title: Cytoplasmic sequestration of wild-type p53 protein impairs the G1 checkpoint after DNA damage.
abstract: Wild-type p53 protein is abnormally sequestered in the cytoplasm of a subset of primary human tumors including neuroblastomas (NB) (U. M. Moll, M. LaQuaglia, J. Benard, and G. Riou, Proc. Natl. Acad. Sci. USA 92:4407-4411, 1995; U. M. Moll, G. Riou, and A. J. Levine, Proc. Natl. Acad. Sci.USA 89:7262-7266, 1992). This may represent a nonmutational mechanism for abrogating p53 tumor suppressor function. To test this hypothesis, we established the first available in vitro model that accurately reflects the wild-type p53 sequestration found in NB tumors. We characterized a series of human NB cell lines that overexpress wild-type p53 and show that p53 is preferentially localized to discrete cytoplasmic structures, with no detectable nuclear p53. These cell lines, when challenged with a variety of DNA strand-breaking agents, all exhibit impaired p53-mediated G1 arrest. Induction analysis of p53 and p53-responsive genes show that this impairment is due to suppression of nuclear p53 accumulation. Thus, this naturally occurring translocation defect compromises the suppressor function of p53 and likely plays a role in the tumorigenesis of these tumors previously thought to be unaffected by p53 alterations.
authors.affiliation: Department of Pathology, State Univeristy of New York at Stony Brook, New York 11792-8691, USA.
authors.forename: U M
authors.initials: UM
authors.lastname: Moll
authors.forename: A G
authors.initials: AG
authors.lastname: Ostermeyer
authors.forename: R
authors.initials: R
authors.lastname: Haladay
authors.forename: B
authors.initials: B
authors.lastname: Winkfield
authors.forename: M
authors.initials: M
authors.lastname: Frazier
authors.forename: G
authors.initials: G
authors.lastname: Zambetti
mesh_terms: D003593:Cytoplasm / Q000378:metabolism; D004249:DNA Damage; D016193:G1 Phase; D006801:Humans; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53