The apoptosis-inducing activity of the two protein phosphatase inhibitors, tautomycin and thyrsiferyl 23-acetate, is not due to the inhibition of protein phosphatases PP1 and PP2A (review).
Thyrsiferyl 23-acetate (TF-23A) has been shown to potently and specifically inhibit PP2A. TF-23A also induced a rapid cell death in various leukemic T- and B-cell lines. The TF-23A induced cell death with a typical apoptotic process. TF-23A and its several analogous compounds showed apoptosis-inducing activity. However, only TF-23A out of these compounds showed an inhibitory activity for PP2A. These results suggest that a portion of TF-23A involved in induction of apoptosis is different from that involved in the PP2A inhibition. Then, the effects of tautomycin and its derivatives on PP1 and PP2A and their apoptosis-inducing activity were examined. The C22-C26 moiety was essential for inhibition of protein phosphatase activity, whereas the C1-C18 moiety was essential for induction of apoptosis. Therefore, different moieties of tautomycin are involved in protein phosphatase inhibition and induction of apoptosis. From these results, it was concluded that the biological effects of phosphatase inhibitors are not necessarily induced by the inhibition of PP1 and PP2A but through other different molecular mechanisms which remain to be elucidated.
Kikuchi
K
K
Section of Biochemistry, Institute of Immunological Science, Hokkaido University, Sapporo 060-0815, Japan.
Shima
H
H
Mitsuhashi
S
S
Suzuki
M
M
Oikawa
H
H
D000818:Animals; D000935:Antifungal Agents / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011714:Pyrans / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013141:Spiro Compounds
D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D011714:Pyrans; D013141:Spiro Compounds; C053079:tautomycin; C091148:thyrsiferyl 23-acetate; D010749:Phosphoprotein Phosphatases