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APOPTIN INDUCES INHIBITION OF BCR-ABL KINASE IN CML CELLS
APOPTIN INDUCES INHIBITION OF BCR-ABL KINASE IN CML CELLS
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机译:凋亡素诱导CML细胞中BCR-ABL激酶的抑制
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摘要
The non-receptor tyrosine kinase activity of fusion gene Bcr-Abl derived oncoproteins is the key factors responsible for development and progress of Philadelphia positive (Ph+) Chronic Myeloid Leukemia (CML) and Ph+ Acute Lymphoblastic Leukemia (ALL). In the search for a peptide-based inhibitor of Bcr- Abl tyrosine kinase, here we investigated a naturally occurring molecule called Apoptin. 'Apoptin1 is a 14 kDa viral protein (chicken anemia virus protein-3, CAV- VP3) and known to induce apoptosis in a wide range of transformed but not in primary cells. During the initial phase of our study an array-based analysis demonstrated that Apoptin interacts with the SH3 domain of AbI. We further investigated the role of Apoptin on Bcr-Abl. High stringent pul!-down and co- immunoprecipitation assays revealed that Apoptin strongly interacts with the fusion protein Bcr-Abl (p210). We also identified Apoptin's ability to significantly inhibit Bcr-Abl kinase and presumably indirectly a series of downstream targets (e.g. CrkL, STATS, c-Myc, etc.). In comparison studies, using lmatinib® we discovered that apoptin has a significant killing efficacy on human and mouse CML celi lines expressing Bcr-Abl. We postulated, the interacting segment of the Apoptin molecule acts as an adaptor and negatively regulates the Bcr-Abl kinase. The obtained data provides foundation for the development of peptide based tyrosine kinase inhibitors as new anti-cancer agents.
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