The estrogen receptor enhances AP-1 activity by two distinct mechanisms with different requirements for receptor transactivation functions

Estrogen receptors (ERs alpha and beta) enhance transcription in response t o estrogens by binding to estrogen response elements (EREs) within target g enes and utilizing transactivation functions (AF-1 and AF-2) to recruit p16 0 coactivator proteins. The ERs also enhance transcription in response to e strogens and antiestrogens by modulating the activity of the AP-1 protein c omplex. Here, we examine the role of AF-1 and AF-2 in ER action at AP-1 sit es. Estrogen responses at AP-1 shes require the integrity of the ER alpha A F-1 and AF-2 activation surfaces and the complementary surfaces on the p160 coactivator GRIP1 (glucocorticoid receptor interacting protein 1), the NID /AF-1 region, and NR boxes. Thus, estrogen-liganded ER alpha utilizes the s ame protein-protein contacts to transactivate at EREs and AP-1 sites. In co ntrast, antiestrogen responses are strongly inhibited by ER alpha AF-1 and weakly inhibited by AF-2. Indeed, ER alpha truncations that lack AF-1 enhan ce AP-1 activity in the presence of antiestrogens, but not estrogens. This phenotype resembles ERP, which naturally lacks constitutive AF-1 activity. We conclude that the ERs enhance AP-1 responsive transcription by distinct mechanisms with different requirements for ER transactivation functions. We suggest that estrogen-liganded ER enhances AP-1 activity via interactions with p160s and speculate that antiestrogen-liganded ER enhances AP-1 activi ty via interactions with corepressors.