Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/95872
Type: Thesis
Title: An investigation of mutant p53 function.
Author: Noll, Jacqueline Elise
Issue Date: 2011
School/Discipline: School of Medicine
Abstract: The TP53 tumour suppressor gene is mutated in approximately 50% of all human cancers. The majority of these mutations are missense mutations resulting in the expression of a mutated form of the full-length p53 protein. This mutant protein exhibits a loss of tumour suppressive activity, dominant-negative activity to inactivate functional p53 and gain-of-function properties to drive tumour progression and metastasis. Investigation into mutant p53-mediated oncogenic pathways and the mechanisms through which they are controlled plays an integral role in identifying new therapeutic targets for a range of mutant p53-expressing tumours. To model the initial events that occur in cancer following sporadic p53 mutation, an isogenic panel of cell lines was established in the p53 null, H1299 lung cancer cell line, expressing wild-type or various p53 hotspot mutants under the control of an inducible promoter. These cell lines were harnessed to investigate a range of wildtype and mutant p53 functions. The induced wild-type p53 protein is demonstrated to be transcriptionally and biologically active, and its function can be further mediated by DNA damaging agents or expression of regulatory proteins. Conversely, induced mutant p53 exhibits a loss of the majority of the normal wild-type transcriptional activity while mediating gain-of-function, oncogenic phenotypes in H1299 cells. This system is demonstrated to provide an important platform with which to investigate both wild-type and mutant p53 function. Mutant p53 is reported to function as an aberrant transcription factor, re-programming the cellular transcriptome to enhance oncogenic pathways. The mechanisms underlying this were specifically examined through expression microarray analysis, which identified a number of mutant p53-regulated targets. Surprisingly, these targets were predominately also direct targets of wild-type p53. A novel mechanism for mutant p53 activity is subsequently suggested, whereby mutant p53 is recruited to the DNA through its interaction with p63. A key function of mutant p53 is its ability to drive tumourigenesis through the initiation of a range of oncogenic pathways. Through utilising the inducible system, mutant p53 is demonstrated to influence mitotic pathways, resulting in multinucleation, and enhance the invasive and migratory properties of cancer cells. Importantly, an endogenous protein, ANKRD11, is identified with the capacity to suppress the oncogenic properties of mutant p53 and provide a potential target for the development of new cancer therapeutics. The role of mutant p53 in driving the invasive and metastatic potential of breast cancer cells was further explored and a relationship between mutant p53 and a micro-RNA (miR-155) established. Mutant p53 expression is shown to correlate with miR-155 expression, with miR-155 target genes involved in invasive pathways. ZNF652 is specifically identified as a target of miR-155 and loss of ZNF-652 is correlated with increased invasion and poor prognosis in breast cancer. Collectively, these studies identify key mechanisms through which mutant p53 functions to enhance tumourigenesis and importantly identify novel targets, ANKRD11, miR-155 and ZNF652, for the development of cancer therapies.
Advisor: Callen, David Frederick
Neilsen, Paul Matthew
Sharma, Raman Kumar
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2011
Keywords: p53; tumour suppressor; cancer
Provenance: This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at: http://www.adelaide.edu.au/legals
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