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Mol Cell Biol, June 1998, p. 3509-3517, Vol. 18, No. 6
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

Rakesh K. Srivastava,1,* Aparna R. Srivastava,2 Stanley J. Korsmeyer,3 Maria Nesterova,4 Yoon S. Cho-Chung,4 and Dan L. Longo1

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.

* 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.

Mol Cell Biol, June 1998, p. 3509-3517, Vol. 18, No. 6
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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