Conformational change and mitochondrial translocation of Bax accompany proteasome inhibitor-induced apoptosis of chronic lymphocytic leukemic cells
Chemotherapy resistance remains a major clinical problem in patients with B-cell chronic lymphocytic leukemia (B-CLL). Proteasome inhibitors are able to induce apoptosis in chemotherapy-resistant B-CLL cells in vitro . Exposure of B-CLL cells to the proteasome inhibitors, MG132 and lactacystin, resu...
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| Veröffentlicht in: | Oncogene 2003-05, Vol.22 (17), p.2643-2654 |
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| creator | Dewson, Grant Snowden, Roger T Almond, Jason B Dyer, Martin J S Cohen, Gerald M |
| description | Chemotherapy resistance remains a major clinical problem in patients with B-cell chronic lymphocytic leukemia (B-CLL). Proteasome inhibitors are able to induce apoptosis in chemotherapy-resistant B-CLL cells
in vitro
. Exposure of B-CLL cells to the proteasome inhibitors, MG132 and lactacystin, resulted in inhibition of proteasomal activity within 30 min of treatment and was accompanied by an increase in the level of ubiquitinated proteins. Proteasome inhibitors did not alter the levels of expression of the proapoptotic Bcl-2 family proteins, Bax and Bid, prior to the onset of apoptosis. Instead, proteasome inhibitors induced a caspase-independent conformational change in Bax (as shown by a conformation-specific Bax antibody) and its translocation to mitochondria, resulting in mitochondrial perturbation, as evidenced by loss of the mitochondrial membrane potential and cytochrome
c
release. Similar conformational change and subcellular localization of Bax were observed during apoptosis induced with fludarabine, chlorambucil and prednisolone. These data suggest that alteration of Bax conformation and its redistribution to mitochondria are common and early features of B-CLL apoptosis in response to proteasome inhibitors and other chemotherapeutic agents. |
| doi_str_mv | 10.1038/sj.onc.1206326 |
| format | Article |
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c
release. Similar conformational change and subcellular localization of Bax were observed during apoptosis induced with fludarabine, chlorambucil and prednisolone. These data suggest that alteration of Bax conformation and its redistribution to mitochondria are common and early features of B-CLL apoptosis in response to proteasome inhibitors and other chemotherapeutic agents.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/sj.onc.1206326</identifier><identifier>PMID: 12730678</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Apoptosis ; Apoptosis - physiology ; Bax protein ; Bcl-2 protein ; bcl-2-Associated X Protein ; BH3 Interacting Domain Death Agonist Protein ; Biological and medical sciences ; Carrier Proteins - metabolism ; Caspase ; Cell Biology ; Cell cycle ; Chemoresistance ; Chemotherapy ; Chlorambucil ; Chronic lymphocytic leukemia ; Classical genetics, quantitative genetics, hybrids ; Conformation ; Cysteine Endopeptidases ; Cytochrome ; Cytochrome c ; Cytochrome c Group - metabolism ; Fludarabine ; Fundamental and applied biological sciences. Psychology ; Genetics of eukaryotes. Biological and molecular evolution ; Hematologic and hematopoietic diseases ; Human ; Human Genetics ; Humans ; Immunohistochemistry ; Internal Medicine ; Kinases ; Lactacystin ; Leukemia ; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Localization ; Lymphatic leukemia ; Lymphocytes B ; Medical sciences ; Medicine ; Medicine & Public Health ; Membrane potential ; Mitochondria ; Mitochondria - metabolism ; Multienzyme Complexes - antagonists & inhibitors ; Oncology ; original-paper ; Prednisolone ; Proteasome Endopeptidase Complex ; Proteasome inhibitors ; Proteasomes ; Protein Conformation ; Protein Transport - physiology ; Proteins ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins c-bcl-2 ; Ubiquitin - metabolism</subject><ispartof>Oncogene, 2003-05, Vol.22 (17), p.2643-2654</ispartof><rights>Springer Nature Limited 2003</rights><rights>2003 INIST-CNRS</rights><rights>COPYRIGHT 2003 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group May 1, 2003</rights><rights>Nature Publishing Group 2003.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c602t-f8416df6ea24dad4e2b8250bb49d65e485cd3f591e832b6c6b1c97b04772a4fd3</citedby><cites>FETCH-LOGICAL-c602t-f8416df6ea24dad4e2b8250bb49d65e485cd3f591e832b6c6b1c97b04772a4fd3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,2727,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14745857$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12730678$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dewson, Grant</creatorcontrib><creatorcontrib>Snowden, Roger T</creatorcontrib><creatorcontrib>Almond, Jason B</creatorcontrib><creatorcontrib>Dyer, Martin J S</creatorcontrib><creatorcontrib>Cohen, Gerald M</creatorcontrib><title>Conformational change and mitochondrial translocation of Bax accompany proteasome inhibitor-induced apoptosis of chronic lymphocytic leukemic cells</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Chemotherapy resistance remains a major clinical problem in patients with B-cell chronic lymphocytic leukemia (B-CLL). Proteasome inhibitors are able to induce apoptosis in chemotherapy-resistant B-CLL cells
in vitro
. Exposure of B-CLL cells to the proteasome inhibitors, MG132 and lactacystin, resulted in inhibition of proteasomal activity within 30 min of treatment and was accompanied by an increase in the level of ubiquitinated proteins. Proteasome inhibitors did not alter the levels of expression of the proapoptotic Bcl-2 family proteins, Bax and Bid, prior to the onset of apoptosis. Instead, proteasome inhibitors induced a caspase-independent conformational change in Bax (as shown by a conformation-specific Bax antibody) and its translocation to mitochondria, resulting in mitochondrial perturbation, as evidenced by loss of the mitochondrial membrane potential and cytochrome
c
release. Similar conformational change and subcellular localization of Bax were observed during apoptosis induced with fludarabine, chlorambucil and prednisolone. These data suggest that alteration of Bax conformation and its redistribution to mitochondria are common and early features of B-CLL apoptosis in response to proteasome inhibitors and other chemotherapeutic agents.</description><subject>Apoptosis</subject><subject>Apoptosis - physiology</subject><subject>Bax protein</subject><subject>Bcl-2 protein</subject><subject>bcl-2-Associated X Protein</subject><subject>BH3 Interacting Domain Death Agonist Protein</subject><subject>Biological and medical sciences</subject><subject>Carrier Proteins - metabolism</subject><subject>Caspase</subject><subject>Cell Biology</subject><subject>Cell cycle</subject><subject>Chemoresistance</subject><subject>Chemotherapy</subject><subject>Chlorambucil</subject><subject>Chronic lymphocytic leukemia</subject><subject>Classical genetics, quantitative genetics, hybrids</subject><subject>Conformation</subject><subject>Cysteine Endopeptidases</subject><subject>Cytochrome</subject><subject>Cytochrome c</subject><subject>Cytochrome c Group - metabolism</subject><subject>Fludarabine</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Genetics of eukaryotes. Biological and molecular evolution</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Human</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Internal Medicine</subject><subject>Kinases</subject><subject>Lactacystin</subject><subject>Leukemia</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - metabolism</subject><subject>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</subject><subject>Localization</subject><subject>Lymphatic leukemia</subject><subject>Lymphocytes B</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Membrane potential</subject><subject>Mitochondria</subject><subject>Mitochondria - metabolism</subject><subject>Multienzyme Complexes - antagonists & inhibitors</subject><subject>Oncology</subject><subject>original-paper</subject><subject>Prednisolone</subject><subject>Proteasome Endopeptidase Complex</subject><subject>Proteasome inhibitors</subject><subject>Proteasomes</subject><subject>Protein Conformation</subject><subject>Protein Transport - physiology</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins c-bcl-2</subject><subject>Ubiquitin - metabolism</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqFks2L1DAYxoMo7jh69aYURW-dzVeT5rgOfsGCFz2HNEm3GdukJi3s_B3-w6ZOYRbZRXJI6Pt78rzN-wDwEsEdgqS-TIdd8HqHMGQEs0dggyhnZVUJ-hhsoKhgKTDBF-BZSgcIIRcQPwUXCHMCGa834Pc--DbEQU0ueNUXulP-xhbKm2JwU9Bd8Ca6XJii8qkP-i9YhLb4oG4LpXUYRuWPxRjDZFUKgy2c71yTtbF03szamkKNYZxCcmnR6S4G73TRH4exC_o4LWc7_7RDPmjb9-k5eNKqPtkX674FPz59_L7_Ul5_-_x1f3VdagbxVLY1Rcy0zCpMjTLU4qbGFWwaKgyrLK0rbUhbCWRrghumWYO04A2knGNFW0O24P3p3tz8r9mmSQ4uLR0ob8OcJCeYIs7wf0FUc06ZIBl8-w94CHPM75okZhQRzAWDmXrzIJUHQ6Dgd666Ub2VLg8pT0AvvvIK1QJnz4xtwe4eKi-zPGfwtnX5-30CHUNK0bZyjG5Q8SgRlEuiZDrInCi5JioLXq_Nzs1gzRlfI5SBdyugklZ9m3OiXTpzlNOqrhbnyxOXcilnLJ7_-kHrVyeFV9Mc7R3rU_0PV8PvbA</recordid><startdate>20030501</startdate><enddate>20030501</enddate><creator>Dewson, Grant</creator><creator>Snowden, Roger T</creator><creator>Almond, Jason B</creator><creator>Dyer, Martin J S</creator><creator>Cohen, Gerald M</creator><general>Nature Publishing Group UK</general><general>Nature Publishing</general><general>Nature Publishing Group</general><scope>IQODW</scope><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>3V.</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20030501</creationdate><title>Conformational change and mitochondrial translocation of Bax accompany proteasome inhibitor-induced apoptosis of chronic lymphocytic leukemic cells</title><author>Dewson, Grant ; Snowden, Roger T ; Almond, Jason B ; Dyer, Martin J S ; Cohen, Gerald M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c602t-f8416df6ea24dad4e2b8250bb49d65e485cd3f591e832b6c6b1c97b04772a4fd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Apoptosis</topic><topic>Apoptosis - physiology</topic><topic>Bax protein</topic><topic>Bcl-2 protein</topic><topic>bcl-2-Associated X Protein</topic><topic>BH3 Interacting Domain Death Agonist Protein</topic><topic>Biological and medical sciences</topic><topic>Carrier Proteins - metabolism</topic><topic>Caspase</topic><topic>Cell Biology</topic><topic>Cell cycle</topic><topic>Chemoresistance</topic><topic>Chemotherapy</topic><topic>Chlorambucil</topic><topic>Chronic lymphocytic leukemia</topic><topic>Classical genetics, quantitative genetics, hybrids</topic><topic>Conformation</topic><topic>Cysteine Endopeptidases</topic><topic>Cytochrome</topic><topic>Cytochrome c</topic><topic>Cytochrome c Group - metabolism</topic><topic>Fludarabine</topic><topic>Fundamental and applied biological sciences. 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Proteasome inhibitors are able to induce apoptosis in chemotherapy-resistant B-CLL cells
in vitro
. Exposure of B-CLL cells to the proteasome inhibitors, MG132 and lactacystin, resulted in inhibition of proteasomal activity within 30 min of treatment and was accompanied by an increase in the level of ubiquitinated proteins. Proteasome inhibitors did not alter the levels of expression of the proapoptotic Bcl-2 family proteins, Bax and Bid, prior to the onset of apoptosis. Instead, proteasome inhibitors induced a caspase-independent conformational change in Bax (as shown by a conformation-specific Bax antibody) and its translocation to mitochondria, resulting in mitochondrial perturbation, as evidenced by loss of the mitochondrial membrane potential and cytochrome
c
release. Similar conformational change and subcellular localization of Bax were observed during apoptosis induced with fludarabine, chlorambucil and prednisolone. These data suggest that alteration of Bax conformation and its redistribution to mitochondria are common and early features of B-CLL apoptosis in response to proteasome inhibitors and other chemotherapeutic agents.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>12730678</pmid><doi>10.1038/sj.onc.1206326</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Apoptosis Apoptosis - physiology Bax protein Bcl-2 protein bcl-2-Associated X Protein BH3 Interacting Domain Death Agonist Protein Biological and medical sciences Carrier Proteins - metabolism Caspase Cell Biology Cell cycle Chemoresistance Chemotherapy Chlorambucil Chronic lymphocytic leukemia Classical genetics, quantitative genetics, hybrids Conformation Cysteine Endopeptidases Cytochrome Cytochrome c Cytochrome c Group - metabolism Fludarabine Fundamental and applied biological sciences. Psychology Genetics of eukaryotes. Biological and molecular evolution Hematologic and hematopoietic diseases Human Human Genetics Humans Immunohistochemistry Internal Medicine Kinases Lactacystin Leukemia Leukemia, Lymphocytic, Chronic, B-Cell - metabolism Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Localization Lymphatic leukemia Lymphocytes B Medical sciences Medicine Medicine & Public Health Membrane potential Mitochondria Mitochondria - metabolism Multienzyme Complexes - antagonists & inhibitors Oncology original-paper Prednisolone Proteasome Endopeptidase Complex Proteasome inhibitors Proteasomes Protein Conformation Protein Transport - physiology Proteins Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-bcl-2 Ubiquitin - metabolism |
| title | Conformational change and mitochondrial translocation of Bax accompany proteasome inhibitor-induced apoptosis of chronic lymphocytic leukemic cells |
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