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Deregulation of Cdk2 causes Bim-mediated apoptosis in p53-deficient tumors following actin damage

Oncogene volume 27, pages 4115–4121 (2008)Cite this article

Abstract

We previously reported that actin damage by treatment with an actin-depolymerizing agent including pectenotoxin-2 induces Bim-mediated apoptosis in p53-deficient human tumors. In this study, we investigated a molecular mechanism underlying Bim-mediated apoptosis of p53-deficient tumor cells following actin damage. We found that actin inhibitors increased the protein levels of p53 and p21 and thereby inactivated both Cdk2 and Cdc2 kinases. However, p53- or p21-knockout cells fail to induce p21 and hence kept both Cdk2 and Cdc2 kinases active even after treatment with actin inhibitor. The p53- or p21-knockout cells became multinucleate and polyploidy in association with induction of apoptosis. Expression of Bcl-xL resulted in accumulation of polyploid cells in association with inhibition of apoptosis. However, expression of a dominant negative mutant (Cdk2dn) and treatment with chemical inhibitors for Cdk2 suppressed not only accumulation of multinucleated cells, but also induction of Bim expression and apoptosis. Therefore, these results suggest that Bim-mediated apoptosis following actin damage due to deregulation of Cdk2 and the cell cycle by the absence of functional p53.

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Acknowledgements

pCMV-Cdk2D145N (Cdk2dn) was given from Dr van den Heuvel (MGH cancer center, MA, USA). This research was supported by Korea Science & Engineering Foundation through the NRL Program, the Aging-Tumorigenesis Research program, and the New Drug target discovery Program, and by Korean Ministry of Health and Welfare through the Cancer Control Program and the Molecular Aging Research Center.

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Authors and Affiliations

  1. Department of Microbiology, National Research Laboratory, Dankook University College of Medicine, Cheonan, Korea

    H D Chae, B M Kim, U J Yun & D Y Shin

  2. Cancer Research Institute, Seoul National University, Seoul, Korea

    H D Chae, B M Kim, U J Yun & D Y Shin

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  1. H D Chae
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Correspondence to D Y Shin.

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Chae, H., Kim, B., Yun, U. et al. Deregulation of Cdk2 causes Bim-mediated apoptosis in p53-deficient tumors following actin damage. Oncogene 27, 4115–4121 (2008). https://doi.org/10.1038/onc.2008.46

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