Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the expression of mRNA of protein kinase C (PKC) isozymes (alpha, beta, gamma, delta, epsilon, xi, and eta) in cultured mast cells (CMC) derived from normal (+/+) mice, CMC derived from genetically mast-cell-deficient (W/W, Wv/Wv, and mi/mi) mice, and murine mast cell lines (IC2, MC9, and P-815) by Northern blotting. In +/+ CMC, abundant expression of PKC delta and moderate expression of PKC alpha and beta was observed, while other PKCs (types gamma, epsilon, xi, and eta) were not detected. In vivo expression of PKC delta was demonstrated in the skin by in situ hybridization. In mast cell lines, the expression pattern of PKC isozymes was similar to that of +/+ CMC, except that the expression of PKC eta was detected in the IC2 cell line. The expression levels of PKC delta in CMC derived from c-kit-deficient mutants, W/W, Wv/Wv, and mi/mi, were lower than that of +/+ mice. These results indicate that PKC delta is the main isozyme in various types of murine mast cells and also suggest that the reduced level of PKC delta expression in mutant mice may be caused by a deficit in the signal transduction system through c-kit receptor.
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PMID:Differential expression of protein kinase C genes in cultured mast cells derived from normal and mast-cell-deficient mice and mast cell lines. 792 28

The murine W and Steel loci encode the Kit receptor tyrosine kinase and its ligand, Steel factor, respectively. Loss of function mutations at either the W or Sl loci lead to a variety of pleiotropic developmental defects, including mast cell deficiency and severe macrocytic anemia. In addition to these loss-of-function mutations, gain-of-function mutations in c-kit, leading to constitutive activation of the Kit receptor, have also been identified in both rodent and human mastocytomas. In this study, we have examined the transforming potential and biologic effects of a point mutation that results in substitution of the aspartic acid at codon 814 in the cytoplasmic kinase domain to tyrosine (D814Y) by introducing either wild-type (Kit) or mutant KitD814Y (KDY) cDNA into an interleukin-3-dependent mast cell line IC2. Stimulation of cells expressing the wild-type Kit receptor (IC2/Kit) with Steel factor in vitro resulted in a short-term growth response, whereas IC2/KDY cells were capable of sustained proliferation in a ligand-independent manner. In addition, expression of KDY resulted in the oncogenic transformation of IC2 cells, as determined by colony formation in vitro in the absence of exogenous growth factors and the formation of mastocytomas in vivo in syngeneic DBA/2 mice. Surprisingly, KDY expression in IC2 cells triggered dramatic changes in cell size and the extent of granulation. In addition, KDY induced the expression of mouse mast cell protease-4 (MMCP-4) and MMCP-6. In contrast, neither of these molecular or cellular changes was observed in IC2/Kit cells treated with Steel factor. These results show that the D814Y mutation in the cytoplasmic kinase domain of the Kit receptor induces ligand-independent mast cell growth in vitro, tumorigenicity in vivo, and mast cell differentiation.
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PMID:A point mutation in the catalytic domain of c-kit induces growth factor independence, tumorigenicity, and differentiation of mast cells. 860 25

Development of modulators of constitutively active, kinase domain mutants of c-Kit has proved to be very difficult. Therefore, a high-throughput differential cytotoxicity assay was developed to screen for compounds that preferentially kill cells expressing constitutively active c-Kit. The cells used in the assay, murine IC2 mast cells, express either the D814Y activating mutation (functionally equivalent to human D816Y) or wild type protein. This assay is robust and highly reproducible. When applied to libraries of natural product extracts (followed by assay-guided fractionation), two differentially active compounds were identified. To assess possible mechanisms of action, the active compounds were tested for inhibitory activity against a panel of signaling enzymes (including wild type and mutant c-Kit). Neither of the compounds significantly affected any of the 73 enzymes tested. The effects of commercially available modulators of known signaling components were also assessed using the screening assay. None of these inhibitors reproduced the differential activity seen with the natural products. Finally, both compounds were found to affect mitochondrial potential in cells expressing c-Kit(D814Y). These results suggest that the newly identified natural products may provide new avenues for intervention in aberrant c-Kit signaling pathways.
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PMID:Natural products active in aberrant c-Kit signaling. 1753 24