Activation of Estrogen Receptor-Beta-Dependent Transcription by Estrogen-Independent Pathways

There are two known receptors for estrogens, ERalpha and ERbeta. The existence of ERbeta was only recently appreciated, and little is understood about its ability to be activated by intracellular signaling pathways in the absence of estrogens. The purpose of this research program is to characterize the ability of ERbeta to be activated by various ligand-independent signaling pathways, and to characterize the structural regions of ERbeta, in comparison to ERalpha, that regulate how this receptor isotype responds to intracellular cross-talk. We have found that the originally published amino acid sequence of ERbeta was incomplete, and have characterized the transcriptional activity and relative expression of the frill-length and truncated forms of ERbeta. In addition, the transcriptional activity of the amino-terminal, activation function of ERalpha is stronger than the corresponding region of ER. Both ERalpha and the short and long forms of ERbeta can be activated by cAMP signaling pathways in the absence of exogenous estrogens, although the antiestrogen, 4- hydroxytamoxifen, only inhibits the activity of ERalpha, but not ERbeta, stimulated in this manner. Taken together, ERalpha and ER are not functionally equivalent, although they do share many features, and differences between the two receptors will be exploited to understand the molecular mechanisms by which they activate transcription in the absence of estrogens.