BEX1 promotes imatinib-induced apoptosis by binding to and antagonizing BCL-2
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-res...
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| creator | Xiao, Qian Hu, Yeting Liu, Yue Wang, Zhanhuai Geng, Haitao Hu, Lifeng Xu, Dengyong Wang, Ke Zheng, Lei Zheng, Shu Ding, Kefeng |
| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0091782 |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0091782</identifier><identifier>PMID: 24626299</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Apoptosis ; Apoptosis - drug effects ; Apoptosis - genetics ; Biology ; Cell Proliferation - drug effects ; Cell Proliferation - genetics ; Drug Resistance, Neoplasm - genetics ; Humans ; Imatinib Mesylate - therapeutic use ; Immunoprecipitation ; Inhibitor drugs ; K562 Cells ; Lymphoma ; Medical screening ; Medicine ; Mitochondria - genetics ; Mitochondria - metabolism ; Nerve Tissue Proteins - genetics ; Nerve Tissue Proteins - metabolism ; Non-Hodgkin's lymphomas ; Protein Binding ; Protein Interaction Maps - genetics ; Proto-Oncogene Proteins c-bcl-2 - genetics ; Proto-Oncogene Proteins c-bcl-2 - metabolism ; Targeted cancer therapy ; Tyrosine ; Yeasts</subject><ispartof>PloS one, 2014-03, Vol.9 (3), p.e91782-e91782</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Xiao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 Xiao et al 2014 Xiao et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-63ff30f149a180eef2359580ac6334125f8c9c352b754d16ca7c86accb1e710f3</citedby><cites>FETCH-LOGICAL-c692t-63ff30f149a180eef2359580ac6334125f8c9c352b754d16ca7c86accb1e710f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3953594/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3953594/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2096,2915,23847,27905,27906,53772,53774,79349,79350</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24626299$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Villunger, Andreas</contributor><creatorcontrib>Xiao, Qian</creatorcontrib><creatorcontrib>Hu, Yeting</creatorcontrib><creatorcontrib>Liu, Yue</creatorcontrib><creatorcontrib>Wang, Zhanhuai</creatorcontrib><creatorcontrib>Geng, Haitao</creatorcontrib><creatorcontrib>Hu, Lifeng</creatorcontrib><creatorcontrib>Xu, Dengyong</creatorcontrib><creatorcontrib>Wang, Ke</creatorcontrib><creatorcontrib>Zheng, Lei</creatorcontrib><creatorcontrib>Zheng, Shu</creatorcontrib><creatorcontrib>Ding, Kefeng</creatorcontrib><title>BEX1 promotes imatinib-induced apoptosis by binding to and antagonizing BCL-2</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.</description><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - genetics</subject><subject>Biology</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Proliferation - genetics</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Humans</subject><subject>Imatinib Mesylate - therapeutic use</subject><subject>Immunoprecipitation</subject><subject>Inhibitor drugs</subject><subject>K562 Cells</subject><subject>Lymphoma</subject><subject>Medical screening</subject><subject>Medicine</subject><subject>Mitochondria - genetics</subject><subject>Mitochondria - metabolism</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Non-Hodgkin's lymphomas</subject><subject>Protein Binding</subject><subject>Protein Interaction Maps - genetics</subject><subject>Proto-Oncogene Proteins c-bcl-2 - genetics</subject><subject>Proto-Oncogene Proteins c-bcl-2 - metabolism</subject><subject>Targeted cancer therapy</subject><subject>Tyrosine</subject><subject>Yeasts</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl2L1DAUhoso7rr6D0QLguhFx3w1aW6E3WHVgZEFv_AupGnSydJJuk0qrr_ezE53mcpeSC9STp7zJu_Jm2XPIVhAzOC7Sz8OTnaL3ju9AIBDVqEH2THkGBUUAfzw4P8oexLCJQAlrih9nB0hQhFFnB9nn8_Of8K8H_zWRx1yu5XROlsX1jWj0k0ue99HH2zI6-u8TlXr2jz6XLq056JsvbN_drWz5bpAT7NHRnZBP5vWk-z7h_Nvy0_F-uLjanm6LhTlKBYUG4OBgYRLWAGtDcIlLysgFcWYQFSaSnGFS1SzkjSQKslURaVSNdQMAoNPspd73b7zQUyTCAKWgCVrtGKJWO2JxstL0Q_J2HAtvLTipuCHVsghWtVpQaVhBFQlgEoTglmtKw21KSGChsgbrffTaWO91Y3SLg6ym4nOd5zdiNb_EpiXyRhJAm8mgcFfjTpEsbVB6a6TTvtxf2_GeQl4Ql_9g97vbqJamQxYZ3w6V-1ExSlhFaMcU5ioxT1U-hq9tSrFxthUnzW8nTUkJurfsZVjCGL19cv_sxc_5uzrA3ajZRc3wXdjtN6FOUj2oBp8CIM2d0OGQOxSfzsNsUu9mFKf2l4cPtBd023M8V_XhfrU</recordid><startdate>20140313</startdate><enddate>20140313</enddate><creator>Xiao, Qian</creator><creator>Hu, Yeting</creator><creator>Liu, Yue</creator><creator>Wang, Zhanhuai</creator><creator>Geng, Haitao</creator><creator>Hu, Lifeng</creator><creator>Xu, Dengyong</creator><creator>Wang, Ke</creator><creator>Zheng, Lei</creator><creator>Zheng, Shu</creator><creator>Ding, Kefeng</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20140313</creationdate><title>BEX1 promotes imatinib-induced apoptosis by binding to and antagonizing BCL-2</title><author>Xiao, Qian ; Hu, Yeting ; Liu, Yue ; Wang, Zhanhuai ; Geng, Haitao ; Hu, Lifeng ; Xu, Dengyong ; Wang, Ke ; Zheng, Lei ; Zheng, Shu ; Ding, Kefeng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-63ff30f149a180eef2359580ac6334125f8c9c352b754d16ca7c86accb1e710f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Apoptosis</topic><topic>Apoptosis - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Xiao, Qian</au><au>Hu, Yeting</au><au>Liu, Yue</au><au>Wang, Zhanhuai</au><au>Geng, Haitao</au><au>Hu, Lifeng</au><au>Xu, Dengyong</au><au>Wang, Ke</au><au>Zheng, Lei</au><au>Zheng, Shu</au><au>Ding, Kefeng</au><au>Villunger, Andreas</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>BEX1 promotes imatinib-induced apoptosis by binding to and antagonizing BCL-2</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-03-13</date><risdate>2014</risdate><volume>9</volume><issue>3</issue><spage>e91782</spage><epage>e91782</epage><pages>e91782-e91782</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24626299</pmid><doi>10.1371/journal.pone.0091782</doi><tpages>e91782</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Apoptosis Apoptosis - drug effects Apoptosis - genetics Biology Cell Proliferation - drug effects Cell Proliferation - genetics Drug Resistance, Neoplasm - genetics Humans Imatinib Mesylate - therapeutic use Immunoprecipitation Inhibitor drugs K562 Cells Lymphoma Medical screening Medicine Mitochondria - genetics Mitochondria - metabolism Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism Non-Hodgkin's lymphomas Protein Binding Protein Interaction Maps - genetics Proto-Oncogene Proteins c-bcl-2 - genetics Proto-Oncogene Proteins c-bcl-2 - metabolism Targeted cancer therapy Tyrosine Yeasts |
| title | BEX1 promotes imatinib-induced apoptosis by binding to and antagonizing BCL-2 |
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