Signal transduction via estrogen receptors (ERs) and estrogen receptor-related receptors (ERRs)

Abstract

Estrogens influence post-natal development and function of the female reproductive system and other organs including bone and cardiovascular system. Estrogens are also involved in the development and growth of certain cancers in e.g. breast and uterine endometrium. The biological effects of estrogens are mediated via two intracellular proteins, the estrogen receptors [alpha] and [beta] (ER[alpha], ER[beta], which belong to a large group of ligand-inducible transcription factors known as the nuclear receptor superfamily. Members of the family regulate transcription through direct interaction with specific DNA binding sites present in promoter regions of target genes. The ERs specifically bind to DNA elements known as estrogen response elements (EREs). These DNA targets were found to be recognized also by another group of nuclear receptors, the orphan estrogen receptor-related receptors (ERRs). The ERRs are, closely related to the ERs but do not bind known estrogens and no ligand has yet been identified for these receptors.

The recently identified ER[beta] shows specific binding to EREs and activation of ERE-containing promoters in response to 17[beta]-estradiol (E2). ER[beta] requires approximately 10-fold higher concentrations of E2 than ER[alpha] for transcriptional activity to occur. The antiestrogenic compound tamoxifen, is described as a mixed agonist/ antagonist on ER[alpha], has in addition been shown to act as a pure antagonist on ER[beta]. ER[alpha] and ER[beta] were found to form functional DNA-binding heterodimeric complexes both in vitro and in cell systems. Analysis of transcriptional activity in the presence of both ERs demonstrated that ER[beta] acts as a dominant modulator of estrogenic response both in a positive and negative manner. ER[beta] represses the transcriptional activity of ERs at low concentrations of E2 and in the presence of tamoxifen in an ER[beta] dose-dependent manner. Genistein is a phytoestrogenic compound which shows ER[beta]-selective affinity, and ER[beta] imparts increased agonistic effect of genistein to ER[alpha] upon co-expression of both receptors. The modulatory effect of ER[beta] on ER[alpha] transcriptional activity appears to involve silencing or enhancement of the N-terminal activation function of ER[alpha].

The ERRs recognize and initiate transcription of so called SFRE (Steroidogenic Factor 1 response elements) DNA sequences in addition to EREs. In contrast to ER[beta], ER[alpha] was found also to bind to and activate transcription from SERE containing promoters, thus demonstrating the first discriminatory difference between the ERs at the DNA binding level. The over-lapping DNA sequence recognition properties shared by ERs and ERRs indicate that they have the ability to regulate common target genes. However, the ERRs are refractory to antagonism by antiestrogens which may be of pharmacological importance in the therapeutic use of such compounds.

In conclusion, signal transduction by ERs. and ERRs involves multiple pathways, depending on tissue-selective expression of different receptor subtypes, nature of DNA target, concentration of agonistic or antagonistic ligand and formation of heterodimeric complexes.