The repository administrator has not yet configured an RDF license.
Plk1 Overexpression Impairs Chromosome Segregation and Suppresses Tumor Development
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.
Plk1 Overexpression Impairs Chromosome Segregation and Suppresses Tumor Development (Other)
Plk1 Overexpression Impairs Chromosome Segregation and Suppresses Tumor Development (PDF)
HTML Summary of #23977 Plk1 Overexpression Impairs Chromosome Segregation and Suppresses Tumor Development
500 Naturwissenschaften und Mathematik
500 Natural sciences and mathematics
570 Biowissenschaften, Biologie
570 Life sciences