title: Cell cycle checkpoint function in bladder cancer.
abstract: BACKGROUND
  Cell cycle checkpoints function to maintain genetic stability by providing additional time for repair of DNA damage and completion of events that are necessary for accurate cell division. Some checkpoints, such as the DNA damage G1 checkpoint, are dependent on p53, whereas other checkpoints, such as the decatenation G(2) checkpoint, are not. Because bladder transitional cell carcinomas (TCCs) often contain numerous chromosomal aberrations and appear to have highly unstable genomes, we analyzed cell cycle checkpoint functions in a panel of TCC lines.
  
  
  METHODS
  Cell cycle arrest was induced in normal human fibroblasts (NHF1-hTERT) and normal human uroepithelial cells (HUCs), and TCC lines and checkpoint functions were quantified using flow cytometry and fluorescence microscopy. The inducers and checkpoints were ionizing radiation (i.e., DNA damage) (G1 and G2 checkpoints), the mitotic inhibitor colcemid (polyploidy checkpoint), or the topoisomerase II catalytic inhibitor ICRF-193 (decatenation G2 checkpoint). Four of the five TCC lines expressed mutant p53.
  
  
  RESULTS
  HUCs had an effective G1 checkpoint response to ionizing radiation, with 68% of cells inhibited from moving from G1 into S phase. By contrast, G1 checkpoint function was severely attenuated (<15% inhibition) in three of the five TCC lines and moderately attenuated (<50% inhibition) in the other two lines. NHF1-hTERT had an effective polyploidy checkpoint response, but three of five TCC lines were defective in this checkpoint. HUCs had effective ionizing radiation and decatenation G2 checkpoint responses. All TCC lines had a relatively effective G2 checkpoint response to DNA damage, although the responses of two of the TCC lines were moderately attenuated relative to HUCs. All TCC lines had a severe defect in the decatenation G2 checkpoint response.
  
  
  CONCLUSIONS
  Bladder TCC lines have defective cell cycle checkpoint functions, suggesting that the p53-independent decatenation G2 checkpoint may cooperate with the p53-dependent G1 checkpoints to preserve chromosomal stability and suppress bladder carcinogenesis.
authors.affiliation: Cancer and Ageing Research Group, School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland.
authors.forename: Sharon C
authors.initials: SC
authors.lastname: Doherty
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: McKeown
authors.forename: Valerie
authors.initials: V
authors.lastname: McKelvey-Martin
authors.forename: C Stephen
authors.initials: CS
authors.lastname: Downes
authors.forename: Anthony
authors.initials: A
authors.lastname: Atala
authors.forename: James J
authors.initials: JJ
authors.lastname: Yoo
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Simpson
authors.forename: William K
authors.initials: WK
authors.lastname: Kaufmann
mesh_terms: D002295:Carcinoma, Transitional Cell / Q000235:genetics / Q000503:physiopathology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D016193:G1 Phase; D016195:G2 Phase; D016147:Genes, Tumor Suppressor; D006801:Humans; D011003:Ploidies; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000503:physiopathology*
chemical_list: D016159:Tumor Suppressor Protein p53