Early G2/M checkpoint failure as a molecular mechanism underlying etoposide-induced chromosomal aberrations
Topoisomerase II (Topo II) inhibitors are cell cycle-specific DNA-damaging agents and often correlate with secondary leukemia with chromosomal translocations involving the mixed-lineage leukemia/myeloid lymphoid leukemia (MLL) gene on chromosome 11 band q23 (11q23). In spite of the clinical importan...
Gespeichert in:
| Veröffentlicht in: | The Journal of clinical investigation 2006-01, Vol.116 (1), p.80-89 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 89 |
|---|---|
| container_issue | 1 |
| container_start_page | 80 |
| container_title | The Journal of clinical investigation |
| container_volume | 116 |
| creator | Nakada, Shinichiro Katsuki, Yoko Imoto, Issei Yokoyama, Tetsuji Nagasawa, Masayuki Inazawa, Johji Mizutani, Shuki |
| description | Topoisomerase II (Topo II) inhibitors are cell cycle-specific DNA-damaging agents and often correlate with secondary leukemia with chromosomal translocations involving the mixed-lineage leukemia/myeloid lymphoid leukemia (MLL) gene on chromosome 11 band q23 (11q23). In spite of the clinical importance, the molecular mechanism for this chromosomal translocation has yet to be elucidated. In this study, we employed 2-color FISH and detected intracellular chromosomal translocations induced by etoposide treatment. Cells such as ataxia-telangiectasia mutated-deficient fibroblasts and U2OS cells, in which the early G2/M checkpoint after treatment with low concentrations of etoposide has been lost, executed mitosis with etoposide-induced DNA double-strand breaks, and 2-color FISH signals located on either side of the MLL gene were segregated in the postmitotic G1 phase. Long-term culture of cells that had executed mitosis under etoposide treatment showed frequent structural abnormalities of chromosome 11. These findings provide convincing evidence for Topo II inhibitor-induced 11q23 translocation. Our study also suggests an important role of the early G2/M checkpoint in preventing fixation of chromosomal abnormalities and reveals environmental and genetic risk factors for the development of chromosome 11 translocations, namely, low concentrations of Topo II inhibitors and dysfunctional early G2/M checkpoint control. |
| doi_str_mv | 10.1172/jci25716 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_1312016</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>19701281</sourcerecordid><originalsourceid>FETCH-LOGICAL-c494t-2b3a56c76bc6a50f099a6b4829e71927b7cdd4067398acb0a0af0e916b5a80263</originalsourceid><addsrcrecordid>eNqFkU1v1DAQhi0EoktB4hcgiwPiEjrjOHZ8QUKrUoqKuMDZmjhO19vEXuwEqf-elK74unCawzzzaGZexp4jvEHU4mzvgmg0qgdsg03TVq2o24dsAyCwMrpuT9iTUvYAKGUjH7MTVHWjjZQbdnNOebzlF-LsE3c7724OKcSZDxTGJXtOhROf0ujdMlLmk3c7iqFMfIm9XwdDvOZ-TodUQu-rEPvF-X4V5TSlkiYaOXU-Z5pDiuUpezTQWPyzYz1lX9-ff9l-qK4-X1xu311VTho5V6KrqVFOq84pamAAY0h1shXGazRCd9r1vQSla9OS64CABvAGVddQC0LVp-ztvfewdJPvnY9zptEecpgo39pEwf7diWFnr9N3izUKwDvBq6Mgp2-LL7OdQnF-HCn6tBSrtAKNCP8F0WhA0eIKvvwH3Kclx_ULVgA0slVKrNDre8jlVEr2w6-VEexdzvbj9vJnziv64s8Tf4PHYOsfU4qkcQ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>200548662</pqid></control><display><type>article</type><title>Early G2/M checkpoint failure as a molecular mechanism underlying etoposide-induced chromosomal aberrations</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>Nakada, Shinichiro ; Katsuki, Yoko ; Imoto, Issei ; Yokoyama, Tetsuji ; Nagasawa, Masayuki ; Inazawa, Johji ; Mizutani, Shuki</creator><creatorcontrib>Nakada, Shinichiro ; Katsuki, Yoko ; Imoto, Issei ; Yokoyama, Tetsuji ; Nagasawa, Masayuki ; Inazawa, Johji ; Mizutani, Shuki</creatorcontrib><description>Topoisomerase II (Topo II) inhibitors are cell cycle-specific DNA-damaging agents and often correlate with secondary leukemia with chromosomal translocations involving the mixed-lineage leukemia/myeloid lymphoid leukemia (MLL) gene on chromosome 11 band q23 (11q23). In spite of the clinical importance, the molecular mechanism for this chromosomal translocation has yet to be elucidated. In this study, we employed 2-color FISH and detected intracellular chromosomal translocations induced by etoposide treatment. Cells such as ataxia-telangiectasia mutated-deficient fibroblasts and U2OS cells, in which the early G2/M checkpoint after treatment with low concentrations of etoposide has been lost, executed mitosis with etoposide-induced DNA double-strand breaks, and 2-color FISH signals located on either side of the MLL gene were segregated in the postmitotic G1 phase. Long-term culture of cells that had executed mitosis under etoposide treatment showed frequent structural abnormalities of chromosome 11. These findings provide convincing evidence for Topo II inhibitor-induced 11q23 translocation. Our study also suggests an important role of the early G2/M checkpoint in preventing fixation of chromosomal abnormalities and reveals environmental and genetic risk factors for the development of chromosome 11 translocations, namely, low concentrations of Topo II inhibitors and dysfunctional early G2/M checkpoint control.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/jci25716</identifier><identifier>PMID: 16357944</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Apoptosis ; Ataxia ; Biomedical research ; Bone Neoplasms ; Cell cycle ; Cell Cycle - physiology ; Cell Division ; Cell Line ; Cell Line, Tumor ; Chromosome Aberrations - chemically induced ; Chromosome Banding ; Chromosomes ; Chromosomes, Human, Pair 11 ; Cloning, Molecular ; DNA damage ; Etoposide - pharmacology ; G2 Phase ; Gene Expression Regulation ; Gene Expression Regulation, Neoplastic ; Genes ; Histone-Lysine N-Methyltransferase ; Humans ; Leukemia ; Myeloid-Lymphoid Leukemia Protein - drug effects ; Myeloid-Lymphoid Leukemia Protein - genetics ; Osteosarcoma ; Translocation, Genetic ; Tumorigenesis ; Tumors</subject><ispartof>The Journal of clinical investigation, 2006-01, Vol.116 (1), p.80-89</ispartof><rights>Copyright American Society for Clinical Investigation Jan 2006</rights><rights>Copyright © 2006, American Society for Clinical Investigation 2006</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c494t-2b3a56c76bc6a50f099a6b4829e71927b7cdd4067398acb0a0af0e916b5a80263</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1312016/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1312016/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16357944$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nakada, Shinichiro</creatorcontrib><creatorcontrib>Katsuki, Yoko</creatorcontrib><creatorcontrib>Imoto, Issei</creatorcontrib><creatorcontrib>Yokoyama, Tetsuji</creatorcontrib><creatorcontrib>Nagasawa, Masayuki</creatorcontrib><creatorcontrib>Inazawa, Johji</creatorcontrib><creatorcontrib>Mizutani, Shuki</creatorcontrib><title>Early G2/M checkpoint failure as a molecular mechanism underlying etoposide-induced chromosomal aberrations</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>Topoisomerase II (Topo II) inhibitors are cell cycle-specific DNA-damaging agents and often correlate with secondary leukemia with chromosomal translocations involving the mixed-lineage leukemia/myeloid lymphoid leukemia (MLL) gene on chromosome 11 band q23 (11q23). In spite of the clinical importance, the molecular mechanism for this chromosomal translocation has yet to be elucidated. In this study, we employed 2-color FISH and detected intracellular chromosomal translocations induced by etoposide treatment. Cells such as ataxia-telangiectasia mutated-deficient fibroblasts and U2OS cells, in which the early G2/M checkpoint after treatment with low concentrations of etoposide has been lost, executed mitosis with etoposide-induced DNA double-strand breaks, and 2-color FISH signals located on either side of the MLL gene were segregated in the postmitotic G1 phase. Long-term culture of cells that had executed mitosis under etoposide treatment showed frequent structural abnormalities of chromosome 11. These findings provide convincing evidence for Topo II inhibitor-induced 11q23 translocation. Our study also suggests an important role of the early G2/M checkpoint in preventing fixation of chromosomal abnormalities and reveals environmental and genetic risk factors for the development of chromosome 11 translocations, namely, low concentrations of Topo II inhibitors and dysfunctional early G2/M checkpoint control.</description><subject>Apoptosis</subject><subject>Ataxia</subject><subject>Biomedical research</subject><subject>Bone Neoplasms</subject><subject>Cell cycle</subject><subject>Cell Cycle - physiology</subject><subject>Cell Division</subject><subject>Cell Line</subject><subject>Cell Line, Tumor</subject><subject>Chromosome Aberrations - chemically induced</subject><subject>Chromosome Banding</subject><subject>Chromosomes</subject><subject>Chromosomes, Human, Pair 11</subject><subject>Cloning, Molecular</subject><subject>DNA damage</subject><subject>Etoposide - pharmacology</subject><subject>G2 Phase</subject><subject>Gene Expression Regulation</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genes</subject><subject>Histone-Lysine N-Methyltransferase</subject><subject>Humans</subject><subject>Leukemia</subject><subject>Myeloid-Lymphoid Leukemia Protein - drug effects</subject><subject>Myeloid-Lymphoid Leukemia Protein - genetics</subject><subject>Osteosarcoma</subject><subject>Translocation, Genetic</subject><subject>Tumorigenesis</subject><subject>Tumors</subject><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><recordid>eNqFkU1v1DAQhi0EoktB4hcgiwPiEjrjOHZ8QUKrUoqKuMDZmjhO19vEXuwEqf-elK74unCawzzzaGZexp4jvEHU4mzvgmg0qgdsg03TVq2o24dsAyCwMrpuT9iTUvYAKGUjH7MTVHWjjZQbdnNOebzlF-LsE3c7724OKcSZDxTGJXtOhROf0ujdMlLmk3c7iqFMfIm9XwdDvOZ-TodUQu-rEPvF-X4V5TSlkiYaOXU-Z5pDiuUpezTQWPyzYz1lX9-ff9l-qK4-X1xu311VTho5V6KrqVFOq84pamAAY0h1shXGazRCd9r1vQSla9OS64CABvAGVddQC0LVp-ztvfewdJPvnY9zptEecpgo39pEwf7diWFnr9N3izUKwDvBq6Mgp2-LL7OdQnF-HCn6tBSrtAKNCP8F0WhA0eIKvvwH3Kclx_ULVgA0slVKrNDre8jlVEr2w6-VEexdzvbj9vJnziv64s8Tf4PHYOsfU4qkcQ</recordid><startdate>20060101</startdate><enddate>20060101</enddate><creator>Nakada, Shinichiro</creator><creator>Katsuki, Yoko</creator><creator>Imoto, Issei</creator><creator>Yokoyama, Tetsuji</creator><creator>Nagasawa, Masayuki</creator><creator>Inazawa, Johji</creator><creator>Mizutani, Shuki</creator><general>American Society for Clinical Investigation</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>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>S0X</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20060101</creationdate><title>Early G2/M checkpoint failure as a molecular mechanism underlying etoposide-induced chromosomal aberrations</title><author>Nakada, Shinichiro ; Katsuki, Yoko ; Imoto, Issei ; Yokoyama, Tetsuji ; Nagasawa, Masayuki ; Inazawa, Johji ; Mizutani, Shuki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c494t-2b3a56c76bc6a50f099a6b4829e71927b7cdd4067398acb0a0af0e916b5a80263</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Apoptosis</topic><topic>Ataxia</topic><topic>Biomedical research</topic><topic>Bone Neoplasms</topic><topic>Cell cycle</topic><topic>Cell Cycle - physiology</topic><topic>Cell Division</topic><topic>Cell Line</topic><topic>Cell Line, Tumor</topic><topic>Chromosome Aberrations - chemically induced</topic><topic>Chromosome Banding</topic><topic>Chromosomes</topic><topic>Chromosomes, Human, Pair 11</topic><topic>Cloning, Molecular</topic><topic>DNA damage</topic><topic>Etoposide - pharmacology</topic><topic>G2 Phase</topic><topic>Gene Expression Regulation</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Genes</topic><topic>Histone-Lysine N-Methyltransferase</topic><topic>Humans</topic><topic>Leukemia</topic><topic>Myeloid-Lymphoid Leukemia Protein - drug effects</topic><topic>Myeloid-Lymphoid Leukemia Protein - genetics</topic><topic>Osteosarcoma</topic><topic>Translocation, Genetic</topic><topic>Tumorigenesis</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nakada, Shinichiro</creatorcontrib><creatorcontrib>Katsuki, Yoko</creatorcontrib><creatorcontrib>Imoto, Issei</creatorcontrib><creatorcontrib>Yokoyama, Tetsuji</creatorcontrib><creatorcontrib>Nagasawa, Masayuki</creatorcontrib><creatorcontrib>Inazawa, Johji</creatorcontrib><creatorcontrib>Mizutani, Shuki</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>eLibrary</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>SIRS Editorial</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nakada, Shinichiro</au><au>Katsuki, Yoko</au><au>Imoto, Issei</au><au>Yokoyama, Tetsuji</au><au>Nagasawa, Masayuki</au><au>Inazawa, Johji</au><au>Mizutani, Shuki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Early G2/M checkpoint failure as a molecular mechanism underlying etoposide-induced chromosomal aberrations</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2006-01-01</date><risdate>2006</risdate><volume>116</volume><issue>1</issue><spage>80</spage><epage>89</epage><pages>80-89</pages><issn>0021-9738</issn><eissn>1558-8238</eissn><abstract>Topoisomerase II (Topo II) inhibitors are cell cycle-specific DNA-damaging agents and often correlate with secondary leukemia with chromosomal translocations involving the mixed-lineage leukemia/myeloid lymphoid leukemia (MLL) gene on chromosome 11 band q23 (11q23). In spite of the clinical importance, the molecular mechanism for this chromosomal translocation has yet to be elucidated. In this study, we employed 2-color FISH and detected intracellular chromosomal translocations induced by etoposide treatment. Cells such as ataxia-telangiectasia mutated-deficient fibroblasts and U2OS cells, in which the early G2/M checkpoint after treatment with low concentrations of etoposide has been lost, executed mitosis with etoposide-induced DNA double-strand breaks, and 2-color FISH signals located on either side of the MLL gene were segregated in the postmitotic G1 phase. Long-term culture of cells that had executed mitosis under etoposide treatment showed frequent structural abnormalities of chromosome 11. These findings provide convincing evidence for Topo II inhibitor-induced 11q23 translocation. Our study also suggests an important role of the early G2/M checkpoint in preventing fixation of chromosomal abnormalities and reveals environmental and genetic risk factors for the development of chromosome 11 translocations, namely, low concentrations of Topo II inhibitors and dysfunctional early G2/M checkpoint control.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>16357944</pmid><doi>10.1172/jci25716</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0021-9738 |
| ispartof | The Journal of clinical investigation, 2006-01, Vol.116 (1), p.80-89 |
| issn | 0021-9738 1558-8238 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_1312016 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Apoptosis Ataxia Biomedical research Bone Neoplasms Cell cycle Cell Cycle - physiology Cell Division Cell Line Cell Line, Tumor Chromosome Aberrations - chemically induced Chromosome Banding Chromosomes Chromosomes, Human, Pair 11 Cloning, Molecular DNA damage Etoposide - pharmacology G2 Phase Gene Expression Regulation Gene Expression Regulation, Neoplastic Genes Histone-Lysine N-Methyltransferase Humans Leukemia Myeloid-Lymphoid Leukemia Protein - drug effects Myeloid-Lymphoid Leukemia Protein - genetics Osteosarcoma Translocation, Genetic Tumorigenesis Tumors |
| title | Early G2/M checkpoint failure as a molecular mechanism underlying etoposide-induced chromosomal aberrations |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-13T18%3A45%3A57IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Early%20G2/M%20checkpoint%20failure%20as%20a%20molecular%20mechanism%20underlying%20etoposide-induced%20chromosomal%20aberrations&rft.jtitle=The%20Journal%20of%20clinical%20investigation&rft.au=Nakada,%20Shinichiro&rft.date=2006-01-01&rft.volume=116&rft.issue=1&rft.spage=80&rft.epage=89&rft.pages=80-89&rft.issn=0021-9738&rft.eissn=1558-8238&rft_id=info:doi/10.1172/jci25716&rft_dat=%3Cproquest_pubme%3E19701281%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=200548662&rft_id=info:pmid/16357944&rfr_iscdi=true |