2006 Fiscal Year Final Research Report Summary
Regulation of degradation of the chronic myelogenous leukemia oncoprotein, BCR-ABL by molecular chaperon
| Project/Area Number |
16590207
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | Tokyo Women's Medical University |
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Principal Investigator |
TSUKAHARA Fujiko Tokyo Women's Medical University, School of Medicine, Instructor, 医学部, 講師 (40119996)
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| Project Period (FY) |
2004 – 2006
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| Keywords | BCR / ABL / CHIP / c-Cbl / Hsc70 / Hsp90 / imatinib / chronic myeloid leukemia / protein degradation |
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| Research Abstract |
Chronic myelogenous leukemia (CML) is a hematopoietic stem cell malignancy caused by the BCR-ABL tyrosine kinase oncoprotein. Despite the efficiency of the BCR-ABL tyrosine kinase inhibitor imatinib for CML, a major concern is drug resistance associated with mutations or increased expression of BCR-ABL. Heat shock protein 90 (Hsp90) inhibitors are expected to overcome the imatinib resistant in CML treatment, since even the mutated BCR-ABL can be degraded by the proteasome machinery. However, the molecular details of the Hsp90 inhibitor-induced degradation of BCR-ABL have not been clarified yet. In the present study, we examined molecular mechanisms of stability and degradation of BCR-ABL by molecular chaperone. We found that both CHIP (carboxyl terminus of the Hsc70-interacting protein) and c-Cbl act as an ubiqitin ligase toward BCR-ABL for degradation. Induced expression of CHIP or c-Cbl specifically inhibited BCR-ABL-dependent growth of hematopoietic Ba/F3 cells. Using a series of BCR-ABL mutants, the regions required for degradation induced by Hsp90 inhibitors, c-Cbl and CHIP were identified. Interaction between Hsp90 inhibitor and imatinib was demonstrated. In addition, we found that N-acetyl-cysteine enhances BCR-ABL kinase-dependent cell growth, which was suppressed by Hsp 90 inhibitor geldanamycin.
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Research Products
(10 results)
