Date of Award
Doctor of Philosophy (PhD)
The tumor suppressor TP53 (p53) is the most frequently mutated gene in cancer and among the most mutated genes in brain cancer. Functionally, p53 is a transcription factor that, when activated by an array of stress stimuli, regulates a complex transcriptional program that contributes to a variety of antiproliferative pathways. The loss of p53 function (LOF), either through mutation, deletion, or inhibition by alterations in the proteins that regulate p53, removes an essential barrier to the unfettered proliferation and genomic instability that drive transformation. Unlike most tumor suppressors, many p53 mutations are missense mutations that lead to stable expression of gain-of-function (GOF) oncogenic variants. In addition to the loss of canonical tumor suppressor function, GOF p53 promotes malignancy through the regulation of a set of oncogenic target genes. Studies investigating p53 mutations across cell types report diverse effects, including increased proliferation and invasion, angiogenesis, drug resistance, and epigenetic reprogramming. Thus, the functional consequences of GOF p53 and p53 depletion involve a complex interplay between cell lineage, cell state, and mechanism of p53 disruption. One of the most important variables contributing to cell state is biological sex. From the moment of fertilization and throughout aging, sexual differentiation influences almost every biological process. Sex differences in wild-type p53 function are known to influence normal development and aging but are understudied in cancer. In glioblastoma (GBM), the most common primary malignant brain tumor, males exhibit higher incidence and greater mortality than females. This bias persists across ages and geography, indicating that neither acute sex hormones nor environmental factors can fully account for these differences. Consequently, understanding the role of sex differences in GBM requires the interrogation of the molecular mechanisms that underlie this disease. We hypothesized that sex differences in p53 would impact the functional outcomes of both p53 loss- and gain-of-function in GBM. This work will present two projects to interrogate this hypothesis. The first project will focus on sex differences in the regulation of tumor suppressors in the absence of functional p53. This work demonstrates that female but not male astrocytes resist transformation following p53 loss by maintaining the regulation of the tumor suppressors p16 and p21. In the second project, I developed a novel astrocyte model to study the sex-specific effects of GBM relevant GOF p53 mutations. Through a combination of phenotyping and next-generation sequencing, I demonstrate that mutant p53 GOF transcriptional activity is dependent on the intersection of the specific missense mutation and the cell sex. Taken together, this work advances our understanding of sex as a biological variable in p53 mediated tumorigenesis. Given that p53 is the most altered gene in cancer, these findings have broad implications for the interpretation of data in both the preclinical and clinical setting and emphasize that sex must be incorporated into p53 studies if we are to decipher the growing complexity surrounding this gene.
Chair and Committee
Joshua B. Rubin
Milan G. Chheda, Barak A. Cohen, Nima Mosammaparast, Jason D. Weber,
Rockwell, Nathan Cuyle, "Discovery of Sex Differences in Response to p53 Loss and Gain-of-Function in Glioblastoma" (2021). Arts & Sciences Electronic Theses and Dissertations. 2526.
Available for download on Tuesday, August 22, 2023