title: Separate pathways for p53 induction by ionizing radiation and N-(phosphonoacetyl)-L-aspartate.
abstract: The tumor suppressor gene product, p53, appears to be a significant participant in signaling pathways that mediate cellular responses to cytotoxic stresses. In particular, p53 appears to be a critical determinant of whether the cell lives or dies and how it progresses through the cell cycle after the cytotoxic exposure. Many of the molecular details for these signaling pathways remain to be elucidated, and whether all cytotoxic signals utilize the same pathway to increase p53 expression is not clear. Here, we demonstrate the existence of cell types in which the induction of p53 and associated G1 arrest by the antimetabolite, N-(phosphonoacetyl)-L-aspartate (PALA), is defective, whereas p53 induction and G1 arrest induced by ionizing radiation are intact. These observations demonstrate the existence of genetic defects that can alter p53 induction and associated cellular outcomes after some, but not all, cytotoxic insults and suggest distinct pathways of p53 induction by PALA and ionizing radiation.
authors.affiliation: Johns Hopkins Oncology Center, Baltimore, Maryland 21205, USA.
authors.forename: C Y
authors.initials: CY
authors.lastname: Chen
authors.forename: I
authors.initials: I
authors.lastname: Hall
authors.forename: T J
authors.initials: TJ
authors.lastname: Lansing
authors.forename: T M
authors.initials: TM
authors.lastname: Gilmer
authors.forename: T D
authors.initials: TD
authors.lastname: Tlsty
authors.forename: M B
authors.initials: MB
authors.lastname: Kastan
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D001483:Base Sequence; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D004249:DNA Damage; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D016158:Genes, p53 / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008969:Molecular Sequence Data; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: D000964:Antimetabolites, Antineoplastic; D016159:Tumor Suppressor Protein p53; D001224:Aspartic Acid; C013195:sparfosic acid; D010746:Phosphonoacetic Acid