title: A gain of function p53 mutant promotes both genomic instability and cell survival in a novel p53-null mammary epithelial cell model.
abstract: 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.
authors.affiliation: Program in Cell and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Murphy
authors.forename: A P
authors.initials: AP
authors.lastname: Dennis
authors.forename: J M
authors.initials: JM
authors.lastname: Rosen
mesh_terms: D019943:Amino Acid Substitution; D000782:Aneuploidy; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics*; D018385:Centrosome / Q000378:metabolism; D002869:Chromosome Aberrations / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D012854:Sister Chromatid Exchange / Q000235:genetics; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53