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)

The recent identification of the mouse White spotting and Steel loci as genes encoding the c-kit receptor and its ligand, respectively, has shed light on the importance of this ligand and receptor in embryogenesis, melanogenesis and hematopoiesis. In order to determine if the c-kit proto-oncogene is involved in human disease, we isolated seven overlapping lambda recombinants, using a fetal brain cDNA, and characterized the normal human gene (KIT). The longest mapped transcript is 5230 bp, is alternatively spliced and includes 21 exons that span more than 70 kb of DNA. From the exon-intron structure, we have localized an alternative splice site to the 3' end of exon 9. The overall c-kit gene structure closely resembles that found in the CSF-1R gene (c-fms). This similarity includes a large first intron, the same number of exons containing translated sequence and very similar exon-intron boundaries. Using pulsed-field gel electrophoresis, we have linked KIT to the platelet-derived growth factor receptor A gene, with both residing on a 700-kb BssHI fragment. These data will allow investigation into the control of KIT expression and the potential to identify mutations or altered expression of this gene in human disease.
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PMID:Cloning and structural analysis of the human c-kit gene. 137 10

The c-kit proto-oncogene encodes a 145- to 160-Kd transmembrane tyrosine kinase, which is a member of the platelet-derived growth factor receptor family and is allelic with the murine white spotting locus (W). W mutations affect several aspects of hematopoiesis, most notably erythroid progenitors and mast cells. A monoclonal antibody, YB5.B8, had been raised against the leukemic blasts of a patient with M1-type acute myelocytic leukemia (AML) and it precipitates a 150-Kd cell surface glycoprotein from leukemic cells. The YB5.B8 epitope is expressed on mast cells, on up to 3% of normal mononuclear bone marrow cells, and it identifies a sub-group of AML patients with a poor prognosis. In view of similarities noted between the cell surface antigen identified by YB5.B8 and the c-kit protein product, we performed experiments to determine whether they are identical. c-kit RNA expression in the cell lines HEL (human erythroleukemia) and A172 (glioblastoma) was shown to parallel the expression of the YB5.B8 epitope in these lines as measured by flow cytometry. Immunoprecipitation analysis with anti-kit serum and YB5.B8 antibody indicated that the two antibodies identified proteins of identical size in HEL (155 Kd) and A172 (145 Kd) cells, and sequential immunoprecipitations with the kit and the YB5.B8 antibodies demonstrated that the two antibodies recognize the same molecule. The proteins identified by both the anti-kit and YB5.B8 antibodies displayed in vitro autophosphorylation activity in immune complex kinase assays. In addition, YB5.B8 was able to inhibit the binding of the kit ligand to HEL cells. These studies provide evidence that the YB5.B8 antigen and the c-kit protein product are identical and raise certain hypotheses regarding the role of c-kit in AML.
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PMID:Monoclonal antibody YB5.B8 identifies the human c-kit protein product. 170 91

A new human gene encoding a receptor-type tyrosine kinase was isolated by a weak cross-hybridization with v-ros oncogene. A cDNA of about 7.7 kb carried a 4.2 kb open reading frame, and the predicted amino acid sequence of 1338 residues contained extracellular, transmembrane and tyrosine kinase domains. Although its extracellular domain is approximately 220 amino acids longer than those of the products of the fms family, i.e. c-fms, c-kit and platelet-derived growth factor receptor genes, the overall structure including cysteine motifs in its extracellular domain and a long peptide insertion in its tyrosine kinase domain indicates that this new gene is closely related to the fms family. Consequently, the gene was designated as flt (fms-like tyrosine kinase) gene. The expression of the flt gene was strongly suppressed in most of the tumor cell lines examined so far, whereas this mRNA was expressed in a variety of normal tissues of adult rat.
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PMID:Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family. 215 38

A purified opioid-binding protein has been characterized by cDNA cloning. The cDNA sequence predicts an extracellularly located glycoprotein of 345 amino acids. This protein does not possess a membrane-spanning domain but contains a C-terminal hydrophobic sequence characteristic of membrane attachment by a phosphatidylinositol linkage. It displays homology to the immunoglobulin protein superfamily, featuring three domains that resemble disulfide-bonded constant regions. More specifically, the protein is most homologous to a subfamily of proteins which includes the neural cell adhesion molecule (NCAM) and myelin-associated glycoprotein (MAG) and one subgroup of the tyrosine kinase growth factor receptors comprising the platelet-derived growth factor receptor (PDGF R), the colony-stimulating factor 1 receptor (CSF-1 R) and the c-kit protooncogene. These sequence homologies suggest that the protein could be involved in either cell recognition and adhesion, peptidergic ligand binding or both.
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PMID:Molecular characterization of a new immunoglobulin superfamily protein with potential roles in opioid binding and cell contact. 272 89

Comparative mapping data suggested that the dominant white coat color in pigs may be due to a mutation in KIT which encodes the mast/stem cell growth factor receptor. We report here that dominant white pigs lack melanocytes in the skin, as would be anticipated for a KIT mutation. We found a complete association between the dominant white mutation and a duplication of the KIT gene, or part of it, in samples of unrelated pigs representing six different breeds. The duplication was revealed by single strand conformation polymorphism (SSCP) analysis and subsequent sequence analysis showing that white pigs transmitted two nonallelic KIT sequences. Quantitative Southern blot and quantitative PCR analysis, as well as fluorescence in situ hybridization (FISH) analysis, confirmed the presence of a gene duplication in white pigs. FISH analyses showed that KIT and the very closely linked gene encoding the platelet-derived growth factor receptor (PDGFRA) are both located on the short arm of Chromosome (Chr) 8 at band 8p12. The result revealed an extremely low rate of recombination in the centromeric region of this chromosome, since the closely linked (0.5 cM) serum albumin (ALB) locus has previously been in situ mapped to the long arm (8q12). Pig Chr 8 shares extensive conserved synteny with human Chr 4, but the gene order is rearranged.
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PMID:Pigs with the dominant white coat color phenotype carry a duplication of the KIT gene encoding the mast/stem cell growth factor receptor. 887 90

Signaling molecules that are responsible for proliferation and differentiation of hematopoietic cells following ectopic expression of receptor tyrosine kinases (RTKs) were investigated in the interleukin 3 (IL-3)-dependent hematopoietic cell line, FDC-P1. Cells were transfected with human platelet-derived growth factor receptor (PDGF-R), macrophage colony stimulating factor-1 receptor (CSF-1R), epidermal growth factor receptor (EGF-R), and chimeras consisting of the extracellular domain of EGF-R and the transmembrane and cytoplasmic domains of either HER2 (HER1-2) or c-kit (EK-R). All FDC-P1 transfectants proliferated in response to the corresponding growth factor in the absence of IL-3. However, only cells expressing PDGF-R, CSF-1R, and EK-R (type III RTKs) differentiated along the monocyte-macrophage lineage after treatment with their activating ligands. Analysis of proteins from these RTK-expressing cells revealed that a Mr 85,000 protein showed in vitro phosphorylation, and V8 protease peptide mapping showed that this protein was p85, the regulatory subunit of phosphatidylinositol 3-kinase (PI3-kinase). Accordingly, activation of PDGF-R-, CSF-1R-, and EK-R-expressing cells led to an increase in PI3-kinase activity. Expression of EK-R mutant Y721F, which lacked the known p85 binding site, blocked differentiation and activation of PI3-kinase, without affecting proliferation. Last, addition of wortmannin to cells expressing PDGF-R, CSF-1R, and EK-R blocked ligand-induced differentiation in a concentration-dependent manner, and this effect correlated with wortmannin's ability to inhibit PI3-kinase. Thus, ectopic expression of both type I and III RTKs could stimulate FDC-P1 proliferation in the absence of IL-3; however, only activation of type III RTKs led to differentiation via selective coupling to p85 and PI3-kinase activation.
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PMID:Activation of phosphatidylinositol 3-kinase is necessary for differentiation of FDC-P1 cells following stimulation of type III receptor tyrosine kinases. 954 91

SU5416 and SU6668 are potent antiangiogenic small-molecule inhibitors of receptor tyrosine kinases, including those of the vascular endothelial growth factor and platelet-derived growth factor receptor families. The stem cell factor (SCF) receptor, c-kit, is structurally related to these receptors and, although not expressed on mature peripheral blood cells, is expressed in leukemic blasts derived from 60% to 80% of acute myeloid leukemia (AML) patients. The c-kit kinase inhibitory activity of SU5416 and SU6668 was evaluated in MO7E cells, a human myeloid leukemia cell line. Tyrosine autophosphorylation of the receptor, induced by SCF, was inhibited in these cells by SU5416 and SU6668 in a dose-dependent manner (inhibitory concentration of 50% [IC(50)] 0.1-1 microM). Inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, a signaling event downstream of c-kit activation, was also inhibited in a dose-dependent manner. Both compounds also inhibited SCF-induced proliferation of MO7E cells (IC(50) 0.1 microM for SU5416; 0.29 microM for SU6668). Furthermore, both SU5416 and SU6668 induced apoptosis in a dose- and time-dependent manner as measured by the increase in activated caspase-3 and the enhanced cleavage of its substrate poly(ADP-ribose) polymerase. These findings with MO7E cells were extended to leukemic blasts from c-kit(+) patients. In patient blasts, both SU5416 and SU6668 inhibited SCF-induced phosphorylation of c-kit and ERK1/2 and induced apoptosis. These studies indicate that SU5416 and SU6668 inhibit biologic functions of c-kit in addition to exhibiting antiangiogenic properties and suggest that the combination of these activities may provide a novel therapeutic approach for the treatment of AML.
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PMID:The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line and in acute myeloid leukemia blasts. 1122 88

Therapeutic agent STI571 (signal transduction inhibitor number 571) is a rationally developed, potent, and selective inhibitor for abl tyrosine kinases, including bcr-abl, as well c-kit and the platelet-derived growth factor receptor tyrosine kinases. Results of clinical trials to date have demonstrated the crucial role of the bcr-abl tyrosine kinase in chronic myelogenous leukemia (CML) pathogenesis and the potential of anticancer agents designed to target specific molecular abnormalities in human cancer. An initial phase I study of STI571 included 83 Ph(+) CML patients who had failed interferon-based therapy. Patients were required to be in chronic phase, defined liberally as less than 15% blasts in blood or bone marrow. Patients were treated with once-daily oral doses of STI571 in 14 successive dose cohorts ranging from 25-1,000 mg. In this phase I study, no dose-limiting toxicity was encountered and toxicity at all dose levels was minimal. The threshold for a maximally effective dose was found at 300 mg; for patients treated at or above this level, complete hematologic response was seen in 98% of patients, with complete cytogenetic responses in 13% and major cytogenetic responses in 31%. With a median duration of follow-up of 310 days, ongoing responses are evident in 96% of patients. In the phase II study of the accelerated phase of CML, 233 patients were treated with either 400 or 600 mg of STI571. With similar follow-up to the chronic phase trial, 91% of patients showed a hematological response; 63% of patients achieved a complete hematological response but not all patients had recovery of peripheral blood counts. In addition to the phase II clinical trials with STI571, a phase III trial randomizing newly diagnosed patients to either interferon with low-dose s.c. cytosine arabinoside versus STI571 is ongoing; this trial accrued rapidly and data collection is ongoing. Integration of STI571 into CML treatment algorithms will require long-term follow-up data from the ongoing phase II and III clinical studies.
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PMID:STI571: targeting BCR-ABL as therapy for CML. 1142 68

Developing drugs to specifically inhibit oncogenes has been a major goal of cancer research for many years. Identifying the appropriate intracellular targets and understanding the signal transduction pathways in which these molecules participate are critical to this process. A large number of the activated oncogenes implicated in the pathogenesis and progression of malignancy are tyrosine kinases. Bcr-Abl, the causative molecular abnormality in chronic myeloid leukemia (CML), is a prototypic oncogenic kinase and an attractive drug target. The tyrosine kinase inhibitor imatinib mesylate (formerly STI571, [Gleevec]; Novartis Pharmaceuticals Corp, East Hanover, NJ) was recently approved for the treatment of CML and provides proof of principle for the strategy of targeted signal transduction inhibition. This drug is effective in the chronic phase of CML, a single gene disorder driven by Bcr-Abl, and in the advanced phases of CML, showing that inhibition of a single oncogene in a multigene disorder also may be of benefit. The success of imatinib mesylate in CML led rapidly to clinical trials in other cancers associated with activation of two other tyrosine kinases known to be sensitive to imatinib mesylate, c-Kit and the platelet-derived growth factor receptor. Gastrointestinal stromal tumors, which have activating mutations in c-Kit, are now also being found to respond to kinase inhibition with the drug. The general approach of specifically targeting activated kinases with small-molecule drugs is likely to be effective in other tumors in the future.
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PMID:The biology of signal transduction inhibition: basic science to novel therapies. 1174 Aug 1

Targeted cancer therapy has long been sought by the oncology community as a potentially better approach than currently available therapies. One targeted therapy that has shown great success is the tyrosine kinase inhibitor imatinib mesylate (formerly STI571, [Gleevec]; Novartis Pharmaceuticals Corp, East Hanover, NJ) which was recently approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML). Basic scientific investigation into the molecular causes and pathogenesis of CML and encouraging preclinical investigations on the mechanism of action of imatinib mesylate led to the initiation of phase I clinical trials. Clinical development of imatinib mesylate continued with three large, multicenter, phase II trials. The majority (88%) of interferon-alpha-resistant or intolerant patients in chronic-phase CML achieved a complete hematologic response to imatinib mesylate. More importantly, approximately half of patients achieved a major cytogenetic response, a result historically associated with improved survival. Furthermore, 21% of patients in accelerated-phase CML and 13.5% of patients in blastic-phase CML (patient populations with typically poor prognosis before the advent of imatinib mesylate) achieved major cytogenetic responses. Results from ongoing studies will determine the durability of these responses and will evaluate ways to optimize treatment in advanced-stage patients using imatinib mesylate in combination with other therapies. Additional trials are planned to investigate the efficacy of imatinib mesylate to treat a variety of solid tumors whose pathogenesis is driven by the other tyrosine kinase targets, c-Kit and platelet-derived growth factor receptor.
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PMID:Imatinib mesylate: clinical results in Philadelphia chromosome-positive leukemias. 1174 Aug 2


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