Elimination of cell-cycle regulators during caspase-3-dependent apoptosis caused by an immunosuppressant, FTY720.
The immunosuppressant, FTY720 causes apoptosis of lymphocytes, reduces numbers of lymphocytes in peripheral blood, and prevents infiltration of lymphocytes into allografts, which may be one of the mechanisms involved in its effects. Here we compared caspase activation and expression of cell-cycle regulators during apoptosis caused by FTY720, and Fas-stimulation in a mouse lymphoma transfected with human Fas antigen. FTY720 activated caspases-3, -8, and -9 as rapidly as did Fas-mediated apoptosis. The activation was blocked by a peptide inhibitor for caspase-3, DEVD-CHO. Fas-induced activation of caspases-8 and -9 was unaffected by the inhibitor. FTY720 eliminated proliferating cell nuclear antigen, retinoblastoma family members, differentiation regulated transcription factor polypetide-1, and cyclin H. These cell-cycle regulators were not eliminated when the peptide inhibitor was used. Dysfunction of cell-cycle regulators may play a critical role in the signal transduction pathway for activation of FTY720-mediated apoptosis.
National Institute of Bioscience and Human Technology, 1-1 Higashi, Tsukuba 305-8566, Japan.
Yun-Sik
YS
Lee
Hiroo
H
Nakajima
Mie
M
Tsuruga
Junji
J
Magae
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011409:Propylene Glycols / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives; D013601:T-Lymphocytes / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D014162:Transfection; D019014:fas Receptor / Q000378:metabolism
D061945:Caspase Inhibitors; D018797:Cell Cycle Proteins; D007166:Immunosuppressive Agents; D007527:Isoenzymes; D009842:Oligopeptides; D018809:Proliferating Cell Nuclear Antigen; D011409:Propylene Glycols; D016160:Retinoblastoma Protein; D014157:Transcription Factors; C108637:aspartyl-glutamyl-valyl-aspartal; D019014:fas Receptor; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine