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Induction of apoptosis by directing oncogenic Bcr-Abl into the nucleus.
|Title||Induction of apoptosis by directing oncogenic Bcr-Abl into the nucleus.|
|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Huang Z-L, Gao M, Li Q-Y, Tao K, Xiao Q, Cao W-X, Feng W-L|
|Date Published||2013 Oct 9|
The chimeric Bcr-Abl oncoprotein, which causes chronic myeloid leukemia, mainly localizes in the cytoplasm, and loses its ability to transform cells after moving into the nucleus. Here we report a new strategy to convert Bcr-Abl to be an apoptotic inducer by altering its subcellular localization. We show that a rapalog nuclear transport system (RNTS) containing six nuclear localization signals directs Bcr-Abl into the nucleus and that nuclear entrapped Bcr-Abl induces apoptosis and inhibits proliferation of CML cells by activating p73 and shutting down cytoplasmic oncogenic signals mediated by Bcr-Abl. Coupling cytoplasmic depletion with nuclear entrapment of Bcr-Abl synergistically enhances the inhibitory effect of nuclear Bcr-Abl on its oncogenicity in mice. These results provide evidence that direction of cytoplasmic Bcr-Abl to the nucleus offers an alternative CML therapy.