Acquisition of aneuploidy drives mutant p53-associated gain-of-function phenotypes.

Autor: Redman-Rivera LN; Department of Biochemistry, Vanderbilt University, Nashville, TN, USA., Shaver TM; Department of Biochemistry, Vanderbilt University, Nashville, TN, USA.; Inscripta, Inc, Boulder, CO, USA., Jin H; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA., Marshall CB; Department of Biochemistry, Vanderbilt University, Nashville, TN, USA.; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA., Schafer JM; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.; Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA., Sheng Q; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA., Hongo RA; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA., Beckermann KE; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA., Wheeler FC; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA., Lehmann BD; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA., Pietenpol JA; Department of Biochemistry, Vanderbilt University, Nashville, TN, USA. j.pietenpol@vumc.org.; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. j.pietenpol@vumc.org.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Aug 31; Vol. 12 (1), pp. 5184. Date of Electronic Publication: 2021 Aug 31.
DOI: 10.1038/s41467-021-25359-z
Abstrakt: p53 is mutated in over half of human cancers. In addition to losing wild-type (WT) tumor-suppressive function, mutant p53 proteins are proposed to acquire gain-of-function (GOF) activity, leading to novel oncogenic phenotypes. To study mutant p53 GOF mechanisms and phenotypes, we genetically engineered non-transformed and tumor-derived WT p53 cell line models to express endogenous missense mutant p53 (R175H and R273H) or to be deficient for p53 protein (null). Characterization of the models, which initially differed only by TP53 genotype, revealed that aneuploidy frequently occurred in mutant p53-expressing cells. GOF phenotypes occurred clonally in vitro and in vivo, were independent of p53 alteration and correlated with increased aneuploidy. Further, analysis of outcome data revealed that individuals with aneuploid-high tumors displayed unfavorable prognoses, regardless of the TP53 genotype. Our results indicate that genetic variation resulting from aneuploidy accounts for the diversity of previously reported mutant p53 GOF phenotypes.
(© 2021. The Author(s).)
Databáze: MEDLINE
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