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  • Original Paper
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Cdc25B activity is regulated by 14-3-3

Oncogene volume 20, pages 4393–4401 (2001)Cite this article

Abstract

In the G2 phase cell cycle checkpoint arrest, the cdc25-dependent activation of cyclin B/cdc2, a critical step in regulating entry into mitosis, is blocked. Studies in yeast have demonstrated that the inhibition of cdc25 function involves 14-3-3 binding to cdc25. In humans, two cdc25 isoforms have roles in G2/M progression, cdc25B and cdc25C, both bind 14-3-3. Abrogating 14-3-3 binding to cdc25C attenuates the G2 checkpoint arrest, but the contribution of 14-3-3 binding to the regulation of cdc25B function is unknown. Here we demonstrate that high level over-expression of cdc25B in G2 checkpoint arrested cells can activate cyclin B/cdc2 and overcome the checkpoint arrest. Mutation of the major 14-3-3 binding site, S323, or removal of the N-terminal regulatory domain are strong activating mutations, increasing the efficiency with which the mutant forms of cdc25B not only overcome the arrest, but also initiate aberrant mitosis. We also demonstrate that 14-3-3 binding to the S323 site on cdc25B blocks access of the substrate cyclin/cdks to the catalytic site of the enzyme, thereby directly inhibiting the activity of cdc25B. This provides direct mechanistic evidence that 14-3-3 binding to cdc25B can regulate its activity, thereby controlling progression into mitosis.

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Acknowledgements

The authors thank Dr Michael Yaffe for the 14-3-3 constructs, Dr Norbert Kienzle for the pRcCMV GFP vector, Joanne Sinnamon for technical assistance, and Professor John Hancock and Dr Matthew O'Connell for critical reading of the manuscript. This work was support by the National Health and Medical Research Council of Australia. B Gabrielli is an Australian Research Fellow.

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  1. Alistair Forrest

    Present address: Institute of Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia

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  1. Department of Pathology, Joint Oncology Program, University of Queensland School of Medicine, Herston Road, Brisbane, 4006, Queensland, Australia

    Alistair Forrest & Brian Gabrielli

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Forrest, A., Gabrielli, B. Cdc25B activity is regulated by 14-3-3. Oncogene 20, 4393–4401 (2001). https://doi.org/10.1038/sj.onc.1204574

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