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

A strategy is described that allows the development of polymorphic genetic markers to be characterized in individual genes. Segments of the 3' untranslated regions are amplified, and polymorphisms are detected by digestion with frequently cutting enzymes and with the detection of single-stranded conformation polymorphisms. This allows these genes, or DNA segments, to be placed on the linkage maps of human chromosomes. Polymorphisms in two genes have been identified using this approach. A HaeIII polymorphism was detected in the KIT proto-oncogene, physically assigned to chromosome 4q11-12. This polymorphism is linked to other chromosome 4p markers and is in linkage disequilibrium with a HindIII polymorphism previously described at this locus. We have also identified in the insulin-like growth factor1 receptor gene (IGF1R) a 2-bp deletion that is present at a frequency of .25 in the Caucasian population. Pedigree analysis with this insertion/deletion polymorphism placed the IGF1R gene at the end of the current linkage map of chromosome 15q, consistent with the physical assignment of 15q2526. Thus, polymorphisms in specific genes can be used to related the physical, genetic, and comparative maps of mammalian genomes and to simplify the testing of candidate genes for human diseases.
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PMID:Detecting high-resolution polymorphisms in human coding loci by combining PCR and single-strand conformation polymorphism (SSCP) analysis. 167 59

A panel of 164 continuous human leukemia-lymphoma cell lines was analyzed for expression of c-kit using Northern blotting and reverse transcriptase-polymerase chain reaction (RT-PCR). The c-kit transcripts were detectable in cell lines assigned to the myeloid (in 7 of 29 by Northern blotting and in 4 of 8 by RT-PCR), monocytic (in 1 of 24 by Northern blotting and in 3 of 6 by RT-PCR), erythroid (in 6 of 8 by Northern blotting and in 5 of 5 by RT-PCR), and megakaryoblastic (in 10 of 10 by Northern blotting) lineages, c-kit expression was not seen by Northern blotting or RT-PCR analysis in any of the 93 lymphoid leukemia, myeloma, or lymphoma cell lines. Treatment of four megakaryoblastic cell lines with protein kinase C activators (phorbol ester 12-O-tetradecanoylphorbol 13-acetate and Bryostatin 1) led to terminal differentiation as assessed by morphologic alterations, changes in the surface marker profile, and growth arrest. These effects were associated with enhanced c-kit mRNA expression. Exposure to all-trans retinoic acid down-regulated c-kit mRNA levels, while simultaneously causing morphologic alterations in all four cell lines. Stimulation with growth factors (interleukin-3, granulocyte macrophage-colony stimulating factor, and insulin-like growth factors I and II), used to assess any role of c-kit in proliferative processes, did not lead to significant upregulation or downregulation of c-kit expression. The finding of constitutive and high expression of c-kit mRNA in all megakaryoblastic leukemia cell lines and its modulation by various reagents might further contribute to the understanding of megakaryopoietic proliferation, differentiation, and leukemogenesis.
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PMID:c-kit expression in human megakaryoblastic leukemia cell lines. 751 41

An important goal for the investigation of the proliferation of mammalian cells is to establish a fully defined condition for culturing them in vitro. Here, we report establishment of a fully defined culture condition that supports the primary culture of normal c-kit+IL-7 receptor (IL-7R)+ B precursor cells without the aid of stromal cell lines. This defined culture condition contains IL-7, the ligand for c-kit, transferrin, insulin, and bovine serum albumin as protein components. By using the cell lines derived from RAG2(-/-) mice, which do not differentiate into c-kit- stage, we have evaluated the role of each protein in the cell cycle progression of c-kit+IL-7R+ B precursor cells. Since B precursor cells can grow without insulin, c-kit remains a sole functional receptor tyrosine kinase for their growth. While both c-kit ligand (KL) and IL-7 are the requisite molecules for sustained proliferation of B precursor cells, each molecule plays distinct roles. IL-7 starvation results in prompt arrest of the cells at G1. An accumulation of the cells in the mitotic phase was also detected. Thus, the major role of IL-7 is to regulate the G1/S transition and the process of cytokinesis of B precursor cells. Although prolonged KL starvation over 48 h resulted in accumulation of G1 cells, its effect could not be detected within 24 h, which is long enough for all the cells to complete one cell cycle. This suggests that KL might be involved in the cell cycle progression of B precursor cells in a manner that its signal could still be effective in the one or two cell cycles that follow. Although molecular nature of the signals underlying the present observation awaits future investigation, the method described in this report would provide a useful model system for investigating the signaling pathways that are involved in the cell cycle progression of B precursor cells.
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PMID:Cell cycle control of c-kit+IL-7R+ B precursor cells by two distinct signals derived from IL-7 receptor and c-kit in a fully defined medium. 754 34

Commitment to B-lymphocyte differentiation is characterized by expression of the B220 form of the common leukocyte antigen (Ly-5) and D-JH rearrangement of the Ig heavy chain gene complex. B-lineage progenitor cells, or pro-B cells, that have initiated Ig gene rearrangement, but do not express detectable Ig heavy or light chain protein, have recently been shown to retain substantial capacity for expansion in vitro in the presence of bone marrow (BM) stromal cells and interleukin-7 (IL-7). Although the potentiating effect of stromal cells on pro-B-cell proliferation can be partially attributed to the ligand for the proto-oncogene receptor c-kit (c-kit ligand [KL] or stem cell factor), several lines of evidence suggest that c-kit-mediated cell signalling is not required for pro-B-cell expansion. Previous studies from this laboratory demonstrated that insulin-like growth factor-1 (IGF-1) potentiated the proliferative effect of IL-7 on nonadherent cells from lymphoid long-term BM cultures in a manner similar to that shown for KL. To further delineate specific cell stages that respond to lymphopoietic cytokines, we derived continuously proliferating pro-B-cell lines from day-14 murine fetal liver in the presence of IL-7 and BM stromal cell clone S10. Initial expansion and continued proliferation of these pro-B-cell lines was absolutely dependent on the presence of both IL-7 and stromal cells. In the absence of KL, IL-7-stimulated proliferation of these cells in short-term cultures and addition of either recombinant IGF-1 or KL significantly potentiated this proliferative response. Although IGF-2 and insulin also potentiated the effect of IL-7, our data suggest that neither IGF-2 nor insulin represent normal regulators of intramyeloid lymphocyte development. IGF-1 and KL activate unique cascades of intracellular signalling events and inclusion of both cytokines in cultures of IL-7-stimulated pro-B cells resulted in additive potentiation of the proliferative response. Taken together, these results suggest that expansion of pro-B cells in vivo is maintained by at least three stromal cell-derived cytokines. IL-7 appears to be unique in delivering the primary proliferative signal for pro-B-cell expansion; however, both KL and IGF-1 potentiate the proliferative effect of IL-7 on these cells. The functional redundancy and additive effects of IGF-1 and KL as amplification signals for developing B-lineage cells underscore the essential nature of clonal expansion and diversification in development of immunocompetent lymphoid cells.
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PMID:Insulin-like growth factor-1 potentiates expansion of interleukin-7-dependent pro-B cells. 769 33

Murine embryonic stem cells are able to differentiate into embryoid bodies (EBs) in vitro in the absence of leukemia-inhibitory factor with the formation of different types of hematopoietic precursors within these EBs. With the aim of determining the in vitro requirements for the continued development of hematopoietic colony-forming cells (CFCs) and their progeny from embryonic stem-derived cells, cells from EBs disrupted after 9 days of formation in the absence of leukemia-inhibitor factor were cultured under different conditions. Low numbers of day-9 EB cells (5 x 10(5) or less) cultured in the presence of several growth factors (interleukin-3 [IL-3], IL-1, c-kit ligand, basic fibroblast growth factor, insulin growth factor-1, IL-6, granulocyte colony-stimulating factor, fetal liver kinase-2 ligand) develop few or no CFCs after 1 week of culture. When these cells are plated on irradiated NIH-3T3 with IL-3 or c-kit ligand or combinations containing these and other growth factors, they are able to generate CFCs for at least 3 weeks. These cultures were found to include granulocytic, monocytic, erythrocytic, and megakaryocytic cells. Transwell cultures in which NIH-3T3 cells were separated from the EB cells and cultures in which cells were replaced by NIH-3T3 conditioned medium showed that the interaction between EB-derived cells and NIH-3T3 is via a soluble factor(s). These studies show that maximal generation of hematopoietic CFCs from precursors present in day-9 EBs is stimulated by a combination of known hematopoietic growth factors and a soluble factor(s) produced by NIH-3T3 cells.
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PMID:Generation of hematopoietic colony-forming cells from embryonic stem cells: synergy between a soluble factor from NIH-3T3 cells and hematopoietic growth factors. 775 44

A novel class of tyrosine kinase blockers represented by the tyrphostins AG1295 and AG1296 is described. These compounds inhibit selectively the platelet-derived growth factor (PDGF) receptor kinase and the PDGF-dependent DNA synthesis in Swiss 3T3 cells and in porcine aorta endothelial cells with 50% inhibitory concentrations below 5 and 1 microM, respectively. The PDGF receptor blockers have not effect on epidermal growth factor receptor autophosphorylation; weak effects on DNA synthesis stimulated by insulin, by epidermal growth factor, or by a combination of both; and over an order of magnitude weaker blocking effect on fibroblast growth factor-dependent DNA synthesis. AG1296 potently inhibits signaling of human PDGF alpha- and beta-receptors as well as of the related stem cell factor receptor (c-Kit) but has no effect on autophosphorylation of the vascular endothelial growth factor receptor KDR or on DNA synthesis induced by vascular endothelial growth factor in porcine aortic endothelial cells. Treatment by AG1296 reverses the transformed phenotype of sis-transfected NIH 3T3 cells but has no effect on src-transformed NIH 3T3 cells or on the activity of the kinase p60c-src(F527) immunoprecipitated from these cells. These potent and selective compounds represent leads for the development of novel agents to combat tumors driven by PDGF or to inhibit PDGF action in other diseases in which PDGF plays a key role, such as restenosis.
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PMID:Selective platelet-derived growth factor receptor kinase blockers reverse sis-transformation. 795 56

This report presents the results of studies investigating the effect of insulin-like growth factor II (IGF-II) on the proliferation and differentiation of CD34+ bone marrow cells in serum-substituted liquid cultures. Bone marrow cells were enriched for CD34+ cells and then placed in liquid cultures supplemented with either interleukin 3 (IL-3) or IL-3 and c-kit ligand with and without the addition of IGF-II. When CD34+ cells were incubated with IL-3, cellularity increased throughout four weeks of culture. Cellularity was twofold greater when cultures also contained IGF-II. IGF-II also promoted an increase in cellularity in cultures with IL-3 and c-kit ligand. In combination with IL-3 or IL-3 and c-kit ligand, IGF-II promoted an earlier differentiation of granulocytes, as well as an increase in the number of megakaryocyte lineage cells. There were approximately two-fold more colony-forming units for granulocytes and macrophages (CFU-GM) and burst-forming units for erythroid cells (BFU-E) in cultures containing both IL-3 and IGF-II than in cultures with IL-3 alone. These results demonstrate that in cytokine-supplemented media, physiological concentrations of IGF-II augmented both the proliferation and differentiation of CD34+ bone marrow cells while maintaining a greater number of progenitor cells. To identify the receptors through which IGF-II enhances in vitro hematopoiesis, IGF-II was substituted with one of the mutant forms of IGF-II that selectively interacts with either IGF-II/CIM6-P receptors or with IGF-I and insulin receptors. The results with the mutant forms of IGF-II demonstrate that IGF-II augments in vitro hematopoiesis primarily through its interaction with IGF-I and possibly insulin receptors, rather than IGF-II/CIM6-P receptors.
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PMID:Comparative effects of insulin-like growth factor II (IGF-II) and IGF-II mutants specific for IGF-II/CIM6-P or IGF-I receptors on in vitro hematopoiesis. 872

We have previously studied the expression of protein tyrosine kinases in different preparations of insulin producing cells by polymerase chain reaction (PCR). Among the tyrosine kinases thus identified were the fibroblast growth factor receptor-4 (FGFR-4), c-Kit, the insulin-like growth factor (IGF-I) receptor, and the cytoplasmic tyrosine kinase Jak2, which associates with the activated receptor for growth hormone (GH). To elucidate the putative biological effects of the receptors identified, fetal islet-like structures were cultured in the absence or presence of the ligands to the receptors identified, namely, acidic FGF (aFGF), stem-cell factor (SCF), IGF-I, and GH, whereafter insulin and DNA contents as well as insulin secretion to the culture medium were determined. Nerve growth factor (NGF), the ligand to the tyrosine kinase receptor Trk-A, was also included. aFGF and GH were found to stimulate insulin release to the culture medium, whereas SCF augmented insulin contents/DNA as well as islet DNA contents. No effects of NGF or IGF-I were detected. Immunohistochemical studies of fetal rat pancreas showed localization of the c-Kit protein to the pancreatic ducts, whereas immuno-reactivity against FGFR-4 could be detected in both endocrine and exocrine parts of the pancreas as well as in the pancreatic ducts. It is concluded that tyrosine kinase receptors may be involved in the maturation of pancreatic beta cells.
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PMID:Effects of certain growth factors on in vitro maturation of rat fetal islet-like structures. 874 Mar 98

In the bone marrow, multipotent and committed hematopoietic progenitors have to closely regulate their balance between sustained proliferation without differentiation (self renewal) and entering a terminal differentiation pathway. A useful model to analyze this regulation at the molecular level is committed avian erythroid progenitors. These are induced to undergo long-term self renewal by the ligand-activated receptor tyrosine kinase (RTK) c-ErbB, in cooperation with steroid hormone receptors. This self-renewal induction by c-ErbB even occurs in the presence of differentiation factors (erythropoietin and insulin). Under the same conditions, the RTK c-Kit is unable to sustain erythroid progenitor self renewal, stimulating cell proliferation without arresting terminal differentiation. Two mechanisms are involved in these differential activities of c-Kit and c-ErbB. The first one, differential regulation of receptor expression, proved to be of minor importance, because c-Kit was unable to induce self renewal, even if exogenously expressed from a retrovirus at high levels. Rather our results support the second mechanism, i.e., that receptor-specific signal transduction is responsible for the differential biological activity of c-Kit and c-ErbB: (a) specific tyrosine kinase inhibitors (tryphostins) were found which selectively inhibited the biological function of either c-Kit or c-ErbB in erythroblasts but did not affect ligand-induced autophosphorylation of either RTK; and (b) c-ErbB selectively induced SHC phosphorylation and STAT5 activation. The Ras pathway was similarly activated by c-Kit and c-ErbB. The c-ErbB-specific tyrphostin AG30 specifically blocked STAT5 activation, implicating this signal transducer in c-ErbB-induced self renewal.
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PMID:Distinct roles of the receptor tyrosine kinases c-ErbB and c-Kit in regulating the balance between erythroid cell proliferation and differentiation. 914

The role of insulin (INS), and insulin-like growth factor-I (IGF-I) in the regulation of human erythropoiesis is not completely understood. To address this issue we employed several complementary strategies including: serum free cloning of CD34+ cells, RT-PCR, FACS analysis, and mRNA perturbation with oligodeoxynucleotides (ODN). In a serum-free culture model, both INS and IGF-I enhanced survival of CD34+ cells, but neither of these growth factors stimulated their proliferation. The influence of INS and IGF-I on erythroid colony development was dependent on a combination of growth factors used for stimulating BFU-E growth. When BFU-E growth was optimally stimulated with erythropoietin (EpO) + kit ligand (KL) the large erythroid colonies developed normally even in the absence of INS or IGF-I. However, the addition of both of these growth factors slightly enhanced colony size. On the other hand, if erythroid colonies were stimulated suboptimally with EpO + IL-3 only, INS or IGF-I increased the number of small erythroid bursts by approximately 30%. Both INS and IGF-I activated signal transduction in maturing human erythropoietic cells as determined by phosphorylation of the insulin receptor substrate-2 (IRS-2) protein. We also found by RT-PCR that mRNA coding for INS-R is expressed in FACS sorted CD34+, c-kit-R+ marrow cells, and in cells isolated from BFU-E and CFU-GM colonies. Expression of INS-R protein on these cells was subsequently confirmed by cytofluorometry. In contrast, the receptor for insulin-like growth factor-I (IGF-IR) was not detected on CD34+ cells, and was first easily detectable on more differentiated cells derived from day 6 BFU-E and CFU-GM colonies. We conclude that INS and IGF-I may be survival factors for human CD34+ cells, but are not required during early erythropoiesis. In contrast, both growth factors may play some role at the final stages of erythroid maturation.
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PMID:The role of insulin (INS) and insulin-like growth factor-I (IGF-I) in regulating human erythropoiesis. Studies in vitro under serum-free conditions--comparison to other cytokines and growth factors. 952 32


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