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00/0 Molecular Endocrinology 19(4):833–842


Printed in U.S.A. Copyright © 2005 by The Endocrine Society
doi: 10.1210/me.2004-0486

MINIREVIEW

Mechanisms of Estrogen Receptor Signaling:


Convergence of Genomic and Nongenomic Actions
on Target Genes
Linda Björnström and Maria Sjöberg
Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden

Estrogen receptors (ERs) act by regulating tran- regulated than the range that can be regulated by
scriptional processes. The classical mechanism of the classical mechanism of ER action alone. This
ER action involves estrogen binding to receptors in review surveys our knowledge about the molecular
the nucleus, after which the receptors dimerize mechanism by which ERs regulate the expression
and bind to specific response elements known as of genes that do not contain EREs, and it gives
estrogen response elements (EREs) located in the examples of the ways in which the genomic and
promoters of target genes. However, ERs can also nongenomic actions of ERs on target genes con-
regulate gene expression without directly binding verge. Genomic and nongenomic actions of ERs
to DNA. This occurs through protein-protein inter- that do not depend on EREs influence the physiol-
actions with other DNA-binding transcription ogy of many target tissues, and thus, increasing
factors in the nucleus. In addition, membrane- our understanding of the molecular mechanisms
associated ERs mediate nongenomic actions of behind these actions is highly relevant for the de-
estrogens, which can lead both to altered func- velopment of novel drugs that target specific re-
tions of proteins in the cytoplasm and to regulation ceptor actions. (Molecular Endocrinology 19:
of gene expression. The latter two mechanisms of 833–842, 2005)
ER action enable a broader range of genes to be

E STROGENS ARE STEROID hormones that regu-


late growth, differentiation, and function in a broad
range of target tissues in the human body. The most
dimerize and bind to specific response elements
known as estrogen response elements (EREs) located
in the promoters of target genes (1). Hormone binding
potent and dominant estrogen in humans is 17␤- also induces a conformational change within the li-
estradiol, but lower levels of the estrogens estrone gand binding domain of the receptors, and this con-
and estriol are also present. The biological effects of formational change allows coactivator proteins to be
estrogens are mediated through estrogen receptor recruited (2). However, evidence for signaling path-
(ER) ␣ and ␤, which are members of a large superfam- ways that deviate from this classical model has
ily of nuclear receptors. These receptors act as ligand- emerged, and it is now accepted that ERs can regulate
activated transcription factors. The classical mecha- gene expression by a number of distinct mechanisms.
nism of ER action involves estrogen binding to Around one third of the genes in humans that are
receptors in the nucleus, after which the receptors regulated by ERs do not contain ERE-like sequences (3).
The molecular mechanisms by which ERs regulate tran-
First Published Online February 3, 2005
scription at alternative response elements are not fully
Abbreviations: AF, Activation function; AP-1, activator pro- understood but are becoming increasingly clear. ERs
tein 1; C/EBP␤, CCAAT/enhancer binding protein ␤; CRE, can regulate gene expression without binding directly to
cAMP response element; CREB, CRE binding protein; DBD, DNA by modulating the function of other classes of tran-
DNA binding domain; EGF, epidermal growth factor; eNOS,
scription factors through protein-protein interactions in
endothelial nitric oxide synthase; ER, estrogen receptor; ERE,
estrogen response element; LDL, low-density lipoprotein; the nucleus (4). The interaction of ERs with the activator
LDL-R, LDL receptor; NF-␬␤, nuclear factor ␬␤; PI, phospho- protein 1 (AP-1) transcription factor complex is a typical
inositol; SERM, selective ER modulators; SRE, serum re- example of such ERE-independent genomic actions. In
sponse element; STAT, signal transducer and activator of addition, a number of estrogen-responsive genes that
transcription.
lack EREs contain ERE half-sites, or binding sites for the
Molecular Endocrinology is published monthly by The
Endocrine Society (http://www.endo-society.org), the
orphan nuclear hormone receptor SF-1 [SF-1 response
foremost professional society serving the endocrine elements (SFREs)] that serve as direct ER binding sites
community. (3). ER␣, but not ER␤, is able to bind to SFREs (5).

833
834 Mol Endocrinol, April 2005, 19(4):833–842 Björnström and Sjöberg • Minireview

Estrogens exert some of their effects through the cuss the responses of ERs to synthetic ligands as a
action of ERs on gene expression, but a number of possibility of designing drugs that target specific re-
other effects of estrogens are so rapid that they cannot ceptor actions.
depend on the activation of RNA and protein synthe-
sis. These actions are known as nongenomic actions
and are believed to be mediated through membrane-
associated ERs. The actions are frequently associated ERE-INDEPENDENT GENOMIC ACTIONS
with the activation of various protein-kinase cascades
(6). However, nongenomic actions of estrogens may A number of studies have shown that ERs can regulate
indirectly influence gene expression, through the ac- transcription without binding directly to DNA. The re-
tivation of signal transduction pathways that eventu- ceptors in such cases are tethered through protein-
ally act on target transcription factors. The functions of protein interactions to a transcription factor complex
many transcription factors, including AP-1, are regu- that contacts the DNA, as illustrated in Fig. 1. ERs
lated through protein kinase-mediated phosphoryla- regulate by this mechanism the expression of a large
tion, and these transcription factors may thus be number of estrogen-responsive genes that do not
targets of nongenomic actions of estrogens. This sig- contain EREs. The mechanism is commonly used by
naling pathway can be referred to as nongenomic-to- members of the nuclear receptor superfamily and is
genomic signaling, and it provides for a mechanism, often referred to as transcriptional cross talk (4).
distinct from protein-protein interactions in the nu- Several genes are activated by 17␤-estradiol
cleus, by which ERs can modulate the functions of through the interaction of ERs with Fos and Jun pro-
transcription factors, and thus regulate the expression teins at AP-1 binding sites. Such genes include those
of genes that do not contain EREs. for ovalbumin (7), IGF-I (8), collagenase (9), and cyclin
This review surveys our knowledge about the mo- D1 (10, 11). Transcription that depends on AP-1 is also
lecular mechanisms by which ERs regulate transcrip- repressed by ERs activated by 17␤-estradiol (12–14).
tion at alternative response elements. We give exam- One gene that is repressed by 17␤-estradiol through
ples that show that genomic and nongenomic actions ER-AP-1 complexes is the choline acetyltransferase
of ERs on target genes converge, and we briefly dis- gene (15). ERs interact with AP-1 proteins in a com-

Fig. 1. Schematic Illustration of ER Signaling Mechanisms


1. Classical mechanism of ER action. Nuclear E2-ERs bind directly to EREs in target gene promoters. 2. ERE-independent
genomic actions. Nuclear E2-ER complexes are tethered through protein-protein interactions to a transcription factor complex
(TF) that contacts the target gene promoter. 3. Ligand-independent genomic actions. Growth factors (GF) activate protein-kinase
cascades, leading to phosphorylation (P) and activation of nuclear ERs at EREs. 4. Nongenomic actions. Membrane E2-ER
complexes activate protein-kinase cascades, leading to altered functions of proteins in the cytoplasm, e.g. activation of eNOS,
or to regulation of gene expression through phosphorylation (P) and activation of a TF.
Björnström and Sjöberg • Minireview Mol Endocrinol, April 2005, 19(4):833–842 835

plex manner, and the involvement of ER activation NONGENOMIC ACTIONS OF ESTROGENS


function (AF) domains depends both on the receptor
subtype and on the type of ligand (16). The activation Evidence is accumulating that estrogens exert non-
of ER␣-AP-1 complexes that is induced by 17␤-estra- genomic actions—actions that are too rapid to be
diol requires the AF-2 domain of the receptor, which accounted for by the activation of RNA and protein
binds p160 coactivators and stabilizes in this way the synthesis. Nongenomic actions are a common prop-
formation of a multiprotein complex containing c-Jun, erty of steroid hormones and are frequently associated
ER␣, and transcriptional coactivators at the promoter with the activation of various protein-kinase cascades
(17, 18). (6).
Genes that contain GC-rich promoter sequences The nongenomic actions of 17␤-estradiol that have
are regulated in a similar manner through the interac- been reported include the mobilization of intracellular
tion of ERs with the Sp1 transcription factor (19). In- calcium (31), and the stimulation of adenylate cyclase
creasing numbers of genes are being found that are activity and cAMP production (32, 33). Activation of
activated by 17␤-estradiol through ER-Sp1 com-
the MAPK signaling pathway by 17␤-estradiol has
plexes, including the LDL-R [low-density lipoprotein
been extensively studied in several cell types, includ-
(LDL) receptor] (20), c-fos (21) and cyclin D1 (22)
ing breast cancer (34), endothelial (35), bone (36, 37),
genes. The actions of ERs at Sp1 binding sites depend
and neuroblastoma (38) cells. 17␤-Estradiol also acti-
on the ligand, the cell type, and the receptor subtype
vates the phosphoinositol (PI) 3-kinase signaling path-
(23), as is the case at for the actions of ERs at AP-1
way in endothelial (35), breast cancer (39), and liver
binding sites (16).
(40) cells.
Repression of the IL-6 gene by 17␤-estradiol is me-
Some authors have suggested that the nongenomic
diated through the interaction of ERs with two tran-
actions of estrogens are mediated through a subpopu-
scription factors, nuclear factor ␬␤ (NF-␬B) and
lation of the classical ERs, ER␣ and ER␤, that is lo-
CCAAT/enhancer binding protein ␤ (C/EBP␤) (24, 25).
cated at the plasma membrane (33, 41). Other authors
In addition, it has been suggested that the repression
disagree (42). In endothelial cells, as in other cell types,
of erythropoiesis by 17␤-estradiol involves the inter-
ERs have been found in caveolae where they activate
action of ERs with the GATA-1 transcription factor
endothelial nitric oxide synthase (eNOS) through pro-
(26).
tein kinase-mediated phosphorylation (43–45). Caveo-
ERs also regulate genes, such as the ␤-casein
gene, that contain signal transducer and activator of lae are specialized membrane invaginations enriched
transcription (STAT) 5 binding sites, but the out- in the scaffold protein caveolin-1. Caveolae facilitate
come of the interaction of ERs with the STAT5 tran- signal transduction by providing a location for various
scription factor is controversial. Some authors have signaling molecules (46). The only membrane recep-
suggested that STAT5-dependent transcription is tors for estrogens that have been found are the clas-
repressed by ERs activated by 17␤-estradiol, and sical ERs, ER␣ and ER␤. However, an isoform of ER␣
that this repression requires an intact ER AF-2 do- that is alternatively spliced (of molecular mass 46 kDa)
main (27, 28). Other authors have suggested that the and that has a truncated N-terminal domain has been
transcriptional activity of STAT5 is increased by ERs identified in endothelial cells (47). ERs do not contain
in a way that does not depend on the ER AF-2 a trans-membrane domain, and the ability of ER␣ to
domain (29). associate with the plasma membrane may be due to
ERE-independent genomic actions that involve teth- palmitoylation of the receptor (47, 48). The plasma
ering of ERs to other DNA binding transcription factors membrane ERs exist as functional dimers when acti-
do not require an interaction between the receptor and vated by estrogens (49).
DNA, as is the case in the classical mechanism of ER It appears that the ligand binding domain of the
action. However, the DNA binding domain (DBD) of the classical ER␣, when targeted to the plasma mem-
receptors is frequently involved, although intact DNA brane, is sufficient for mediating nongenomic actions
binding activity per se is not required (7–10, 13, 15, 25, of estrogens (50). However, other functional domains
28, 29). Mutational analysis has revealed specific res- of the receptors might contribute to the magnitude of
idues within the second zinc finger structure of the these actions by participating in various protein-pro-
ER␤ DBD that discriminate between the classical tein interactions. It is likely that the interaction of ERs
mechanism of ER action and the modulation of AP-1 with various scaffold or signaling molecules facilitates
and STAT5 activities through tethering (14). This re- the activity. ERs at the plasma membrane associate
gion is well conserved among nuclear receptors, and with the scaffold protein caveolin-1 (44, 51), and with
GR-mediated repression of AP-1 activity depends on a variety of proximal signaling molecules such as G
residues within the second zinc finger structure of the proteins (33, 52), Src kinase, and ras (34, 53), the p85␣
GR DBD (30). The DBD may be required for proper regulatory subunit of PI3-kinase (54) and Shc (55).
protein-protein interactions or it may be involved in Furthermore, the scaffold protein MNAR promotes the
recruiting additional coregulator proteins to the pro- interaction of ER␣ activated by 17␤-estradiol with Src
moter region. kinase, leading to an increase in Src kinase activity,
836 Mol Endocrinol, April 2005, 19(4):833–842 Björnström and Sjöberg • Minireview

and hence activation of the MAPK signaling pathway pathway by 17␤-estradiol results in enhanced AP-1
(56). DNA binding activity and transcriptional activation (40,
Membrane ERs also activate membrane tyrosine 67, 70). In contrast, inhibition of the c-jun amino-
kinase receptors in various cell types, including breast terminal kinase signaling pathway by 17␤-estradiol re-
cancer cells. ER␣ activated by 17␤-estradiol interacts sults in repression of AP-1 activity (65). The latter
directly with the IGF-I receptor, leading to activation of observation agrees with previous results showing that
the IGF-I receptor, and hence activation of the MAPK the c-jun amino-terminal kinase signaling pathway,
signaling pathway (57). ER␣ also interacts directly with and hence AP-1 phosphorylation and transcriptional
ErbB2 (HER-2/neu) (58). In addition, ER␣ activated by activation, are inhibited by other ligand-activated nu-
17␤-estradiol activates the epidermal growth factor clear receptors (71, 72).
(EGF) receptor by a mechanism that involves activa- The NF-␬B transcription factor complex is a target
tion of G proteins, Src kinase, and matrix metallopro- for phosphorylation by the Akt kinase (protein kinase
teinases, leading to an increase in MAPK and Akt B) (73, 74), and activation of the PI3-kinase/Akt sig-
(protein kinase B) activities (59). naling pathway by 17␤-estradiol leads to the expres-
The studies described above suggest that the mo- sion of genes that contain NF-␬B binding sites (75).
lecular mechanisms underlying the nongenomic ac- Tyrosine phosphorylation of the STAT family of tran-
tions of estrogens are specific for the cell type. The scription factors is required for their nuclear trans-
responses to estrogens may depend on a number of location and DNA binding activity (76). It has been
conditions, such as the set of signal transduction mol- suggested that additional serine phosphorylation
ecules and downstream targets present in the target modulates the maximal transcriptional activity of
cell, and thus, the responses are likely to be diverse. STATs (77). It has been reported that the phosphory-
lation of endogenous STAT3 and STAT5 on tyrosine
and serine residues is induced by 17␤-estradiol in
endothelial cells, and that STAT-dependent transcrip-
NONGENOMIC-TO-GENOMIC SIGNALING: A tion, by a mechanism that is dependent on ERs and
NOVEL MODE OF REGULATING TRANSCRIPTION that requires intact MAPK, PI3-kinase, and Src kinase
activities, is activated by 17␤-estradiol (78). These ob-
Signal transduction pathways may connect the non- servations disagree with a previous study showing that
genomic actions of estrogens to genomic responses. the tyrosine phosphorylation and DNA binding activity
The functions of many transcription factors are regu- of overexpressed STAT5 is decreased by ERs in
lated through protein kinase-mediated phosphoryla- COS-1 cells, both in the presence and in the absence
tion, and these transcription factors may thus be of 17␤-estradiol (79). The discrepancies between
targets for nongenomic actions of estrogens, as illus- these studies may be explained by differences in ex-
trated in Fig. 1. This type of nongenomic-to-genomic perimental conditions, such as the use of different
signaling is a distinct mechanism by which ERs can types of cells and the analysis of endogenous or over-
regulate transcription at alternative response ele- expressed proteins.
ments. This mechanism functions in addition to the It is important to note that ER␣ and ER␤ are also
ERE-independent genomic actions described above targets of phosphorylation by the MAPK signaling
that involve protein-protein interactions in the nucleus. pathway (80, 81). Thus, nongenomic actions of estro-
The transcription factors Elk-1 (60), C/EBP␤ (61), gens may modulate the functions of ERs themselves,
and CREB [cAMP response element (CRE) binding and in this way augment the classical mechanism of
protein] (62) are all targets for phosphorylation by the ER action. In addition, phosphorylation of the steroid
MAPK signaling pathway. Two processes have been receptor coactivator-3 is induced by 17␤-estradiol,
demonstrated in several cell types. These processes leading to increased transcriptional potency of ERs
are the phosphorylation of Elk-1 that is induced by (82). In the absence of estrogens, other signaling path-
17␤-estradiol, and the activation of serum response ways, such as the IGF-I and EGF signaling pathways,
elements (SREs) by a mechanism that is dependent on can modulate the functions of ERs through phosphor-
ERs and that requires intact MAPK activity (55, 63–65). ylation of the receptors on certain residues (83), as
C/EBP␤ and CREB are phosphorylated after the illustrated in Fig. 1.
MAPK signaling pathway has been activated by 17␤-
estradiol (65), and the phosphorylation of CREB leads
to the expression of genes that contain CREs (65–67).
CREB is a target for phosphorylation by the cAMP/ CONVERGENCE OF GENOMIC AND
protein kinase A signaling pathway (68), in addition to NONGENOMIC ACTIONS ON TARGET GENES
its MAPK-mediated activation. Thus, CREB may also
be activated by 17␤-estradiol through the stimulation The studies described above suggest that ERs can
of cAMP production. modulate the functions of transcription factors, and in
The transcriptional activity of the AP-1 transcription this way regulate gene expression, by at least two
factor complex is regulated through MAPK-mediated distinct mechanisms. These mechanisms are protein-
phosphorylation (69). Activation of the MAPK signaling protein interactions in the nucleus and activation of
Björnström and Sjöberg • Minireview Mol Endocrinol, April 2005, 19(4):833–842 837

signal transduction pathways at the plasma mem- has been activated by 17␤-estradiol with Src kinase
brane. These mechanisms function in addition to the and the p85␣ regulatory subunit of PI3-kinase in
classical mechanism of ER action that is extensively breast cancer cells (39). In liver (40) and endometrial
reviewed elsewhere (1). Natural gene promoters are (87) cells, activation of the cyclin D1 gene by 17␤-
often regulated by a large number of transcription estradiol is mediated through the AP-1 binding site,
factors that bind to distinct regulatory sites. Thus, the and this activation requires intact MAPK activity (40).
possible convergence of genomic and nongenomic Furthermore, opposing actions of ER␣ and ER␤ at the
actions at multiple response elements provides an cyclin D1 promoter have been observed (11), adding
extremely fine degree of control for the regulation of to the complexity of cyclin D1 gene regulation by ERs.
transcription by ERs, as illustrated in Fig. 2. The cyclin D1 promoter also contains binding sites for
Cyclin D1 is a well-defined target for estrogens in STAT5 and NF-␬B, and these may be targets for ERs
breast cancer cells, and it is important for the progres- through both genomic and nongenomic actions.
sion of cells through the G1 phase of the cell cycle (84, Regulation of the immediate early c-fos gene by ERs
85). The cyclin D1 promoter is complex and contains is also mediated through both genomic and non-
binding sites for several transcription factors, but no genomic actions. The interaction of ERs with the Sp1
ERE-like sequences have been identified (86). It has transcription factor at GC-rich promoter sequences
been suggested that activation of the cyclin D1 gene results in activation of the c-fos gene by 17␤-estradiol
by 17␤-estradiol results mainly from the interaction of (21), and this activation also results from activation of
ERs with the Sp1 transcription factor at GC-rich pro- the MAPK and PI3-kinase signaling pathways (64, 88).
moter sequences (22), and with c-Jun/ATF-2 het- Thus, the nongenomic actions involve activation of
erodimers at a variant CRE (10). However, it has also both MAPK and PI3-kinase signaling pathways, which
been reported that activation of the CRE by 17␤- target the Elk-1 and the SRF transcription factors,
estradiol results from activation of the cAMP/protein respectively. These transcription factors bind to the
kinase A signaling pathway (22), suggesting that non- SRE located in the c-fos promoter. The c-fos promoter
genomic actions are involved. In addition, the cyclin also contains a sis-inducible element recognized by
D1 gene is activated by the association of ER␣ that STATs and a cAMP response element, and these may

Fig. 2. Schematic Illustration of How Genomic and Nongenomic Actions of ERs on a Target Gene Promoter May Converge
Nuclear E2-ER complexes bind to EREs, and to transcription factor complexes, e.g. AP-1, STATs, ATF-2 (activation transcrip-
tion factor 2)/c-Jun, Sp1, and NF-␬B, that are bound to their cognate DNA binding sites. Membrane E2-ER complexes activate
protein-kinase cascades, leading to phosphorylation (P) of target transcription factors, e.g. AP-1, STATs, Elk-1, SRF (serum
response factor), CREB, and NF-␬B. The phosphorylation results in their transcriptional activation and/or in modulation of the
transcriptional activities of ER-AP-1, ER-STAT, ER-Sp1, and ER-NF-␬B complexes at the promoter. Protein-kinase cascades also
target ERs themselves and steroid receptor coactivator coactivators, resulting in enhanced transcriptional activity of ERs at EREs.
The distinct actions of ERs at multiple response elements provide an extremely fine degree of control for the regulation of target
gene transcription.
838 Mol Endocrinol, April 2005, 19(4):833–842 Björnström and Sjöberg • Minireview

be targets for ERs through both genomic and non- (92, 93). Furthermore, a number of genes that contain
genomic actions. ERE half-sites in proximity to Sp1 binding sites, both
Estrogens increase the clearance of LDL and they of which must be occupied for maximal activation, are
lower plasma LDL cholesterol levels in postmeno- activated by 17␤-estradiol. Such genes include those
pausal women, and these may be the mechanisms by for retinoic acid receptor ␣ (94), TGF␣ (95), and pro-
which estrogens reduce the risk of cardiovascular dis- gesterone receptor (96).
ease (89). The LDL-R gene is activated by 17␤-estra- It is evident that the regulation of gene expression
diol in the liver, although the LDL-R promoter does not by ERs is a multifactorial process, involving both
contain any ERE-like sequences (90). It has been re- genomic and nongenomic actions that often converge
ported that the interaction of ERs with the Sp1 tran- at certain response elements located in the promoters
scription factor at GC-rich promoter sequences gives of target genes. The final gene responses, however,
rise to activation of the LDL-R gene by 17␤-estradiol may depend on a number of conditions such as the
(20). In addition, tyrosine-kinase activity is required for combination of transcription factors bound to a spe-
the 17␤-estradiol-induced activation of the LDL-R cific gene promoter, the cellular localization of ERs,
gene (91), suggesting that nongenomic actions are the expression levels of various coregulator proteins
involved. The tyrosine-kinase pathway may be con- and signal transduction components, and the nature
nected with Sp1-dependent transcription. The LDL-R of extracellular stimuli. These variables are highly spe-
promoter also contains an SRE and this may be the cific for the cell type. Thus, estrogens may use differ-
target for ERs through nongenomic actions that in- ent signaling pathways depending on the cellular con-
volve activation of the MAPK and PI3-kinase signaling text, and in this way evoke distinct gene responses in
pathways. different types of target cells, as illustrated in Fig. 3.
Some estrogen-responsive genes contain a combi-
nation of direct ER binding sites and binding sites to
which ERs indirectly associate through tethering. One
such gene is the vascular endothelial growth factor RESPONSES TO SYNTHETIC LIGANDS
gene that contains a variant ERE that specifically binds
ERs activated by 17␤-estradiol, and G/GC-rich se- ER actions at alternative response elements have ag-
quences that bind ER-Sp1 and ER-Sp3 complexes onist and antagonist profiles that differ from the pro-

Fig. 3. Schematic Illustration of How ERs May Regulate Transcription at a Putative Target Gene Promoter in Different Types of
Target Cells
The signaling pathways used, i.e. ER actions at EREs or ERE-independent genomic and nongenomic actions of ERs, depend
on the cellular localization of ERs, and in this way, the magnitude of the gene response evoked by E2 may differ between target
cells.
Björnström and Sjöberg • Minireview Mol Endocrinol, April 2005, 19(4):833–842 839

files of the classical mechanism of ER action. The It appears that different functional domains of ERs
different responses to synthetic ligands may enable are involved in different receptor actions. Thus, natu-
the use of such compounds to dissociate between rally occurring splice variants such as ER␤cx (102),
distinct signaling pathways, and hence between gene ER␤␦3 (103), and the 46-kDa ER␣ (47), although un-
responses. able to regulate transcription at EREs, may act through
It has been suggested that estrogen-responsive alternative signaling pathways in their target tissues. If
genes containing AP-1 binding sites contribute to the this is the case, it will have important biological
difference in response that particular tissues make to significance.
selective ER modulators (SERMs). These differences, Further knowledge about the molecular mecha-
it is suggested, arise through differences in the acti- nisms by which ERs regulate transcription at alterna-
vation of ER␣ and ER␤ in the nucleus (97). Differential tive response elements may enable drug design to
activation of ER␣-Sp1 and of ER␤-Sp1 complexes at target specific receptor actions. Drugs that have been
GC-rich promoters takes place also in the presence of designed to differently affect ER actions at specific
SERMs (98). More recent studies, however, suggest cellular locations in a manner that depends on the cell
that some of the responses to SERMs are mediated type would widely expand the pharmacological pos-
through nongenomic actions, which subsequently sibilities open to physicians.
lead to genomic responses (70, 99). It may be possi-
ble, therefore, to develop of novel tissue-specific Acknowledgments
drugs that modulate the function of ERs at specific
cellular locations. Received December 7, 2004. Accepted January 25, 2005.
It has been claimed that estren, a synthetic estro- Address all correspondence and requests for reprints to:
gen, exerts only nongenomic actions (50). However, Maria Sjöberg, Department of Cell and Molecular Biology,
Karolinska Institutet, SE-171 77 Stockholm, Sweden. E-mail:
estren also affects ER actions in the nucleus (70), and maria.sjoberg@cmb.ki.se.
it activates transcription at EREs, although the tran-
scriptional potency of estren is lower that of 17␤-
estradiol (100).
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