title: Exit from arsenite-induced mitotic arrest is p53 dependent.
abstract: BACKGROUND
  Arsenic is both a human carcinogen and a chemotherapeutic agent, but the mechanism of neither arsenic-induced carcinogenesis nor tumor selective cytotoxicity is clear. Using a model cell line in which p53 expression is regulated exogenously in a tetracycline-off system (TR9-7 cells) , our laboratory has shown that arsenite disrupts mitosis and that p53-deficient cells [p53(-)], in contrast to p53-expressing cells [p53(+)], display greater sensitivity to arsenite-induced mitotic arrest and apoptosis.
  
  
  OBJECTIVE
  Our goal was to examine the role p53 plays in protecting cells from arsenite-induced mitotic arrest.
  
  
  METHODS
  p53(+) and p53(-) cells were synchronized in G2 phase using Hoechst 33342 and released from synchrony in the presence or absence of 5 microM sodium arsenite.
  
  
  RESULTS
  Mitotic index analysis demonstrated that arsenite treatment delayed exit from G2 in p53(+) and p53(-) cells. Arsenite-treated p53(+) cells exited mitosis normally, whereas p53(-) cells exited mitosis with delayed kinetics. Microarray analysis performed on mRNAs of cells exposed to arsenite for 0 and 3 hr after release from G2 phase synchrony showed that arsenite induced inhibitor of DNA binding-1 (ID1) differentially in p53(+) and p53(-) cells. Immunoblotting confirmed that ID1 induction was more extensive and sustained in p53(+) cells.
  
  
  CONCLUSIONS
  p53 promotes mitotic exit and leads to more extensive ID1 induction by arsenite. ID1 is a dominant negative inhibitor of transcription that represses cell cycle regulatory genes and is elevated in many tumors. ID1 may play a role in the survival of arsenite-treated p53(+) cells and contribute to arsenic carcinogenicity.
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Samuel C
authors.initials: SC
authors.lastname: McNeely
authors.forename: Xiaogiang
authors.initials: X
authors.lastname: Xu
authors.forename: B Frazier
authors.initials: BF
authors.lastname: Taylor
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Zacharias
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McCabe
authors.forename: J Christopher
authors.initials: JC
authors.lastname: States
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D018053:Arsenites / Q000633:toxicity*; D001562:Benzimidazoles / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D016195:G2 Phase / Q000187:drug effects / Q000502:physiology; D016158:Genes, p53 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism; D007700:Kinetics; D046228:Microarray Analysis; D008938:Mitosis / Q000187:drug effects* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D017670:Sodium Compounds / Q000633:toxicity; D013997:Time Factors
chemical_list: D018053:Arsenites; D001562:Benzimidazoles; D051798:Inhibitor of Differentiation Protein 1; D012333:RNA, Messenger; D017670:Sodium Compounds; C017947:sodium arsenite; C015001:arsenite; C017807:bisbenzimide ethoxide trihydrochloride