Serine-70 is one of the critical sites for drug-induced Bcl2 phosphorylation in cancer cells.
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.
Haldar
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Department of Pharmacology, Ireland Cancer Center, Case Western Reserve University, Cleveland, Ohio 44109, USA. shaldar@research.mhmc.org
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D000409:Alanine / Q000502:physiology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D047630:Depsipeptides; D006801:Humans; D016297:Mutagenesis, Site-Directed; D015739:Nocodazole / Q000494:pharmacology; D019319:Okadaic Acid / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000502:physiology*; D012694:Serine / Q000502:physiology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D047630:Depsipeptides; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; D019319:Okadaic Acid; D012694:Serine; C064570:dolastatin 10; D000409:Alanine; D017239:Paclitaxel; D015739:Nocodazole