Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Mice of genotype W/Wv and Sl/Sld have been considered as a model of instinct hemopoietic disorders. W/Wv mice have a defect in hemopoietic stem cells and Sl/Sld mice have a defect in the microenvironment. The W locus in murine chromosome 5 encodes the c-kit proto-oncogene and the Sl locus in chromosome 10 encodes the ligand for c-kit, which has been named stem cell factor (SCF), mast cell growth factor (MGF), kit ligand (KL) and steel factor (SL). The cDNA sequence of SCF suggest that it is synthesized as an integral transmembrane protein and that it has common tertiary structure with M-CSF. SCF enhances the proliferation of hemopoietic stem cells and progenitor cells as well as mast cell in combination with other growth factors. Furthermore, it plays an important role in the proliferation and migration of embryonic stem cell, primordial germ cell and melanocyte.
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PMID:[Function, molecular structure and gene expression of stem cell factor (SCF)]. 127 39

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

Transplantation of spleen cells from primary reconstituted mice expressing the v-src oncogene to secondary and tertiary irradiated recipients resulted in the emergence of erythroid precursors with a transformed phenotype. When cultured in methyl cellulose, these precursors generated colonies of undifferentiated cells that could be expanded into continuously growing factor-dependent cell lines in liquid culture. All lines tested had a similar phenotype and expressed the v-src oncogene. In addition they responded to factors that regulate normal erythroid development, namely erythropoietin (Epo), interleukin-3 (IL-3), and mast cell growth factor (MGF), the ligand to the c-kit encoded receptor. When cells from one of the lines were maintained in the absence of factor, a "factor independent" subpopulation emerged that appeared to grow in an autocrine fashion. Conditioned medium from these cells stimulated their own growth as well as the growth of broad spectrum of normal precursors. Studies with neutralizing antibodies indicated that the predominant colony-stimulating factor produced by these cells is IL-3.
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PMID:Factor-dependent erythroid cell lines derived from mice transplanted with hematopoietic cells expressing the v-src oncogene. 137 Feb 2

The kit ligand (KL), also termed stem cell factor (SCF), is a recently discovered hematopoietic growth factor that augments response of early progenitor cells to other growth factors and supports proliferation of continuous mast cell lines. Histological studies suggest that the receptor for SCF/KL, the c-kit proto-oncogene product, is present in bone marrow megakaryocytes. We studied the effects of SCF/KL on immortalized human megakaryocytic cell lines (CMK, CMK6, and CMK11-5) and on isolated human marrow megakaryocytes. Human SCF/KL alone or in combination with the hematopoietic growth factors, interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-6, stimulated proliferation of these megakaryocytic cell lines. SCF/KL treatment did not alter expression of gpIb, gpIIb/IIIa, LFA-1, ICAM-1, or GMP-140 in CMK cells. No effect on ploidy was observed. Furthermore, human SCF/KL induced expression of IL-1 alpha, IL-1 beta, IL-2, and IL-6 in CMK cells. In a fibrin clot system, SCF/KL modestly potentiated megakaryocyte colony formation when added alone to cultures containing CD34+, DR+ bone marrow cells. Addition of SCF/KL with IL-3 or GM-CSF to these cultures resulted in a more marked marrow megakaryocytic cells. SCF/KL may directly affect megakaryocytopoiesis, as well as secondarily modulate hematopoiesis through induction of cytokines in target cells.
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PMID:Effects of the stem cell factor, c-kit ligand, on human megakaryocytic cells. 137 Mar 86

To test the hypothesis that the c-kit ligand plays an important role in the regulation of early events occurring during human hematopoiesis, we determined the effect of a recombinant form of c-kit ligand, termed mast cell growth factor (MGF), on the high-proliferative potential colony-forming cell (HPP-CFC) and the cell responsible for initiating long-term hematopoiesis in vitro (LTBMIC). MGF alone did not promote HPP-CFC colony formation by CD34+ DR- CD15- marrow cells, but synergistically augmented the ability of a combination of granulocyte-monocyte colony-stimulating factor (GM-CSF) interleukin (IL)-3 and a recombinant GM-CSF/IL-3 fusion protein (FP) to promote the formation of HPP-CFC-derived colonies. MGF had a similarly profound effect on in vitro long-term hematopoiesis. Repeated additions of IL-3, GM-CSF, or FP alone to CD34+ DR- CD15- marrow cells in a stromal cell-free culture system increased cell numbers 10(3)-fold by day 56 of long-term bone marrow culture (LTBMC), while combinations of MGF with IL-3 or FP yielded 10(4)- and 10(5)-fold expansion of cell numbers. Expansion of the number of assayable colony-forming unit-granulocyte-monocyte (CFU-GM) generated during LTBMC was also markedly enhanced when MGF was added in combination with IL-3 or FP. In addition, MGF, IL-3, and FP individually led to a twofold to threefold increase in HPP-CFC numbers after 14 to 21 days of LTBMC. Furthermore, the effects of these cytokines on HPP-CFC expansion during LTBMC were additive. Throughout the LTBMC, cells receiving MGF possessed a higher cloning efficiency than those receiving IL-3, GM-CSF, or FP alone. These data indicate that the c-kit ligand synergistically interacts with a number of cytokines to directly augment the proliferative capacity of primitive human hematopoietic progenitor cells.
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PMID:Role of c-kit ligand in the expansion of human hematopoietic progenitor cells. 137 Jun 37

Mast cells accumulate at sites of neovascularization, solid tumors, and many immune reactions. Such accumulation requires directed migration of mature mast cells or their precursors. The nature of the chemoattractants that regulate mast cell motility and the identity of the receptors that mediate the chemotactic response are poorly understood. We have tested the ability of stem cell factor (SCF), a mast cell growth factor, to stimulate mast cell migration. Our results show that SCF is a potent mast cell attractant that stimulates directional motility of both mucosal and connective tissue-type mast cells. The activity is potentiated by costimulation with interleukin-3 (IL-3), another mast cell chemoattractant. SCF, a known ligand for the c-kit tyrosine kinase receptor, was unable to stimulate motility in W42 mutant mast cells, which have a defective c-kit tyrosine kinase. However, W42 mast cells were still able to migrate in response to IL-3. These results show that SCF is a chemotactic factor as well as a growth factor and that the c-kit receptor can transduce signals leading to both cell proliferation and increased directional cell motility.
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PMID:The c-kit receptor ligand functions as a mast cell chemoattractant. 137 Oct 80

The interaction of the mouse c-kit receptor, designated Kit receptor, and steel factor promotes the proliferation and differentiation of hematopoietic progenitor cells. Monoclonal antibodies against the extracellular portion of the mouse Kit receptor were established. Five percent to 10% of total bone marrow cells expressed the Kit receptor, and half of them lack the expression of lineage markers. The Kit receptor was expressed on 70-80% of Thy-1.1lo Lin-Sca-1+ cells, which express Thy-1.1 antigen at a low level and constitute approximately 0.05% of adult bone marrow and fetal liver; by previous studies, these cells have been shown to be highly enriched for multipotent hematopoietic stem cells (HSCs) and are the only hematopoietic cell subset with this activity. Spleen colony formation and long-term multilineage reconstitution activities were contained in the Kit+ but not in the Kit- subpopulations of Thy-1lo Lin-Sca-1+ cells from adult bone marrow, suggesting that the Kit receptor is expressed on HSCs from the earliest stage-i.e., pluripotent HSCs. The role of steel factor in the development and self-renewal of HSCs was tested with Sl/Sl homozygote fetuses, which lack genes to encode functional steel factor. They were shown to have 30-40% of the number of HSCs on days 13-15 when compared with normal litermates. However, the absolute number of HSCs increased during fetal development in the Sl/Sl mice. The results suggest that the Kit receptor-steel factor interaction may not be essential for the initiation of hematopoiesis and the self-renewal of (at least) fetal HSCs.
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PMID:Evidence that hematopoietic stem cells express mouse c-kit but do not depend on steel factor for their generation. 137 59

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

Recently, a novel growth factor has been cloned that has growth promoting activities on a wide variety of hematopoietic cell lineages. This factor has been referred to as mast cell growth factor, stem cell factor, or kit ligand, and will be referred to here as steel factor. Steel factor stimulates the growth of cells via its interaction with the c-kit proto-oncogene, which is a tyrosine kinase receptor that is expressed on the surface of a number of different cell types. In addition to its effects on hematopoiesis, this factor also plays a role in the development of melanocytes and germ cells. The discovery of this growth factor provided the final piece of the puzzle to explain the molecular defects associated with several well known genetic mutations in mice, and has opened the door to understanding the role of this factor in development. Similar genetic defects may exist in humans as well. The aim of this paper is to review the biological structure and activities of this new growth factor, and to discuss its potential applications in clinical medicine.
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PMID:Biological activities and potential therapeutic uses of steel factor. A new growth factor active on multiple hematopoietic lineages. 137 88

The proto-oncogene c-Kit, a transmembrane receptor tyrosine kinase, is an important regulator of cell growth whose constitutively active oncogenic counterpart, v-kit, induces sarcomas in cats. Mutations in murine c-kit that reduce the receptor tyrosine kinase activity cause deficiencies in the migration and proliferation of melanoblasts, hematopoietic stem cells, and primordial germ cells. We therefore investigated whether c-Kit regulates normal human melanocyte proliferation and plays a role in melanomas. We show that normal human melanocytes respond to mast cell growth factor (MGF), the Kit-ligand that stimulates phosphorylation of tyrosyl residues in c-Kit and induces sequential phosphorylation of tyrosyl residues in several other proteins. One of the phosphorylated intermediates in the signal transduction pathway was identified as an early response kinase (mitogen-activated protein [MAP] kinase). Dephosphorylation of a prominent 180-kDa protein suggests that MGF also activates a phosphotyrosine phosphatase. In contrast, MGF did not induce proliferation, the cascade of protein phosphorylations, or MAP kinase activation in the majority of cells cultured from primary nodular and metastatic melanomas that grow independently of exogenous factors. In the five out of eight human melanoma lines expressing c-kit mRNAs, c-Kit was not constitutively activated. Therefore, although c-Kit-kinase is a potent growth regulator of normal human melanocytes, its activity is not positively associated with malignant transformation.
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PMID:c-Kit-kinase induces a cascade of protein tyrosine phosphorylation in normal human melanocytes in response to mast cell growth factor and stimulates mitogen-activated protein kinase but is down-regulated in melanomas. 137 24


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