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.