Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven By Different P53 Mutants

<p>Missense mutations in the DNA binding domain of the <em>Trp53</em> gene are characterized as structural (<em>p53R172H</em>) or contact (<em>p53R245W</em>) mutations based on their effect on the conformation of the protein. These mutations show gain-of-function activities such as increased metastatic incidence as compared to <em>p53</em> loss, often mediated by their interaction with a repertoire of transcription factors. These interactions are largely context specific. In order to understand the mechanisms by which these mutations drive osteosarcoma progression, we created a mouse model, wherein either the p53 structural mutant p53R172H, or the contact mutant, p53R245W, are expressed specifically in osteoblasts, yielding osteosarcoma tumor development. We observed a significant decrease in survival and increased metastatic incidence in mice expressing <em>p53</em> mutants as compared to <em>p53</em>-null mice, suggesting gain of function. RNA-sequencing of primary osteosarcomas revealed that tumors expressing these missense mutants had vastly different gene expression profiles as compared to <em>p53</em>-null tumors. Further, p53R172H and p53R245W regulated unique transcriptomes, that affected distinct pathways, through interactions with a unique repertoire of transcription factors. Validation assays showed that p53R245W, but not p53R172H, interacts with KLF15 to drive migration and invasion in osteosarcoma cell lines, and metastases in allo-transplantation models. Additionally, analyses of p53R248W ChIP peaks showed enrichment of KLF15 motifs in human osteoblasts. Taken together, these data suggest that the structural and contact mutants of <em>p53</em> have unique mechanisms of action.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2023

Authors dc:creator

• Chachad, Dhruv
• <p>0000-0003-3131-7679</p>

Contributors dc:contributor

• Guillermina Lozano
• Patrick Lin
• Michael Andreeff

• p53
• osteosarcoma
• KLF15
• GEMMs
• Cancer Biology
• Computational Biology
• Genomics
• Molecular Genetics

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1277

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2334