https://scholars.lib.ntu.edu.tw/handle/123456789/189645
標題: | P210(Bcr-Abl) Desensitizes Cdc42 Gtpase Signaling for Sdf-1 Alpha- Directed Migration in Chronic Myeloid Leukemia Cells | 作者: | CHANG, YUAN-CHEN TIEN, S-C TIEN, HWEI-FANG |
關鍵字: | chronic myeloid leukemia (CML);p210(Bcr-Abl);Cdc42;chemotaxis;stromal-derived factor-1 alpha (SDF-1 alpha) | 公開日期: | 2009 | 卷: | v.28 | 期: | n.46 | 起(迄)頁: | 4105-4115 | 來源出版物: | ONCOGENE | 摘要: | Chronic myeloid leukemia (CML) is a lethal hematological disorder caused by the p210(Bcr-Abl) oncogene. Previous studies have suggested that p210( Bcr-Abl) transformation contributes to homing and retention defects, typical of immature myeloid cells in CML, by attenuating chemotactic response to stromal-derived factor-1 alpha (SDF-1 alpha). As Rho family GTPases are key regulators of the cytoskeleton and have been previously found to interact with p210(Bcr-Abl ), this study aimed to determine whether p210(Bcr-Abl) signaling affects SDF-1 alpha chemotaxis through Rho GTPase signaling. We found that SDF-1 alpha stimulated Cdc42 GTPase activation in myeloid progenitor 32D, but not in p210( BcrAbl)-transformed (32Dp210) cells. In fact, the basal level of active Cdc42 was elevated in 32Dp210 cells and mononuclear cells isolated from bone marrow of CML patients. Inhibition of p210(Bcr-Abl) kinase activity decreased basal Cdc 42 activity and restored SDF-1 alpha-induced Cdc42 and migration responses . Transduction of active Tat-Cdc42V12 abolished this reconstituted chemotactic response. As Cdc42 is particularly important in cytoskeletal remodeling and directional sensing, these results suggest that sustained activation of Cdc42 GTPase through p210(Bcr-Abl) tyrosine kinase signaling in CML cells contributes to defects in SDF- 1 alpha-chemotactic response due to desensitization of the actin polarization signal required for directional migration . |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/185836 |
顯示於: | 醫學系 |
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