CROSSTALK DURING CA2-INDUCED, CAMP-INDUCED, AND GLUCOCORTICOID-INDUCED GENE-EXPRESSION IN LYMPHOCYTES()

In the WEHI7.2 thymoma cell line, cAMP, glucocorticoids, or increases in cytosolic Ca2+ concentration lead to cell death by apoptosis. In th e present study, we examined the effects of these compounds on cAMP re sponse element (CRE)-mediated gene expression. Thapsigargin and A23187 were employed to increase cytosolic Ca2+ levels and induce apoptosis. Both compounds enhanced transcription from a CRE preceding apoptotic death. Moreover, the transcriptional response to the combination of fo rskolin and either thapsigargin or A23187 was synergistic mirroring th e effect on cell death. Importantly, dexamethasone treatment, which ca uses an efflux of Ca2+ from the ER [1,2], induced transcription from a CRE alone or in synergy with forskolin. The increase in CRE-controlle d gene expression correlated with a decrease in cell viability. Follow ing treatment with forskolin, thapsigargin, or dexamethasone, the CRE binding protein (CREB) was phosphorylated at levels correlating with t he level of induced gene expression. These data suggest that transcrip tional crosstalk between independent signaling pathways occurs in lymp hocytes, and CREB may play a central role in the mediation of CRE-depe ndent transcription by these diverse set of apoptotic agents. (C) 1997 Elsevier Science Ireland Ltd.