Cell cycle checkpoint function in bladder cancer

SC Doherty, Stephanie McKeown, Valerie McKelvey-Martin, Stephen Downes, A Atala, JJ Yoo, DA Simpson, WK Kaufmann

    Research output: Contribution to journalArticle

    54 Citations (Scopus)

    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 G(1) 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) (G(1) and G(2) checkpoints), the mitotic inhibitor colcemid (polyploidy checkpoint), or the topoisomerase 11 catalytic inhibitor ICRF-193 (decatenation G(2) checkpoint). Four of the five TCC lines expressed mutant p53. Results: HUCs had an effective G(1) checkpoint response to ionizing radiation, with 68% of cells inhibited from moving from G(1) into S phase. By contrast, G(1) 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 G(2) checkpoint responses. All TCC lines had a relatively effective G(1) 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 G(2) checkpoint response. Conclusion: Bladder TCC lines have defective cell cycle checkpoint functions, suggesting that the p53-independent decatenation G(2) checkpoint may cooperate with the p53-dependent G(1) checkpoints to preserve chromosomal stability and suppress bladder carcinogenesis.
    LanguageEnglish
    Pages1859-1868
    JournalJNCI: Journal of the National Cancer Institute
    Volume95
    Issue number24
    DOIs
    Publication statusPublished - Dec 2003

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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
    Chromosomal Instability
    S Phase
    Fluorescence Microscopy
    Chromosome Aberrations
    Cell Division
    Flow Cytometry
    Carcinogenesis
    Fibroblasts
    Genome

    Cite this

    Doherty, SC., McKeown, S., McKelvey-Martin, V., Downes, S., Atala, A., Yoo, JJ., ... Kaufmann, WK. (2003). Cell cycle checkpoint function in bladder cancer. JNCI: Journal of the National Cancer Institute, 95(24), 1859-1868. https://doi.org/10.1093/jnci/djg120
    Doherty, SC ; McKeown, Stephanie ; McKelvey-Martin, Valerie ; Downes, Stephen ; Atala, A ; Yoo, JJ ; Simpson, DA ; Kaufmann, WK. / Cell cycle checkpoint function in bladder cancer. In: JNCI: Journal of the National Cancer Institute. 2003 ; Vol. 95, No. 24. pp. 1859-1868.
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    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 G(1) 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) (G(1) and G(2) checkpoints), the mitotic inhibitor colcemid (polyploidy checkpoint), or the topoisomerase 11 catalytic inhibitor ICRF-193 (decatenation G(2) checkpoint). Four of the five TCC lines expressed mutant p53. Results: HUCs had an effective G(1) checkpoint response to ionizing radiation, with 68{\%} of cells inhibited from moving from G(1) into S phase. By contrast, G(1) 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 G(2) checkpoint responses. All TCC lines had a relatively effective G(1) 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 G(2) checkpoint response. Conclusion: Bladder TCC lines have defective cell cycle checkpoint functions, suggesting that the p53-independent decatenation G(2) checkpoint may cooperate with the p53-dependent G(1) checkpoints to preserve chromosomal stability and suppress bladder carcinogenesis.",
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    Doherty, SC, McKeown, S, McKelvey-Martin, V, Downes, S, Atala, A, Yoo, JJ, Simpson, DA & Kaufmann, WK 2003, 'Cell cycle checkpoint function in bladder cancer', JNCI: Journal of the National Cancer Institute, vol. 95, no. 24, pp. 1859-1868. https://doi.org/10.1093/jnci/djg120

    Cell cycle checkpoint function in bladder cancer. / Doherty, SC; McKeown, Stephanie; McKelvey-Martin, Valerie; Downes, Stephen; Atala, A; Yoo, JJ; Simpson, DA; Kaufmann, WK.

    In: JNCI: Journal of the National Cancer Institute, Vol. 95, No. 24, 12.2003, p. 1859-1868.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Cell cycle checkpoint function in bladder cancer

    AU - Doherty, SC

    AU - McKeown, Stephanie

    AU - McKelvey-Martin, Valerie

    AU - Downes, Stephen

    AU - Atala, A

    AU - Yoo, JJ

    AU - Simpson, DA

    AU - Kaufmann, WK

    PY - 2003/12

    Y1 - 2003/12

    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 G(1) 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) (G(1) and G(2) checkpoints), the mitotic inhibitor colcemid (polyploidy checkpoint), or the topoisomerase 11 catalytic inhibitor ICRF-193 (decatenation G(2) checkpoint). Four of the five TCC lines expressed mutant p53. Results: HUCs had an effective G(1) checkpoint response to ionizing radiation, with 68% of cells inhibited from moving from G(1) into S phase. By contrast, G(1) 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 G(2) checkpoint responses. All TCC lines had a relatively effective G(1) 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 G(2) checkpoint response. Conclusion: Bladder TCC lines have defective cell cycle checkpoint functions, suggesting that the p53-independent decatenation G(2) checkpoint may cooperate with the p53-dependent G(1) 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 G(1) 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) (G(1) and G(2) checkpoints), the mitotic inhibitor colcemid (polyploidy checkpoint), or the topoisomerase 11 catalytic inhibitor ICRF-193 (decatenation G(2) checkpoint). Four of the five TCC lines expressed mutant p53. Results: HUCs had an effective G(1) checkpoint response to ionizing radiation, with 68% of cells inhibited from moving from G(1) into S phase. By contrast, G(1) 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 G(2) checkpoint responses. All TCC lines had a relatively effective G(1) 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 G(2) checkpoint response. Conclusion: Bladder TCC lines have defective cell cycle checkpoint functions, suggesting that the p53-independent decatenation G(2) checkpoint may cooperate with the p53-dependent G(1) checkpoints to preserve chromosomal stability and suppress bladder carcinogenesis.

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    JO - JNCI: Journal of the National Cancer Institute

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    Doherty SC, McKeown S, McKelvey-Martin V, Downes S, Atala A, Yoo JJ et al. Cell cycle checkpoint function in bladder cancer. JNCI: Journal of the National Cancer Institute. 2003 Dec;95(24):1859-1868. https://doi.org/10.1093/jnci/djg120