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Mol Cell Biol, June 1998, p. 3509-3517, Vol. 18, No. 6
Laboratory of Immunology, National Institute
on Aging, National Institutes of Health, Baltimore, Maryland
21224-68231;
Greater Baltimore Medical
Center, Baltimore, Maryland 212042;
Washington University School of Medicine, St. Louis, Missouri
631103; and
National Cancer
Institute, National Institutes of Health, Bethesda, Maryland
208924
Received 19 September 1997/Returned for modification 6 January
1998/Accepted 2 March 1998
The Bcl2 family of proteins plays a significant role in regulation
of apoptosis. In this study, the microtubule-damaging drugs paclitaxel, vincristine, and vinblastine induced Bcl2
hyperphosphorylation and apoptosis in MCF-7 and
MDA-MB-231 cells and reduced Bcl2-Bax dimerization. Paclitaxel or
vincristine induced increased expression of Bax, while overexpression
of Bcl2 in these cell lines counteracted the effects of low doses of
these drugs. In addition, paclitaxel- and vincristine-induced
activation of cyclic AMP (cAMP)-dependent protein kinase
(protein kinase A [PKA]) induced Bcl2
hyperphosphorylation and apoptosis, which were
blocked by the PKA inhibitor Rp diastereomers of cAMP (Rp-cAMP). This
finding suggests that activation of PKA due to microtubule damage is
an important event in Bcl2 hyperphosphorylation and induction of apoptosis. These microtubule-damaging drugs
caused growth arrest in G2-M phase of the cell cycle and
had no effect on p53 induction, suggesting that
hyperphosphorylation mediated inactivation of
Bcl2 and apoptosis without the involvement of p53. By
comparison, the DNA-damaging drugs methotrexate and doxorubicin had no
effect on Bcl2 hyperphosphorylation but induced p53
expression. Interestingly, paclitaxel or vincristine induced activation
of caspase 3 and cleavage of poly(ADP-ribose) polymerase downstream of
Bcl2 hyperphosphorylation. These data suggest that
there may be a signaling cascade induced by agents that disrupt or
damage the cytoskeleton that is distinct from (i.e., p53 independent), but perhaps related to (i.e., involves kinase activation and leads to
apoptosis), the cellular response to DNA damage.
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Involvement of Microtubules in the Regulation of Bcl2
Phosphorylation and Apoptosis through Cyclic AMP-Dependent
Protein Kinase
*
Corresponding author. Mailing address: Laboratory of
Immunology, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Dr., Box 28, Baltimore, MD 21224-6825. Phone: (410)
558-8480. Fax: (410) 558-8284. E-mail:
rakeshs{at}vax.grc.nia.nih.gov.
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