CYTOKINE SUPPRESSION OF PROTEASE ACTIVATION IN WILD-TYPE P53-DEPENDENT AND P53-INDEPENDENT APOPTOSIS

M1 myeloid leukemic cells overexpressing wild-type p53 undergo apoptos is, This apoptosis can be sup pressed by some cytokines, protease inhi bitors, and antioxidants. We now show that induction of apoptosis by o verexpressing wild-type p53 is associated with activation of interleuk in-1 beta-converting enzyme (ICE)-like proteases, resulting in cleavag e of poly(ADP-ribose) polymerase and the proenzyme of the ICE-like pro tease Nedd-2, Activation of these proteases and apoptosis were suppres sed by the cytokine interleukin 6 or by a combination of the cytokine interferon gamma and the antioxidant butylated hydroxyanisole, and act ivation of poly(ADP-ribose) polymerase and apoptosis were suppressed b y some protease inhibitors, In a clone of M1 cells that did not expres s p53, vincristine or doxorubicin induced protease activation and apop tosis that were not suppressed by protease inhibitors, but were suppre ssed by interleukin 6, In another myeloid leukemia (7-M12) doxorubicin also induced protease activation and apoptosis that were not suppress ed by protease inhibitors, but were suppressed by granulocyte-macropha ge colony-stimulating factor. The results indicate that (i) overexpres sion of wild-type p53 by itself or treatment with cytotoxic compounds in wild-type p53-expressing or p53-nonexpressing myeloid leukemic cell s is associated with activation of ICE-like proteases; (ii) cytokines exert apoptosis-suppressing functions upstream of protease activation; (iii) the cytotoxic compounds induce additional pathways in apoptosis ; and (iv) cytokines can also suppress these other components of the a poptotic machinery.