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Cytoskeletal defects lead to cytokinesis failure and genomic instability in cancer cells

Wu, Qian (2008) Cytoskeletal defects lead to cytokinesis failure and genomic instability in cancer cells. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Cancer cells typically have unstable genomes and ploidy, and these changes play an important part of malignant transformation in most tumorigenesis models. I observe that cancer cells can increase ploidy by failure of cell division producing a single daughter with a doubled genome. Cytokinesis failure usually is followed by the formation of multipolar spindles in the tested cell lines. Some of these cells are still capable of dividing and the daughters of multipolar division have an even greater chance of being multinucleated and multicentrosomal due to failure of cytokinesis and thus likely enter another round of multipolar division. However, some of the daughters inherit a single nucleus and centrosome, suggesting that they may escape a cycle of multipolarity and give rise to centrosomally-stable clones. I also show here that failure of cytokinesis in cancer cells is associated with cytoskeleton abnormalities. One type of defect is caused by decreased phosphorylation of the myosin regulatory light chain, a key regulatory element of cortical contraction during cell division. Reduced phosphorylation is often associated with high expression of myosin phosphatase and/or reduced myosin light chain kinase (MLCK) levels in a variety of cancer cell lines. When myosin light chain phosphorylation is restored to normal levels by phosphatase knockdown, the mitotic defects of malignant cells, including cytokinesis failure, multinucleation, and multipolar mitosis are all markedly reduced. Both overexpression of myosin phosphatase and inhibition of the MLCK can recapitulate the multinucleation in nonmalignant cells. These results show that ploidy defects in tumor cells can be caused by deficiencies in myosin light chain phosphorylation resulting from high expression of myosin phosphatase and low activity of MLCK. GpIb¦Á, a membrane glycoprotein, which is widely upregulated in cancer cells, has been shown here for the first time to play a role in cytokinesis, possibly also through regulating cytoskeleton remodeling. The overexpression of GpIb¦Á in p53-knockdown primary cells induces cytokinesis failure, tetraploidization, genomic instability and tumorigenesis. In addition, knockdown of GpIb¦Á reduces chromosome segregation defects in cancer cells. Together, these observations support a model that cytoskeleton-defect-mediated cytokinesis failure plays a major role influencing the chromosomal instability of cancer cells.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Wu,, chianwoo@hotmail.comQIW9
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairSaunders, William Swsaund@pitt.eduWSAUND
Committee MemberSchwacha, Anthonyschwacha@pitt.eduSCHWACHA
Committee MemberHildebrand, Jeffrey Djeffh@pitt.eduJEFFH
Committee MemberBrodsky, Jeffrey Ljbrodsky@pitt.eduJBRODSKY
Committee MemberWatkins, Simon Cswatkins@pitt.eduSWATKINS
Date: 7 November 2008
Date Type: Completion
Defense Date: 17 April 2008
Approval Date: 7 November 2008
Submission Date: 24 April 2008
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Biological Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: actin; cancer; centrosome; cytokinesis; cytoskeleton; GpIba; MLC; MLCK; multinucleation; multipolarity; myosin phosphatase; phosphorylation; tetraploidy
Other ID:, etd-04242008-170912
Date Deposited: 10 Nov 2011 19:42
Last Modified: 15 Nov 2016 13:42


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