title: Plk1 Overexpression Impairs Chromosome Segregation  and Suppresses Tumor Development
creator: Venkateswaran, Sharavan Vishaan
subject: ddc-500
subject: 500 Natural sciences and mathematics
subject: ddc-570
subject: 570 Life sciences
description: Polo-like kinase 1 (Plk1) is a serine-threonine protein kinase widely accepted as one  of the master regulators of cell cycle. Overexpression of Plk1 is a frequent  occurrence in an array of different human tumor types and it is usually correlated  with poor prognosis in patients. However, very little is known about the exact role of  Plk1 in tumorigenesis. Here, we use inducible mouse models to determine the in vivo  consequences of Plk1 overexpression. During this study, we established that Plk1 is  not an oncogene and overexpression of Plk1 has a strong tumor suppressive effect  on Her2 or Kras driven breast cancer. Furthermore, tumors with elevated levels of  Plk1 displayed evidence of whole genome doubling coupled with increased levels of  aneuploidy. Histological characterization of murine mammary glands prior to tumor  development affirmed a correlation between Plk1 overexpression and increase in  genomic content at an early stage. Utilizing in vitro culture systems, we demonstrate  that overexpression of Plk1 leads to reduced proliferation and causes polyploidy.  Time-lapse imaging of mammary organoid cultures and mouse embryonic fibroblasts  (MEFs) overexpressing Plk1 revealed that the polyploid cells originate due to  impaired chromosome segregation as well as a failure of cytokinesis occurring during  mitosis. Increased mitotic aberrations and supernumerary centrosomes  accompanied these defective cell division processes. Mechanistically, the observed  phenotype can be partially attributed to decrease of Shugoshin 1 (Sgo1) a target of  Plk1, which is responsible for maintaining cohesion at the centromeres thus holding  the sister chromatids together prior to anaphase. Premature loss of Sgo1 during  prometaphase caused a partial or complete loss of cohesion.  In this dissertation, we report that one of the major consequences of Plk1  overexpression is a staggering tumor suppressive effect, although this does not  necessarily negate the possibility that Plk1 could promote tumor development under  a different set of circumstances. Despite these findings, Plk1 inhibition in human  tumors could still have a beneficial outcome because the kinase is indispensable for  cell division. This work is not aimed at discouraging further research on Plk1  inhibitors; rather it provides a testament to the use of genetically engineered mouse  models (GEMMs) that closely mimic human disease for pre-clinical testing. It is  imperative to understand the molecular mechanisms and cellular processes leading  up to tumor onset prior to the development of therapeutic strategies.
date: 2018
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/23977/1/PhD_Thesis_Sharavan_20170928.pdf
identifier: DOI:10.11588/heidok.00023977
identifier: urn:nbn:de:bsz:16-heidok-239774
identifier:   Venkateswaran, Sharavan Vishaan  (2018) Plk1 Overexpression Impairs Chromosome Segregation and Suppresses Tumor Development.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/23977/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng