Multipolar Spindle Pole Coalescence Is a Major Source of Kinetochore Mis-Attachment and Chromosome Mis-Segregation in Cancer Cells 英文参考文献.docVIP

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Multipolar Spindle Pole Coalescence Is a Major Source of Kinetochore Mis-Attachment and Chromosome Mis-Segregation in Cancer Cells 英文参考文献.doc

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Multipolar Spindle Pole Coalescence Is a Major Source of Kinetochore Mis-Attachment and Chromosome Mis-Segregation in Cancer Cells 英文参考文献

MultipolarSpindlePoleCoalescenceIsaMajorSourceof KinetochoreMis-AttachmentandChromosomeMis- SegregationinCancerCells WilliamT.Silkworth1,IsaacK.Nardi1,LindseyM.Scholl2,DanielaCimini1* 1VirginiaTech,DepartmentofBiologicalSciences,Blacksburg,Virginia,UnitedStatesofAmerica,2DepartmentofBiology,OberlinCollege,Oberlin,Ohio,UnitedStatesof America Abstract ManycancercellsdisplayaCIN(ChromosomeInstability)phenotype,bywhichtheyexhibithighratesofchromosomeloss or gain at each cell cycle. Over the years, a number of different mechanisms, including mitotic spindle multipolarity, cytokinesisfailure,andmerotelickinetochoreorientation,havebeenproposedascausesofCIN.However,acomprehensive theoryofhowCINisperpetuatedisstilllacking.WeusedCINcolorectalcancercellsasamodelsystemtoinvestigatethe possiblecellularmechanism(s)underlyingCIN.WefoundthatCINcellsfrequentlyassembledmultipolarspindlesinearly mitosis. However, multipolar anaphase cells were very rare, and live-cell experiments showed that almost all CIN cells divided in a bipolar fashion. Moreover, fixed-cell analysis showed high frequencies of merotelically attached lagging chromosomes in bipolar anaphase CIN cells, and higher frequencies of merotelic attachments in multipolar vs. bipolar prometaphases.Finally,wefoundthatmultipolarCINprometaphasestypicallypossessedc-tubulinatallspindlepoles,and thatasignificantfractionofbipolarmetaphase/earlyanaphaseCINcellspossessedmorethanonecentrosomeatasingle spindle pole. Taken together, our data suggest a model by which merotelic kinetochore attachments can easily be established in multipolar prometaphases. Most of these multipolar prometaphase cells would then bi-polarize before anaphase onset, and the residual merotelic attachments would produce chromosome mis-segregation due to anaphase lagging chromosomes. We propose this spindle pole coalescence mechanism as a major contributor to chromosome instabilityincancercells. Citation: Silkworth WT, Nardi IK, Scholl LM, Cimini D (2009) Multipo