Inhibition of PLK1 by p53 and by PLK1-targeted drugs
type: CreativeWork
description: Polo like kinase 1 (PLK1) has many functions in the orchestration of cell division. It is an oncogene and its overexpression is associated with poor prognosis. PLK1 is a cell cycle-dependent protein; its levels are low in the early phases of the cell cycle and increase as cells go through the cycle, peaking in G2/M. In this thesis, our focus has been on two critical areas in PLK1 research. 1. Tumour suppressor p53 mediates transcriptional repression of PLK1. There have been several mechanisms suggested for this repression both by direct and indirect p53 involvement. In light of the recently proposed mechanism suggesting that p53-p21-DREAM-CDE/CHR is responsible for p53 mediated repression of G2/M proteins (including PLK1), we reassessed the event(s) by which p53 downregulates PLK1. While investigating the effect of different p53 stabilising agents on PLK1 levels, different agents were found to give rise to different cell cycle profiles. This could account for differences in the extent of PLK1 downregulation in response to different agents: i.e. that the levels of PLK1 after treatment reflect the phase in which the cycle is arrested. Further investigation showed that p53 mediated repression of PLK1 is partly p21 dependent, consistent with repression occurring (partly) through DREAM. Also, we found that different cells use different or overlapping mechanisms for this repression. Thus While in HCT116 cells, mutation of CDE/CHR elements (through which DREAM acts) abolished the PLK1 repression, U2OS cells were only partly dependent on CDE/CHR elements for this repression. Additionally, Serine 15 phosphorylation was found to be partly required for the repression and only wild type p53 (but not mutated forms of p53 that lack transactivation capacity) could repress PLK1 expression. These data are consistent with the idea that p53 repression is indirect, but do not rule out other mechanisms. 2. PLK1 has been extensively studied as a target for cancer therapeutics. PLK1 inhib…
abstract: Polo like kinase 1 (PLK1) has many functions in the orchestration of cell division. It is an oncogene and its overexpression is associated with poor prognosis. PLK1 is a cell cycle-dependent protein; its levels are low in the early phases of the cell cycle and increase as cells go through the cycle, peaking in G2/M. In this thesis, our focus has been on two critical areas in PLK1 research. 1. Tumour suppressor p53 mediates transcriptional repression of PLK1. There have been several mechanisms suggested for this repression both by direct and indirect p53 involvement. In light of the recently proposed mechanism suggesting that p53-p21-DREAM-CDE/CHR is responsible for p53 mediated repression of G2/M proteins (including PLK1), we reassessed the event(s) by which p53 downregulates PLK1. While investigating the effect of different p53 stabilising agents on PLK1 levels, different agents were found to give rise to different cell cycle profiles. This could account for differences in the extent of PLK1 downregulation in response to different agents: i.e. that the levels of PLK1 after treatment reflect the phase in which the cycle is arrested. Further investigation showed that p53 mediated repression of PLK1 is partly p21 dependent, consistent with repression occurring (partly) through DREAM. Also, we found that different cells use different or overlapping mechanisms for this repression. Thus While in HCT116 cells, mutation of CDE/CHR elements (through which DREAM acts) abolished the PLK1 repression, U2OS cells were only partly dependent on CDE/CHR elements for this repression. Additionally, Serine 15 phosphorylation was found to be partly required for the repression and only wild type p53 (but not mutated forms of p53 that lack transactivation capacity) could repress PLK1 expression. These data are consistent with the idea that p53 repression is indirect, but do not rule out other mechanisms. 2. PLK1 has been extensively studied as a target for cancer therapeutics. PLK1 inhib…
author: Ahmadi, Maryam
language: eng
date published: 2018
date modified: 2026-07-24T02:08:39Z
provider: University of Dundee
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Dundee