Dimeric p53 mutant elicits unique tumor-suppressive activities through an altered metabolic program

Authors: GENCEL-AUGUSTO, JOVANKA - Md Anderson Cancer Center; SU, XIAOPING - Md Anderson Cancer Center; QI, YUAN - Md Anderson Cancer Center; WHITLEY, ELIZABETH - Md Anderson Cancer Center; PANT, VINOD - Md Anderson Cancer Center; XIONG, SHUNBIN - Md Anderson Cancer Center; SHAH, VRUTANT - Md Anderson Cancer Center; LIN, JEROME - Md Anderson Cancer Center; PEREZ, ENCARNACION - Md Anderson Cancer Center; FIOROTTO, MARTA - Children'S Nutrition Research Center (CNRC); JAIN, ABHINAV - Md Anderson Cancer Center; LORENZI, PHILIP - Md Anderson Cancer Center; NAVIN, NICHOLAS - Md Anderson Cancer Center; RICHIE, ELLEN - Md Anderson Cancer Center; LOZANO, GUILLERMINA - Md Anderson Cancer Center

Submitted to: Cancer Discovery
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/27/2023
Publication Date: 5/4/2023
Citation: Gencel-Augusto, J., Su, X., Qi, Y., Whitley, E.M., Pant, V., Xiong, S., Shah, V., Lin, J., Perez, E., Fiorotto, M.L., Jain, A.K., Lorenzi, P.L., Navin, N.E., Richie, E.R., Lozano, G. 2023. Dimeric p53 mutant elicits unique tumor-suppressive activities through an altered metabolic program. Cancer Discovery. 13(5):1230-1249. https://doi.org/10.1158/2159-8290.cd-22-0872.
DOI: https://doi.org/10.1158/2159-8290.cd-22-0872

Interpretive Summary: The transcription factor p53 is a tumor suppressor that during times of cellular stress and DNA damage binds to DNA to inhibit cell processes which otherwise lead to cancer. p53 is the most frequently mutated gene in human cancers. To function four p53 molecules must come together to form a complex (a tetramer) that can bind to DNA. However, some mutations allow only 2 molecules to combine (a dimer) and previously were thought to be nonfunctional. Using a mouse model that replicates such human mutations, this study discovered that p53 dimers also can act as tumor suppressors. However, their mechanism of action is different from how normal p53 tetramers work. Specifically, when these dimers are present, they activate the transcription factor peroxisome proliferator-activated receptor (PPAR) signaling pathways and increase mitochondrial metabolism, specifically fat oxidation. Mice carrying this mutation were also more active. The metabolic pathways affected are usually found to be down-regulated in the presence of cancer, but in this model they were activated even in unstressed conditions. These novel findings have identified new potential therapies for patients that carry the same p53, dimer-forming gene mutation.

Technical 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.