BCL-2 INHIBITS C-FOS INDUCTION BY CALCIUM

Transient elevation of cytosolic Ca2+ induces the expression of a vari ety of genes involved in cell growth and transformation, including the early response gene c-fos. Previously, we reported that Bcl-2 inhibit s the transient elevation of cytosolic Ca2+ induced by thapsigargin (T G), a selective inhibitor of the endoplasmic reticulum-associated Ca2-ATPase. Therefore, to determine if the effect of Bcl-2 on cytosolic C a2+ elevation modulates Ca2+ signaling, we investigated the induction of c-fos by TG in WEHI7.2 mouse lymphoma cells, control transfectants (WEHI7.2-neo), and transfectants that stably express a high level of B cl-2 (W.Hb12 and W.Hb15). TG induced 20-fold elevation of c-fos mRNA i n WEHI7.2 and WEHI7.2-neo cells, but c-fos mRNA induction by TG was on ly fivefold in W.Hb12 and W.Hb15 cells, In contrast, phorbol 12-myrist ate acetate induced marked c-fos mRNA elevation in both WEHI7.2 and W. Hb12 cells, indicating that the inhibitory effect of Bcl-2 is selectiv e for induction of c-fos by Ca2+. To measure c-fos promoter activity, WEHI7.2 and W.Hb12 cells were transiently transfected with a c-fos pro moter-luciferase reporter plasmid, TG induced c-fos promoter activity in WEHI7.2 cells, but not in W.Hb12 cells. In WEHI7.2 cells, the signa l for c-fos induction by TG was cytosolic Ca2+ elevation, as the incre ase in both c-fos mRNA level and promoter activity were prevented by l owering extracellular Ca2+ concentration, a condition that inhibits cy tosolic Ca2+ elevation by reducing the TG-mobilizable Ca2+ pool, In su mmary, the findings indicate that Bcl-2 regulates Ca2+ signaling.