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 G(2)-M phase of the cell cycle, with concomitan t apoptosis in malignant cells derived from a variety of human maligna ncies, including leukemia, lymphoma, and breast and prostate cancer. W e have investigated the ability of another antineoplastic drug, dolast atin 10, in inducing Bcl2 phosphorylation and apoptosis. We also inves tigated the effects of a phosphatase inhibitor okadaic acid in the reg ulation of Bcl2 phosphorylation, cell cycle arrest, and programmed cel l 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 (pho sphorylation) of Bcl2 protein at multiple serine residues. Interesting ly, mutation of a serine residue at position 70 to alanine can signifi cantly decrease drug-induced posttranslational modification (phosphory lation) of Bcl2 protein. Apparently, Ser(70) seems to be a critical si te for drug-induced posttranslational modification (phosphorylation) o f the Bcl2 protein.