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

Authors: Scatena, C D; Stewart, Z A; Mays, D; Tang, L J; Keefer, C J; Leach, S D; Pietenpol, J A

Published In J Biol Chem, (1998 Nov 13)

Abstract: 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.

PubMed ID: 9804855 Exiting the NIEHS site

MeSH Terms: Antineoplastic Agents, Phytogenic/pharmacology*; Apoptosis; CDC2 Protein Kinase/metabolism; Cell Death; Cell Division/drug effects; Cyclin B/metabolism; Cyclin B1; G2 Phase; Humans; Mitosis*; Paclitaxel/pharmacology*; Phosphorylation; Proto-Oncogene Proteins c-bcl-2/metabolism*; Tumor Cells, Cultured

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