Calyculin A, a potent inhibitor of phosphatases-1 and -2A, prevents apoptosis.
Exposure of the Burkitt's lymphoma cell line BM13674 cells to gamma-radiation or heat results in extensive DNA fragmentation and morphological changes characteristic of apoptosis. When cells were gamma-irradiated in the presence of calyculin A, a potent inhibitor of the catalytic subunit of phosphatases 1 and 2A, apoptosis was prevented. This was shown to be concentration dependent with maximal inhibition occurring at 20nM. Both DNA fragmentation and the morphological features characteristic of apoptosis were prevented by incubation with calyculin A. The concentration required to inhibit apoptosis (20 nM) was considerably less than that reported previously for okadaic acid (500 nM), also an inhibitor of phosphatase activity as well as apoptosis. In addition, while okadaic acid caused a marked condensation of nuclear material in both control and irradiated cells, while preventing apoptosis, no such changes in chromatin were evident in the presence of calyculin A. It is clear from these data and other results with protein synthesis inhibitors that the complete machinery for apoptosis, induced under certain conditions, preexists in the cell, and phosphatase activity plays a key role in this process.
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Queensland Cancer Fund Research Unit, Queensland Institute of Medical Research, Bancroft Centre, Australia.
Lavin
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MF
D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D002051:Burkitt Lymphoma; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects / Q000302:isolation & purification / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D005720:Gamma Rays; D006801:Humans; D008387:Marine Toxins; D010080:Oxazoles / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D008387:Marine Toxins; D010080:Oxazoles; C059041:calyculin A; D010749:Phosphoprotein Phosphatases