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Article: MAD2ΔC induces aneuploidy and promotes anchorage-independent growth in human prostate epithelial cells

TitleMAD2ΔC induces aneuploidy and promotes anchorage-independent growth in human prostate epithelial cells
Authors
Issue Date2008
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
Citation
Oncogene, 2008, v. 27 n. 3, p. 347-357 How to Cite?
AbstractThe mitotic arrest deficient 2 (MAD2) is suggested to play a key role in a functional mitotic checkpoint because of its inhibitory effect on anaphase-promoting complex/cyclosome (APC/C) during mitosis. The binding of MAD2 to mitotic checkpoint regulators MAD1 and Cdc20 is thought to be crucial for its function and loss of which leads to functional inactivation of the MAD2 protein. However, little is known about the biological significance of this MAD2 mutant in human cells. In this study, we stably transfected a C-terminal-deleted MAD2 gene (MAD2ΔC) into a human prostate epithelial cell line, Hpr-1 and studied its effect on chromosomal instability, cell proliferation, mitotic checkpoint control and soft agar colony-forming ability. We found that MAD2ΔC was able to induce aneuploidy through promoting chromosomal duplication, which was a result of an impaired mitotic checkpoint and cytokinesis, suggesting a crucial role of MAD2-mediated mitotic checkpoint in chromosome stability in human cells. In addition, the MAD2ΔC- transfected cells displayed anchorage-independent growth in soft agar after challenged by 7,12-dimethylbenz[A]anthracene (DMBA), demonstrating a cancer-promoting effect of a defective mitotic checkpoint in human cells. Furthermore, the DMBA-induced transformation was accompanied by a complete loss of DNA damage-induced p53 response and activation of the MAPK pathway in MAD2ΔC cells. These results indicate that a defective mitotic checkpoint alone is not a direct cause of tumorigenesis, but it may predispose human cells to carcinogen-induced malignant transformation. The evidence presented here provides a link between MAD2 inactivation and malignant transformation of epithelial cells. © 2008 Nature Publishing Group All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/67722
ISSN
2015 Impact Factor: 7.932
2015 SCImago Journal Rankings: 4.047
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorToHo, KWen_HK
dc.contributor.authorCheung, HWen_HK
dc.contributor.authorLing, MTen_HK
dc.contributor.authorWong, YCen_HK
dc.contributor.authorWang, Xen_HK
dc.date.accessioned2010-09-06T05:57:40Z-
dc.date.available2010-09-06T05:57:40Z-
dc.date.issued2008en_HK
dc.identifier.citationOncogene, 2008, v. 27 n. 3, p. 347-357en_HK
dc.identifier.issn0950-9232en_HK
dc.identifier.urihttp://hdl.handle.net/10722/67722-
dc.description.abstractThe mitotic arrest deficient 2 (MAD2) is suggested to play a key role in a functional mitotic checkpoint because of its inhibitory effect on anaphase-promoting complex/cyclosome (APC/C) during mitosis. The binding of MAD2 to mitotic checkpoint regulators MAD1 and Cdc20 is thought to be crucial for its function and loss of which leads to functional inactivation of the MAD2 protein. However, little is known about the biological significance of this MAD2 mutant in human cells. In this study, we stably transfected a C-terminal-deleted MAD2 gene (MAD2ΔC) into a human prostate epithelial cell line, Hpr-1 and studied its effect on chromosomal instability, cell proliferation, mitotic checkpoint control and soft agar colony-forming ability. We found that MAD2ΔC was able to induce aneuploidy through promoting chromosomal duplication, which was a result of an impaired mitotic checkpoint and cytokinesis, suggesting a crucial role of MAD2-mediated mitotic checkpoint in chromosome stability in human cells. In addition, the MAD2ΔC- transfected cells displayed anchorage-independent growth in soft agar after challenged by 7,12-dimethylbenz[A]anthracene (DMBA), demonstrating a cancer-promoting effect of a defective mitotic checkpoint in human cells. Furthermore, the DMBA-induced transformation was accompanied by a complete loss of DNA damage-induced p53 response and activation of the MAPK pathway in MAD2ΔC cells. These results indicate that a defective mitotic checkpoint alone is not a direct cause of tumorigenesis, but it may predispose human cells to carcinogen-induced malignant transformation. The evidence presented here provides a link between MAD2 inactivation and malignant transformation of epithelial cells. © 2008 Nature Publishing Group All rights reserved.en_HK
dc.languageengen_HK
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/oncen_HK
dc.relation.ispartofOncogeneen_HK
dc.subject.mesh9,10-Dimethyl-1,2-benzanthracene - toxicityen_HK
dc.subject.meshAneuploidyen_HK
dc.subject.meshCalcium-Binding Proteins - geneticsen_HK
dc.subject.meshCarcinogens - toxicityen_HK
dc.subject.meshCell Cycle Proteins - geneticsen_HK
dc.subject.meshCell Lineen_HK
dc.subject.meshCell Proliferationen_HK
dc.subject.meshCell Transformation, Neoplastic - chemically induced - genetics - pathologyen_HK
dc.subject.meshEpithelial Cells - metabolismen_HK
dc.subject.meshHumansen_HK
dc.subject.meshMaleen_HK
dc.subject.meshMitosisen_HK
dc.subject.meshProstate - metabolism - pathologyen_HK
dc.subject.meshProstatic Neoplasms - chemically induced - genetics - pathologyen_HK
dc.subject.meshRepressor Proteins - geneticsen_HK
dc.subject.meshSequence Deletionen_HK
dc.subject.meshTumor Suppressor Protein p53 - metabolismen_HK
dc.titleMAD2ΔC induces aneuploidy and promotes anchorage-independent growth in human prostate epithelial cellsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0950-9232&volume=27&spage=347&epage=357&date=2008&atitle=MAD2ΔC+induces+aneuploidy+and+promotes+anchorage-independent+growth+in+human+prostate+epithelial+cells.++en_HK
dc.identifier.emailLing, MT:patling@hkucc.hku.hken_HK
dc.identifier.emailWong, YC:ycwong@hkucc.hku.hken_HK
dc.identifier.authorityLing, MT=rp00449en_HK
dc.identifier.authorityWong, YC=rp00316en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/sj.onc.1210633en_HK
dc.identifier.pmid17621272-
dc.identifier.scopuseid_2-s2.0-38049115127en_HK
dc.identifier.hkuros147317en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-38049115127&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume27en_HK
dc.identifier.issue3en_HK
dc.identifier.spage347en_HK
dc.identifier.epage357en_HK
dc.identifier.isiWOS:000252256000011-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridToHo, KW=23393958200en_HK
dc.identifier.scopusauthoridCheung, HW=7201839381en_HK
dc.identifier.scopusauthoridLing, MT=7102229780en_HK
dc.identifier.scopusauthoridWong, YC=7403041798en_HK
dc.identifier.scopusauthoridWang, X=7501854829en_HK
dc.identifier.citeulike1445538-

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