P53 Dimers Elicit Unique Tumor Suppressive Activities Through An Altered Metabolic Program

<p>p53 is the most frequently mutated tumor suppressor in human cancer. As a tetrameric transcription factor, mutation of the p53 Tetramerization Domain (TD) is a mechanism by which cancers abrogate wild-type (WT) p53 function. p53 TD mutations result in a protein that preferentially forms monomers or dimers. These are also normal p53 states under basal cellular conditions. Although it is accepted that tetrameric p53 is required for full tumor suppressive activities, the physiological relevance of monomeric and dimeric states of p53 is not well understood. We have established in vivo models for monomeric and dimeric p53 which model Li-Fraumeni Syndrome (LFS) patients with germline TP53 TD alterations. Detailed studies showed p53 monomers are inactive forms of the protein. Unexpectedly, p53 dimers conferred some tumor suppression that is not mediated by canonical stress-activated WT p53 activities. Mechanistically, p53 dimers upregulate a novel transcriptional program of PPAR activation. These activities are associated with lower prevalence of thymic lymphomas and inhibition of immature CD8+ T cell accumulation. Lymphomas derived from dimeric p53 mice show cooperating genomic alterations including those in the PPAR pathway, further implicating a role for these activities in tumor suppression. Intriguingly, dimeric p53 tumor suppression is mediated by Mdm2, by allowing interaction with PPARs. Combined, our data reveal novel functions for p53 dimers and support the exploration of PPAR agonists as anti- cancer therapies.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2023

Authors dc:creator

• Gencel-Augusto, Jovanka
• <p>0000-0003-1333-415X</p>

Contributors dc:contributor

• Guillermina Lozano, PhD
• Michelle Barton, PhD
• Marina Konopleva, PhD

• p53
• tetramerization
• mouse models
• tumor suppression
• Cancer Biology
• Genetics

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1238

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2295