Cyclic AMP-Independent Mechanisms of Nuclear Signal Transduction by PGE(2)

Arachidonic acid-derived mediators induce transcription of several immediate early genes, but the molecular mechanisms underlying these responses remain poorly characterized. We designed experiments to explore the mechanisms by which PGE(2) induces expression of transcription factor c-fos in glomerular mesangial cells. Binding of PGE(2) to prostaglandin receptors in mesangial cells stimulates both adenylate cyclase and phospholipase C-linked signaling pathways. Prostaglandin E(2) (PGE(2)) induced marked and transient accumulation of c-fos mRNA, but induction of the c-fos gene occurred independent of PGE(2)-stimulated adenylate cyclase activity. These results contrast with previous experiments in NIH 3T3 cells in which PGE(2) stimulated c-fos accumulation by a cAMP-dependent mechanism. We further showed that PGE(2) induces c-fos gene expression by increasing the transactivating capacity of the serum response element. Collectively, these results provide evidence of a cAMP-independent pathway linking PGE(2) receptors to transcriptional activation in the nucleus. Thus, activation of PGE(2) receptors in different cell types leads to both cAMP-independent and -dependent pathways for gene expression.