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Rammelkamp Center for Education and Research, Department of Pharmacology, Ireland Cancer Center, Case Western Reserve University, Cleveland, Ohio 44109 [S. H., A. B.]; and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 [C. M. C.]
Taxoids and other microtubule-damaging drugs are known to induce Bcl2 phosphorylation at the G2-M phase of the cell cycle, with concomitant apoptosis in malignant cells derived from a variety of human malignancies, including leukemia, lymphoma, and breast and prostate cancer. We have investigated the ability of another antineoplastic drug, dolastatin 10, in inducing Bcl2 phosphorylation and apoptosis. We also investigated the effects of a phosphatase inhibitor okadaic acid in the regulation of Bcl2 phosphorylation, cell cycle arrest, and programmed cell death. Moreover, site-directed mutagenesis studies were performed to determine the specific serine residue(s) responsible for drug-induced Bcl2 phosphorylation. Our results indicate that these antimicrotubule agents or okadaic acid can induce posttranslational modification (phosphorylation) of Bcl2 protein at multiple serine residues. Interestingly, mutation of a serine residue at position 70 to alanine can significantly decrease drug-induced posttranslational modification (phosphorylation) of Bcl2 protein. Apparently, Ser70 seems to be a critical site for drug-induced posttranslational modification (phosphorylation) of the Bcl2 protein.
1 This work was supported by American Cancer Society Grant RPG-97-032-01-DHP and National Cancer Institute Grant CA 39860.
2 To whom requests for reprints should be addressed, at Room 657, 2500 MetroHealth Drive, Cleveland, OH 44109-1998. Phone: (216) 778-1167; Fax: (216) 778-2770; E-mail: shaldar@research.mhmc.org.
Received 1/28/98. Accepted 3/13/98.
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