Sm. Aronica et al., ESTROGEN ACTION VIA THE CAMP SIGNALING PATHWAY - STIMULATION OF ADENYLATE-CYCLASE AND CAMP-REGULATED GENE-TRANSCRIPTION, Proceedings of the National Academy of Sciences of the United Statesof America, 91(18), 1994, pp. 8517-8521
Estrogenic hormones, believed to exert most of their effects via the d
irect interaction of their receptors with chromatin, are found to incr
ease cAMP in target breast cancer and uterine cells in culture and in
the intact uterus in vivo. Increases in intracellular cAMP are evoked
by very low concentrations of estradiol (half maximal at 10 pM) and by
other physiologically active estrogens and antiestrogens, but not by
an inactive estrogen stereoisomer. These increases in cAMP result from
enhanced membrane adenylate cyclase activity by a mechanism that does
not involve genomic actions of the hormones (are not blocked by inhib
itors of RNA and protein synthesis). The estrogen-stimulated levels of
cAMP are sufficient to activate transcription from cAMP response elem
ent-containing genes and reporter plasmid constructs. Our findings doc
ument a nongenomic action of estrogenic hormones that involves the act
ivation of an important second-messenger signaling system and suggest
that estrogen regulation of cAMP may provide an additional mechanism b
y which this steroid hormone can alter the expression of genes.