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

Nature volume 401, pages 616–620 (1999)Cite this article

An Author Correction to this article was published on 22 August 2023

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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.

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Figure 1: Generation of human cells deficient in 14-3-3σ.
Figure 2: Mitotic catastrophe in 14-3-3σ-/- cells.
Figure 3: Cells deficient in 14-3-3σ are sensitive to DNA-damage.
Figure 4: -3-3σ-deficient cells cannot sequester cdc2 and cyclin B1 in the cytoplasm following DNA damage.
Figure 5: Model for G2/M checkpoint compartmentalization.

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Acknowledgements

We thank the members of the Vogelstein/Kinzler Laboratory for helpful discussions. We thank M. Yoshida for the gift of leptomycin B and D. Tomasallo for helpful advice. Under an agreement between CalBiochem and Johns Hopkins University, K.W.K. and B.V. are entitled to a share of the sales royalty for the p21 antibody received by the University from CalBiochem. The terms of these arrangements are managed by the University in accordance with its conflict of interest policies. This work was supported by the Clayton Fund, the Medical Scientist Training Program and the NIH.

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  1. The Johns Hopkins Oncology Center, Program in Human Genetics, and The Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, 424 N. Bond Street, Baltimore, 21231, Maryland, USA

    Timothy A. Chan, Heiko Hermeking, Christoph Lengauer, Kenneth W. Kinzler & Bert Vogelstein

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  1. Timothy A. Chan
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Correspondence to Bert Vogelstein.

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Chan, T., Hermeking, H., Lengauer, C. et al. 14-3-3σ is required to prevent mitotic catastrophe after DNA damage. Nature 401, 616–620 (1999). https://doi.org/10.1038/44188

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