title: BEX1 promotes imatinib-induced apoptosis by binding to and antagonizing BCL-2.
abstract: An enhanced anti-apoptotic capacity of tumor cells plays an important role in the process of breakpoint cluster region/Abelson tyrosine kinase gene (BCR/ABL)-independent imatinib resistance. We have previously demonstrated that brain expressed X-linked 1 (BEX1) was silenced in secondary imatinib-resistant K562 cells and that re-expression of BEX1 can restore imatinib sensitivity resulting in the induction of apoptosis. However, the mechanism by which BEX1 executes its pro-apoptotic function remains unknown. We identified B-cell lymphoma 2 (BCL-2) as a BEX1-interacting protein using a yeast two-hybrid screen. The interaction between BEX1 and BCL-2 was subsequently confirmed by co-immunoprecipitation assays. Like BCL-2, BEX1 was localized to the mitochondria. The region between 33K and 64Q on BEX1 is important for its localization to the mitochondria and its ability to interact with BCL-2. Additionally, we found that this region is essential for BEX1-regulated imatinib-induced apoptosis. Furthermore, we demonstrated that the interaction between BCL-2 and BEX1 promotes imatinib-induced apoptosis by suppressing the formation of anti-apoptotic BCL-2/BCL-2-associated X protein (BAX) heterodimers. Our results revealed an interaction between BEX1 and BCL-2 and a novel mechanism of imatinib resistance mediated by the BEX1/BCL-2 pathway.
authors.affiliation: The Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, The Key Laboratory of Molecular Biology in Medical Sciences of Zhejiang Province, Cancer Institute, Hangzhou, Zhejiang, China; The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: The Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, The Key Laboratory of Molecular Biology in Medical Sciences of Zhejiang Province, Cancer Institute, Hangzhou, Zhejiang, China; The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Yeting
authors.initials: Y
authors.lastname: Hu
authors.affiliation: The Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, The Key Laboratory of Molecular Biology in Medical Sciences of Zhejiang Province, Cancer Institute, Hangzhou, Zhejiang, China; The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Liu
authors.affiliation: The Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, The Key Laboratory of Molecular Biology in Medical Sciences of Zhejiang Province, Cancer Institute, Hangzhou, Zhejiang, China; The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Zhanhuai
authors.initials: Z
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, The Key Laboratory of Molecular Biology in Medical Sciences of Zhejiang Province, Cancer Institute, Hangzhou, Zhejiang, China; The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Geng
authors.affiliation: The Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, The Key Laboratory of Molecular Biology in Medical Sciences of Zhejiang Province, Cancer Institute, Hangzhou, Zhejiang, China; The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Hu
authors.affiliation: The Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, The Key Laboratory of Molecular Biology in Medical Sciences of Zhejiang Province, Cancer Institute, Hangzhou, Zhejiang, China; The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Dengyong
authors.initials: D
authors.lastname: Xu
authors.affiliation: The Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, The Key Laboratory of Molecular Biology in Medical Sciences of Zhejiang Province, Cancer Institute, Hangzhou, Zhejiang, China; The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.affiliation: The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Department of Oncology and Department of Surgery, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Lei
authors.initials: L
authors.lastname: Zheng
authors.affiliation: The Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, The Key Laboratory of Molecular Biology in Medical Sciences of Zhejiang Province, Cancer Institute, Hangzhou, Zhejiang, China; The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Zheng
authors.affiliation: The Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, The Key Laboratory of Molecular Biology in Medical Sciences of Zhejiang Province, Cancer Institute, Hangzhou, Zhejiang, China; The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Kefeng
authors.initials: K
authors.lastname: Ding
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use; D047468:Immunoprecipitation; D020014:K562 Cells; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D060066:Protein Interaction Maps / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: C469586:BEX1 protein, human; D009419:Nerve Tissue Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000068877:Imatinib Mesylate