What are comparative studies telling us about the mechanism of ERbeta action in the ERE-dependent E2 signaling pathway?

Estrogen hormone (E2) signaling is primarily conveyed by the estrogen receptors (ER) alpha and beta. ERs are encoded by two distinct genes and share varying degrees of domain-specific structural/functional similarities. ERs mediate a complex array of nuclear and non-nuclear events critical for the homeodynamic regulation of various tissue functions. The canonical nuclear signaling involves the interaction of ERalpha and ERbeta with specific DNA sequences, the so-called estrogen responsive elements (EREs). This interaction constitutes the initial step in ERE-dependent signaling in which ERbeta is a weaker transcription factor than ERalpha in response to E2. However, it remains unclear why transactivation potencies of ER subtypes differ. Studies suggest that the amino-terminus, the least conserved structural region, of ERbeta, but not that of ERalpha, impairs the ability of the receptor to bind to ERE independent of E2. Although the impaired ERbeta-ERE interaction contributes, it is not sufficient to explain the weak transactivation potency of the receptor. It appears that the lack of transactivation ability and of the capability of the amino-terminus of ERbeta, as opposed to that of ERalpha, to functionally interact with the carboxyl-terminal hormone-dependent activation domain is also critical for the receptor-specific activity. Thus, the structurally distinct amino-termini of ERs are important determinants in defining the function of ER-subtypes in the ERE-dependent pathway. This could differentially affect the physiology and pathophysiology of E2 signaling.