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)

A peculiar point mutation results in constitutive activation of c-kit receptor tyrosine kinase (KIT) in three different tumor mast cell lines; ie, the HMC-1, P-815, and RBL-2H3. Because constitutive activation of KIT was also observed in the FMA3 mouse mastocytoma cell line, we investigated the molecular mechanism. Sequencing of the whole coding region of the c-kit showed that the point mutation found in HMC-1, P-815, and RBL-2H3 cells was absent in FMA3 cells and that the c-kit cDNA of FMA3 cells carried an in-frame deletion of 21 base pairs (bp) encoding Thr-Gln-Leu-Pro-Tyr-Asp-His at codons 573 to 579 at the juxtamembrane domain. The FMA3-type c-kit cDNA with 21 bp deletion was introduced into the IC-2 cell line, which was derived from murine cultured mast cells. IC-2 cells were dependent on interleukin (IL)-3 and did not express KIT on the surface. In IC-2 cells introduced with the FMA3-type c-kit cDNA, KIT was constitutively phosphorylated on tyrosines and activated. Moreover, the FMA3-type KIT was dimerized without the stimulation by stem cell factor (SCF), a ligand for KIT. The spontaneously dimerized FMA3-type KIT without SCF binding was not internalized even after the activation. IC-2 cells expressing the FMA3-type KIT grew in suspension culture without IL-3 and SCF and became leukemic in nude athymic mice. The deletion of seven amino acids at the juxtamembrane domain appeared to be a new activating mutation of KIT that might be involved in neoplastic growth of mast cells.
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PMID:Constitutive activation of c-kit in FMA3 murine mastocytoma cells caused by deletion of seven amino acids at the juxtamembrane domain. 854 52

Recombinant chicken stem cell factor (SCF) was produced in bacteria as a histidine-tagged protein (His delta SCF) and purified by affinity chromatography on an Ni(2+)-NTA agarose column. His delta SCF is devoid of signal peptide and transmembrane domains and therefore mimics a soluble form of SCF. We demonstrate that the factor is biologically fully active in supporting sustained proliferation of SCF-dependent red blood progenitor cells of chicken in vitro. Polyclonal SCF-specific antibodies were raised in rabbits and shown to display potent SCF-neutralizing activity. Thus, recombinant chicken His delta SCF together with the SCF-specific antibody provide valuable tools for studying the role of SCF and c-kit receptor in development, growth and differentiation of avian haematopoietic cells.
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PMID:Avian stem cell factor (SCF): production and characterization of the recombinant His-tagged SCF of chicken and its neutralizing antibody. 874 62

Mast cell disease (MCD), a proliferation of mast cells (MC), is occasionally associated with hematologic malignancies. Neoplastic MC have activating c-kit mutations. c-kit is a receptor tyrosine kinase required for the development, proliferation, and survival of MC. Interaction of c-kit with its ligand stem cell factor induces dimerization, receptor phosphorylation, and signal transduction. The most common c-kit mutation detected in neoplastic MCD is Asp816Val, which results in ligand-independent autophosphorylation of the receptor leading to MC proliferation. We describe the rare occurrence of MCD associated with acute myeloid leukemia, report a novel c-kit mutation Asp816 His, and discuss the pathogenesis of MCD associated with hematologic malignancies.
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PMID:Mast cell disease associated with acute myeloid leukemia: detection of a new c-kit mutation Asp816His. 1107 60

Dermatofibrosarcoma protuberans (DFSP) is a rare superficial sarcoma usually affecting the trunk, with significant risk of local recurrence. It is characterized by the presence of ring chromosomes or chromosomal translocations fusing the promoter of the collagen gene COL1A1 to the platelet-derived growth factor beta-chain gene PDGFB, increasing the production of PDGF locally and promoting autocrine or paracrine tumor growth. Fewer than 5% of patients with DFSP develop metastatic sarcoma, with a poor subsequent prognosis. Imatinib (STI-571) was developed as an inhibitor of the PDGF receptor tyrosine kinase and has proven clinical activity against chronic myelogenous leukemia (expressing bcr-abl) and gastrointestinal stromal tumors (expressing c-kit). We describe 2 patients with metastatic and unresectable metastases from DFSP treated with imatinib. After confirmation of negative CD117 status of 2 sarcomas arising from DFSP, patients were given imatinib 400 mg po qd and assessed at regular intervals for their tolerance and response to therapy. One patient had a transient response, then progressed rapidly and died of disease. Another patient showed a partial response to therapy after 2 months, with resolution of superior vena cava syndrome and shrinking of metastatic lung lesions. His response is ongoing after 6 months of therapy. These clinical data confirm findings from models of DFSP and support the use of imatinib in the rare setting of metastatic DFSP. Imatinib may be useful for patients with locally advanced DFSP, when other options for local therapy are limited.
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PMID:Differential sensitivity to imatinib of 2 patients with metastatic sarcoma arising from dermatofibrosarcoma protuberans. 1220 98

STI571 (imatinib mesylate; Gleevec) is a selective inhibitor of the bcr-abl, c-kit, and platelet-derived growth factor receptor tyrosine kinases. Mild periorbital edema has been noted as a common side effect in Phase I and II trials of this drug for the treatment of patients with chronic myelogenous leukemia and gastrointestinal stromal tumors. The authors report the case of male patient age 63 years who developed severe periorbital edema after treatment with STI571 for chronic myelogenous leukemia. His edema was severe enough to cause visual obstruction due to lower eyelid festoons that ultimately required surgical debulking. Histopathologic analysis of specimens of the excised upper and lower eyelid tissue revealed dermal dendrocytes that expressed the platelet-derived growth factor receptor and c-kit tyrosine kinases, suggesting a possible role for dermal dendrocytes in the development of this toxic effect.
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PMID:Severe periorbital edema secondary to STI571 (Gleevec). 1220 33

The cytokine stem cell factor (SCF) and its interaction with its receptor c-kit plays an important role in the development of germ cells in eutherians. To investigate the putative roles of the SCF/c-kit system in marsupials, recombinant Australian brushtail possum (Trichosurus vulpecula) SCF was purified after secretion by the methylotrophic yeast Pichia pastoris. The purification procedure utilized Ni2+ affinity chromatography with a poly-histidine tag engineered onto the C-terminus of the recombinant SCE The recombinant possum SCF had a molecular weight of 48 kDa, as determined by sodium dodecyl sulphate-polyacrylamide gel electrophoresis, and was biologically active with respect to its ability to maintain and induce proliferation of marsupial primordial germ cells in vitro. Furthermore, the recombinant possum SCF stimulated proliferation of the cell line TF1 and this bioactivity could be inhibited using an antibody directed against recombinant mouse SCF. This source of biologically active marsupial SCF may prove useful in future studies of marsupial development.
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PMID:Production of a biologically active recombinant marsupial growth factor using the methylotrophic yeast Pichia pastoris. 1246 57

We established and characterized a c-kit positive cell line from the bone marrow of a patient with biphenotypic acute leukemia (BAL). The cell line, designated TMBL-1, carried a His-175 mutant p53. The immunophenotype of the primary leukemia cells at diagnosis was cytoplasmic CD3+, CD7+, CD13+, CD33-, interleukin-7 (IL-7) receptor+ and c-kit -. However, leukemia cells in relapse and TMBL-1 cells were CD33+ and c-kit +. Immunophenotypically, TMBL-1 is a BAL cell line that coexpresses T-lymphoid and myeloid markers which fulfill the criteria of the European Group for the Immunological Characterization of Leukemia. Stem cell factor (SCF), a key regulator of hematopoiesis signaling through c-kit, enhanced the proliferation of TMBL-1 cells. Direct sequencing revealed the conversion at codon 175 of the p53 gene in the TMBL-1 cells. Primary leukemia cells in relapse also carried the same point mutation but not at diagnosis. Moreover, TMBL-1 cells are sensitive to paclitaxel, which could induce p53-independent apoptosis. The biphenotypic features and p53 mutation may be associated with progression to a more malignant type. This cell line may provide new information on the role of SCF in the overlapping area between early T-lymphoid/myeloid cells, and help in the design of new therapies targeted towards p53 mutations.
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PMID:A novel c-kit positive biphenotypic acute leukemia cell line, TMBL-1, carrying a p53 point mutation. 1280 25

Porcine haematological studies have been hampered by the lack of monoclonal antibodies against porcine CD34 or CD117 expressed on haematological progenitors. The present report describes the enumeration, phenotyping and isolation of porcine haematopoietic progenitor cells expressing stem cell factor (SCF, c-kit ligand) receptor (c-kit, CD117). Recombinant porcine (rp) SCF and granulocyte-macrophage colony-stimulating factor (GM-CSF) were expressed in the mammalian HEK293 cell-based expression system. Both were biologically active and induced the proliferation of the human erythroleukemic cell line TF-1, as well as of porcine bone marrow haematopoietic cells (BMHC), in a concentration-dependent manner. The effect of rpSCF on BMHC proliferation was synergistic with rpGM-CSF. Furthermore, rpSCF had a synergistic effect on the generation of BMHC-derived dendritic cells (DC) induced by GM-CSF and TNF-alpha. RpSCF was expressed with a 6-histidine epitope, permitting both its purification and immunological detection. Binding studies with BMHC demonstrated ligation of SCF to 4-11% of BMHC. These cells represented the SWC3(low/-)SWC8- BMHC subset, with characteristics of immature proliferative progenitor BMHC. In contrast, no expression was noted on the SWC3+SWC8- monocytic, the SWC3+SWC8+ granulocytic or the SWC3-SWC8+ B cell lineage cells. Using magnetic or fluorescence-activated cell sorting, SCF-ligating BMHC were enriched for pluripotent progenitor cells. In this manner, porcine haematological studies can be pursued in a detailed manner not before possible.
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PMID:C-kit positive porcine bone marrow progenitor cells identified and enriched using recombinant stem cell factor. 1297 92

A 75-year-old man underwent partial resection of the small intestine for GIST in January 2000. A recurrent tumor revealed in the intra pelvic space was removed by two operations, and imatinib (400 mg/day) was given after the third operation. As successive administration was not able to be continued due to side effects such as anorexia and fatigue, the recurrent tumor enlarged. After imatinib was given at 200 mg/day, the defecation trouble was improved and the tumor decreased partially on CT image. His partial response has continued over one year. Mutation analysis revealed deletion and point mutation in exon 11 of c-kit gene. Low-dose imatinib administration should be considered in case of side effects at the standard dose.
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PMID:[A case of recurrent GIST successfully treated with low-dose imatinib mesilate]. 1677 Jan

We report a case of vitiligo with localized repigmentation induced by imatinib mesylate. An elderly Chinese man has been characterized with recurrent gastrointestinal stromal tumors originated from interstitial cells of Cajal with gain-of-function c-kit mutation. His recurrent tumors have responded to imatinib mesylate therapy. To our surprise, his decade-long vitiligo was dramatically ameliorated by localized repigmentation, which is considered to be the side effect of imatinib mesylate. Hypopigmentation induced by imatinib mesylate with possible molecular blockage to a melanin-dependent KIT signal has been well documented; however, our case with repigmentation suggested that KIT signal of melanin formation would be much more sophisticated than we have believed.
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PMID:Imatinib mesylate-induced repigmentation of vitiligo lesions in a patient with recurrent gastrointestinal stromal tumors. 1911 32


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