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Induction of apoptosis by directing oncogenic Bcr-Abl into the nucleus.


ABSTRACT: 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.

SUBMITTER: Huang ZL 

PROVIDER: S-EPMC3926824 | biostudies-other | 2013 Dec

REPOSITORIES: biostudies-other

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Induction of apoptosis by directing oncogenic Bcr-Abl into the nucleus.

Huang Zheng-Lan ZL   Gao Miao M   Li Qian-Yin QY   Tao Kun K   Xiao Qing Q   Cao Wei-Xi WX   Feng Wen-Li WL  

Oncotarget 20131201 12


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 prol  ...[more]

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