Li-Fraumeni Syndrome-Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death.

Autor:	Choe JH; Department of Biological Sciences, Columbia University, New York, New York., Kawase T; Department of Biological Sciences, Columbia University, New York, New York.; Astellas Pharma Inc., Tsukuba, Ibaraki, Japan., Xu A; Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas., Guzman A; Department of Biological Sciences, Columbia University, New York, New York., Obradovic AZ; Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, New York.; Department of Systems Biology, Columbia University, New York, New York., Low-Calle AM; Department of Biological Sciences, Columbia University, New York, New York., Alaghebandan B; Department of Biological Sciences, Columbia University, New York, New York., Raghavan A; Department of Biological Sciences, Columbia University, New York, New York., Long K; Department of Biological Sciences, Columbia University, New York, New York., Hwang PM; Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland., Schiffman JD; Department of Pediatrics, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.; Peel Therapeutics, Inc., Salt Lake City, Utah., Zhu Y; Department of Biological Sciences, St. John's University, New York, New York., Zhao R; Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas., Lee DF; Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas.; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, Texas.; Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, Texas.; Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas Health Science Center at Houston, Houston, Texas., Katz C; Department of Biological Sciences, Columbia University, New York, New York., Prives C; Department of Biological Sciences, Columbia University, New York, New York.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2023 May 04; Vol. 13 (5), pp. 1250-1273.
DOI:	10.1158/2159-8290.CD-22-0882
Abstrakt:	Cancer-relevant mutations in the oligomerization domain (OD) of the p53 tumor suppressor protein, unlike those in the DNA binding domain, have not been well elucidated. Here, we characterized the germline OD mutant p53(A347D), which occurs in cancer-prone Li-Fraumeni syndrome (LFS) patients. Unlike wild-type p53, mutant p53(A347D) cannot form tetramers and exists as a hyperstable dimeric protein. Further, p53(A347D) cannot bind or transactivate the majority of canonical p53 target genes. Isogenic cell lines harboring either p53(A347D) or no p53 yield comparable tumorigenic properties, yet p53(A347D) displays remarkable neomorphic activities. Cells bearing p53(A347D) possess a distinct transcriptional profile and undergo metabolic reprogramming. Further, p53(A347D) induces striking mitochondrial network aberration and associates with mitochondria to drive apoptotic cell death upon topoisomerase II inhibition in the absence of transcription. Thus, dimer-forming p53 demonstrates both loss-of-function (LOF) and gain-of-function (GOF) properties compared with the wild-type form of the protein. Significance: A mutant p53 (A347D), which can only form dimers, is associated with increased cancer susceptibility in LFS individuals. We found that this mutant wields a double-edged sword, driving tumorigenesis through LOF while gaining enhanced apoptogenic activity as a new GOF, thereby yielding a potential vulnerability to select therapeutic approaches. See related commentary by Stieg et al., p. 1046. See related article by Gencel-Augusto et al., p. 1230. This article is highlighted in the In This Issue feature, p. 1027. (©2023 American Association for Cancer Research.)
Databáze:	MEDLINE
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