title: 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.
authors.affiliation: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: Zheng-Lan
authors.initials: ZL
authors.lastname: Huang
authors.forename: Miao
authors.initials: M
authors.lastname: Gao
authors.forename: Qian-Yin
authors.initials: QY
authors.lastname: Li
authors.forename: Kun
authors.initials: K
authors.lastname: Tao
authors.forename: Qing
authors.initials: Q
authors.lastname: Xiao
authors.forename: Wei-Xi
authors.initials: WX
authors.lastname: Cao
authors.forename: Wen-Li
authors.initials: WL
authors.lastname: Feng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D048708:Cell Growth Processes / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008809:Mice, Inbred C3H
chemical_list: D016044:Fusion Proteins, bcr-abl