A mutation in separase causes genome instability and increased susceptibility to epithelial cancer
Proper chromosome segregation is essential for maintenance of genomic integrity and instability resulting from failure of this process may contribute to cancer. Here, we demonstrate that a mutation in the mitotic regulator separase is responsible for the cell cycle defects seen in the zebrafish muta...
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| Veröffentlicht in: | Genes & development 2007-01, Vol.21 (1), p.55-59 |
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| creator | Shepard, Jennifer L Amatruda, James F Finkelstein, David Ziai, James Finley, K Rose Stern, Howard M Chiang, Ken Hersey, Candace Barut, Bruce Freeman, Jennifer L Lee, Charles Glickman, Jonathan N Kutok, Jeffery L Aster, Jon C Zon, Leonard I |
| description | Proper chromosome segregation is essential for maintenance of genomic integrity and instability resulting from failure of this process may contribute to cancer. Here, we demonstrate that a mutation in the mitotic regulator separase is responsible for the cell cycle defects seen in the zebrafish mutant, cease&desist (cds). Analysis of cds homozygous mutant embryos reveals high levels of polyploidy and aneuploidy, spindle defects, and a mitotic exit delay. Carcinogenesis studies demonstrated that cds heterozygous adults have a shift in tumor spectrum with an eightfold increase in the percentage of fish bearing epithelial tumors, indicating that separase is a tumor suppressor gene in vertebrates. These data strongly support a conserved cross-species role for mitotic checkpoint genes in genetic stability and epithelial carcinogenesis. |
| doi_str_mv | 10.1101/gad.1470407 |
| format | Article |
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Here, we demonstrate that a mutation in the mitotic regulator separase is responsible for the cell cycle defects seen in the zebrafish mutant, cease&desist (cds). Analysis of cds homozygous mutant embryos reveals high levels of polyploidy and aneuploidy, spindle defects, and a mitotic exit delay. Carcinogenesis studies demonstrated that cds heterozygous adults have a shift in tumor spectrum with an eightfold increase in the percentage of fish bearing epithelial tumors, indicating that separase is a tumor suppressor gene in vertebrates. 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Here, we demonstrate that a mutation in the mitotic regulator separase is responsible for the cell cycle defects seen in the zebrafish mutant, cease&desist (cds). Analysis of cds homozygous mutant embryos reveals high levels of polyploidy and aneuploidy, spindle defects, and a mitotic exit delay. Carcinogenesis studies demonstrated that cds heterozygous adults have a shift in tumor spectrum with an eightfold increase in the percentage of fish bearing epithelial tumors, indicating that separase is a tumor suppressor gene in vertebrates. These data strongly support a conserved cross-species role for mitotic checkpoint genes in genetic stability and epithelial carcinogenesis.</description><subject>Animals</subject><subject>Bromodeoxyuridine</subject><subject>Carcinoma, Pancreatic Ductal - etiology</subject><subject>Carcinoma, Pancreatic Ductal - pathology</subject><subject>Cell Cycle</subject><subject>Cell Cycle Proteins - genetics</subject><subject>Danio rerio</subject><subject>Disease Susceptibility</subject><subject>Embryo, Nonmammalian - cytology</subject><subject>Embryo, Nonmammalian - metabolism</subject><subject>Endopeptidases - genetics</subject><subject>Genomic Instability</subject><subject>Heterozygote</subject><subject>Homozygote</subject><subject>Intestinal Neoplasms - etiology</subject><subject>Intestinal Neoplasms - pathology</subject><subject>Mitosis</subject><subject>Mutation</subject><subject>Neoplasms, Glandular and Epithelial - etiology</subject><subject>Neoplasms, Glandular and Epithelial - pathology</subject><subject>Ploidies</subject><subject>Research Communication</subject><subject>Separase</subject><subject>Spindle Apparatus - genetics</subject><subject>Spindle Apparatus - pathology</subject><subject>Zebrafish - genetics</subject><subject>Zebrafish - growth & development</subject><subject>Zebrafish - metabolism</subject><issn>0890-9369</issn><issn>1549-5477</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkctLxDAQh4Mo7vo4eZeevEjXSds0zUVYxBcIXvQcpu10N9KXSSr43xvZ4uMUht_HNxl-jJ1xWHEO_GqD9YpnEjKQe2zJRaZikUm5z5ZQKIhVmqsFO3LuDQByyPNDtuAy4SCLYsnKddRNHr0Z-sj0kaMRLTqKKpwcuWhD_dBRSJzH0rTGf0bY12GuLAWsjtzkKhq9mUM_RDQav6XWYBskfUX2hB002Do6nd9j9np3-3LzED893z_erJ_iKpO5j1WTU1Km2FBa1mlBJaoC6kIUKcgyayRHTplAIRQIWTREwBHzSjQyEQQJT4_Z9c47TmVHdUW9t9jq0ZoO7ace0Oj_SW-2ejN8aC6FUgBBcDEL7PA-kfO6M-G6tsWehslprkSqgMsAXu7Ayg7OWWp-lnDQ353o0ImeOwn0-d9__bJzCekXikGKrg</recordid><startdate>20070101</startdate><enddate>20070101</enddate><creator>Shepard, Jennifer L</creator><creator>Amatruda, James F</creator><creator>Finkelstein, David</creator><creator>Ziai, James</creator><creator>Finley, K Rose</creator><creator>Stern, Howard M</creator><creator>Chiang, Ken</creator><creator>Hersey, Candace</creator><creator>Barut, Bruce</creator><creator>Freeman, Jennifer L</creator><creator>Lee, Charles</creator><creator>Glickman, Jonathan N</creator><creator>Kutok, Jeffery L</creator><creator>Aster, Jon C</creator><creator>Zon, Leonard I</creator><general>Cold Spring Harbor Laboratory Press</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>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20070101</creationdate><title>A mutation in separase causes genome instability and increased susceptibility to epithelial cancer</title><author>Shepard, Jennifer L ; Amatruda, James F ; Finkelstein, David ; Ziai, James ; Finley, K Rose ; Stern, Howard M ; Chiang, Ken ; Hersey, Candace ; Barut, Bruce ; Freeman, Jennifer L ; Lee, Charles ; Glickman, Jonathan N ; Kutok, Jeffery L ; Aster, Jon C ; Zon, Leonard I</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c476t-9f6e2b3afe3bd38eba980d858307b4f71a1e45a5590578fee01aa6c5f725e0213</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Animals</topic><topic>Bromodeoxyuridine</topic><topic>Carcinoma, Pancreatic Ductal - etiology</topic><topic>Carcinoma, Pancreatic Ductal - pathology</topic><topic>Cell Cycle</topic><topic>Cell Cycle Proteins - genetics</topic><topic>Danio rerio</topic><topic>Disease Susceptibility</topic><topic>Embryo, Nonmammalian - cytology</topic><topic>Embryo, Nonmammalian - metabolism</topic><topic>Endopeptidases - genetics</topic><topic>Genomic Instability</topic><topic>Heterozygote</topic><topic>Homozygote</topic><topic>Intestinal Neoplasms - etiology</topic><topic>Intestinal Neoplasms - pathology</topic><topic>Mitosis</topic><topic>Mutation</topic><topic>Neoplasms, Glandular and Epithelial - etiology</topic><topic>Neoplasms, Glandular and Epithelial - pathology</topic><topic>Ploidies</topic><topic>Research Communication</topic><topic>Separase</topic><topic>Spindle Apparatus - genetics</topic><topic>Spindle Apparatus - pathology</topic><topic>Zebrafish - genetics</topic><topic>Zebrafish - growth & development</topic><topic>Zebrafish - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shepard, Jennifer L</creatorcontrib><creatorcontrib>Amatruda, James F</creatorcontrib><creatorcontrib>Finkelstein, David</creatorcontrib><creatorcontrib>Ziai, James</creatorcontrib><creatorcontrib>Finley, K Rose</creatorcontrib><creatorcontrib>Stern, Howard M</creatorcontrib><creatorcontrib>Chiang, Ken</creatorcontrib><creatorcontrib>Hersey, Candace</creatorcontrib><creatorcontrib>Barut, Bruce</creatorcontrib><creatorcontrib>Freeman, Jennifer L</creatorcontrib><creatorcontrib>Lee, Charles</creatorcontrib><creatorcontrib>Glickman, Jonathan N</creatorcontrib><creatorcontrib>Kutok, Jeffery L</creatorcontrib><creatorcontrib>Aster, Jon C</creatorcontrib><creatorcontrib>Zon, Leonard I</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Genes & development</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shepard, Jennifer L</au><au>Amatruda, James F</au><au>Finkelstein, David</au><au>Ziai, James</au><au>Finley, K Rose</au><au>Stern, Howard M</au><au>Chiang, Ken</au><au>Hersey, Candace</au><au>Barut, Bruce</au><au>Freeman, Jennifer L</au><au>Lee, Charles</au><au>Glickman, Jonathan N</au><au>Kutok, Jeffery L</au><au>Aster, Jon C</au><au>Zon, Leonard I</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A mutation in separase causes genome instability and increased susceptibility to epithelial cancer</atitle><jtitle>Genes & development</jtitle><addtitle>Genes Dev</addtitle><date>2007-01-01</date><risdate>2007</risdate><volume>21</volume><issue>1</issue><spage>55</spage><epage>59</epage><pages>55-59</pages><issn>0890-9369</issn><eissn>1549-5477</eissn><abstract>Proper chromosome segregation is essential for maintenance of genomic integrity and instability resulting from failure of this process may contribute to cancer. Here, we demonstrate that a mutation in the mitotic regulator separase is responsible for the cell cycle defects seen in the zebrafish mutant, cease&desist (cds). Analysis of cds homozygous mutant embryos reveals high levels of polyploidy and aneuploidy, spindle defects, and a mitotic exit delay. Carcinogenesis studies demonstrated that cds heterozygous adults have a shift in tumor spectrum with an eightfold increase in the percentage of fish bearing epithelial tumors, indicating that separase is a tumor suppressor gene in vertebrates. These data strongly support a conserved cross-species role for mitotic checkpoint genes in genetic stability and epithelial carcinogenesis.</abstract><cop>United States</cop><pub>Cold Spring Harbor Laboratory Press</pub><pmid>17210788</pmid><doi>10.1101/gad.1470407</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Bromodeoxyuridine Carcinoma, Pancreatic Ductal - etiology Carcinoma, Pancreatic Ductal - pathology Cell Cycle Cell Cycle Proteins - genetics Danio rerio Disease Susceptibility Embryo, Nonmammalian - cytology Embryo, Nonmammalian - metabolism Endopeptidases - genetics Genomic Instability Heterozygote Homozygote Intestinal Neoplasms - etiology Intestinal Neoplasms - pathology Mitosis Mutation Neoplasms, Glandular and Epithelial - etiology Neoplasms, Glandular and Epithelial - pathology Ploidies Research Communication Separase Spindle Apparatus - genetics Spindle Apparatus - pathology Zebrafish - genetics Zebrafish - growth & development Zebrafish - metabolism |
| title | A mutation in separase causes genome instability and increased susceptibility to epithelial cancer |
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