Differences in the abilities of estrogen receptors to integrate activation functions are critical for subtype-specific transcriptional responses.

Estrogen receptors (ER) alpha and beta are members of a superfamily of nuclear receptors and mediate estrogen [17beta-estradiol (E2)] signaling. ERbeta has considerably less transcription potency than ERalpha in heterologous expression systems that use E2 response elements (ERE) in tandem as the trans-acting unit. We show here that despite similar intracellular characteristics, ERbeta, in contrast to ERalpha, fails to induce gene transcription synergistically in response to E2 from tandem EREs. Moreover, our results indicate that ERalpha-specific partial agonistic activity of antagonists occurs additively. Although synergy contributes, it is not sufficient for differences in the transcription potencies between the ER subtypes. We demonstrate here that differences in the abilities of ERs to integrate activation functions through functional interactions between amino and carboxyl termini are critical for the transcriptional strength of ER subtypes.