Estrogen receptors: orchestrators of pleiotropic cellular responses

Abstract

Estrogen receptors (ERs) orchestrate both transcriptional and non-genomic functions in response to estrogens, xenoestrogens and signals emanating from growth factor signalling pathways. The pleiotropic and tissue-specific effects of estrogens are likely to be mediated by the differential expression of distinct estrogen receptor subtypes (ERalpha and ERbeta) and their coregulators. The recent analysis of transcription complexes associated with estrogen-responsive promoters has revealed unexpected levels of complexity in the dynamics of ER-mediated transcription. Furthermore, a small fraction of ERs also appears to directly interact with components of the cytosolic signalling machinery. Analysis of the interrelationship between these distinct modes of ER action is likely to reveal novel aspects of estrogen signalling that will impact on nuclear receptor biology and human health.

Fig. 1. Functional domains of ERα and ERβ. Both ER subtypes exhibit functional domains characteristic of the nuclear receptor superfamily. These include an agonist-independent transcriptional activation function (AF-1), a conserved DNA-binding domain, a hinge region and a ligand-binding domain which encompasses both an agonist-dependent transcriptional activation function (AF-2) and a dimerization region.

Fig. 2. Chromatin modifying proteins involved in ERα-mediated transcription. (A) In the presence of agonist, ERα recruits an ATP-dependent chromatin remodelling complex (SWI/SNF) and histone modifying enzymes to estrogen-responsive promoters, including the HATs p160, CBP, p300 and pCAF. Additional histone modifying enzymes, including methyltransferases and kinases, are also implicated in ER-mediated transcription. (B) Unliganded-ERα can recruit HATs via cyclin D1. (C) A number of cofactors repress ER-mediated transcription by targeting HDACs to ERα-bound promoters. Although the dynamics of ERβ transcription complexes have not yet been extensively studied, ERβ exhibits distinct interactions to ERα (see text and Figure 4).

Fig. 3. ERs integrate signals through multiple protein kinase cascades. ERs respond to a wide variety of extracellular signals, including steroid hormones, growth factors and xenoestrogens. ER-mediated transcription in the nucleus involves ligand-dependent and ligand-independent mechanisms, both of which are coordinated by a complex pattern of reversible phosphorylation events emanating from cytosolic protein kinases. ERs can also mediate rapid non-genomic responses to steroid hormones.

Fig. 4. Distinct ER subtypes may mediate tissue-specific responses to estrogenic compounds. (A) Tissue-specific responses to estrogenic compounds are likely to be mediated by a combination of the differential expression of ER subtypes, the ligand specificity of ER subtypes and ligand-independent signalling pathways. Both ER subtypes integrate signals by recruiting common and/or subtype-specific cofactors. ER heterodimer-specific cofactors may also exist in cells expressing both ER subtypes. (B) ERs can bind to the promoters of estrogen-responsive genes either directly through estrogen response elements (ERE) or indirectly through DNA-bound transcription factors such as AP1. The ligand-independent association of ERs with promoters is mediated, at least in part, via protein kinase cascades in response to a variety of non-steroidal signals. Although specific promoter DNA sequences may favour the binding of each ER subtype, the relative occupancy of estrogen-responsive promoters by ERα and ERβ is not yet clear.