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

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.

SIGNIFICANCE:

New mouse models with TP53R342P (monomer) or TP53A347D (dimer) mutations mimic Li-Fraumeni syndrome. Although p53 monomers lack function, p53 dimers conferred noncanonical tumor-suppressive activities. We describe novel activities for p53 dimers facilitated by PPARs and propose these are "basal" p53 activities. See related commentary by Stieg et al., p. 1046. See related article by Choe et al., p. 1250. This article is highlighted in the In This Issue feature, p. 1027.

• 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
• Journal: Cancer discovery (Cancer Discov) Vol. 13 Issue 5 Pg. 1230-1249 (05 04 2023) ISSN: 2159-8290 [Electronic] United States
• PMID: 37067911 (Publication Type: Editorial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Comment)
• Copyright: ©2023 American Association for Cancer Research.

Chemical References

• Tumor Suppressor Protein p53
• Peroxisome Proliferator-Activated Receptors

Topics

• Animals
• Mice
• Li-Fraumeni Syndrome (genetics, metabolism)
• Tumor Suppressor Protein p53 (metabolism)
• Transcriptional Activation
• Peroxisome Proliferator-Activated Receptors (genetics, metabolism)
• Cell Death