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

Mast cells (MC) play a central role in extrinsic allergic reactions such as asthma and may participate in other inflammatory and fibrotic processes. However, with the exception of immunoglobulin E (IgE) receptor-dependent stimulation, no secretagogues of human lung MC have yet been described. It is also unclear whether mediator release can be regulated by certain cytokines as demonstrated previously in basophils and other human inflammatory effector cells. Here, we show that the c-kit ligand (KL), a recently identified stem cell growth factor, at concentrations 10-100 times lower than that required to promote cell proliferation, enhances the release of histamine and leukotriene C4 in response to IgE receptor crosslinking of human lung MC. KL does not induce mediator release per se, but increases the sensitivity of MC to anti-IgE receptor stimulation and also enhances mediator release to maximally effective concentrations of anti-IgE receptor antibody. By contrast, a large number of cytokines examined, including the mast cell growth factors/agonists in rodents, interleukin 3 (IL-3), IL-4, IL-9, and nerve growth factor, were ineffective in this respect. These findings suggest a unique role of KL in regulating effector functions of human mucosal MC.
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PMID:c-kit ligand: a unique potentiator of mediator release by human lung mast cells. 137 May 29

Piebaldism is an autosomal dominant disorder of melanocyte development and is characterized by congenital white patches of skin and hair from which melanocytes are completely absent. A similar disorder of the mouse, "dominant white spotting" (W), results from mutations of the c-kit proto-oncogene, which encodes the cellular tyrosine kinase receptor for the mast/stem cell growth factor. We have identified c-kit gene mutations in three patients with piebaldism. A missense substitution (Phe----Leu) at codon 584, within the tyrosine kinase domain, is associated with a severe piebald phenotype, whereas two different frameshifts, within codons 561 and 642, are both associated with a variable and relatively mild piebald phenotype. This is consistent with a possible "dominant negative" effect of missense c-kit polypeptides on the function of the dimeric receptor.
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PMID:Dominant negative and loss of function mutations of the c-kit (mast/stem cell growth factor receptor) proto-oncogene in human piebaldism. 137 75

Previously we have reported that rodent mast cells synthesize the mRNA encoding the alpha and beta integrin chains (alpha 4, beta 1 and beta 7) of the lymphocyte Peyer's patch adhesion molecule (LPAM)-1 and LPAM-2 lymphocyte homing receptors, and that they possess an alpha 4-containing integrin complex on their cell surface. In this report, we have examined the expression of these integrin chain genes by mature connective tissue mast cells (CTMC) and by bone marrow-derived mast cells (BMMC) differentiated from bone marrow precursor cells in the presence of interleukin (IL)-3 and/or the c-kit ligand (also known as mast cell growth factor and stem cell growth factor). High levels of both the beta 7 and beta 1 transcripts were present in mature CTMC while those encoding the alpha 4 chain were absent. Similarly, when BMMC were grown in IL-3 for 28 days and analyzed for integrin chain transcripts, those specific for the alpha 4 chain were also diminished compared to beta 7 and beta 1 transcripts. To compare the expression of these integrin genes during mucosal mast cell and CTMC development, BMMC were derived in the presence of IL-3 alone, c-kit alone, or IL-3/c-kit together. These experiments indicated that c-kit inhibited the transcription of the beta 7 and Fc epsilon RI genes while enhancing alpha 4 transcript levels. The enhancement of alpha 4 levels, however, was abrogated with the addition of IL-3. Similarly, the c-kit-induced depression of beta 7 and Fc epsilon RI transcript levels was overcome by the addition of IL-3. These data suggest that the integrin complexes synthesized by the mast cells may differ depending upon their path of differentiation and that another alpha chain integrin may be synthesized to complex with the beta 7 and/or beta 1 chains.
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PMID:Modulation of integrin expression during mast cell differentiation. 138 93

Piebaldism is a rare autosomal dominant disorder of pigmentation, characterized by congenital patches of white skin and hair from which melanocytes are absent. We have previously shown that piebaldism can result from missense and frameshift mutations of the KIT proto-oncogene, which encodes the cellular receptor tyrosine kinase for the mast/stem cell growth factor. Here, we report two novel KIT mutations associated with human piebaldism. A proximal frameshift is associated with a mild piebald phenotype, and a splice-junction mutation is associated with a highly variable piebald phenotype. We discuss the apparent relationship between the predicted impact of specific KIT mutations on total KIT-dependent signal transduction and the severity of the resultant piebald phenotypes.
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PMID:Mutations of the KIT (mast/stem cell growth factor receptor) proto-oncogene account for a continuous range of phenotypes in human piebaldism. 138 25

Mutations at the dominant white spotting (W) and Steel (Sl) loci in mouse exert deleterious effects on three migratory cell lineages (primordial germ cells, melanocytes and hematopoietic stem cells) resulting in loss of pigmentation, reduced fertility and anemia. The W locus encodes the c-kit protein tyrosine kinase (TK) receptor. More recently, the Sl locus has been shown to encode a ligand for c-kit, which is variously known as mast cell growth factor (MGF), stem cell growth factor and c-kit ligand. Here we report an in situ hybridization analysis comparing the expression profiles of MGF and c-kit transcripts during mouse embryogenesis. The data are consistent with the c-kit receptor-ligand complex providing a homing mechanism during stem cell migration in early development and in stem cell proliferation, differentiation, or survival in late development. In the nervous system, an unexpected and complex pattern of expression is uncovered that suggests involvement of the W and Sl gene products in the organization of the neural tube and brain.
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PMID:Embryonic RNA expression patterns of the c-kit receptor and its cognate ligand suggest multiple functional roles in mouse development. 171 75

The c-kit proto-oncogene is the receptor gene for the stem cell growth factor. Little is known about the distribution and role of this gene product in malignant hematopoiesis. We analysed here the expression of c-kit in myeloproliferative disorders (MPDs), including chronic myelogenous leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), and idiopathic myelofibrosis (IMF) and in the myelodysplastic syndromes (MDS). The c-kit expression of peripheral blood mononuclear cells was measured both at the messenger RNA level using Northern analysis, the RNA dot blot technique with densitometric quantification, the sensitive reverse transcription polymerase chain reaction, and at the protein level using immunofluorescence with monoclonal antibodies. There was a statistically significant increase in c-kit messenger levels in CML, ET, PV, IMF, and MDS as compared with controls (healthy volunteers). The percentage of c-kit protein expressing cells was also higher than in the controls in these disorders. There was a significant correlation of the c-kit protein expression with the CD34 antigen of the cells. Expression correlated with the phase of the disease, being highest in the blast crisis of CML and in the RAEB/RAEBt phases of MDS. The data suggest that increased amounts of circulating stem/progenitor cells with c-kit receptor are found in MPDs and MDS. It is possible that elevated c-kit expression could maintain the affected clone in MPDs and MDS.
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PMID:Expression of the c-kit proto-oncogene in myeloproliferative disorders and myelodysplastic syndromes. 751 74

In previous studies, we have characterized the nature and function of the proto-oncogene c-kit, which encodes a receptor tyrosine kinase. This receptor together with its ligand, a stem cell growth factor, constitutes a cell signaling system which is crucial for the development of hematopoietic, melanocytic and germ cells. The expression of the gene correlates with its protein functions in specific cell lineages and is temporally and spatially regulated during fetal and adult life. As a start point to study the gene regulation, we have characterized the promoter of the c-kit gene. A single transcription initiation site located 58 bases upstream of the ATG start codon has been identified. The sequence upstream to the initiation site reveals a TATA-less, non-GC rich promoter. Several potential binding sites for transcription factors pertinent to c-kit expression, such as Sp-1, GATA-1, myb and Oct-4, have been identified. Promoter activities of different lengths of the 5' sequence have been analyzed in transient expression assay. The 2.7 kb of the 5' sequence facilitates the expression of the CAT gene in several cell lines while the sequence further upstream from 2.7 to 5.0 kb shows a negative regulatory activity. This study reveals a unique promoter of the c-kit gene and provides a basis for further elucidation of the regulatory mechanism of c-kit gene expression.
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PMID:Characterization of the promoter of the proto-oncogene c-kit. 753 32

Piebaldism is an autosomal dominant genetic disorder of pigmentation characterized by congenital patches of white skin and hair that lack melanocytes. Piebaldism results from mutations of the KIT proto-oncogene, which encodes the cellular receptor transmembrane tyrosine kinase for mast/stem cell growth factor. Here we describe two novel KIT mutations associated with human piebaldism. These amino acid substitutions, located in the most highly conserved sections of the KIT kinase domain, would be expected to dominant-negatively inhibit KIT-dependent signal transduction, resulting in aberrant melanocyte proliferation or migration during embryologic development.
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PMID:Novel mutations of the KIT (mast/stem cell growth factor receptor) proto-oncogene in human piebaldism. 768 67

During the last 5 years significant advances have been achieved in defining the endocrine, paracrine and cellular interactions required for normal testicular development. Numerous paracrine factors are likely to regulate spermatogenesis throughout the cycle of the seminiferous epithelium. These factors create the local hormonal milieu required for germ cell proliferation, meiosis and differentiation. The studies of the c-kit oncogene and the stem cell growth factor in the migration and survival of the primordial germ cells to the genital ridge during development have defined at least 1 important role of growth factors in spermatogenesis. 72, 142-146, 148, 149, 154, 159 It is likely that in the next 5 years the role of many of these other paracrine factors in the regulation of testicular development will be determined.
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PMID:Growth factors and testicular development. 832 3

Greater than 95% of ovarian cancers originate from the epithelial cells on the surface of the ovary termed ovarian surface epithelium (OSE). A normal aspect of OSE function is repeated proliferation after ovulation, and this is postulated to be involved in part in the onset of ovarian cancer. The hypothesis tested is that locally produced growth factors have an important role in controlling OSE proliferation. The current study investigates the potential role of the growth factor kit ligand (KL)/stem cell growth factor and its receptor c-kit in normal OSE biology and ovarian cancer. Human tumors from borderline, stage I, and stage III cases of ovarian cancer were found to express KL and c-kit protein in the epithelial cell component by ICC analysis. The stromal cell component of human ovarian tumors contained little immunostaining. Bovine ovarian physiology and endocrinology are similar to the human such that cow ovaries were used as a model system to investigate normal OSE functions. KL and c-kit proteins were detected in the OSE from both normal human and bovine ovaries. Adjacent ovarian stromal tissue contained less intense but positive KL and c-kit immunostaining. To extend the ICC results, RNA was collected from normal bovine OSE and ovarian stromal cells to examine KL gene expression. KL transcripts were detected in cultured OSE and stromal cells by Northern blot analysis. KL gene expression was found to be high in freshly isolated OSE but low in freshly isolated stroma using a quantitative polymerase chain reaction procedure. Levels of KL gene expression in cultured OSE and stroma increased to high levels. Observations indicate that normal OSE expresses high levels of KL in vivo and in vitro. The actions of KL on the growth of both normal OSE cells and ovarian cancer cells was investigated. KL was found to stimulate the growth of normal OSE cells in a similar manner to epidermal growth factor. Observations demonstrate the production and action of KL by normal OSE cells and ovarian cancer cells. Coexpression of KL and c-kit by normal OSE suggests that KL can act as an autocrine factor for OSE. The local production and action of KL on OSE provides insight into normal OSE biology, and a factor that may be involved in the onset and progression of ovarian cancer.
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PMID:Expression and action of kit ligand/stem cell factor in normal human and bovine ovarian surface epithelium and ovarian cancer. 1081 61


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