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)

The cytokine stem cell factor (SCF) synergizes with IL-7 to enhance the proliferation of thymocytes. We therefore investigated the role of the SCF receptor, the protooncogene c-kit, in the pathogenesis of pediatric T-lineage malignancies. Expression and regulation of c-kit in cells from children with non-Hodgkin's lymphoma (T-NHL) or acute lymphoblastic leukemia (T-ALL) and the proliferative effect of SCF on these cells were examined in seven cell lines and 21 biopsy tumor cell preparations. Inducibility of c-kit receptors by SCF, IL-1beta, IL-2, IL-7, TGF-beta, TNF-alpha, PMA or calcium ionophore A23187 was studied by flow cytometry (FCM). C-kit receptors were detected in three out of seven T-lymphoblastic cell lines and in nine out of 21 biopsy tumor cell preparations. Upregulation of c-kit could be induced by cultivation, and to a higher extent by cultivation and addition of IL-1beta, TNF-alpha, TGF-beta or A23187. Downregulation of c-kit occurred in the presence of SCF or PMA. SCF caused a downregulation of c-kit receptors in eight of nine, and a proliferative response in three of 11 c-kit-positive T-lymphoblastic cell preparations. We conclude that c-kit is able to transduce a growth stimulatory signal in some T-lymphoblastic cells and that its expression may not be detectable in a resting metabolic or proliferative state.
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PMID:Expression and regulation of c-kit receptor and response to stem cell factor in childhood malignant T-lymphoblastic cells. 969 76

The aminopyrimidine inhibitor AMN107 (Nilotinib) was rationally designed to antagonize the aberrant tyrosine kinase activity of Bcr-Abl-positive cells. We here evaluated, whether AMN107 is also able to induce apoptosis in Bcr-Abl-negative cells of lymphatic origin. The B-cell lines DOHH-2 and WSU-NHL and the T-cell lines Jurkat and HUT78 were incubated with increasing amounts of AMN107 corresponding to clinically achievable dosages. Subsequently, induced molecular changes were assessed by FACS analysis, Western blot, and enzyme activity assays. Although AMN107 exhibited only a minor apoptosis-inducing effect in the T-cell lines, it exerted a considerable, dose-dependent cytotoxicity in the B-cell lines. Using selective caspase-inhibitors, we show that apoptosis in responder cell lines critically relies on activation of caspase-6 and caspase-9. Cell lines sensitive and resistant towards AMN107 can be discriminated by their differential expression of Src-kinases. Although the AMN107-sensitive cell lines DOHH-2 and WSU-NHL exhibited low or no expression of the Src-kinases Lck, phosphorylated Lck, and Yes with a concomitant high expression of Hck, Lyn, and phosphorylated Lyn, the expression pattern of these kinases was inverse in the AMN107-resistant T-cell lines. In conclusion, this is the first report providing evidence that activity of AMN107 is not restricted to Bcr-Abl, c-Kit, or PDGFR-positive cells, but also extends to lymphatic cell lines of B-cell origin.
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PMID:The tyrosine kinase inhibitor AMN107 (Nilotinib) exhibits off-target effects in lymphoblastic cell lines. 1761 67