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Generation of an indestructible cyclin B1 by caspase-6-dependent cleavage during mitotic catastrophe

Oncogene volume 28, pages 170–183 (2009)Cite this article

Abstract

Overriding the G2 DNA damage checkpoint permits precocious entry into mitosis that ultimately leads to mitotic catastrophe. Mitotic catastrophe is manifested by an unscheduled activation of CDK1, caspase activation and apoptotic cell death. We found that although cyclin B1 was required for mitotic catastrophe, it was cleaved into a ∼35 kDa protein by a caspase-dependent mechanism during the process. Cyclin B1 cleavage occurred after Asp123 in the motif ILVD123↓, and mutation of this motif attenuated the cleavage. Cleavage was abolished by a pan-caspase inhibitor as well as by specific inhibitors for the effector caspase-6 and the initiator caspase-8. Cleavage created a truncated cyclin B1 lacking part of the NH2-terminal regulatory domain that included the destruction box sequence. Although cleavage of cyclin B1 itself was not absolutely required for mitotic catastrophe, expression of the truncated product enhanced cell death. In support of this, ectopic expression of this truncated cyclin B1 was not only sufficient to induce mitotic block and apoptosis but also enhanced mitotic catastrophe induced by ionizing radiation and caffeine. These data underscore a possible linkage between mitotic and apoptotic functions by caspase-dependent processing of mitotic activators.

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Acknowledgements

Many thanks are due to members of the Poon Lab for constructive criticism on the manuscript. We thank Julian Gannon, Tim Hunt and Katsumi Yamashita for generous gifts of reagents. We also thank Talha Arooz and Wai Yi Siu for technical assistance and Jeremy PK Chow for the original observation of cyclin B1 cleavage. This work was supported in part by the Hong Kong Research Grants Council Grants 66207 and HKUST6439/06M to RYCP.

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  1. Y W Chan

    Present address: 2Current address: Department of Cell Biology, Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany,

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  1. Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong

    Y W Chan, Y Chen & R Y C Poon

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Correspondence to R Y C Poon.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Chan, Y., Chen, Y. & Poon, R. Generation of an indestructible cyclin B1 by caspase-6-dependent cleavage during mitotic catastrophe. Oncogene 28, 170–183 (2009). https://doi.org/10.1038/onc.2008.369

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