Rapamycin inhibits didemnin B-induced apoptosis in human HL-60 cells: evidence for the possible involvement of FK506-binding protein 25.
In the present paper we show that the immunosuppressant rapamycin inhibits the induction of apoptosis by didemnin B in human promyeloid HL-60 cells. The mechanism of this inhibition is investigated using FK506, which competes with rapamycin for binding to their common target FK506-binding protein (FKBP)12. The lack of competition for rapamycin-mediated inhibition of didemnin B-induced apoptosis by FK506 suggests that rapamycin inhibits apoptosis through some mechanism other than inhibition of p70 S6 kinase activation. The lack of inhibition of didemnin B-induced apoptosis by inhibitors of phosphatidylinositol 3-kinase and mitogen-activated protein (MAP) kinase kinase further supports the conclusion that rapamycin does not inhibit didemnin B-induced apoptosis through inhibition of the MAP kinase pathway. Furthermore, didemnin B-induced apoptosis is not inhibited by the inhibitors of cyclin-dependent kinase, roscovitine and olomoucine. This indicates that rapamycin does not act through inhibition of cyclin-dependent kinases. Together with the lack of competition for the effect of rapamycin by FK506, our data suggest the possible involvement of the FK506-binding protein, FKBP25, which is localized in the nucleus. This interpretation of our data gains support from the fact that didemnin B does not induce apoptosis in enucleated HL-60 cells, which supports the possible involvement of FKBP25 in the inhibition of apoptosis by rapamycin.
Johnson
K L
KL
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
Lawen
A
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D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D047630:Depsipeptides; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D020104:Immunophilins / Q000378:metabolism / Q000502:physiology; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D020123:Sirolimus / Q000378:metabolism / Q000494:pharmacology*; D016559:Tacrolimus / Q000378:metabolism / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins; D013997:Time Factors; D000077191:Wortmannin
D000730:Androstadienes; D047630:Depsipeptides; D007166:Immunosuppressive Agents; D010456:Peptides, Cyclic; C074856:FKBP3 protein, human; C030051:didemnins; D018844:Cyclin-Dependent Kinases; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins; D020123:Sirolimus; D016559:Tacrolimus; D000077191:Wortmannin