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14-3-3σ is required to prevent mitotic catastrophe after DNA damage

Author

Listed:
  • Timothy A. Chan

    (The Johns Hopkins Oncology Center, Program in Human Genetics, and The Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine)

  • Heiko Hermeking

    (The Johns Hopkins Oncology Center, Program in Human Genetics, and The Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine)

  • Christoph Lengauer

    (The Johns Hopkins Oncology Center, Program in Human Genetics, and The Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine)

  • Kenneth W. Kinzler

    (The Johns Hopkins Oncology Center, Program in Human Genetics, and The Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine)

  • Bert Vogelstein

    (The Johns Hopkins Oncology Center, Program in Human Genetics, and The Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine)

Abstract

14-3-3σ is a member of a family of proteins that regulate cellular activity by binding and sequestering phosphorylated proteins. It has been suggested that 14-3-3σ promotes pre-mitotic cell-cycle arrest following DNA damage, and that its expression can be controlled by the p53 tumour suppressor gene1. Here we describe an improved approach to the generation of human somatic-cell knockouts, which we have used to generate human colorectal cancer cells in which both 14-3-3σ alleles are inactivated. After DNA damage, these cells initially arrested in the G2 phase of the cell cycle, but, unlike cells containing 14-3-3σ, the 14-3-3σ-/- cells were unable to maintain cell-cycle arrest. The 14-3-3σ-/- cells died (‘mitotic catastrophe’) as they entered mitosis. This process was associated with a failure of the 14-3-3σ-deficient cells to sequester the proteins (cyclin B1 and cdc2) that initiate mitosis and prevent them from entering the nucleus. These results may indicate a mechanism for maintaining the G2 checkpoint and preventing mitotic death.

Suggested Citation

  • Timothy A. Chan & Heiko Hermeking & Christoph Lengauer & Kenneth W. Kinzler & Bert Vogelstein, 1999. "14-3-3σ is required to prevent mitotic catastrophe after DNA damage," Nature, Nature, vol. 401(6753), pages 616-620, October.
    • Handle: RePEc:nat:nature:v:401:y:1999:i:6753:d:10.1038_44188
    DOI: 10.1038/44188
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