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)

Carcinoma-in-situ of the testis (CIS) is the precursor of invasive germ cell tumours. It is believed that CIS cells may originate from early fetal gonocytes. Recently, the proto-oncogene c-kit has been implicated as crucial for the development and migration of primordial germ cells. In this study, CIS and overtly invasive human male germ cell tumours were analysed immunohistochemically for expression of the c-kit proto-oncogene protein product. Testicular tissue samples from 36 patients with various types of testicular germ cell neoplasia and 19 control specimens were stained using an indirect immunoperoxidase method. High expression of c-kit was found in almost all cases of CIS, both when the lesion was the only pathology, and when CIS was adjacent to invasive tumours. The Kit staining was retained in seminomas with variable intensity; the majority of cells in tumour mass exhibited c-kit expression in 61% of the samples while focal expression was observed in 39% of the samples studied. No expression of c-kit was detected in non-seminomas or in normal testicular germ cells. High expression of the proto-oncogene in CIS cells supports the hypothesis of their origin from primordial germ cells. In addition, we propose that the c-kit protein product is a new marker for carcinoma-in-situ of the testis.
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PMID:Expression of the c-kit protein product in carcinoma-in-situ and invasive testicular germ cell tumours. 751 17

Kit ligand, or stem cell factor, is a recently identified growth factor, which binds to and activates the c-kit proto-oncogene, and which has been shown to act synergistically with other haematopoietic growth factors in the bone marrow. We have previously shown that several isoforms of kit ligand, which arise due to alternative splicing, are expressed in human placenta. In order to elucidate the role of c-kit and its ligand during human placental development we have investigated the expression of c-kit and kit ligand in human first trimester and term placenta as well as in pregnant and non-pregnant endometrium, by immunocytochemistry and flow cytometric analysis. In non-pregnant endometrium no expression of kit ligand was seen. By contrast, in first trimester decidua, kit ligand was strongly expressed by the arterial media of maternal blood vessels. Kit ligand was also expressed throughout pregnancy by invasive fetal extravillous trophoblast, and by fetal fibroblasts within the placental villi. c-kit was found to be expressed on Hofbauer cells within the chorionic villi, and by decidual macrophages at all stages in pregnancy. c-kit was also detected on the small CD56dim subset of uterine large granular lymphocytes which form the major leukocyte population in human first trimester decidua. Our results suggest that kit ligand may be involved in the regulation of fetal macrophages, and in particular in signalling between invading extravillous trophoblast which expresses kit ligand, and maternal leukocytes bearing the c-kit receptor.
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PMID:Expression of c-kit and kit ligand at the human maternofetal interface. 751 62

Mutations at the mouse W/c-kit locus have pleiotropic defects including impaired development of the melanocyte lineage. We have characterized the molecular basis of the Wei mutation. We show here that Wei is the result of a missense mutation in the ATP binding site domain of c-kit proto-oncogene which affects the tyrosine kinase function of the receptor. As a result, few melanoblasts survive during embryogenesis in heterozygous Wei/+ foetuses. Therefore the adult skin is partly devoid of differentiated pigmented cells giving rise to a mottled coat colour phenotype. However, three per cent of Wei/+ mice exhibit spots of wild-type pigmentation on the coat which is otherwise of mutant phenotype. Such areas are known as phenotypic reversions. To dissect the molecular events responsible for the phenotypic instability of the Wei mutation, we have isolated pure cultures of continuously proliferating melanocytes from two independent reversion spots. These melanocyte lines, designated Wei-R1 and Wei-R2, were shown to exhibit none of the characteristics associated with transformed melanocytes. We have used a polymorphic restriction site generated by the Wei mutation to show that both melanocyte lines are still heterozygous at the W focus. Furthermore, Wei-R1 and Wei-R2 melanocytes express both the mutated and the wild-type c-kit RNA. These results indicate that the somatic mutation events responsible for reversion spots are not necessarily associated with loss of heterozygosity at the W/c-kit locus. Together with previous data, this points to the fact that several mechanisms account for the coat colour reversion phenotype.
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PMID:Instability at the W/c-kit locus in mice: analysis of melanocyte cell lines derived from reversion spots. 752 Jan 49

The proto-oncogene c-kit, encoding a receptor-type tyrosine kinase, is allelic with the W locus of the mouse. The stromal cell line OP9, capable of supporting long-term hematopoiesis, was newly established from a newborn B6C3F1-op/op mouse calvaria. When bone marrow cells of WBB6F1-W/Wv mice were cocultured with the OP9 cells in liquid medium, hematopoiesis declined to a level one-thousandth of that in the cocultures of bone marrow cells of WBB6F1-+/+ mice and stromal cells by day 21. In contrast, when bone marrow cells of W/Wv mice were cocultured with OP9 cells in semisolid medium, at least 61% of the number of colonies were detected until the end of our observation period of 42 days when compared with that in control cocultures, although colonies formed by hematopoietic stem cells of W/Wv mice were significantly smaller than those of normal stem cells. After a 24-hour incubation with OP9 cells, fewer stem cells of W/Wv mice than normal ones adhered to the stromal cells. Adhesion of normal stem cells to stromal cells was inhibited by the addition of an antagonists anti-c-kit monoclonal antibody, ACK2. These results demonstrate that the c-kit receptor plays an important role not only in the proliferative response of hematopoietic stem cells but also in their adhesion to stromal cells.
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PMID:Involvement of the c-kit receptor in the adhesion of hematopoietic stem cells to stromal cells. 752 85

Tumor necrosis factor alpha (TNF alpha), as a modulator of hematopoiesis, interacts with many growth factor receptors, such as interleukin-3, granulocyte-macrophage colony-stimulating factor (CSF), and granulocyte-CSF receptors. Here, we studied the interactions between TNF alpha and the stem cell factor (SCF) receptor, c-kit, in normal CD34+ hematopoietic progenitors and their leukemic counterpart, ie, acute myeloid leukemic (AML) CD34+ cells coexpressing c-kit antigen. The results showed that (1) incubation of normal bone marrow mononuclear cells with 200 U/mL rhTNF alpha for 20 hours induced a diminution of 31.2% +/- 5.2% of CD34+ cells coexpressing c-kit; (2) the same decrease was observed using purified CD34+ cells and, furthermore, their proliferative response to SCF was inhibited by 31.5% +/- 7.3% after exposure to TNF alpha; (3) similar experiments performed on CD34+ c-kit+ AML cells from 11 patients gave comparable results. Further analysis at the mRNA level indicated that TNF alpha decreased c-kit mRNA transcripts. Moreover, using monoclonal antibodies against the two types of TNF alpha receptors, p75 and p55, we showed that the downregulation of c-kit proto-oncogene product by TNF alpha, on normal and leukemic CD34+ cells, was exclusively mediated by the TNF alpha p55 receptor. Therefore, we conclude that TNF alpha acts as a downregulator of the SCF receptor expression.
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PMID:Tumor necrosis factor alpha (TNF alpha) downregulates c-kit proto-oncogene product expression in normal and acute myeloid leukemia CD34+ cells via p55 TNF alpha receptors. 752 32

The c-kit proto-oncogene encodes a transmembrane tyrosine kinase receptor, which is important for the normal development of hematopoietic cells, melanoblasts, and germ cells. Autophosphorylation of c-kit receptor on tyrosine creates binding sites for cellular src homology 2 (SH2)-containing signaling molecules. The discovery of phosphotyrosine phosphatases that contain SH2 domains suggests roles for these molecules in growth factor signaling pathways. We found that Syp, a phosphotyrosine phosphatase widely expressed in all the tissues in mammals, associates with c-kit receptor after activation with its ligand, steel factor, in the factor-dependent cell line, M07e. Both NH2-terminal and COOH-terminal SH2 domains of Syp, made as glutathione S-transferase fusion proteins, were able to bind to the activated c-kit receptor in vitro. Furthermore, Syp became marginally phosphorylated on tyrosine upon c-kit receptor activation, and tyrosine-phosphorylated Syp was found to be complexed with Grb2 in steel factor-stimulated M07e cells. Direct binding between Syp and Grb2 was also observed in vitro. Last, Ras and Raf interacts in vitro as a result of steel factor-stimulated Ras activation. These results suggest that Syp may be an important signaling component downstream of the c-kit receptor and involved in activation of the Ras signaling pathway in hematopoietic cells.
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PMID:The ubiquitously expressed Syp phosphatase interacts with c-kit and Grb2 in hematopoietic cells. 752 81

We examined the expression of Fc epsilon-RI and Fc gamma-RII/III on mouse bone marrow cells enriched for hematopoietic progenitors including mast cell progenitors. Bone marrow cells were depleted of mature hematopoietic lineages and a primitive population of cells that express the proto-oncogene c-kit (KIT+ lineage- cells) was isolated. KIT+ lineage- cells stain positively using the Ab 2.4G2, indicating surface expression of Fc gamma-RII and/or Fc gamma-RIII. Fluorescent staining of intracytoplasmic domains of Fc gamma-RII and Fc gamma-RIII revealed that these cells express primarily Fc gamma-RII on their surface. KIT+ lineage- cells did express Fc gamma RIII alpha-chain protein, but predominately in the nuclear/perinuclear area. We could not detect surface expression of Fc epsilon-RI by KIT+ lineage- cells, although a heterogeneous population of KIT- cells does bind IgE with high affinity and may reflect cells of the basophilic lineage. KIT+ lineage- cells cultured with SCF and IL-3 generate numerous mast cells, whereas equivalent numbers of KIT- cells or naive bone marrow cells do not. In these cultures, surface expression of Fc epsilon-RI is detected on a small number of cells by day 3 of culture with increased surface expression levels correlating roughly with metachromatic granule formation. The fact that Fc gamma-RIII and Fc epsilon-RI are not expressed on the cell surface of KIT+ lineage- cells but appear later in hematopoietic development makes it unlikely that these receptors influence early hematopoietic differentiation. The role that might justify such a complete surface expression of Fc gamma-RII by bone marrow progenitors remains to be identified.
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PMID:Murine KIT+ lineage- bone marrow progenitors express Fc gamma-RII but do not express Fc epsilon-RI until mast cell granule formation. 752 15

Stem cell factor (SCF), the ligand for the c-kit proto-oncogene, has been shown to play a critical role in the migration of melanocytes and germ cells during embryogenesis as well as in the proliferative control of the hematopoietic compartment. In this study we investigated the expression of both the soluble and transmembrane SCF forms in purified peripheral blood populations and in several hematopoietic cell lines. Expression of both transcripts, though in different ratios, was identified in whole bone marrow, in bone marrow stromal cells and in human peripheral blood. In peripheral blood, SCF expression could be ascribable to polymorphonuclear leukocytes (PMN), whereas no SCF expression was detected in isolated lymphocytes, monocytes and in some T lymphoid cell lines. Conversely, some hematopoietic myeloid cell lines, such as HL-60, KG1 and K562, express SCF with similar patterns.
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PMID:Human peripheral blood granulocytes and myeloid leukemic cell lines express both transcripts encoding for stem cell factor. 752 92

The proto-oncogene c-kit encodes the receptor for a stem cell factor (c-kit molecule). Expression of the c-kit molecule on the gated leukemic blast cells from newly diagnosed patients with leukemia was analysed by flow cytometry using the monoclonal antibody (17F11). Among 35 myeloid leukemia cases examined, significant c-kit-positive blast cells were detected in 24 cases (69%), even though the percentage of positive cells was widely variable. The correlation between the percentage of cells positive for the c-kit molecule and the percentage of cells positive for CD34 was found to be statistically significant (rs = 0.36, p < 0.05). Fifteen cases of myeloid leukemia were positive for lymphoid markers. The mean percentage of the cells expressing c-kit molecule among the lymphoid marker-positive cases was significantly larger than that among the lymphoid marker-negative cases (p < 0.05). All 19 lymphoid leukemia cases were c-kit-negative, including 8 cases which were positive for some myeloid markers. Stem cell factor enhanced the colony growth in five out of six acute myeloblastic leukemia cases expressing the c-kit molecule. On the other hand, SCF did not stimulate colony growth in any of the four cases which were not positive for the c-kit molecule. These findings indicated that the distribution of flow cytometrically detectable c-kit molecules on leukemic cells is related to the morphologic and immunologic classification of these leukemic cells and to the expression of the CD34 cell surface molecule on some myeloid leukemic cells. On such cells, expression of the c-kit molecule may have a functional role and be related to the maturation process.
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PMID:The c-kit molecule and the surface immunophenotype of human acute leukemia. 752 77

Recent findings suggest an important role of the proto-oncogene c-kit, a surface membrane receptor of the tyrosine kinase family, and its ligand stem cell factor (SCF) in normal spermatogenesis and possibly in the pathogenesis of certain testicular germ cell tumors. To further investigate this potential role, the expression of c-kit and SCF was studied in normal and malignant human testicular tissue specimens at the mRNA and protein level by Northern blot analysis and immunohistochemistry, respectively. The detection of the c-kit receptor in normal human germ cells and its natural ligand SCF in Sertoli cells suggests the presence of a local trophic regulatory system that may be active in human spermatogenesis. Additionally, c-kit expression was detected in the seminoma but not in the nonseminoma subtype of human testicular germ cell tumors (GCT). Stem cell factor was not expressed at the mRNA level in tissue from either subtype of GCT as determined by Northern blot analysis; however, the protein was detected immunohistochemically in the cytoplasm of rare tumor cells.
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PMID:Expression of the c-kit proto-oncogene and its ligand stem cell factor (SCF) in normal and malignant human testicular tissue. 752 38


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