<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Plk1 Overexpression Impairs Chromosome Segregation\r\nand Suppresses Tumor Development"^^ . "Polo-like kinase 1 (Plk1) is a serine-threonine protein kinase widely accepted as one\r\nof the master regulators of cell cycle. Overexpression of Plk1 is a frequent\r\noccurrence in an array of different human tumor types and it is usually correlated\r\nwith poor prognosis in patients. However, very little is known about the exact role of\r\nPlk1 in tumorigenesis. Here, we use inducible mouse models to determine the in vivo\r\nconsequences of Plk1 overexpression. During this study, we established that Plk1 is\r\nnot an oncogene and overexpression of Plk1 has a strong tumor suppressive effect\r\non Her2 or Kras driven breast cancer. Furthermore, tumors with elevated levels of\r\nPlk1 displayed evidence of whole genome doubling coupled with increased levels of\r\naneuploidy. Histological characterization of murine mammary glands prior to tumor\r\ndevelopment affirmed a correlation between Plk1 overexpression and increase in\r\ngenomic content at an early stage. Utilizing in vitro culture systems, we demonstrate\r\nthat overexpression of Plk1 leads to reduced proliferation and causes polyploidy.\r\nTime-lapse imaging of mammary organoid cultures and mouse embryonic fibroblasts\r\n(MEFs) overexpressing Plk1 revealed that the polyploid cells originate due to\r\nimpaired chromosome segregation as well as a failure of cytokinesis occurring during\r\nmitosis. Increased mitotic aberrations and supernumerary centrosomes\r\naccompanied these defective cell division processes. Mechanistically, the observed\r\nphenotype can be partially attributed to decrease of Shugoshin 1 (Sgo1) a target of\r\nPlk1, which is responsible for maintaining cohesion at the centromeres thus holding\r\nthe sister chromatids together prior to anaphase. Premature loss of Sgo1 during\r\nprometaphase caused a partial or complete loss of cohesion.\r\nIn this dissertation, we report that one of the major consequences of Plk1\r\noverexpression is a staggering tumor suppressive effect, although this does not\r\nnecessarily negate the possibility that Plk1 could promote tumor development under\r\na different set of circumstances. Despite these findings, Plk1 inhibition in human\r\ntumors could still have a beneficial outcome because the kinase is indispensable for\r\ncell division. This work is not aimed at discouraging further research on Plk1\r\ninhibitors; rather it provides a testament to the use of genetically engineered mouse\r\nmodels (GEMMs) that closely mimic human disease for pre-clinical testing. It is\r\nimperative to understand the molecular mechanisms and cellular processes leading\r\nup to tumor onset prior to the development of therapeutic strategies."^^ . "2018" . . . . . . . "Sharavan Vishaan"^^ . "Venkateswaran"^^ . "Sharavan Vishaan Venkateswaran"^^ . . . . . . "Plk1 Overexpression Impairs Chromosome Segregation\r\nand Suppresses Tumor Development (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Plk1 Overexpression Impairs Chromosome Segregation\r\nand Suppresses Tumor Development (PDF)"^^ . . . "PhD_Thesis_Sharavan_20170928.pdf"^^ . . . "Plk1 Overexpression Impairs Chromosome Segregation\r\nand Suppresses Tumor Development (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Plk1 Overexpression Impairs Chromosome Segregation\r\nand Suppresses Tumor Development (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Plk1 Overexpression Impairs Chromosome Segregation\r\nand Suppresses Tumor Development (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Plk1 Overexpression Impairs Chromosome Segregation\r\nand Suppresses Tumor Development (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #23977 \n\nPlk1 Overexpression Impairs Chromosome Segregation \nand Suppresses Tumor Development\n\n" . "text/html" . . . "500 Naturwissenschaften und Mathematik"@de . "500 Natural sciences and mathematics"@en . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .