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Sahasrabudhe, Ruta (2012) IDENTIFCATION OF THE CAUSES OF CYTOKINESIS FAILURE IN CANCER CELLS. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Tetraploidy and chromosomal instability are common phenotypes of malignant cells and cytokinesis failure is a known source of tetraploidy. However, the causes of cytokinesis failure are not yet identified. An essential step in the process of cytokinesis is phosphorylation of myosin regulatory light chain (MLC), required for actin–myosin interaction and the formation of the cleavage furrow. Our data indicate that cancer cells are deficient in MLC phosphorylation and this deficiency is the cause of cytokinesis failure. Myosin light chain kinase (MLCK) is a key enzyme that phosphorylates MLC during cytokinesis and is inhibited in cancer cells. Aurora B kinase is an essential regulator of cytokinesis that is commonly over-expressed in cancer cells and can phosphorylate MLCK in vitro. Therefore we hypothesize that Aurora B over-expression is the cause of MLCK inhibition in cancer cells. Consistent with our hypothesis, we demonstrate that Aurora B kinase indeed is an MLCK inhibitor in vitro and in cultured mammalian cells. Cytokinesis failure resulting from Aurora B over-expression can largely be suppressed by constitutively active MLCK or phosphomimetic MLC and reducing protein levels of Aurora B in cancer cells increases MLCK activity and decreases cytokinesis failure. These data thus describe a novel pathway that drives Aurora B induced cytokinesis failure.
Cytokinesis failure is often observed in only a subset of cancer cells but the trigger for this divisional failure in that subset is unknown. One strong possibility is the presence of lingering chromatin at the cleavage site that has been previously proposed to block cytokinesis completion. However, the mechanism linking lingering chromatin and cytokinesis failure is still a mystery. In this study we demonstrate that lingering chromatin causes cytokinesis failure by inducing over-expression of Aurora B and the resultant inhibition of MLCK and phosphorylated MLC. Together, my results define a novel pathway for Aurora B mediated regulation of cytokinesis and contribute to our understanding of the genomic destabilizing events of tumorigenesis.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Sahasrabudhe, Rutarms62@pitt.eduRMS62
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairSaunders, Williamwsaund@pitt.eduWSAUND
Committee MemberBrodsky, Jeffreyjbrodsky@pitt.eduJBRODSKY
Committee MemberKiselyov, Kirillkiselyov@pitt.eduKISELYOV
Committee MemberProchownik,
Committee MemberSchwacha, Anthonyschwacha@pitt.eduSCHWACHA
Date: 2 October 2012
Date Type: Publication
Defense Date: 24 May 2012
Approval Date: 2 October 2012
Submission Date: 5 June 2012
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 178
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: cancer, cytokinesis, MLCK, Aurora B kinase
Date Deposited: 02 Oct 2012 19:03
Last Modified: 02 Oct 2017 05:15


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