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A gain of function p53 mutant promotes both genomic instability and cell survival in a novel p53-null mammary epithelial cell model

KRISTEN L. MURPHY^*,, ANDREW P. DENNIS and JEFFREY M. ROSEN¹

^* Program in Cell and Molecular Biology and
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA

¹Correspondence: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. E-mail: jrosen{at}bcm.tmc.edu

Approximately 40% of human breast cancers contain alterations in the tumor suppressor p53. The p53 172R-H gain-of-function mutant (equivalent to the common 175R-H human breast cancer mutant) has been shown to promote aneuploidy and tumorigenesis in the mammary gland in transgenic mice and may affect genomic stability in part by causing centrosome abnormalities. The precise mechanism of action of these gain-of-function mutants is not well understood, and has been studied primarily in fibroblast cell lines. A novel p53-null mouse mammary epithelial cell line developed from p53-null mice has been used in adenovirus-mediated transient transfection experiments to study the properties of this p53 mutant. Marked centrosome amplification and an increased frequency of aberrant mitoses were observed within 72 h of introduction of p53 172R-H. However, few cells with aberrant centrosome numbers were observed in cells stably expressing the p53 172R-H mutant. Furthermore, stable expression of this p53 mutant reduced both basal and DNA damage-induced apoptosis. This result may be mediated in part through abrogation of p73 function. The p53 172R-H mutant, therefore, appears to influence tumorigenesis at the molecular level in two distinct ways: promoting the development of aneuploidy in cells while also altering their apoptotic response after DNA damage.—Murphy, K. L., Dennis, A. P., Rosen, J. M. A gain of function p53 mutant promotes both genomic instability and cell survival in a novel p53-null mammary epithelial cell model.

Key Words: mutant p53 • apoptosis • aneuploidy • centrosome abnormalities

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