DIFFERENT MECHANISMS FOR SUPPRESSION OF APOPTOSIS BY CYTOKINES AND CALCIUM MOBILIZING COMPOUNDS

Overexpression of wild-type p53 in M1 myeloid leukemia cells induces a poptotic cell death that was suppressed by the calcium ionophore A2318 7 and the calcium ATPase inhibitor thapsigargin (TG). This suppression of apoptosis by A23187 or TG was associated with suppression of caspa se activation but not with suppression of wild-type-p53-induced expres sion of WAF-1, mdm-2, or FAS. In contrast to suppression of apoptosis by the cytokines interleukin 6 (IL-6) and interferon gamma, a protease inhibitor, or an antioxidant, suppression of apoptosis by A23187 or T G required extracellular Ca2+ and was specifically abolished by the ca lcineurin inhibitor cyclosporin A. IL-6 induced immediate early activa tion of junB and zif/268 (Egr-1) but A23187 and TG did not. A23187 and TG also suppressed induction of apoptosis by doxorubicin or vincristi ne in M1 cells that did not express p53 by a cyclosporin A-sensitive m echanism. Suppression of apoptosis by A23187 or TG was not associated with autocrine production of IL-6. Apoptosis induced in IL-6-primed M1 cells after IL-6 withdrawal was not suppressed by A23187 or TG but wa s suppressed by the cytokines IL-6, IL-3, or interferon gamma. The res ults indicate that these Ca2+-mobilizing compounds can suppress some p athways of apoptosis suppressed by cytokines but do so by a different mechanism.