Browsing by Author "Blough, Michael Donald"
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- ItemOpen Accessp53, mgmt, and temozolomide sensitivity in high grade astrocytic gliomas(2012) Blough, Michael Donald; Cairncross, J. GregoryGlioblastoma multiforme (GBM) is a uniformly fatal type of brain cancer. Despite intensive research, only minor progress has been made in improving prognosis. Current treatment modalities for GBM involve surgical resection, followed by chemoradiotherapy, with the same treatment generally administered to all patients. Intriguingly, differential patient outcomes are not uncommon: some patients respond favourably, some do not, suggesting that tumour subsets with unique molecular alterations that determine the effectiveness of treatment must exist. If the nature and consequence of these alterations can be clarified, it may be possible to individualize patient treatments. Indeed, ensuring effective treatments for treatment-responsive cases, while eliminating unnecessary treatments and side effects from administering ineffective therapeutics is envisioned. The work presented in this dissertation focuses on the tumour suppressor p53 and the DNA repair protein 06-methylguanine DNA methyl transferase (MGMT). Specifically, we investigate the roles these proteins play in response of GBM to the chemotherapeutic Temozolomide (TMZ). The following three objectives are presented, aimed at improving our understanding of how these two molecules are related and the role they play in treatment response: i) examine the relationship between p53 and MGMT expression, two genes commonly altered in GBM; ii) define the relationship between p53 and response to TMZ; and iii) determine the link between MGMT and TMZ sensitivity in brain tumour initiating cells (BTICs), a potential 'disease reservoir' for GBM. Successful completion of these objectives provides an improved understanding of how p53 relates to MGMT expression and TMZ response, and whether MGMT determines TMZ sensitivity in BTICs.
- ItemOpen AccessThe effects of ionizing radiation on p53 and p21CIP1(2004) Blough, Michael Donald; Lee, Patrick W. K.; Woods, Donald E.In response to ionizing radiation (IR) cells undergo cell cycle arrest and/or apoptosis. These responses are mediated by the tumor suppressor protein p53, and are thought to be essential for maintaining genomic stability and integrity. Although it has long been assumed that the mechanisms by which p53 regulates these processes were ubiquitous, the advent of new experimental techniques and technologies has begun to demonstrate variations. As such, the purpose of this thesis was to re-investigate the effects of IR on p53, and one of its key downstream targets, the cyclin dependent kinase inhibitor p21 CIPl, with some of the more recent observations in mind. The results presented within this thesis contradict much of the previous data on the effects of IR on p53 and p21 CIPl; it is demonstrated that p53 activity and protein levels are unaltered in response to IR, and that p21 ClPl exists in a heterogeneous population of isoforms. Most importantly, it is shown that p21 CIPl may be differentially modified in response to IR. Based on the results contained within this thesis a theoretical model is proposed by which p53/p21ClPl mediated cell cycle arrest occurs in response to IR.