Cell cycle checkpoint function in bladder cancer

Sharon C. Doherty, Stephanie R. McKeown, Valerie McKelvey-Martin, C. Stephen Downes, Anthony Atala, James J. Yoo, Dennis A. Simpson, William K. Kaufmann

Research output: Contribution to journalArticle

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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 G2 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)1859-1868
Number of pages10
JournalJournal of the National Cancer Institute
Volume95
Issue number24
StatePublished - Dec 17 2003
Externally publishedYes

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Transitional Cell Carcinoma
Cell Cycle Checkpoints
Urinary Bladder Neoplasms
Cell Line
DNA Damage
Ionizing Radiation
Urinary Bladder
Polyploidy
Demecolcine
M Phase Cell Cycle Checkpoints
Topoisomerase II Inhibitors
Chromosomal Instability
S Phase
Fluorescence Microscopy
Chromosome Aberrations
Cell Division
Flow Cytometry
Carcinogenesis
Fibroblasts
Genome

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Doherty, S. C., McKeown, S. R., McKelvey-Martin, V., Downes, C. S., Atala, A., Yoo, J. J., ... Kaufmann, W. K. (2003). Cell cycle checkpoint function in bladder cancer. Journal of the National Cancer Institute, 95(24), 1859-1868.

Cell cycle checkpoint function in bladder cancer. / Doherty, Sharon C.; McKeown, Stephanie R.; McKelvey-Martin, Valerie; Downes, C. Stephen; Atala, Anthony; Yoo, James J.; Simpson, Dennis A.; Kaufmann, William K.

In: Journal of the National Cancer Institute, Vol. 95, No. 24, 17.12.2003, p. 1859-1868.

Research output: Contribution to journalArticle

Doherty, SC, McKeown, SR, McKelvey-Martin, V, Downes, CS, Atala, A, Yoo, JJ, Simpson, DA & Kaufmann, WK 2003, 'Cell cycle checkpoint function in bladder cancer', Journal of the National Cancer Institute, vol. 95, no. 24, pp. 1859-1868.
Doherty SC, McKeown SR, McKelvey-Martin V, Downes CS, Atala A, Yoo JJ et al. Cell cycle checkpoint function in bladder cancer. Journal of the National Cancer Institute. 2003 Dec 17;95(24):1859-1868.
Doherty, Sharon C. ; McKeown, Stephanie R. ; McKelvey-Martin, Valerie ; Downes, C. Stephen ; Atala, Anthony ; Yoo, James J. ; Simpson, Dennis A. ; Kaufmann, William K. / Cell cycle checkpoint function in bladder cancer. In: Journal of the National Cancer Institute. 2003 ; Vol. 95, No. 24. pp. 1859-1868.
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AU - Doherty, Sharon C.

AU - McKeown, Stephanie R.

AU - McKelvey-Martin, Valerie

AU - Downes, C. Stephen

AU - Atala, Anthony

AU - Yoo, James J.

AU - Simpson, Dennis A.

AU - Kaufmann, William K.

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N2 - 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 G2 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. Conclusion: 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.

AB - 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 G2 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. Conclusion: 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.

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