Induction of apoptosis by diverse exogenous signals is dependent on elevation of intracellular Ca²⁺. This process of cell death can be blocked by actinomycin D, indicating that it requires gene transcription events. To identify genes that are required for apoptosis, we used thapsigargin (TG), which inhibits endoplasmic reticulum-dependent Ca²⁺-ATPase and thereby increases cytosolic Ca²⁺. Exposure to TG led to induction of the zinc finger transcription factor, EGR-1, and apoptosis in human melanoma cells, A375-C6. To determine the functional relevance of EGR-1 expression in TG-inducible apoptosis, we employed a dominant negative mutant which functionally competes with EGR-1 in these cells. Interestingly, the dominant negative mutant inhibited TG-inducible apoptosis. Consistent with this observation, an antisense oligomer directed against Egr-1 also led to a diminution of the number of cells that undergo TG-inducible apoptosis. These results suggest a novel regulatory role for EGR-1 in mediating apoptosis that is induced by intracellular Ca²⁺ elevation. We have previously shown that in these melanoma cells, EGR-1 acts to inhibit the growth arresting action of interleukin-1. Together, these results imply that EGR-1 plays inducer-specific roles in growth control.