Review

Estrogen receptor interaction with co-activators and co-repressors☆☆

Structural domains of ERα and ERβ

ERα and ERβ have six domains named A through F from N- to C terminus, encoded by 8–9 exons [5] (Fig. 1). The three major functional domains of the ER are: 1) a variable N terminus (domains A and B) that modulates transcription in a gene and cell-specific manner through its N-terminal Activation Function-1 (AF-1); 2) a central DNA-binding domain (DBD, consisting of the C domain), comprised of two functionally distinct zinc fingers through which the receptor interacts directly with the DNA

ER interaction with estrogen response elements

ERα and ERβ bind with high affinity to specific DNA sequences called estrogen response elements (EREs). The minimal consensus ERE sequence is a palindromic inverted repeat (IR): 5′-GGTCAnnnTGACC-3′, where n = any nucleotide [30], and differs in only 2 bp from the GRE [31]. Extension of the length of the ERE palindrome, e.g. 5′-CAGGTCAnnnTGACCTG-3′, forming a 17bp palindromic IR, and the sequences immediately flanking the ERE are important in determining the affinity with which ERα binds the ERE

Regulation of gene transcription by the estrogen receptor

Initiation of transcription is a complex event occurring through the cooperative interaction of multiple factors at the target gene promoter. When bound to an ERE, ER interacts with basal transcription factors and with other proteins, including co-activators, that may stabilize basal transcription factor binding and promote the assembly of the transcription initiation complex. Once the transcription initiation complex is complete, RNA polymerase II is recruited to the transcription start site

Interaction of estrogen receptor with basal transcription factors

For RNA polymerase II to initiate transcription, basal transcription factors TFIIA, TFIIB, TFIID, TFIIE, TFIIF, and TFIIH must assemble on the core promoter (reviewed in [76], [77]). TFIID consists of the TATA box binding protein (TBP) and at least eight tightly associated factors (TAFs) of 18 through 250 kDa [78].

Steroid receptors interact with basal transcription factors TFIIB, TBP, and various TAFs of TFIID (reviewed in [79]). ERα and PR interact directly with TFIIB [80]. ERα interacts

Interaction of ER with co-activators

ERα has been shown to interact with a number of nuclear proteins in vitro. ERα interaction with some of these proteins has functional consequences on transcription. Early experiments showed that overexpression of one type of NR could inhibit, or ‘squelch’ the activation of transcription mediated by a different steroid hormone receptor in a dose-dependent manner, hinting that steroid receptors compete for limited amounts of a factor(s) required for transcription [86]. Over the past 5 years, at

Interaction of ER with co-repressors

Corepressors were first identified as binding to Class II NR including RAR, RXR, and TR that are bound to DNA in the absence of ligand and are constitutively bound by the co-repressors NCoR [233], [234] and SMRT [235]. NCoR and SMRT silence transcription until the appropriate ligand is bound [27], [233], [234]. Several isoforms of SMRT and NCoR have been reported, including the newly identified SMRTe that contains an additional N terminal domain that exhibits striking similarity to NCoR [236].

Conclusions

The discovery of co-activators and co-repressors that interact with ERα and ERβ has changed the focus of estrogen regulation of target gene expression from identifying estrogen-regulated genes and examining ER-promoter interaction to determining tissue-specific patterns of expression of co-activators and co-repressors and exploring how the ER ligand influences ER interaction with co-activators and co-repressors. The models that emerge from these studies grow increasingly complex.

Accumulated