Cd. Scatena et al., MITOTIC PHOSPHORYLATION OF BCL-2 DURING NORMAL-CELL CYCLE PROGRESSIONAND TAXOL-INDUCED GROWTH ARREST, The Journal of biological chemistry, 273(46), 1998, pp. 30777-30784
There is increasing evidence that prolonged mitotic arrest initiates a
poptosis; however, little is known about the signaling pathways involv
ed. Several studies have associated deregulated Cdc2 activity with apo
ptosis, Herein, we report that the anti-apoptotic protein, Bcl-2, unde
rgoes cell cycle-dependent phosphorylation during mitosis when there i
s elevated Cdc2 activity. We found that paclitaxel (Taxol(R)) treatmen
t of epithelial tumor cells induced a prolonged mitotic arrest, elevat
ed levels of mitotic kinase activity, hyperphosphorylation of Bcl-2, a
nd subsequent cell death. The Taxol-induced BcI-2 phosphorylation was
dose-dependent. Furthermore, phosphorylated Bcl-2 remained complexed w
ith Bar in Taxol-treated cells undergoing apoptosis, Immunoprecipitati
on experiments revealed a Bcl-2-associated kinase capable of phosphory
lating histone H1 in vitro. However, the kinase was likely not cyclin
B1/Cdc2, since cyclin B1/Cdc2 was not detectable in Bcl-2 immunoprecip
itates, 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, t
he role, if any, of prolonged Bcl-2 phosphorylation in Taxol-mediated
apoptosis awaits further definition of Bcl-2 mechanism of action. Taxo
l may increase cellular susceptibility to apoptosis by amplifying the
normal downstream events associated with mitotic kinase activation.