Mitotic phosphorylation of Bcl-2 during normal cell cycle progression and Taxol-induced growth arrest.

Scatena CD, Stewart ZA, Mays D, Tang LJ, Keefer CJ, Leach SD, Pietenpol JA
J Biol Chem. 1998 273 (46): 30777-84

PMID: 9804855 · DOI:10.1074/jbc.273.46.30777

There is increasing evidence that prolonged mitotic arrest initiates apoptosis; however, little is known about the signaling pathways involved. Several studies have associated deregulated Cdc2 activity with apoptosis. Herein, we report that the anti-apoptotic protein, Bcl-2, undergoes cell cycle-dependent phosphorylation during mitosis when there is elevated Cdc2 activity. We found that paclitaxel (Taxol(R)) treatment of epithelial tumor cells induced a prolonged mitotic arrest, elevated levels of mitotic kinase activity, hyperphosphorylation of Bcl-2, and subsequent cell death. The Taxol-induced Bcl-2 phosphorylation was dose-dependent. Furthermore, phosphorylated Bcl-2 remained complexed with Bax in Taxol-treated cells undergoing apoptosis. Immunoprecipitation experiments revealed a Bcl-2-associated kinase capable of phosphorylating histone H1 in vitro. However, the kinase was likely not cyclin B1/Cdc2, since cyclin B1/Cdc2 was not detectable in Bcl-2 immunoprecipitates, nor was recombinant Bcl-2 phosphorylated in vitro by cyclin B1/Cdc2. The results of this study further define a link between mitotic kinase activation and the apoptotic machinery in the cell. However, the role, if any, of prolonged Bcl-2 phosphorylation in Taxol-mediated apoptosis awaits further definition of Bcl-2 mechanism of action. Taxol may increase cellular susceptibility to apoptosis by amplifying the normal downstream events associated with mitotic kinase activation.

MeSH Terms (14)

Antineoplastic Agents, Phytogenic Apoptosis CDC2 Protein Kinase Cell Death Cell Division Cyclin B Cyclin B1 G2 Phase Humans Mitosis Paclitaxel Phosphorylation Proto-Oncogene Proteins c-bcl-2 Tumor Cells, Cultured

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