Doi:10.1016/j.tem.2004.01.008

Christian J. Gruber, Doris M. Gruber, Isabel M.L. Gruber, Fritz Wieserand Johannes C. Huber Division of Gynecologic Endocrinology and Reproductive Medicine, Department of Obstetrics and Gynecology,University of Vienna Medical School, Wa¨hringer Gu¨rtel 18 – 20, A-1090, Vienna, Austria Estrogens exert their regulatory potential on gene therefore yield different transcriptional effects at the same expression through different nuclear and non-nuclear site . On activation of the ER by agonist ligand binding, mechanisms. A direct nuclear approach is the inter- conformational changes are induced and intracytoplasmic action of estrogen with specific target sequences of chaperones, such as heat-shock proteins 70 and 90, DNA, estrogen response elements (ERE) or units. EREs dissociate from the receptor molecule The receptor can be grouped into perfect and imperfect palindromic then interacts with DNA and the transcriptional response sequences with the imperfect sequences differing from is modulated by the recruitment of co-regulatory proteins the consensus sequence in one or more nucleotides and . A site of attachment for nuclear co-activators within being less responsive to the activated estrogen – estro- the ligand-binding domain (LBD) of the ERa is formed by gen receptor (ER) complex. Differences in the ERE helix 12 when the receptor is occupied by an agonist ligand sequence and the ER subtype involved can substantially . Anti-estrogens displace part of the receptor, which alter ER– ERE interaction. In addition, cross-talk between then occludes the site and blocks co-activator access ERs and other nuclear transcription factors profoundly ERs are members of a large family of nuclear receptors influences gene expression. Here, we focus on the that probably arose from a common ancestral receptor recent advances in the understanding of the structure molecule . This hypothesis is supported by the similar of EREs and how ERs are recruited to these. Identifying modes of action of nuclear steroid receptors and a rather known target genes for estrogen action could help us conserved DNA-binding domain (DBD). The LBDs of to understand the potential risks and benefits of the nuclear steroid receptors differ markedly in structure, administration of this steroid to humans.
even between the receptor subtypes ERa and ERb,reflecting different binding affinities for physiological Estrogens are now known to influence the expression of a ligands Glucocorticoid, mineralocorticoid, androgen wide range of genes by different mechanisms in the and progesterone receptors bind to derivatives of a reproductive tract and other areas A direct genomic interaction occurs between the estrogen receptor (ER) different to this response element. However, when the ligand complex and specific sequences of DNA known as DBD of ERa is switched experimentally with the DBD of estrogen response elements (ERE). Alternatively, ERs can the glucocorticoid receptor, the chimeric receptor binds to be activated independently of a hormonal ligand .
However, the different anatomy of EREs, the two subtypesof ERs involved (ERa and ERb), the variety of interacting –8–7–6–5–4–3–2 +2+3+4+5+6+7+8 nuclear co-regulatory proteins and the substantial cross-talk between nuclear transcription factors can yield 5′-C A G G T C A nnn T G A C C T G-3′ various responses to estrogen stimulation. By focusing on the structure of natural EREs and on how ERs are 3′-G T C C A G T nnn A C T G G A C-5′ recruited to these, a better understanding of the complex-ity of the action of this steroid when administered tohumans can be achieved.
TRENDS in Endocrinology & Metabolism Activated ERs are transcription factors that bind indimeric form to specific sequences of DNA in the Figure 1. Sequence of the ERE and GRE. (a) A consensus ERE has been derived regulatory region of target genes, the EREs. Generally, from several highly estrogen-responsive sequences from the African clawed frogXenopus laevis genes encoding vitellogenin A1, A2, B1, B2 and the chicken apo- ERa and ERb can form both homo- and heterodimers VLDL II gene. It is a 13 bp perfect palindromic inverted repeat with a 3 bp spacing before attaching to DNA Both receptor subtypes have of variable bases (red). (b) The sequence of the consensus GRE . As indicated, different affinities for different response elements and can replacement of the adenine base at position þ 4 by thymine results in the gener-ation of a GRE. Positions þ 2, þ 3 and þ 6 are conserved in both the ERE and GRE.
Abbreviations: ERE, estrogen response element; GRE, glucocorticoid response Corresponding author: C.J. Gruber (christian_gruber@chello.at).
1043-2760/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tem.2004.01.008 the glucocorticoid response element (GRE) but is activated within the ERE are contacted with highest affinity by the by 17b-estradiol . This indicates the high specificity of P-Box amino acids because different laboratory techniques give different results However, recent studies Highly conserved regions in the DBD of ERa and ERb indicate that both ERa and ERb contact the same are the two cysteine – cysteine zinc fingers which allow nucleotides in the consensus ERE . It is therefore contact between the major groove of DNA and the sugar– assumed at this time that the two ER subtypes interact phosphate backbone. The resulting ER – ERE complex is stabilized by ligand binding and the high mobility As mentioned previously, ER conformation differs when group proteins 1 and 2 which are architectural occupied by different ligands. Also, the structure of the proteins that facilitate chromatin function.
ERE alters the conformation of the receptor. As seen incrystallographic studies, the ERa reacts to a specific single nucleotide alteration within the ERE by changing its DBD Highly estrogen-responsive and perfectly palindromic conformation by means of a side-chain rearrangement sequences have been found in the African clawed frog With these modifications, a rearrangment in the local Xenopus laevis genes encoding vitellogenin A1, A2, B1 and hydrogen bond network between DNA bases and receptor B2 From these natural EREs and similar sequences amino acids is achieved and alternative base contacts a minimal consensus sequence for EREs has been derived At position þ 2, the ER attaches to Thus, ER conformation is dependent on two factors: the first thymine base of a half site by interacting with the (i) the ligand and (ii) the specific ERE sequence. As 50-methyl group. The thymine base at this position is also indicated by protease sensivity assays, which rely on the conserved in thyroid hormone and glucocorticoid/pro- ability of a protease to cleave the receptor protein at gesterone response elements (GRE/PRE). At position þ 3, accessible amino acids, the ERa obtained a different the guanine base is also conserved throughout all three conformation when complexed with the different EREs hormone reponse elements but the adenine at position þ 4 from the Xenopus laevis vitellogenin A2 and B1 genes and of the half site is crucial for discrimination between the the genes encoding human pS2 and human oxytocin three . Replacement of the adenine base by thymine is This can yield a differential recruitment of co-regulatory incompatible with ER binding, resulting in the generation proteins to the ER – ERE complex and might therefore of a GRE. An ERE with a cytosine or guanine base at constitute a mechanism for modulation of gene transcrip- position þ 3 is still functional although it is less tran- tion at different EREs. The recruitment of activation scriptionally active. In all EREs position þ 5 is occupied by function 2 (AF-2) dependent cofactor to ERa and ERb, for a cytosine in at least one-half-palindrome. Position þ 6 is instance, is affected by both the ligand and the ERE sequence occupied by a cytosine in both ERE and GRE When the ERs are liganded with 17b-estradiol (E However, in the human genome, most estrogen target the recruitment is primarily dependent on the ERE genes do not contain an ERE palindrome in their promoter sequence. By contrast, when the ERs are occupied by but have non-palindromic EREs through which estrogenregulation is mediated Sequence requirements for anti-estrogens, the ERE sequence loses its influence on imperfect EREs have been determined in vitro . If an ERa homodimer attempts to bind to an ERE differing in asingle base pair from the consensus sequence, binding is ER affinity and transcriptional activation from different abolished unless rescued by appropriate flanking. A purine base immediately flanking the element on the 50 Few natural EREs have been examined with respect to their side at position 2 7 of each strand is required in an ERE exact ER affinity and strength of transcriptional activation.
with one base mutation. Two, but not three mutations can These points are especially difficult to summarize because of be compensated for by appropriate 2 7 and 2 8 flanking.
the multiple detection systems that have been used.
Mutations in both halves of the element also abolished Generally, mutant variants of the consensus sequence receptor binding in this study In accordance, natural function with less transcriptional potency and their ability to EREs in vivo lose affinity for the ER with increasing bind the ER is significantly weaker For the few genes numbers of nucleotide changes from the consensus that have been examined that contain natural EREs, a direct sequence, particularly if these alterations affect both correlation between ER–ERE binding affinity and tran- halves of the ERE palindrome The flanking sequence scriptional activation has been observed for both ER immediately adjacent to the ERE was also shown in vivo to subtypes . In a further study, it was confirmed that impact the transcriptional potency of the element. An both ERa and ERb bind to the same EREs but that ERa does enhancement of the transcriptional potency was particu- so with an approximately twofold higher affinity larly noticeable with a AT-rich flanking DNA When the Xenopus laevis vitellogenin A2 and B1 ERE were compared with the human pS2 and oxytocin ERE by means of transient co-transfection and chloramphenicol Three specific amino acids within the proximal box (P-Box) acetyltransferase assay in HeLa cells, the most potent of the first zinc finger of the ER bind to the ERE in a transcriptional activation (10.5-fold) was observed with sequence-specific manner The second zinc finger is vitellogenin A2, followed by a 9.5-fold induction with the involved in receptor molecule dimerization and ERE half- oxytocin ERE, a 2.7-fold induction with the pS2 ERE and site spacing recognition. It is unclear which nucleotides 1.6-fold induction with the vitellogenin B1 ERE enhance the transcriptional activity of AP-1. In this path- Often more than one ERE-like sequence is seen in the way, the ER is part of the co-activator complex for Jun/Fos regulatory region of estrogen target-genes, which lead to without binding to the AP-1 response element . It the concept of the estrogen response unit (ERU) . An thereby confers estrogen responsiveness to genes encoding ERU comprises imperfect palindromic elements or even human ovalbumin, c-fos, collagenase, and insulin-like half elements, sometimes separated by hundreds of base growth factor . Interestingly, estrogenic activity at AP-1 pairs. Estrogenic inducibility of gene transcription is then sites depends on both the ER subtype and the ligand, and can accomplished by transcriptional synergism of these separ- either yield induction or inhibition of transcription Similarily to AP-1, the binding of ERa and ERb to the reported for ER binding to natural ERUs, such as the nuclear transcription factor Sp-1 and the transcriptional Xenopus laevis vitellogenin B1 ERU , and also to effect of this interaction is cell type-, ligand- and promoter- synthetic ERUs The exact mechanism of transcrip- dependent. The ER – Sp-1 complex binds to a consensual tional synergism remains to be elucidated, but might GC-rich promoter sequence of a gene in which only the include cooperative recruitment of co-activators, direct Sp-1 protein attaches to DNA . Physical interaction interaction between ER dimers, and allosteric modu- between ERs and AP-1 or Sp-1 proteins is mediated by the lations between the DNA – ER complexes. Sometimes, ER domains that harbour the transactivation function EREs overlap with other hormone response-elements, (AF) 1 and 2. Binding of Sp-1 to its recognition site confers creating elements that mediate multihormonal sensitivity estrogen responsiveness to the human creatine kinase B, Additionally, ERa was shown to bind to direct repeats c-myc, retinoic acid receptor a, heat shock protein 27, of ERE half-sites and activate transcription, presumably with highest affinity when the direct repeats are separated Another pathway of estrogen action involves the ER-related receptors (ERR), nuclear orphan receptors Because rules for sequence requirements of ERUs with significant homology to ERs, which do not bind await further clarification, putative estrogen responsive estrogen and have unknown physiological ligands. ERRs sequences must be verified experimentally to determine are known to bind to the steroidogenic factor 1 response their biological importance . Multiple systems have been element (SFRE), an ERE half-site preceeded by a used to demonstrate the functionality of EREs or ERUs.
thymine – cytosine – adenine trinucleotide but they Band-shift assays and electrophoretic gel mobility-shift also bind to classic EREs, in which they exert a con- assays test the binding of the ER protein to a putative ERE stitutive transcriptional activity. In turn, ERa but not the sequence in vitro and the specificity of the reaction can be ERb homodimers can activate transcription through enhanced by ER-reactive antibodies. However, these assays binding to SFREs. This alternative mode of action has do not demonstrate whether a putative ERE is biologically been demonstrated for the murine osteopontin gene functional or not. Functionality can be verified in transient Similar cross-talk between ERs and ERRs has been transfection experiments by fusing the putative ERE observed in the transcriptional regulation of the human sequence with a reporter gene (chloramphenicol acetyl- breast cancer marker gene pS2, the promoter of which is transferase assay, luciferase assay) and measuring the not only activated by ERs but also by ERRs, particularly resulting enzyme activity. Subsequent deletion or mutagen- ERRa. Consistent with the well-characterized ERE, a esis of the tested sequence in the transient transfection assay functional SFRE is present in the pS2 promoter at position further increases the specificity of the result.
2 269 to 2 260. Both the ERE and the SFRE are required However, multiple genes known to be influenced by the for full response to ER and ERR pathways action of the ER and its ligand lack classic EREs or ERUs.
Here, we summarize examples of natural EREs and Here, we summarize alternative pathways of ER action.
ERUs in human DNA. It has become evident in recentyears that substantial cross-talk between the classic ERE- mediated pathway and alternative pathways can occur.
Some genes are regulated by an estrogenic pathwayreferred to as tethering, in which the ER does not neces- EREs differing by one to three nucleotides from the sarily bind to DNA but interacts with another DNA-bound transcription factor. Well-characterized examples of these Examples of EREs differing by one to three nucleotides include the transcription factors activating protein (AP)-1 from the consensus sequence are described below and and specificity protein 1 (Sp-1). No direct receptor binding, listed in . As indicated above, base mutations from but E2-dependent loading of the upstream stimulatory the consensus sequence decrease the binding affinity factors (USF)-1 and -2 to the promoter is required for activation of the gene encoding cathepsin D, which is also (i) Oxytocin: An early characterized ERE differing in one nucleotide is the human oxytocin ERE. Optimal function of The AP-1 transcription factor is the heterodimer from this sequence is independent of other regulatory elements in the Jun/Fos gene products that binds to the phorbol diester the promoter in transient transfection experiments (TPA) response element as well as to the AP-1 binding site (ii) pS2: Another example of this category is the gene of DNA. Activated ERs directly interact with the nuclear co- encoding human pS2, in which expression is controlled by activators CREB-binding protein (CBP) and gluco- estrogens in human breast cancer cells via mediation of an corticoid receptor interacting protein (GRIP) recruited imperfect ERE (2405 to 2394) In transfected HeLa by Jun/Fos, which completes the co-activator complex to cells a 4,5-fold increase in the estrogen induction of a Table 1. EREs differing from consensus ERE in 1, 2 or 3 nucleotides in humans ERE consensus sequence: 50- G G T C A nnn T G A C C - 30Peptide/protein No. of nucleotides differing from the consensus reporter gene was observed with the pS2–ERE .
was observed in cells co-transfected with ERb. Site- Additionally, a cooperative SFRE is required in the promoter directed mutagenesis of this sequence abolished induc- region for full response to ER and ERR pathways .
tion of gene expression by estradiol.
sequence at positions 2 24 to 2 11 between the TATA box Half-palindromic elements that mediate estrogen and transcriptional initiation site of the gene encoding human angiotensinogen contains a cytosine/adenine poly- Although half-EREs only confer weak estrogen respon- morphism at 2 20. When adenine is present at 2 20, the siveness, genes are known for which transcription is sequence binds to the estrogen receptor and increases induced by two or more ERE half-sites. Examples are (iv) Cathepsin D: Estrogens induce the expression of (i) Corticotropin-releasing hormone (CRH): Four half the gene encoding cathepsin D, a lysosomal proteinase EREs sites occur in the promoter of human CRH gene produced in excess in human breast cancer cell-lines .
that respond to estrogen administration. In co-transfected Within the proximal promoter sequence, three EREs have been found, among which one is functional (2 270 to 2 249) analysis, these five half-elements induced estrogen . This sequence requires cooperation with other regu- responsiveness by , 10% – 20% of the strength of the latory elements, a homologous sequence upstream, general regulatory sites downstream (e.g. Sp1) and a TATA box .
(ii) Platelet-activating factor receptor (PAFR): The gene (v) Glial fibrillary acidic protein (GFAP): The induction encoding the human PAFR has two different promoters, of transcription of the GFAP is consistent with the which yield two transcripts of the receptor DNA in a presence of a functionally imperfect ERE (2 149 to tissue-specific manner In PAFR transcript 2, an ERU 2 137) in the upstream region of the rat gene promoter occurs in the gene promoter, comprising two half ERE The identical sequence is present in the human GFAP sites separated by 153 bp (2 257 to 2 93) In a promoter region (at 2 150) and verified by site-directed chloramphenicol acetyltransferase assay of transfected JR-St cells, estrogen induced transcriptional activity 2.5- (vi) Complement C3: The human complement C3 ERE is located at position 2 226 to 2 214. Another sequence in (iii) Prothymosin a: Prothymosin a gene expression is that promoter (þ 33 to þ 45) also exhibits similarity to the consensus ERE, but has been characterized as nonfunc- contains two half-palindromic EREs at position 2 750 tional In transfected HeLa cells a fourfold activation (vii) Vascular endothelial growth factor (VEGF): A Combinations with half-palindromic elements mediating variant ERE (2 1560 to 2 1548), differing by three nucleotides from the consensus sequence, is located ERE half-sites can act in synergy with other regulatory 1.5 kb upstream from the transcriptional start site of the elements within the promoter region of a gene. Examples gene encoding human VEGF In cells co-trans- fected with ERa, estradiol induced 3.2-fold induction in (i) Lactoferrin: In the lactoferrin gene promoter, a VEGF-promoter luciferase activity. A 2.3-fold increase composite hormone-response element can be found that Table 2. Half-palindromic elements and combinations that mediate estrogen inducibility ERE consensus sequence: 50- G G T C A nnn T G A C C - 30Peptide/protein (a) Half-palindromic elementsCorticotropin releasing hormone Platelet activating receptor transcript 2 (b) Combinations with half-palindromic elementsLactoferrin Table 3. Other variations involving ERE-like sequences ERE consensus sequence: 50- G G T C A nnn T G A C C - 30Protein/peptide CGGCA gcg TGACC overlapping with two sequences homologous to the core sequence of AP-1 transcriptionbinding sites comprises a retinoic acid response element that overlaps estrogen regulation occur other than those currently known? with an ERE (2 349 to 2 337). The two AGGTCA motifs Second, more insight into the nuclear environments and the can be activated by the retinoic acid X receptor and one mechanisms leading to estrogen-induced gene stimulation AGGTCA half also responds to estrogen application or restriction is needed. From these points, a better under- (ii) Heat shock protein (HSP) 27: In the promoter of the standing of the tissue-selective effects of estrogenic com- gene encoding HSP 27, an ERE half-element (2 88) is pounds can be achieved and the knowledge more easily present, which acts synergistically with a GGGCGGG Sp1 transferred to clinical settings. Because estrogens have direct access to the human genome, administration of thissteroid in humans should therefore occur with care. Under- Other variations involving ERE- like sequences standing the molecular actions of estrogens and the variety Often ERE-related sequences display synergistic action of genes affected might help us to understand the potential with or overlap with other regulatory elements within the risks and benefits of hormone replacement therapy and of promoter region of a gene. Examples are described below (i) c-fos: Functional EREs have been identified in the c-fos 50-flanking DNA, comprising one imperfect palin- 1 Gruber, C.J. et al. (2002) Production and action of estrogens. N. Engl.
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