BMEC in hematopoiesis.
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PMID:BMEC-1: a human bone marrow microvascular endothelial cell line with primary cell characteristics. 895 64

Mast cells represent a potential source of interleukin-6 (IL-6) and other cytokines that have been implicated in host defense, tissue maintenance/remodeling, immunoregulation, and many other biologic responses. In acquired immune responses to parasites or allergens, the extensive IgE-dependent activation of mast cells via Fc epsilonRI can result in the release of large quantities of biogenic amines that are stored in the cells' cytoplasmic granules as well as the production of lipid mediators and many cytokines; these products together can orchestrate an intense inflammatory response. We now report that activation of mouse mast cells via c-kit, the receptor for the pleiotropic survival/growth factor, stem cell factor (SCF), can induce the release of IL-6. Upon challenge with SCF, bone marrow-derived cultured mouse mast cells (BMCMCs) released amounts of IL-6 that were greater than 100-fold more than those produced by unstimulated cells, but that were substantially less than those produced in response to IgE and specific antigen. Moreover, BMCMCs released IL-6 upon challenge with concentrations of SCF that resulted in little or no detectable release of tumor necrosis factor-alpha, leukotriene C4, histamine, or serotonin. These findings indicate that SCF, a widely expressed protein that is critical for mast cell development and survival, can also regulate the differential release of mast cell mediators.
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PMID:Differential release of mast cell interleukin-6 via c-kit. 910 82

The expression and activity of receptor tyrosine kinases (RTK) at the cell surface can be modulated by several different pathways including the proteolytic release of the extracellular domain as a soluble receptor. We investigated the regulation of tie receptor expression, an orphan RTK restricted to cells of hematopoietic and endothelial lineages, on primary human endothelial cells and a stably transfected Chinese hamster ovary (CHO) cell line. Tie was expressed in cells as a doublet of 135 and 125 kD; the 135-kD band represented mature cell surface receptor containing sialic acid and N-linked oligosaccharide residues, whereas the 125-kD band represented an intracellular pool of immature receptor. Phorbol 12-myristate 13-acetate (PMA) had dramatic effects on tie expression at the cell surface. Within 15 minutes of PMA treatment, the 135-kD band disappeared from the cell surface and was accompanied by the appearance of a 100-kD band in cell supernatants. The 100-kD band continued to accumulate in the media throughout the duration of PMA treatment during which mature tie receptor was undetectable on the cell surface by fluorescence-activated cell sorting (FACS) or in cell lysates by immunoblot analysis. Using specific antibodies, this 100-kD species was shown to be a soluble form of the tie receptor containing the extracellular domain. PMA-dependent release of soluble tie was mediated through the activation of protein kinase C (PKC); soluble tie was not released in the presence of PKC inhibitors, an inactive PMA analog, or following the downregulation of PKC through chronic PMA treatment. These results indicate that tie receptor expression on endothelial cells is regulated by the release of a soluble extracellular fragment following activation of PKC. Parallel pathways regulating c-kit, tumor necrosis factor (TNF), and colony-stimulating factor (CSF) receptor expression suggest that the release of extracellular receptor fragments represents an alternative mechanism through which cells modulate responses to growth factors and cytokines.
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PMID:Regulation of tie receptor expression on human endothelial cells by protein kinase C-mediated release of soluble tie. 922 71

New sources of human and mouse mast cells, which were isolated from individual organs (i.e., lung, colon, synovium, skin, uterus, heart), developed from progenitors in vitro in the presence of stem cell factor and/or interleukin (IL)-3, or enriched from fetal or adult blood, spleen or bone marrow by cell sorting, have made possible new studies of the cell biology of mast cells. Advances resulting from these new mast cell sources as well as from new methods for labeling specific products in subcellular sites and structures in resting and functional mast cells are the subject of this review. Specific advances discussed are as follows: identification of an Fc epsilonRI+ c-kit- mouse basophil population from bone marrow and spleen that is associated with IL-4 production and an Fc epsilonRI- c-kit- granulated mouse mast cell progenitor in fetal blood; identification of hyperplasia and functional activation of human skin mast cells in vivo when exposed to recombinant stem cell factor and spontaneous degranulation in X-linked immunodeficient mouse mast cells; use of an enzyme-affinity-gold method to detect histamine in mature and immature human mast cell granules, in secretion and recovery of histamine during anaphylactic degranulation of human lung mast cells ex vivo, and in secretion of histamine in vivo by piecemeal degranulation of IL-4 transgenic mouse mast cells in inflammatory eye disease and of human gut mast cells in inflammatory bowel disease; use of immunogold methods to localize cyclooxygenase and tumor necrosis factor-alpha to subcellular structures in human and rat mast cells and to localize the Charcot-Leyden crystal protein in human basophils to aid in the identification of mast cells arising in mixed cellular populations; use of a low-density lipoprotein (LDL)-gold affinity method to demonstrate a rat mast cell granule-mediated uptake of LDL by macrophages in peritoneal fluid.
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PMID:New aspects of mast cell biology. 930 24

The distribution of myeloid lineage-associated cytokine receptors and lysosomal proteins was analyzed in human CD34+ cord blood cell (CB) subsets at different stages of myeloid commitment by reverse-transcriptase polymerase chain reaction (RT-PCR). The highly specific granulomonocyte-associated lysosomal proteins myeloperoxidase (MPO) and lysozyme (LZ), as well as the transcription factor PU.1, were already detectable in the most immature CD34+Thy-1+ subset. Messenger RNA (mRNA) levels for the granulocyte-colony stimulating factor (G-CSF) receptor, granulocyte-macrophage (GM)-CSF receptor alpha subunit and tumor necrosis factor (TNF) receptors I (p55) and II (p75) were also detected in this subset in addition to c-kit and flt-3, receptors known to be expressed on progenitor cells. By contrast, the monocyte-macrophage colony stimulating factor (M-CSF) receptor was largely absent at this stage and in the CD34+Thy-1-CD45RA- subsets. The M-CSF receptor was first detectable in the myeloid-committed CD34+Thy-l-CD45RA+ subset. All other molecules studied were found to be expressed at this stage of differentiation. Different cocktails of the identified ligands were added to sorted CD34+Thy-1+ single cells. Low proliferative capacity was observed after 1 week in culture in the presence of stem cell factor (SCF) + Flt-3 ligand (FL) + G-CSF. Addition of GM-CSF to this basic cocktail consistently increased the clonogenic capacity of single CD34+Thy-1+ cells, and this effect was further enhanced (up to 72.3 +/- 4.3% on day 7) by the inclusion of TNF-alpha. In conclusion, the presence of myeloid-associated growth factor receptor transcripts in CD34+ CB subsets does not discriminate the various stages of differentiation, with the exception of the M-CSF receptor. In addition, we show that TNF-alpha is a potent costimulatory factor of the very immature CD34+Thy-1+ CB subset.
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PMID:Analysis of myeloid-associated genes in human hematopoietic progenitor cells. 932 52

Patients with head and neck squamous cell carcinoma (HNSCC) have profound immune deficiencies. In 65% of these patients, there is an increased intra-tumoral presence of immune-suppressive CD34+ progenitor cells. The goal of the present study was to determine whether CD34+ cell levels were also increased in the peripheral blood of HNSCC patients and if these immune-suppressive cells could be differentiated into dendritic cells. Our results showed that CD34+ cell levels are increased in the peripheral blood of HNSCC patients. To assess if these CD34+ cells could differentiate into dendritic cells, they were isolated from the blood of HNSCC patients and cultured for 12 days with various cytokine combinations. Culturing CD34+ cells with stem cell factor (c-kit ligand) plus granulocyte-macrophage colony-stimulating factor resulted in the appearance of a significant proportion of cells expressing phenotypic markers characteristic of dendritic cells. Also, including tumor necrosis factor-alpha yielded a significant proportion of cells resembling the bipotential precursor cells for dendritic cells and monocytes (CD14+CD1a+), in addition to the dendritic-like cells. When the differentiation inducer 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] was added along with the cytokine combinations, the yield of cells having characteristics of dendritic cells was further increased. Cells that were derived from CD34+ cell cultures containing 1,25(OH)2D3 had a more potent capacity to present the recall antigen tetanus toxoid to autologous peripheral blood leukocytes and to stimulate a mixed leukocyte response compared to cultures to which 1,25(OH)2D3 had not been added. Our results show that CD34+ cells, whose frequency is increased in HNSCC patients, can be differentiated into cells that phenotypically and functionally resemble dendritic cells and that 1,25(OH)2D3 accentuates this differentiation.
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PMID:Increased presence of CD34+ cells in the peripheral blood of head and neck cancer patients and their differentiation into dendritic cells. 939 43

We reported previously that stem cell factor (SCF) is produced mainly by neurons and that its receptor (c-kitR), encoded by the protooncogene c-kit, is expressed in microglia, suggesting that SCF/c-kitR signaling may be involved in neuron-microglia interactions. We now report that SCF supports microglial survival in cultures, maintains them in process-bearing morphology, and inhibits microglial proliferation induced by colony stimulating factor-1. SCF potentiates microglial expression of the mRNAs of nerve growth factor, brain-derived neurotrophic factor and ciliary neurotrophic factor, and downregulates microglial expression of the inflammation-associated cytokines, tumor necrosis factor-a (TNF-alpha), and interleukin-1beta (IL-1beta). SCF potentiates lipopolysaccharide-stimulated, but attenuates interferon-gamma TFNalpha mediated expression of the mRNAs of IL-1beta and TNF-alpha. The SCF-induced expression of neurotrophin mRNAs is enhanced by the addition of lipopolysaccharide (LPS) but is reduced by IFNgamma. The interactions between SCF and LPS or IFNgamma in the regulation of inflammation-associated cytokine gene expression are accompanied by the differential regulation of c-kitR in microglia. These observations suggest that SCF/c-kitR signaling modulates microglial activity.
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PMID:Modulation of microglia by stem cell factor. 967 Sep 90

Human rhabdomyosarcoma cells produce autocrine and paracrine growth factors that can sustain their growth and malignancy. Here we report constitutive production of stem cell factor (SCF) by 5 of 5 human rhabdomyosarcoma cell lines both of alveolar and embryonal histotype. SCF production, ranging from 30 to 162 pg/ml, was independent from the degree of myogenic differentiation and was not modulated by exogenous addition of retinoic acid (RA) or tumor necrosis factor-alpha (TNF-alpha). Four of 5 rhabdomyosarcoma cell lines expressed the mRNA for SCF receptor c-kit, while the 5th cell line became weakly positive for c-kit mRNA only after stimulation with retinoic acid. On the cell surface, c-kit protein was detectable at very low levels in only 1 of 5 rhabdomyosarcoma cell lines and was not up-regulated by RA or TNF-alpha. Addition of anti-c-kit and anti-SCF blocking antibodies, or of exogenous SCF did not alter the in vitro growth ability of rhabdomyosarcoma cells. In conclusion, our data show that rhabdomyosarcoma cells produce consistent amounts of SCF but did not demonstrate autocrine growth modulation. SCF secretion may thus have a paracrine, rather than an autocrine activity in this tumor.
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PMID:Production of stem cell factor and expression of c-kit in human rhabdomyosarcoma cells: lack of autocrine growth modulation. 979 32

Mast cells are thought to contribute significantly to the pathology and mortality associated with anaphylaxis and other allergic disorders. However, studies using genetically mast cell-deficient WBB6F1-KitW/KitW-v and congenic wild-type (WBB6F1-+/+) mice indicate that mast cells can also promote health, by participating in natural immune responses to bacterial infection. We previously reported that repetitive administration of the c-kit ligand, stem cell factor (SCF), can increase mast cell numbers in normal mice in vivo. In vitro studies have indicated that SCF can also modulate mast cell effector function. We now report that treatment with SCF can significantly improve the survival of normal C57BL/6 mice in a model of acute bacterial peritonitis, cecal ligation and puncture (CLP). Experiments in mast cell-reconstituted WBB6F1-KitW/KitW-v mice indicate that this effect of SCF treatment reflects, at least in part, the actions of SCF on mast cells. Repetitive administration of SCF also can enhance survival in mice that genetically lack tumor necrosis factor (TNF)-alpha, demonstrating that the ability of SCF treatment to improve survival after CLP does not solely reflect effects of SCF on mast cell- dependent (or -independent) production of TNF-alpha. These findings identify c-kit and mast cells as potential therapeutic targets for enhancing innate immune responses.
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PMID:The c-kit ligand, stem cell factor, can enhance innate immunity through effects on mast cells. 985 20


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