Transcriptional effects of estrogen on neuronal neurotensin gene expression involve cAMP/protein kinase A-dependent signaling mechanisms

Steroid hormones exert dramatic effects on neuronal expression of genes that encode neuropeptides. Expression of the neurotensin/neuromedin (NT/N) gene in preoptic area neurons is dramatically enhanced by estrogen in vivo, even though its promoter lacks palindromic estrogen response elements. We report here that estrogen promotes transcription of this gene by interactions with the cAMP cascade in a neuronal cell line, SK-N-SH, and in a mouse model. In neuroblastoma cells, estrogen increases cAMP and the phosphorylation of the cAMP response element-binding protein in a time frame that precedes induction of NT/N gene transcription. Interference with the cAMP/protein kinase A signal transduction cascade blocks the ability of estrogen to elicit increases in transcription of this gene. Furthermore, in studies performed in vivo using mice deficient in protein kinase A, estrogen fails to induce increases in NT/N mRNA but retains its ability to promote estrogen response element-dependent progesterone receptor gene transcription. These data represent the first report of a nonclassical effect of estrogen on the expression of an endogenous estrogen-regulated neuropeptide gene through cAMP-mediated mechanisms both in a neuroblastoma cell line and in hypothalamic neurons. More importantly, this 'cross-talk' may represent a more generalized mechanism by which steroid hormones act through other signal transduction cascades to regulate the expression of other genes in the brain.