Date of Award

2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Shelley L. Berger

Abstract

The human TP53 gene encodes the most potent tumor suppressor protein p53. More than half of all human cancers contain mutations in the TP53 gene, while the majority of the remaining cases involve other mechanisms to inactivate wild-type p53 function. In the first part of my dissertation research, I have explored the mechanism of suppressed wild-type p53 activity in teratocarcinoma. In the teratocarcinoma cell line NTera2, we show that wild-type p53 is mono-methylated at Lysine 370 and Lysine 382. These post-translational modifications contribute to the compromised tumor suppressive activity of p53 despite a high level of wild-type protein in NTera2 cells. This study provides evidence for an epigenetic mechanism that cancer cells can exploit to inactivate p53 wild-type function. The paradigm provides insight into understanding the modes of p53 regulation, and can likely be applied to other cancer types with wild-type p53 proteins. On the other hand, cancers with TP53 mutations are mostly found to contain missense substitutions of the TP53 gene, resulting in expression of full length, but mutant forms of p53 that confer tumor-promoting “gain-of-function” (GOF) to cancer. In the second section of my dissertation, I have investigated the mechanism of this GOF property by examining genome-wide p53 binding profiles in multiple cancer cell lines bearing p53 mutations. This reveals an epigenetic mechanism underlying mutant p53 GOF. Various GOF p53 mutants bind to and upregulate genes including MLL1, MLL2, and MOZ, leading to genome-wide changes of histone modifications. These studies also demonstrate a critical functional role of the MLL pathway in mediating mutant p53 GOF cancer phenotypes, and that genetic or pharmacological perturbation of MLL function can achieve specific inhibition of GOF p53 cell proliferation. Overall, studies described in this dissertation demonstrate the crosstalk between p53 signaling and chromatin regulatory pathways, contribute to our knowledge of p53 cancer biology with respect to epigenetic regulation, and in the long term suggest new therapeutic opportunities in targeting cancers according to their p53 mutational status.

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