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

There are two known receptors for estrogens, ER alpha and ER beta. The existence of ER beta 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 ER beta to by activated by various ligand-independent signaling pathways, and to characterize the structural regions of ER beta, in comparison to ER alpha, that regulate how this receptor isotype responds to intracellular crosstalk. We have found that stimulation of He La cells with forskolin and IBMX results in the activation of ER alpha and ER beta dependent expression in a receptor-dependent and promoter context-dependent manner, and that protein kinase A mediates this response. Factors that interact with an AP-1 binding site contribute to forskoliiv IBMX activation of estrogen receptor-dependent gene expression, and do so in a manner that does not require the AB domain of either receptor. ER alpha and ER beta differ in their requirement for interaction with the putative AP-1 binding site factor. ER3-mediated transcription is dependent on this site suggesting that forskolin activation reflects the synergistic action between ER beta and other transcription factor, while ER alpa can activate gene expression in a AP-1- independent manner.