Exploration of novel regulators of mutant p53 in cancer cells: a role for NDFIP1
AffiliationSir Peter MacCallum Department of Oncology
Document TypePhD thesis
Access StatusThis item is embargoed and will be available on 2021-08-08.
© 2019 Dr. Reshma Vijayakumaran
Mutations in the tumour suppressor gene, TP53 occur in more than 50% of human cancers. Mutant p53 proteins not only lose their tumour suppressive capacities, but also gain oncogenic functions, broadly referred to as gain of function (GOF). Cancer cells frequently accumulate mutant p53 and may become addicted to this protein for their survival. During development, mutant p53, like its wild-type counterpart, is inherently labile, however in cancer cells mutant p53 frequently accumulates. In part, this is due to the interrupted auto-regulatory loop with MDM2. However, MDM2 alone cannot explain the stability of mutant p53 in many cancer contexts. We therefore argued that additional factors are responsible for its stability in cancer cells. In order to identify the major players in the regulation of mutant p53, we performed a high-throughput RNAi screen through which we evaluated 18,120 genes for their effects on mutant p53 levels in two different mutant p53 expressing cell lines. Based on network analyses, pathway analyses and extensive literature mining, we selected 37 candidate genes to be validated through p53 immunoblotting. From the validated genes, we have selected one candidate for further studies. The results described in this thesis highlight a previously unknown mode of mutant p53 regulation in cancer cells. Future studies will explore in greater depth the functional consequences of this new interaction with mutant p53. Excitingly, these studies expose new vulnerabilities for therapeutic intervention and these opportunities for targeting aggressive cancers with mutant p53 will also be the focus of ongoing research.
Keywordscancer; mutant p53; exosomes
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