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)

Progression of melanoma is associated with loss of the transcription factor AP-2alpha and tyrosine-kinase receptor c-kit. However, the mechanisms by which these two proteins are down-regulated have not been fully elucidated. Fifty non-selected melanomas comprising ten superficial spreading melanomas (five exhibiting a radial growth phase and five a vertical growth phase), ten primary nodular melanomas, 30 melanoma metastases, and 16 naevi were investigated by direct sequencing analysis of the AP-2alpha and c-kit genes and by immunohistochemistry for the respective proteins. Because it has recently been demonstrated that AP-2alpha is preferentially cleaved by caspase-6 and to a lesser extent by caspase-3, immunohistochemistry for the cleaved (activated) forms of caspase-6 (c-casp-6) and caspase-3 (c-casp-3) was carried out. No mutations were identified in the c-kit gene, but three different point mutations were demonstrated in the activation motif of AP-2alpha in four tumours: one vertical growth phase superficial spreading melanoma, one nodular melanoma, and two metastases. Immunohistochemistry revealed progressive loss of the AP-2alpha and c-kit proteins in primary melanomas and metastases when compared with naevi. The decrease of both markers was more accentuated in the dermal component of all primary tumours, with c-kit more affected than AP-2alpha. All invasive melanomas and metastases expressed c-casp-6. c-casp-3 was expressed by 83% of the metastases and in the dermal component of one nodular melanoma. These findings suggest that the loss of AP-2alpha protein expression during the progression of melanoma could be related to mutation of the gene in only a small number of tumours, whereas the expression and activation of caspases, most prominently caspase-6, may be an important factor for the down-regulation of AP-2alpha protein. Furthermore, this study supports recent data that the activation of caspases does not inevitably result in apoptosis, but may also contribute to tumour progression in melanomas.
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PMID:Expression of AP-2alpha, c-kit, and cleaved caspase-6 and -3 in naevi and malignant melanomas of the skin. A possible role for caspases in melanoma progression? 1451 45

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