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)

Diamond-Blackfan anemia is a congenital disorder of erythropoiesis in humans, characterized by a macrocytic anemia often associated with physical anomalies. Mutations at either the W or Steel loci in the mouse also leads to a severe macrocytic anemia, as well as other developmental abnormalities. The W locus encodes the proto-oncogene c-kit, a member of the receptor tyrosine kinase family, while the Steel locus encodes a potent hematopoietic growth factor that is the ligand for c-kit. Growth of clonogenic marrow erythroid progenitor cells in vitro in the presence of the recombinant hematopoietic growth factors interleukin-3 (IL-3) and Steel was used to characterize this disease at the cellular level. Three patterns of in vitro marrow response to both recombinant IL-3 or Steel were observed among 10 Diamond-Blackfan patients: those that responded quantitatively and qualitatively almost as well as cells from normal marrow, those that responded at an intermediate level, and those that did not respond at all. These results provide evidence for cellular heterogeneity underlying the pathogenesis of this disorder and therefore raise the possibility that there may be more than one underlying molecular basis for the disease. No gross abnormalities in the structure of either the c-kit or Steel loci were observed in these patients. The normal response in culture of the progenitor cells from at least some patients to Steel with or without IL-3 raises the possibility of using this novel growth factor as a therapeutic agent in Diamond-Blackfan anemia.
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PMID:Diamond-Blackfan anemia: heterogenous response of hematopoietic progenitor cells in vitro to the protein product of the steel locus. 171 89

The molecular cloning for most of the hematopoietic growth factor receptors has been achieved over the past few years and revealed that they can by assigned to two discrete receptor families, namely the hematopoietic growth factor superfamily (HRS) and the receptor tyrosine kinase family (RTK). The members of the HRS, including granulocyte-macrophage colony-stimulating factor receptor (GM-CSF-R), interleukin 3 receptor (IL-3-R), granulocyte CSF receptor (G-CSF-R) and erythropoietin receptor (Epo-R), share a common binding domain and the absence of a tyrosine kinase domain in their cytoplasmic portion. In some cases (e.g., GM-CSF-R), the high-affinity receptor structure is obtained through the association of the low-affinity binding chain (alpha chain) with an accessory protein (beta chain). It is conceivable that this protein might also represent the common subunit shared by GM-CSF-R and by IL-3-R when they are co-expressed to form the putative GM-CSF-R/IL-3-R complex. Although tyrosine phosphorylation following ligand receptor activation seems to be a common event in the HRS, its role in the signal transduction mechanisms is unknown. Due to the structural analogies among the members of this family any new insight into one particular receptor member, such as its subunit structure and its signal transduction pathways, will be generalizable to the other family members. The subclass III of the RTK family, including the CSF-1-R and c-kit, is characterized by an additional insert into the kinase domain that recognizes and binds protein substrates. Ligand induced activation of the kinase domain and its signaling potential are mediated by receptor oligomerization which stabilizes interactions between adjacent cytoplasmic domains and leads to activation of kinase function by molecular interaction. Interestingly, the receptors included in this subclass are the products of well known cellular proto-oncogenes. A large variety of structural alteration found in receptor-derived oncogene products may lead to constitutive activation of receptor signals that, consequently, result in the subversion of the mechanisms controlling the cell growth.
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PMID:Hematopoietic growth factor receptors. 189 57

Stem cell factor (SCF) is a hematopoietic growth factor produced by fibroblasts and endothelial cells that stimulates the growth of primitive hematopoietic cells. SCF triggers cell growth by binding to the c-kit receptor. Because endothelial cells can respond to certain hematopoietic growth factors, we tested human umbilical vein endothelial cells for display of the c-kit receptor and examined the effect of SCF on endothelial cell proliferation, adhesion molecule expression, and production of tissue factor. Quantitative binding experiments with 125I-SCF showed both high-affinity (Kd = 42 pmol/L) and low-affinity (Kd = 1.7 nmol/L) c-kit receptors. There were approximately 1,100 high-affinity c-kit receptors, and 5,400 low-affinity c-kit receptors per endothelial cell. Enzyme immunoassays showed that endothelial cells released soluble c-kit receptor and SCF. The transmembrane form of SCF was detected by indirect immunofluorescence analysis using monoclonal or polyclonal anti-SCF receptor antibodies. The addition of SCF (100 ng/mL) did not alter endothelial cell proliferation over a 7-day period. Similarly, there was no change in the release of tissue factor or expression of inducible endothelial adhesion molecules (intercellular adhesion molecule-1, endothelial-leukocyte adhesion molecule-1, and vascular cell adhesion molecule-1) measured by enzyme-linked immunosorbant assay at 4 and 24 hours after SCF addition. The neutralizing anti-c-kit receptor monoclonal antibody SR-1 blocked binding of 125I-SCF to the c-kit receptor by 98% but did not alter endothelial cell proliferation or adhesion-molecule expression. c-kit receptors were also detected on adult endothelial cells lining small blood vessels in normal human lymph nodes. These data indicate that normal human endothelial cells produce SCF and show high-affinity c-kit receptors that have the capacity to dimerize. The lack of response to exogenous SCF may be because of intracellular activation of the c-kit receptor via autocrine production of SCF. Alternatively, SCF and c-kit may play a role other than stimulation of proliferation, adhesion-molecule display, or tissue factor production by endothelial cells. The production of soluble c-kit receptors by normal human endothelial cells may serve to regulate the bioactivity of SCF within the bone marrow microenvironment.
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PMID:Human umbilical vein endothelial cells display high-affinity c-kit receptors and produce a soluble form of the c-kit receptor. 751 42

The human stem cell factor (SCF), also termed c-Kit ligand (KL), is a hematopoietic growth factor produced by mesenchymal cells that induces proliferation of bone marrow progenitor cells, megakaryocytes, and mast cells via interaction with c-Kit, its cognate receptor. Expression of the c-kit gene was identified in human platelets by the polymerase chain reaction technique. The presence of the c-Kit receptor was demonstrated by the specific binding of 125I-KL/SCF to ADP-stimulated platelets. The identity of the c-Kit protein was confirmed by immunoreactivity with an anti-c-Kit-specific antibody and by its characterization as a phosphotyrosine-containing protein. Under constitutive conditions, c-Kit was found to be tyrosine-phosphorylated and was associated with a 85-kDa phosphoprotein that could be a fragment of phosphatidylinositol 3-kinase. These data indicate the presence of a new platelet surface molecule that could function in platelet activation. We demonstrate that the secondary wave of platelet aggregation and serotonin secretion induced by epinephrine and ADP, but not by the thromboxane analog U46619, was augmented by KL/SCF. The effect of KL/SCF on epinephrine/ADP-induced platelet activation appeared to be mediated in part through the thromboxane pathway. These data suggest that KL/SCF could modulate hemostasis via interaction with platelets, particularly in conditions where mesenchymal cells are exposed to circulating blood elements, such as in wound healing or atherosclerosis.
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PMID:Human kit ligand (stem cell factor) modulates platelet activation in vitro. 752 Apr 41

Stem cell factor is a recently identified earliest-acting hematopoietic growth factor and a ligand for the c-kit proto-oncogen. Based on our recent observations that recombinant rat interleukin-3 (IL3), human interleukin-6 (IL6) and murine granulocyte-macrophage colony stimulating factor (GM-CSF) possessed different degrees of suppressive activities on the proliferation of LT 12 cell line derived from BNML rat leukemic model, SCF was evaluated alone and in combination with either IL3, IL6 or GM-CSF for effects on leukemopoiesis in vitro. The results indicated that SCF alone had suppressive effect on DNA synthesis and colony forming unit-leukemic blast (CFU-L) in LT12 cells. 100ng/ml of SCF caused substantial reduction in colony number and 3H-TdR uptake although this suppression was of lower magnitude than those induced by IL3, IL6 or GM-CSF. Enhanced suppression on the proliferation of LT12 cells was observed when SCF was used in combination with one of these three factors. Among these combinations, SCF+GM-CSF or SCF+IL6 resulted in more suppression on LT12 cells than SCF+IL3 did. Combination of SCF with two or three factors produced even more suppression. No apparent effect on the size of leukemic colony was seen. Furthermore, in growth kinetics study of LT12 cells in the presence of SCF production of LT12 cells declined. Thus, SCF appears to have divergent hematopoietic activities on BNML rat model: effective stimulation of granulopoiesis and weak suppression of leukemopoiesis.
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PMID:[Effects of recombinant stem cell factor on the proliferation in vitro of LT12 acute promyelocytic leukemic cell line]. 752 53

Hematopoietic cell proliferation and differentiation is dependent in part on the interaction of hematopoietic stem and progenitor cells with cells making up the hematopoietic microenvironment (HM). Direct cell-cell interactions appear to be important in the hematopoietic microenvironment. One mechanism to accomplish such interactions is the expression of membrane-associated growth factors. Stem cell factor (SCF), the product of the steel gene in mice (also termed mast cell growth factor, c-kit ligand, or Steel factor), is a hematopoietic growth factor demonstrating substantial synergistic activity with a number of other cytokines on primitive hematopoietic stem and progenitor cells. Cloned SCF cDNA encode both a membrane-associated and a secreted growth factor. The physiologic relevance of these isoforms is unknown at present. In order to better understand the physiologic role of these SCF isoforms in normal hematopoiesis, we have established multiple stromal cell lines expressing each isoform. We have used these cell lines to study protein sequences that are required for appropriate post-translational processing of SCF protein in HM-derived stromal cell lines. These lines have also been used to study the interaction of membrane-associated and secreted SCF with murine and human hematopoietic cells. In addition, we have generated transgenic mice expressing each isoform of murine and human SCF. These transgenic mice will be used to study the function of each isoform in hematopoiesis in vivo.
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PMID:Analysis of steel factor (stem cell factor) isoforms in the hematopoietic microenvironment. 753 48

Stem cell factor (SCF), a hematopoietic growth factor, is the ligand of the tyrosine kinase receptor encoded by the c-kit proto-oncogene. Beside the important role of this receptor-ligand complex in hematopoiesis, gametogenesis and melanogenesis, SCF and its receptor have been shown to be expressed in the brain. We have studied the expression of SCF and c-kit in 20 human malignant glioma cell lines at the mRNA as well as at the protein level. In addition, recombinant human (rh) SCF was tested in [3H]thymidine uptake assays for a mitogenic effect on these cells. SCF and c-Kit proteins were detected in the cytoplasm of glioma cells by alkaline phosphatase-monoclonal anti-alkaline phosphatase immunostaining and Western blot analysis. However, neither SCF nor c-Kit were seen on the cell surface by flow cytometry. Furthermore, none of the proliferation assays showed a mitogenic effect for exogenously added rhSCF. Blocking studies using an anti-SCF antibody failed to demonstrate modulating effects on the growth of selected cell lines. These results suggest that SCF and c-Kit may mediate non-proliferative signals or may employ intracellular mechanisms for autocrine growth regulation of glioma cells.
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PMID:Coexpression of stem cell factor and its receptor c-Kit in human malignant glioma cell lines. 753 28

Pluripotent hematopoietic stem cells (PHSCs) were highly enriched from mouse bone marrow by counterflow centrifugal elutriation, lineage subtraction, and fluorescence-activated cell sorting based on high c-kit receptor expression (c-kitBR). We used reverse transcriptase polymerase chain reaction to assay the c-kitBR subset and the subsets expressing low (c-kitDULL) and no (c-kitNEG) c-kit receptor for expression of mRNA encoding hematopoietic growth factor receptors and transcription factors. The c-kitBR cells had approximately 3.5-fold more c-kit mRNA than unfractionated bone marrow cells. The c-kitDULL cells had 47-58% of the c-kit mRNA found in c-kitBR cells and the c-kitNEG cells had 4-9% of the c-kit mRNA present in c-kitBR cells. By comparing mRNA levels in c-kitBR cells (enriched for PHSCs) with those of unfractionated bone marrow, we demonstrated that c-kitBR cells contained low or undetectable levels of mRNA for c-fms, granulocyte colony-stimulating factor receptor, interleukin 5 receptor (IL-5R), and IL-7R. These same cells had moderate levels of mRNA for erythropoietin receptor, IL-3R subunits IL-3R alpha (SUT-1), AIC-2A, and AIC-2B, IL-6R and its partner gp-130, and the transcription factor GATA-1 and high levels of mRNA for transcription factors GATA-2, p45 NF-E2, and c-myb. We conclude from these findings that PHSCs are programmed to interact with stem cell factor, IL-3, and IL-6 but not with granulocyte or macrophage colony-stimulating factor. These findings also indicate that GATA-2, p45 NF-E2, and c-myb activities may be involved in PHSC maintenance or proliferation.
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PMID:Pluripotent hematopoietic stem cells contain high levels of mRNA for c-kit, GATA-2, p45 NF-E2, and c-myb and low levels or no mRNA for c-fms and the receptors for granulocyte colony-stimulating factor and interleukins 5 and 7. 753 77

Protein tyrosine phosphorylation and dephosphorylation have been implicated in the growth and functional responses of hematopoietic cells. Recent studies have identified a novel protein tyrosine phosphatase, termed hematopoietic cell phosphatase (HCP) or PTP1C, that is predominantly expressed in hematopoietic cells. HCP encodes a cytoplasmic phosphatase that contains two src homology 2 (SH2) domains. Since SH2 domains have been shown to target the association of signal-transducing molecules with activated growth factor receptors containing intrinsic protein kinase activity, we assessed the association of HCP with two hematopoietic growth factor receptors, c-Kit and c-Fms. The results demonstrate that HCP transiently associates with ligand-activated c-Kit but not c-Fms and that this association occurs through the SH2 domains. In both colony-stimulating factor 1- and stem cell factor-stimulated cells, there is a marginal increase in tyrosine phosphorylation of HCP. Lastly, HCP can dephosphorylate autophosphorylated c-Kit and c-Fms in in vitro reactions. The potential role of HCP in stem cell factor signal transduction is discussed.
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PMID:Association of hematopoietic cell phosphatase with c-Kit after stimulation with c-Kit ligand. 768 96

Recently, a new hematopoietic growth factor, stem cell factor, the ligand for the c-kit-proto-oncogene, has been cloned. The gene for this factor or for its receptor are deleted in two well known series of mice mutants which display pleiotropic stem cell defects. Therefore, this factor supposedly plays an important role in stem cell biology. This paper reviews some of the elegant genetic work which led to the discovery of the factor and of its receptor, the biological effects that this factor exerts in the hematopoietic system in normal individuals and in patients with Diamond-Blackfan anemia and speculates on some of its potential clinical applications.
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PMID:The biology of stem cell factor, a new hematopoietic growth factor involved in stem cell regulation. 768 57


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