You are on page 1of 10


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


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
lack EREs contain ERE half-sites, or binding sites for the
Molecular Endocrinology is published monthly by The
Endocrine Society (, 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).

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-
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
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
it activates transcription at EREs, although the tran-
scriptional potency of estren is lower that of 17␤-
estradiol (100).
The full estrogen antagonist ICI 182,780, on the REFERENCES
other hand, is unable to exert nongenomic actions
mediated through classical receptors, and this antag- 1. Nilsson S, Makela S, Treuter E, Tujague M, Thomsen J,
onist blocks completely the nongenomic actions of Andersson G, Enmark E, Pettersson K, Warner M,
Gustafsson JA 2001 Mechanisms of estrogen action.
estrogens (40, 50, 55, 63–65, 67, 78). However, ICI Physiol Rev 81:1535–1565
182,780 is a potent agonist to both ER␣ and ER␤ when 2. Rosenfeld MG, Glass CK 2001 Coregulator codes of
the receptors are tethered to the AP-1 (13, 14, 97), Sp1 transcriptional regulation by nuclear receptors. J Biol
(98, 101), and STAT5 (29) transcription factors in the Chem 276:36865–36868
nucleus. Thus, not all signaling pathways are inhibited 3. O’Lone R, Frith MC, Karlsson EK, Hansen U 2004
Genomic targets of nuclear estrogen receptors. Mol
by this antagonist. Endocrinol 18:1859–1875
4. Gottlicher M, Heck S, Herrlich P 1998 Transcriptional
cross-talk, the second mode of steroid hormone recep-
CONCLUDING REMARKS tor action. J Mol Med 76:480–489
5. Vanacker JM, Pettersson K, Gustafsson JA, Laudet V
1999 Transcriptional targets shared by estrogen recep-
It is evident that many genes are regulated by ERs and tor-related receptors (ERRs) and estrogen receptor (ER)
that these genes are of two types: those that contain ␣, but not by ER␤. EMBO J 18:4270–4279
EREs and those that do not. The latter genes contain 6. Losel R, Wehling M 2003 Nongenomic actions of steroid
binding sites for a variety of heterogeneous transcrip- hormones. Nat Rev Mol Cell Biol 4:46–56
7. Gaub MP, Bellard M, Scheuer I, Chambon P, Sassone-
tion factors. ER actions at alternative response ele- Corsi P 1990 Activation of the ovalbumin gene by the
ments enable a broader range of genes to be regulated estrogen receptor involves the fos-jun complex. Cell
than the range that can be regulated by the classical 63:1267–1276
mechanism of ER action alone. It is important to note 8. Umayahara Y, Kawamori R, Watada H, Imano E, Iwama
N, Morishima T, Yamasaki Y, Kajimoto Y, Kamada T
that the nongenomic actions of estrogens target many 1994 Estrogen regulation of the insulin-like growth fac-
of the transcription factors, such as AP-1, that partic- tor I gene transcription involves an AP-1 enhancer.
ipate in protein-protein interactions with ERs in the J Biol Chem 269:16433–16442
nucleus. The possible convergence of genomic and 9. Webb P, Lopez GN, Uht RM, Kushner PJ 1995 Tamox-
nongenomic actions on target genes is an attractive ifen activation of the estrogen receptor/AP-1 pathway:
potential origin for the cell-specific estrogen-like effects
mechanism by which ERs can finely regulate gene of antiestrogens. Mol Endocrinol 9:443–456
expression. The relative contributions of genomic and 10. Sabbah M, Courilleau D, Mester J, Redeuilh G 1999
nongenomic actions to certain gene responses in vivo, Estrogen induction of the cyclin D1 promoter: involve-
however, remain to be elucidated. The molecular ment of a cAMP response-like element. Proc Natl Acad
Sci USA 96:11217–11222
mechanisms underlying the effects of estrogens are 11. Liu MM, Albanese C, Anderson CM, Hilty K, Webb P,
likely to be specific for the cell type, and thus, the gene Uht RM, Price Jr RH, Pestell RG, Kushner PJ 2002
responses are likely to be diverse. Opposing action of estrogen receptors ␣ and ␤ on
840 Mol Endocrinol, April 2005, 19(4):833–842 Björnström and Sjöberg • Minireview

cyclin D1 gene expression. J Biol Chem 277: 29. Björnström L, Kilic E, Norman M, Parker MG, Sjöberg M
24353–24360 2001 Cross-talk between Stat5b and estrogen recep-
12. Philips A, Teyssier C, Galtier F, Rivier-Covas C, Rey JM, tor-␣ and -␤ in mammary epithelial cells. J Mol Endo-
Rochefort H, Chalbos D 1998 FRA-1 expression level crinol 27:93–106
modulates regulation of activator protein-1 activity by 30. Heck S, Kullmann M, Gast A, Ponta H, Rahmsdorf HJ,
estradiol in breast cancer cells. Mol Endocrinol 12: Herrlich P, Cato AC 1994 A distinct modulating domain
973–985 in glucocorticoid receptor monomers in the repression
13. Jakacka M, Ito M, Weiss J, Chien PY, Gehm BD, Jame- of activity of the transcription factor AP-1. EMBO J
son JL 2001 Estrogen receptor binding to DNA is not 13:4087–4095
required for its activity through the nonclassical AP1 31. Improta-Brears T, Whorton AR, Codazzi F, York JD,
pathway. J Biol Chem 276:13615–13621 Meyer T, McDonnell DP 1999 Estrogen-induced activa-
14. Björnström L, Sjöberg M 2002 Mutations in the estrogen tion of mitogen-activated protein kinase requires mobi-
receptor DNA-binding domain discriminate between the lization of intracellular calcium. Proc Natl Acad Sci USA
classical mechanism of action and cross-talk with 96:4686–4691
Stat5b and activating protein 1 (AP-1). J Biol Chem 32. Aronica SM, Kraus WL, Katzenellenbogen BS 1994 Es-
277:48479–48483 trogen action via the cAMP signaling pathway: stimula-
15. Schmitt M, Bausero P, Simoni P, Queuche D, Geoffroy tion of adenylate cyclase and cAMP-regulated gene
V, Marschal C, Kempf J, Quirin-Stricker C 1995 Positive transcription. Proc Natl Acad Sci USA 91:8517–8521
and negative effects of nuclear receptors on transcrip- 33. Razandi M, Pedram A, Greene GL, Levin ER 1999 Cell
tion activation by AP-1 of the human choline acetyl- membrane and nuclear estrogen receptors (ERs) origi-
transferase proximal promoter. J Neurosci Res 40: nate from a single transcript: studies of ER␣ and ER␤
152–164 expressed in Chinese hamster ovary cells. Mol Endo-
16. Kushner PJ, Agard DA, Greene GL, Scanlan TS, Shiau crinol 13:307–319
AK, Uht RM, Webb P 2000 Estrogen receptor pathways 34. Migliaccio A, Di Domenico M, Castoria G, de Falco A,
to AP-1. J Steroid Biochem Mol Biol 74:311–317 Bontempo P, Nola E, Auricchio F 1996 Tyrosine kinase/
17. Webb P, Nguyen P, Valentine C, Lopez GN, Kwok GR, p21ras/MAP-kinase pathway activation by estradiol-re-
McInerney E, Katzenellenbogen BS, Enmark E, Gustafs- ceptor complex in MCF-7 cells. EMBO J 15:1292–1300
son JA, Nilsson S, Kushner PJ 1999 The estrogen 35. Chen Z, Yuhanna IS, Galcheva-Gargova Z, Karas RH,
receptor enhances AP-1 activity by two distinct Mendelsohn ME, Shaul PW 1999 Estrogen receptor ␣
mechanisms with different requirements for receptor mediates the nongenomic activation of endothelial nitric
transactivation functions. Mol Endocrinol 13:1672–1685 oxide synthase by estrogen. J Clin Invest 103:401–406
18. Teyssier C, Belguise K, Galtier F, Chalbos D 2001 Char- 36. Endoh H, Sasaki H, Maruyama K, Takeyama K, Waga I,
acterization of the physical interaction between estro- Shimizu T, Kato S, Kawashima H 1997 Rapid activation
gen receptor ␣ and JUN proteins. J Biol Chem 276: of MAP kinase by estrogen in the bone cell line. Bio-
36361–36369 chem Biophys Res Commun 235:99–102
19. Porter W, Saville B, Hoivik D, Safe S 1997 Functional 37. Jessop HL, Sjoberg M, Cheng MZ, Zaman G, Wheeler-
synergy between the transcription factor Sp1 and the Jones CP, Lanyon LE 2001 Mechanical strain and es-
estrogen receptor. Mol Endocrinol 11:1569–1580 trogen activate estrogen receptor ␣ in bone cells.
20. Li C, Briggs MR, Ahlborn TE, Kraemer FB, Liu J 2001 J Bone Miner Res 16:1045–1055
Requirement of Sp1 and estrogen receptor ␣ interaction 38. Watters JJ, Campbell JS, Cunningham MJ, Krebs EG,
in 17␤-estradiol-mediated transcriptional activation of Dorsa DM 1997 Rapid membrane effects of steroids in
the low density lipoprotein receptor gene expression. neuroblastoma cells: effects of estrogen on mitogen
Endocrinology 142:1546–1553 activated protein kinase signalling cascade and c-fos
21. Duan R, Porter W, Safe S 1998 Estrogen-induced c-fos immediate early gene transcription. Endocrinology 138:
protooncogene expression in MCF-7 human breast 4030–4033
cancer cells: role of estrogen receptor Sp1 complex 39. Castoria G, Migliaccio A, Bilancio A, Di Domenico M, de
formation. Endocrinology 139:1981–1990 Falco A, Lombardi M, Fiorentino R, Varricchio L, Barone
22. Castro-Rivera E, Samudio I, Safe S 2001 Estrogen reg- MV, Auricchio F 2001 PI3-kinase in concert with Src
ulation of cyclin D1 gene expression in ZR-75 breast promotes the S-phase entry of oestradiol-stimulated
cancer cells involves multiple enhancer elements. J Biol MCF-7 cells. EMBO J 20:6050–6059
Chem 276:30853–30861 40. Marino M, Acconcia F, Bresciani F, Weisz A, Trenta-
23. Safe S 2001 Transcriptional activation of genes by 17 lance A 2002 Distinct nongenomic signal transduction
␤-estradiol through estrogen receptor-Sp1 interactions. pathways controlled by 17␤-estradiol regulate DNA
Vitam Horm 62:231–252 synthesis and cyclin D(1) gene transcription in HepG2
24. Ray A, Prefontaine KE, Ray P 1994 Down-modulation of cells. Mol Biol Cell 13:3720–3729
interleukin-6 gene expression by 17 ␤-estradiol in the 41. Pappas TC, Gametchu B, Watson CS 1995 Membrane
absence of high affinity DNA binding by the estrogen estrogen receptors identified by multiple antibody label-
receptor. J Biol Chem 269:12940–12946 ing and impeded-ligand binding. FASEB J 9:404–410
25. Stein B, Yang MX 1995 Repression of the interleukin-6 42. Toran-Allerand CD, Guan X, MacLusky NJ, Horvath TL,
promoter by estrogen receptor is mediated by NF-␬B Diano S, Singh M, Connolly Jr ES, Nethrapalli IS, Tin-
and C/EBP ␤. Mol Cell Biol 15:4971–4979 nikov AA 2002 ER-X: a novel, plasma membrane-asso-
26. Blobel GA, Sieff CA, Orkin SH 1995 Ligand-dependent ciated, putative estrogen receptor that is regulated
repression of the erythroid transcription factor GATA-1 during development and after ischemic brain injury.
by the estrogen receptor. Mol Cell Biol 15:3147–3153 J Neurosci 22:8391–8401
27. Stoecklin E, Wissler M, Schaetzle D, Pfitzner E, Groner 43. Kim HP, Lee JY, Jeong JK, Bae SW, Lee HK, Jo I 1999
B 1999 Interactions in the transcriptional regulation ex- Nongenomic stimulation of nitric oxide release by es-
erted by Stat5 and by members of the steroid hormone trogen is mediated by estrogen receptor ␣ localized in
receptor family. J Steroid Biochem Mol Biol 69:195–204 caveolae. Biochem Biophys Res Commun 263:257–262
28. Faulds MH, Pettersson K, Gustafsson JA, Haldosen LA 44. Chambliss KL, Yuhanna IS, Mineo C, Liu P, German Z,
2001 Cross-talk between ERs and signal transducer Sherman TS, Mendelsohn ME, Anderson RG, Shaul PW
and activator of transcription 5 is E2 dependent and 2000 Estrogen receptor ␣ and endothelial nitric oxide
involves two functionally separate mechanisms. Mol synthase are organized into a functional signaling mod-
Endocrinol 15:1929–1940 ule in caveolae. Circ Res 87:E44–E52
Björnström and Sjöberg • Minireview Mol Endocrinol, April 2005, 19(4):833–842 841

45. Chambliss KL, Yuhanna IS, Anderson RG, Mendelsohn 62. Bonni A, Brunet A, West AE, Datta SR, Takasu MA,
ME, Shaul PW 2002 ER␤ has nongenomic action in Greenberg ME 1999 Cell survival promoted by the Ras-
caveolae. Mol Endocrinol 16:938–946 MAPK signaling pathway by transcription-dependent
46. Shaul PW, Anderson RG 1998 Role of plasmalemmal and -independent mechanisms. Science 286:
caveolae in signal transduction. Am J Physiol 275: 1358–1362
L843–L851 63. de Jager T, Pelzer T, Muller-Botz S, Imam A, Muck J,
47. Li L, Haynes MP, Bender JR 2003 Plasma membrane Neyses L 2001 Mechanisms of estrogen receptor action
localization and function of the estrogen receptor ␣ in the myocardium. Rapid gene activation via the
variant (ER46) in human endothelial cells. Proc Natl ERK1/2 pathway and serum response elements. J Biol
Acad Sci USA 100:4807–4812 Chem 276:27873–27880
48. Acconcia F, Ascenzi P, Fabozzi G, Visca P, Marino M 64. Duan R, Xie W, Burghardt RC, Safe S 2001 Estrogen
2004 S-Palmitoylation modulates human estrogen re- receptor-mediated activation of the serum response el-
ceptor-␣ functions. Biochem Biophys Res Commun ement in MCF-7 cells through MAPK-dependent phos-
316:878–883 phorylation of Elk-1. J Biol Chem 276:11590–11598
49. Razandi M, Pedram A, Merchenthaler I, Greene GL, 65. Kousteni S, Han L, Chen JR, Almeida M, Plotkin LI,
Levin ER 2004 Plasma membrane estrogen receptors Bellido T, Manolagas SC 2003 Kinase-mediated regu-
exist and functions as dimers. Mol Endocrinol 18: lation of common transcription factors accounts for the
2854–2865 bone-protective effects of sex steroids. J Clin Invest
50. Kousteni S, Bellido T, Plotkin LI, O’Brien CA, Bodenner 111:1651–1664
DL, Han L, Han K, DiGregorio GB, Katzenellenbogen 66. Zhou Y, Watters JJ, Dorsa DM 1996 Estrogen rapidly
JA, Katzenellenbogen BS, Roberson PK, Weinstein RS, induces the phosphorylation of the cAMP response el-
Jilka RL, Manolagas SC 2001 Nongenotropic, sex-non- ement binding protein in rat brain. Endocrinology 137:
specific signaling through the estrogen or androgen 2163–2166
receptors: dissociation from transcriptional activity. Cell 67. Dos Santos EG, Dieudonne MN, Pecquery R, Le Moal V,
104:719–730 Giudicelli Y, Lacasa D 2002 Rapid nongenomic E2 ef-
51. Razandi M, Oh P, Pedram A, Schnitzer J, Levin ER 2002 fects on p42/p44 MAPK, activator protein-1, and cAMP
ERs associate with and regulate the production of response element binding protein in rat white adipo-
caveolin: implications for signaling and cellular actions. cytes. Endocrinology 143:930–940
Mol Endocrinol 16:100–115 68. Shaywitz AJ, Greenberg ME 1999 CREB: a stimulus-
52. Wyckoff MH, Chambliss KL, Mineo C, Yuhanna IS, induced transcription factor activated by a diverse array
Mendelsohn ME, Mumby SM, Shaul PW 2001 Plasma of extracellular signals. Annu Rev Biochem 68:821–861
membrane estrogen receptors are coupled to endothe- 69. Karin M 1995 The regulation of AP-1 activity by mito-
lial nitric-oxide synthase through G␣(i). J Biol Chem gen-activated protein kinases. J Biol Chem 270:
70. Björnström L, Sjöberg M 2004 Estrogen receptor-de-
53. Migliaccio A, Piccolo D, Castoria G, Di Domenico M,
pendent activation of AP-1 via non-genomic signalling.
Bilancio A, Lombardi M, Gong W, Beato M, Auricchio F
Nucl Recept 2:3
1998 Activation of the Src/p21ras/Erk pathway by pro-
71. Caelles C, Gonzalez-Sancho JM, Munoz A 1997 Nu-
gesterone receptor via cross-talk with estrogen recep-
clear hormone receptor antagonism with AP-1 by inhi-
tor. EMBO J 17:2008–2018
bition of the JNK pathway. Genes Dev 11:3351–3364
54. Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K,
72. Gonzalez MV, Jimenez B, Berciano MT, Gonzalez-San-
Chin WW, Liao JK 2000 Interaction of oestrogen recep- cho JM, Caelles C, Lafarga M, Munoz A 2000 Glucocor-
tor with the regulatory subunit of phosphatidylinositol- ticoids antagonize AP-1 by inhibiting the Activation/
3-OH kinase. Nature 407:538–541 phosphorylation of JNK without affecting its subcellular
55. Song RX, McPherson RA, Adam L, Bao Y, Shupnik M, distribution. J Cell Biol 150:1199–1208
Kumar R, Santen RJ 2002 Linkage of rapid estrogen 73. Romashkova JA, Makarov SS 1999 NF-␬B is a target of
action to MAPK activation by ER␣-Shc association and AKT in anti-apoptotic PDGF signalling. Nature 401:
Shc pathway activation. Mol Endocrinol 16:116–127 86–90
56. Wong CW, McNally C, Nickbarg E, Komm BS, Cheskis 74. Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM,
BJ 2002 Estrogen receptor-interacting protein that Donner DB 1999 NF-␬B activation by tumour necrosis
modulates its nongenomic activity-crosstalk with Src/ factor requires the Akt serine-threonine kinase. Nature
Erk phosphorylation cascade. Proc Natl Acad Sci USA 401:82–85
99:14783–14788 75. Kawagoe J, Ohmichi M, Takahashi T, Ohshima C, Ma-
57. Kahlert S, Nuedling S, van Eickels M, Vetter H, Meyer R, buchi S, Takahashi K, Igarashi H, Mori-Abe A, Saitoh M,
Grohe C 2000 Estrogen receptor ␣ rapidly activates the Du B, Ohta T, Kimura A, Kyo S, Inoue M, Kurachi H 2003
IGF-1 receptor pathway. J Biol Chem 275:18447–18453 Raloxifene inhibits estrogen-induced up-regulation of
58. Chung YL, Sheu ML, Yang SC, Lin CH, Yen SH 2002 telomerase activity in a human breast cancer cell line.
Resistance to tamoxifen-induced apoptosis is associ- J Biol Chem 278:43363–43372
ated with direct interaction between Her2/neu and cell 76. Darnell Jr JE 1997 STATs and gene regulation. Science
membrane estrogen receptor in breast cancer. Int J 277:1630–1635
Cancer 97:306–312 77. Decker T, Kovarik P 2000 Serine phosphorylation of
59. Razandi M, Pedram A, Park ST, Levin ER, Oh P, STATs. Oncogene 19:2628–2637
Schnitzer J 2003 Proximal events in signaling by plasma 78. Björnström L, Sjöberg M 2002 Signal transducers and
membrane estrogen receptors ERs associate with and activators of transcription as downstream targets of
regulate the production of caveolin: implications for sig- nongenomic estrogen receptor actions. Mol Endocrinol
naling and cellular actions. J Biol Chem 278:2701–2712 16:2202–2214
60. Cruzalegui FH, Cano E, Treisman R 1999 ERK activation 79. Wyszomierski SL, Yeh J, Rosen JM 1999 Glucocorti-
induces phosphorylation of Elk-1 at multiple S/T-P mo- coid receptor/signal transducer and activator of tran-
tifs to high stoichiometry. Oncogene 18:7948–7957 scription 5 (STAT5) interactions enhance STAT5 activa-
61. Buck M, Poli V, van der Geer P, Chojkier M, Hunter T tion by prolonging STAT5 DNA binding and tyrosine
1999 Phosphorylation of rat serine 105 or mouse thre- phosphorylation. Mol Endocrinol 13:330–343
onine 217 in C/EBP ␤ is required for hepatocyte prolif- 80. Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S,
eration induced by TGF ␣. Mol Cell 4:1087–1092 Sasaki H, Masushige S, Gotoh Y, Nishida E, Kawashima
842 Mol Endocrinol, April 2005, 19(4):833–842 Björnström and Sjöberg • Minireview

H, Metzger D, Chambon P 1995 Activation of the es- 93. Stoner M, Wang F, Wormke M, Nguyen T, Samudio I,
trogen receptor through phosphorylation by mitogen- Vyhlidal C, Marme D, Finkenzeller G, Safe S 2000 Inhi-
activated protein kinase. Science 270:1491–1494 bition of vascular endothelial growth factor expression
81. Tremblay A, Tremblay GB, Labrie F, Giguere V 1999 in HEC1A endometrial cancer cells through interactions
Ligand-independent recruitment of SRC-1 to estrogen of estrogen receptor ␣ and Sp3 proteins. J Biol Chem
receptor ␤ through phosphorylation of activation func- 275:22769–22779
tion AF-1. Mol Cell 3:513–519 94. Rishi AK, Shao ZM, Baumann RG, Li XS, Sheikh MS,
82. Wu RC, Qin J, Yi P, Wong J, Tsai SY, Tsai MJ, O’Malley Kimura S, Bashirelahi N, Fontana JA 1995 Estradiol
BW 2004 Selective phosphorylations of the SRC-3/AIB1 regulation of the human retinoic acid receptor ␣ gene in
coactivator integrate genomic reponses to multiple cel- human breast carcinoma cells is mediated via an im-
lular signaling pathways. Mol Cell 15:937–949 perfect half-palindromic estrogen response element
83. Driggers PH, Segars JH 2002 Estrogen action and cy- and Sp1 motifs. Cancer Res 55:4999–5006
toplasmic signaling pathways. Part II: the role of growth 95. Vyhlidal C, Samudio I, Kladde MP, Safe S 2000 Tran-
factors and phosphorylation in estrogen signaling. scriptional activation of transforming growth factor ␣ by
Trends Endocrinol Metab 13:422–427 estradiol: requirement for both a GC-rich site and an
84. Planas-Silva MD, Weinberg RA 1997 Estrogen-depen- estrogen response element half-site. J Mol Endocrinol
dent cyclin E-cdk2 activation through p21 redistribu- 24:329–338
tion. Mol Cell Biol 17:4059–4069 96. Petz LN, Nardulli AM 2000 Sp1 binding sites and an
85. Prall OW, Sarcevic B, Musgrove EA, Watts CK, Suther- estrogen response element half-site are involved in reg-
land RL 1997 Estrogen-induced activation of Cdk4 and ulation of the human progesterone receptor A promoter.
Cdk2 during G1-S phase progression is accompanied Mol Endocrinol 14:972–985
by increased cyclin D1 expression and decreased 97. Paech K, Webb P, Kuiper GG, Nilsson S, Gustafsson J,
cyclin-dependent kinase inhibitor association with cy- Kushner PJ, Scanlan TS 1997 Differential ligand activa-
clin E-Cdk2. J Biol Chem 272:10882–10894 tion of estrogen receptors ER␣ and ER␤ at AP1 sites.
86. Herber B, Truss M, Beato M, Muller R 1994 Inducible
Science 277:1508–1510
regulatory elements in the human cyclin D1 promoter.
98. Saville B, Wormke M, Wang F, Nguyen T, Enmark E,
Oncogene 9:2105–2107
Kuiper G, Gustafsson JA, Safe S 2000 Ligand-, cell-,
87. Shiozawa T, Miyamoto T, Kashima H, Nakayama K,
and estrogen receptor subtype (␣/␤)-dependent activa-
Nikaido T, Konishi I 2004 Estrogen-induced proliferation
tion at GC-rich (Sp1) promoter elements. J Biol Chem
of normal endometrial glandular cells is initiated by tran-
scriptional activation of cyclin D1 via binding of c-Jun to
an AP-1 sequence. Oncogene 23:8603–8610 99. Singleton DW, Feng Y, Burd CJ, Khan SA 2003 Non-
88. Duan R, Xie W, Li X, McDougal A, Safe S 2002 Estrogen genomic activity and subsequent c-fos induction by
regulation of c-fos gene expression through phospha- estrogen receptor ligands are not sufficient to promote
tidylinositol-3-kinase-dependent activation of serum re- deoxyribonucleic acid synthesis in human endometrial
sponse factor in MCF-7 breast cancer cells. Biochem adenocarcinoma cells. Endocrinology 144:121–128
Biophys Res Commun 294:384–394 100. Moverare S, Dahllund J, Andersson N, Islander U, Carl-
89. Walsh BW, Schiff I, Rosner B, Greenberg L, Ravnikar V, sten H, Gustafsson JA, Nilsson S, Ohlsson C 2003
Sacks FM 1991 Effects of postmenopausal estrogen Estren is a selective estrogen receptor modulator with
replacement on the concentrations and metabolism of transcriptional activity. Mol Pharmacol 64:1428–1433
plasma lipoproteins. N Engl J Med 325:1196–1204 101. Zou A, Marschke KB, Arnold KE, Berger EM, Fitzgerald
90. Croston GE, Milan LB, Marschke KB, Reichman M, P, Mais DE, Allegretto EA 1999 Estrogen receptor ␤
Briggs MR 1997 Androgen receptor-mediated antago- activates the human retinoic acid receptor ␣-1 promoter
nism of estrogen-dependent low density lipoprotein re- in response to tamoxifen and other estrogen receptor
ceptor transcription in cultured hepatocytes. Endocri- antagonists, but not in response to estrogen. Mol En-
nology 138:3779–3786 docrinol 13:418–430
91. Distefano E, Marino M, Gillette JA, Hanstein B, Pallottini 102. Ogawa S, Inoue S, Watanabe T, Orimo A, Hosoi T,
V, Bruning J, Krone W, Trentalance A 2002 Role of Ouchi Y, Muramatsu M 1998 Molecular cloning and
tyrosine kinase signaling in estrogen-induced LDL re- characterization of human estrogen receptor ␤cx: a po-
ceptor gene expression in HepG2 cells. Biochim Bio- tential inhibitor of estrogen action in human. Nucleic
phys Acta 1580:145–149 Acids Res 26:3505–3512
92. Mueller MD, Vigne JL, Minchenko A, Lebovic DI, Leit- 103. Price Jr RH, Butler CA, Webb P, Uht R, Kushner P,
man DC, Taylor RN 2000 Regulation of vascular endo- Handa RJ 2001 A splice variant of estrogen receptor ␤
thelial growth factor (VEGF) gene transcription by es- missing exon 3 displays altered subnuclear localization
trogen receptors ␣ and ␤. Proc Natl Acad Sci USA and capacity for transcriptional activation. Endocrinol-
97:10972–10977 ogy 142:2039–2049

Molecular Endocrinology is published monthly by The Endocrine Society (, the foremost
professional society serving the endocrine community.