title: Role of p53 in the responses of human urothelial cells to genotoxic damage.
abstract: Loss of p53 function is a feature of many types of malignancy, including transitional-cell carcinoma (TCC), where it is associated with high-grade lesions and the development of muscle-invasive disease. Genotoxic agents used as part of the treatment strategy may contribute to tumour progression by inducing further non-lethal DNA damage in surviving cells. To determine the role of p53 in cellular responses to genotoxic agents, we used cultured normal human urothelial (NHU) cells and NHU cells with disabled p53 function. Mitomycin C and gamma-radiation caused normal cells to undergo an extended period of cell-cycle arrest, followed by complete recovery of proliferative potential. In contrast, cells with disabled p53 function, whether karyotypically normal (HU-E6 cells) or post-crisis with karyotypic abnormalities (HU-E6P cells), underwent extensive apoptosis. Overall survival was dose-dependent, and surviving HU-E6 cells from low-dose treatments showed clonal karyotypic abnormalities. These findings demonstrate that p53 status is a crucial factor in determining the ability of urothelial cells to survive DNA damage and suggest caution in the use of genotoxic treatments for low-grade tumours as our data imply that malignancies that have not yet lost p53 function will show the same "repair-and-recovery" response as normal cells.
authors: Jack Birch Unit of Molecular Carcinogenesis, Department of Biology, University of York, York Y010 5YW, United Kingdom.
authors: C P
authors: CP
authors: Diggle
authors: E
authors: E
authors: Pitt
authors: P
authors: P
authors: Harnden
authors: L K
authors: LK
authors: Trejdosiewicz
authors: J
authors: J
authors: Southgate
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005720:Gamma Rays; D006801:Humans; D007621:Karyotyping; D016685:Mitomycin / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D019459:Urothelium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects
chemical_list: D000477:Alkylating Agents; D018797:Cell Cycle Proteins; D016159:Tumor Suppressor Protein p53; D016685:Mitomycin