ANTIAPOPTOSIS POTENTIAL OF BCL-2 ONCOGENE BY DEPHOSPHORYLATION

The antiapoptosis potential of bcl-2 has now been well established. Bu t the biochemical mechanism of bcl-2 action is still poorly understood . Using the phosphatase inhibitor okadaic acid (OA) or chemotherapeuti c agents such as Taxol and 5'-fluorouracil, we found that bcl-2 can be phosphorylated. Since OA or Taxol treatment leads to apoptosis, it se ems that phosphorylation of bcl-2 leads to its inactivation. Exposure of several lymphoid cell lines expressing differential amounts of bcl- 2 protein to OA resulted in apoptosis of the cells and hyperphosphoryl ation of bcl-2. Interestingly, the lymphoblastoid cell lines that did not phosphorylate bcl-2 following OA exposure did not undergo apoptosi s. Moreover, pro-B cells isolated from patients with acute lymphoblast ic leukemias exhibited endogenous phosphorylated forms of bcl-2 and a large number of apoptotic cells, even without OA treatment. Treatment with the phosphatase inhibitor or with chemotherapeutic agents (Taxol, 5'-fluorouracil) led to severe apoptosis of these cells, along with h yperphosphorylation of bcl-2. Phosphoamino acid analysis reveals that bcl-2 is phosphorylated at a serine residue. In summary, our investiga tion indicates that the phosphorylation pathway involving bcl-2 can be the determinant of cell death in lymphocytes.