Dimeric p53 Mutant Elicits Unique Tumor-Suppressive Activities through an Altered Metabolic Program

Authors

Jovanka Gencel-Augusto
Xiaoping Su
Yuan Qi
Elizabeth M Whitley
Vinod Pant
Shunbin Xiong
Vrutant Shah
Jerome Lin
Encarnacion Perez
Marta L Fiorotto
Iqbal Mahmud
Abhinav K Jain
Philip L Lorenzi
Nicholas E Navin
Ellen R Richie
Guillermina Lozano

Publication Date

5-4-2023

Journal

Cancer Discovery

Abstract

Cancer-related alterations of the p53 tetramerization domain (TD) abrogate wild-type (WT) p53 function. They result in a protein that preferentially forms monomers or dimers, which are also normal p53 states under basal cellular conditions. However, their physiologic relevance is not well understood. We have established in vivo models for monomeric and dimeric p53, which model Li-Fraumeni syndrome patients with germline p53 TD alterations. p53 monomers are inactive forms of the protein. Unexpectedly, p53 dimers conferred some tumor suppression that is not mediated by canonical WT p53 activities. p53 dimers upregulate the PPAR pathway. These activities are associated with lower prevalence of thymic lymphomas and increased CD8+ T-cell differentiation. Lymphomas derived from dimeric p53 mice show cooperating alterations in the PPAR pathway, further implicating a role for these activities in tumor suppression. Our data reveal novel functions for p53 dimers and support the exploration of PPAR agonists as therapies.

Keywords

Animals, Mice, Li-Fraumeni Syndrome, Tumor Suppressor Protein p53, Transcriptional Activation, Peroxisome Proliferator-Activated Receptors, Cell Death

Comments

Supplementary Materials

PMID: 37067911