The immediate early gene, cyr61, is transcriptionally activated within minutes by serum and serum growth factors. The encoded Cyr61 protein is secreted into the extracellular matrix and promotes cell adhesion and migration. In this study, we sought to examine the expression profile of cyr61 gene during neuronal cell death induced by various toxic stimuli and the mechanisms involved. Our data show that toxic stimuli, such as etoposide, significantly increased cyr61 mRNA levels in immortalized hippocampal progenitor (H19-7) cells. Cyr61 transcriptional activation was corroborated at the protein level as well. To identify the upstream signaling cascades involved in cyr61 gene induction, the blocking effect of either JNK or p38 kinase-signaling pathway on cyr61 induction in response to etoposide was tested. Transfection of the cells with a kinase-deficient mutant MEKK, an upstream activator of JNK, significantly decreased the cyr61 expression induced by etoposide. In contrast, cyr61 mRNA levels did not change after pretreatment with SB203580, the p38 kinase inhibitor. When the induction of cyr61 was tested by using several of its deleted promoters driving the expression of reporter gene, the promoter activation occurred primarily within the region containing an SRE-like CArG box. In addition, the SRF, which binds to the CArG site, was directly phosphorylated by active JNK. Furthermore, the blockade of cyr61 gene expression using an antisense encoding cyr61 sequence significantly inhibited the cell death induced by etoposide. Overall, these results suggest that the induction of the immediate early gene, cyr61, is important for neuronal cell death in the central nervous system hippocampal progenitor cells, and JNK activation, but not of p38, as well as the subsequent SRF phosphorylation are involved in cyr61 gene induction.