Abstract
Treatment of cells with microtubule inhibitors results in activation of the mitotic spindle assembly checkpoint, leading to mitotic arrest before anaphase. Upon prolonged treatment, however, cells can adapt and exit mitosis aberrantly, resulting in the occurrence of tetraploid cells in G1. Those cells subsequently arrest in postmitotic G1 due to the activation of a p53-dependent G1 checkpoint. Failure of the G1 checkpoint leads to endoreduplication and further polyploidization. Using HCT116 and isogenic p53-deficient or spindle checkpoint compromised derivatives, we show here that not only p53 but also a functional spindle assembly checkpoint is required for postmitotic G1 checkpoint function. During transient mitotic arrest, p53 stabilization and activation is triggered by a pathway independent of ATM/ATR, Chk1 and Chk2. We further show that a prolonged spindle checkpoint-mediated mitotic arrest is required for proper postmitotic G1 checkpoint function. In addition, we demonstrate that polyploid cells are inhibited to re-enter mitosis by an additional checkpoint acting in G2. Thus, during a normal cell cycle, polyploidization and subsequent aneuploidization is prevented by the function of the mitotic spindle checkpoint, a p53-dependent G1 checkpoint and an additional G2 checkpoint.
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Acknowledgements
We thank Dr Bert Vogelstein, Dr Loren Michel and Dr Robert Benezra for providing HCT116 and derivative cell lines. We are grateful to Dr Heike Krebber for suggestions and critically reading the manuscript, and we thank the Developmental Therapeutics Program of the National Cancer Institute for provinding UCN-01. This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB397), the Deutsche Krebshilfe and the PE Kempkes Stiftung.
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Vogel, C., Kienitz, A., Hofmann, I. et al. Crosstalk of the mitotic spindle assembly checkpoint with p53 to prevent polyploidy. Oncogene 23, 6845–6853 (2004). https://doi.org/10.1038/sj.onc.1207860
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DOI: https://doi.org/10.1038/sj.onc.1207860
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