Role of cyclin B1/Cdc2 in mediating Bcl-XL phosphorylation and apoptotic cell death following nocodazole-induced mitotic arrest
Article first published online: 4 SEP 2012
© 2012 Wiley Periodicals, Inc.
Volume 53, Issue 2, pages 125–137, February 2014
How to Cite
Choi, H. J. and Zhu, B. T. (2014), Role of cyclin B1/Cdc2 in mediating Bcl-XL phosphorylation and apoptotic cell death following nocodazole-induced mitotic arrest. Mol. Carcinog., 53: 125–137. doi: 10.1002/mc.21956
- Issue published online: 22 JAN 2014
- Article first published online: 4 SEP 2012
- Manuscript Accepted: 1 AUG 2012
- Manuscript Revised: 18 JUL 2012
- Manuscript Received: 16 MAR 2012
- National Institutes of Health. Grant Number: CA097109
- mitotic arrest;
- cyclin B1;
Treatment of cancer cells with microtubule inhibitors causes mitotic arrest, which subsequently leads to cell death via activation of the intrinsic apoptotic pathway. Mitotically arrested cells typically display increased phosphorylation (i.e., inactivation) of two key anti-apoptotic proteins, Bcl-2 and Bcl-XL, but the mechanisms that regulate their phosphorylation as well as their role in apoptotic cell death following mitotic arrest are still poorly understood at present, which are the focus of this study. We recently showed that cyclin B1 and cell division cycle 2 (Cdc2) proteins are strongly up-regulated in human breast cancer cells following treatment with nocodazole (a prototypical microtubule inhibitor), and their up-regulation plays a critical role in the development of mitotic prometaphase arrest. In this study, we present evidence showing that the up-regulated cyclin B1/Cdc2 complex in nocodazole-treated human breast cancer cells is also responsible for the increased phosphorylation of Bcl-2 and Bcl-XL. However, only the increased phosphorylation of Bcl-XL, but not the phosphorylation of Bcl-2, contributes to subsequent activation of the intrinsic cell death pathway. In addition, evidence is presented to show that mitotic arrest deficient 2 (MAD2) is a key upstream mediator of the up-regulation of cyclin B1/Cdc2 as well as the subsequent increase in phosphorylationof Bcl-2 and Bcl-XL in nocodazole-treated cancer cells. Together, these results reveal that the up-regulated cyclin B1/Cdc2 complex not only mediates prometaphase arrest in nocodazole-treated cells, but also activates the subsequent intrinsic cell death pathway in these cells via increased phosphorylation of Bcl-XL. © 2012 Wiley Periodicals, Inc.