Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Biochemistry & Molecular Biophysics

First Advisor

Maureen E. Murphy

Abstract

The tumor suppressor gene TP53 is the most frequently mutated gene in cancer and plays a key role in mediating several processes that are critical for preventing tumor formation and progression. Known as the guardian of the genome, p53 regulates hundreds of genes involved in various pathways such as apoptosis, cell cycle arrest and senescence. In recent years, the role of p53 in metabolism, redox state and ferroptosis has begun to emerge. Our lab has identified an African-specific polymorphic variant of p53 that encodes a serine residue instead of a proline at amino acid 47 (hereafter S47) and predisposes carriers to cancer. The S47 variant is impaired for tumor suppression and ferroptosis, and S47 cells have an altered redox state. We sought to use the tumor prone S47 model as a tool to better understand the role of p53 in tumor suppression. Our results demonstrate that mice carrying the S47 variant have greater metabolic efficiency compared to those with WT p53, along with increased mTOR activity. This difference in mTOR stems from an impaired protein-protein interaction that occurs in S47, ultimately due to a difference in cellular redox state. We next identified PLTP as a p53 target gene that shows decreased transactivation in the S47 variant and mediates ferroptosis resistance by enhancing lipid storage in HepG2 cells. Taken together, this work sheds light on the emerging roles p53 plays in tumor suppression, metabolism and ferroptosis. It also provides a better understanding of an ethnic genetic variant of p53. We expect this work will enable better personalized medicine approaches and therapeutic options for people who carry this variant.

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