Antiapoptosis potential of bcl-2 oncogene by dephosphorylation.
The antiapoptosis potential of bcl-2 has now been well established. But the biochemical mechanism of bcl-2 action is still poorly understood. Using the phosphatase inhibitor okadaic acid (OA) or chemotherapeutic agents such as Taxol and 5'-fluorouracil, we found that bcl-2 can be phosphorylated. Since OA or Taxol treatment leads to apoptosis, it seems 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 hyperphosphorylation of bcl-2. Interestingly, the lymphoblastoid cell lines that did not phosphorylate bcl-2 following OA exposure did not undergo apoptosis. Moreover, pro-B cells isolated from patients with acute lymphoblastic 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 hyperphosphorylation of bcl-2. Phosphoamino acid analysis reveals that bcl-2 is phosphorylated at a serine residue. In summary, our investigation indicates that the phosphorylation pathway involving bcl-2 can be the determinant of cell death in lymphocytes.
Haldar
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Jefferson Cancer Institute, Jefferson Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Jena
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Croce
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D017209:Apoptosis / Q000235:genetics*; D004988:Ethers, Cyclic / Q000494:pharmacology; D005456:Fluorescent Dyes; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000473:pathology; D019319:Okadaic Acid; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D019908:Proto-Oncogene Proteins c-raf; D011519:Proto-Oncogenes; D014407:Tumor Cells, Cultured
D004988:Ethers, Cyclic; D005456:Fluorescent Dyes; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019319:Okadaic Acid; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D017239:Paclitaxel; D005472:Fluorouracil