Minireview: Genomic Organization of the Human ER
Gene Promoter Region
Martin Ko
,
George Reid,
Stefanie Denger and
Frank Gannon
European Molecular Biology Laboratory, D-69117 Heidelberg,
Germany
Address all correspondence and requests for reprints to: Dr. Martin Kos, European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69117, Heidelberg, Germany. E-mail: kos{at}embl-heidelberg.de
ABSTRACT
The ER
gene has been intensively studied for more than a decade.
During this long time, multiple promoters used in ER
expression have
been discovered in several species. Although an already large body of
literature describing various aspects of the regulation of ER
expression and utilization of different promoters is constantly
growing, the inconsistent terminology used by individual authors makes
the interpretation and comparison of data very difficult. Furthermore,
completion of the human genome project now allows all known human ER
promoters to be placed on a physical map. This review describes
promoters used in the generation of ER
transcripts in human and in
other species and suggests a consistent nomenclature. The possible role
of multiple promoters in the differential expression of ER
in
tissues and during development is also discussed.
ESTROGENS PLAY A crucial role in sexual
development and reproduction as well as in many physiological processes
in various tissues. They are also known to be involved in many
pathological processes such as breast and endometrial cancer
(1) and osteoporosis (2). The effects of
estrogens are mediated by their intracellular receptors (3, 4). To date, two nuclear ERs have been describedER
(NR3A1)
(5) and ERß (NR3A2; Refs. 6 and
7). Both belong to the superfamily of nuclear receptors
and family of steroid receptors that act as ligand-inducible
transcription factors (8, 9). For a detailed overview of
the nuclear receptor superfamily, their structural features, and
interactions with cofactors, see Refs. 10, 11, 12, 13, 14 .
The human ER
cDNA was cloned in 1986 (5, 15) and the
genomic organization was described 2 yr later (16).
Everything seemed to be clearthe gene consists of 8 exons spanning
140 kb of the chromosome 6q25.1 locus (17, 18). A
comparison of ER
cDNA sequence from human with those of chicken
(19), rat (20), and mouse (21)
showed a high level of conservation between species with the exception
of the 5'- end. However, evidence from the analysis of other nuclear
receptor family members indicated that multiple promoters might be a
common feature of steroid hormone receptors (22, 23). To
date, several exons encoding 5'-untranslated regions (UTRs) of ER
mRNAs have been identified. Unfortunately, different terminology
has been used by individual researchers and has resulted in confusion
regarding the different promoters used in ER
expression.
The aim of this review is to describe chronologically the discoveries
of all human ER
exons upstream of the translational start site,
which is in exon 1 (16). Various names for each of these
exons are listed and a unified nomenclature is suggested. Furthermore,
the genomic organization of the promoter region of the human ER
gene
is elucidated using sequences of two overlapping genomic contigs
sequenced and assembled by Sanger centre. Multiple promoters and
upstream exons of the human ER
gene are compared with known exons
and promoters in ER
genes from other species. Finally, some possible
functions of multiple promoters in regulation of ER
expression are
discussed.
PROMOTER REGION OF THE HUMAN ER
GENE
In the following paragraphs we will try to clearly describe the
discovery of human ER
upstream exons, and we ask readers to refer to
Fig. 1
whenever they feel confused.

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Figure 1. Genomic Organization of the Promoter Region of the
Human ER Gene
In the upper part of the figure the exons and the names
used for them by individual research groups are depicted in
chronological order from the top. On the
bottom the genomic location of multiple promoters and
upstream exons described to date is shown. Two genomic contigs covering
the region are outlined below. Colored boxes represent
upstream exons with names according to the suggested nomenclature.
Promoters are depicted as broken arrows. Numbers
below exons correspond to the distance from the originally
described transcription start site +1 in base pairs. Numbers
between exons show the size of major introns in kilobase pairs.
Broken lines symbolize observed splicing, and the common
acceptor splice site in exon 1 is represented by an open
triangle. *, These exons were described incorrectly as
contiguous.
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In 1991, Keaveney et al. (24) analyzed
sequences of genomic clones containing 5'-flanking regions of the human
ER
gene. A region with high homology to the first exon of the mouse
ER
gene (21) and the 5'-end of the rat ER
cDNA
(20) was found approximately 2 kb upstream of the
transcription start site identified by Green et al.
(5). Moreover, a potential acceptor splice site located in
exon 1 of human ER
at position +163 was found to be conserved
between species. It was proposed that the identified region, called at
that time "exon 1'," was spliced to this acceptor splice site +163.
This transcript was indeed isolated from human uterus
(24). Other laboratories subsequently confirmed this
finding (25, 26). Piva et al. (27)
then described an ER
transcript containing the 1' exon found by
Keaveney et al. but extending approximately 1.1 kb upstream.
It was suggested that a putative promoter exists further upstream of
the one proposed by Keaveney et al. (based by then on the
homology with mouse ER
gene) and that two major transcription start
sites are used to transcribe these two mRNAs (27).
However, the longer mRNA variant suggested by Piva et al.
(27) has not been detected in experiments designed to map
the 5'-ends of various ER
mRNAs performed by others
(28, 29, 30). These results indicated that the human ER
gene is transcribed from at least two promoters and the resulting
transcripts differ in their 5'-UTR. The corresponding promoters were
referred to originally as proximal and distal or simply as P0 or P1.
This was not the end of the story. Grandien (28) screened
various human cell lines and tissues and isolated from liver a new
ER
mRNA variant that had a distinct 5'-UTR. This established that
another promoter and 5'-exon exist in the human ER
gene. This exon
is also spliced to the acceptor splice site at position +163. As this
was the third exon to be identified, it was called "C" and the
previously identified exons were renamed "A" and "B." However,
1 yr later three new 5'-exons were isolated from a cDNA library
prepared from MCF7 cells (29). Screening of the cDNA
library yielded clones with two new transcripts that varied in their
5'-end from the previously described human ER
mRNA variants. These
were named by Thompson et al. (29) as "E"
and "H." Sequence searches in databases that are now available show
that exon E is located in the intronic region between exons 1' and 1,
respectively, which had been sequenced previously (24, 25). Part of the H transcript turned out to be identical to the
3'-part of exon C described by Grandien (28), but both
sequences varied in their 5'-ends. Further analysis of a genomic
library revealed that the 5'-end of the H transcript is encoded by two
separate exons called "Ha" and "Hb" by Thompson et
al., and these were separated by an intronic sequence of more than
9 kb. Exon Hb is common to two separate transcripts that result from
the splicing of exon C (the 5'-unique part) or Ha to exon Hb, which is
then spliced to the splice acceptor site +163 in exon 1 of the human
ER
gene (29). Only one year later another 5'-exon of
the human ER
was reported (30). Using the rapid
amplification of cDNA ends technique, a new exon D was cloned
from MCF7 cells and localized to approximately 3.7 kb upstream of exon
1. The other previously identified mRNA variants were also isolated and
their 5'-ends mapped confirming the promoter and exon structure
reported previously. Authors tried to simplify the nomenclature and
renamed all the 5'-upstream exons using capital letters starting from
the originally identified exon as exon 1A and going upstream in
alphabetical order to 1F. This order has been recently again disrupted
by two new exons isolated from testis total RNA (Brand, H., M.
Ko
, S. Denger, G. Flouriot, F. Gannon, and
G. Reid, manuscript submitted). Sequence search shows that
T1 and T2 exons are separated by 101-bp intron and are located
approximately 15 kb upstream of exon 1. Exon T1 can splice to exon T2
or directly to the acceptor splice site +163 (Brand et al.,
submitted).
In summary, the human ER
gene is transcribed from at least seven
promoters into multiple transcripts that all vary in their 5'-UTRs. All
upstream exons are spliced to the acceptor splice site at position +163
in coding exon 1. The scheme of the genomic organization of the human
ER
promoter region with all reported alternative splicing is shown
in Fig. 1
. This was constructed using the sequence of two genomic
contigs, available from the Sanger centre, that we found overlapped
with each other by 100 bp. We have confirmed this overlap by PCR using
primers that amplified a genomic region of 800 bp spanning the contig
junction (data not shown). A similar, but less complete, genomic
organization has been recently reported (31). The human
ER
gene is a large genetic unit that spans approximately 300 kb of
chromosome 6 [including the 140 kb containing the 8 protein coding
exons (16)]. It is likely that other promoters and exons
exist that are perhaps used in only a selected range of cell types or
tissues and which have remained undiscovered to date. The description
of the testis transcript is perhaps a foretaste of such a
proliferation. Any nomenclature system will be inevitably affected by
future discoveries of new upstream exons. Although we are aware that an
"ideal" nomenclature is an impossible task, we would like to
suggest that the nomenclature shown in Fig. 1
is used in the future and
that any new exon is named using capital letters fitting into an
alphabetical order if possible, or a letter referring to the tissue to
which an expression of such exon is restricted (e.g. T1 and
T2 for testis). It is hoped that this will alleviate some of the
existing confusion.
ER
GENE IN OTHER SPECIES
Are ER
genes of other species as complex as the human gene?
Although ER
cDNA from many species is known, only the genomic
structure of ER
from chicken, mouse, rat, and rainbow trout has been
extensively studied. The genomic organization of the 5'-region of the
ER
gene of these species compared with human is shown in Fig. 2
.

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Figure 2. Comparison of Promoter Regions of ER Genes of
Human and Other Species
All symbols are as in Fig. 1 . Exons conserved between human and other
species are depicted in the same color, and their
homology to human sequence in percentages of identity is shown
above each exon. Exons that dont have a known
counterpart in human are shown in light gray.
Dark gray represents exons conserved between species but
not known in the human. The genomic location of most exons in other
species is arbitrary, as their genomic organization is not known and is
indicated by question marks instead of the size of
introns. The originally described transcription start sites in all
species are represented by +1. The first coding exon is depicted as
exon 1 (except trout).
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Two species with relatively well characterized ER
genomic
organization are the closely related rat and mouse. The first exon of
the mouse corresponds to exon C of the human and is also located
approximately 2 kb upstream of the second exon, which contains the
translation start site. Thus, exon 2 of the mouse is equal to exon 1 of
the human, etc. For simplicity we number the exons according to the
human gene: exon 1 is the exon that contains the translation start
site. The same applies to the rat ER
gene. At least six upstream
exons (A, B, C, F1, F2, and H) exist in the ER
gene of the mouse
(32) and four upstream exons (called 0 or B, 0S, 0N, and
liver-specific C) in the rat (33, 34, 35). Mouse promoters and
exons A and B are equivalent to human A and B; however, their
expression is very low in all tissues tested so far (32).
There is no functional A promoter in the rat (35). Human
and mouse exon C and rat exon 0/B share a high homology. Also the
sequences of the exons F of the human, F1 of the mouse, and part of
exon 0S of the rat are highly conserved between these species. Although
exons H of the mouse and C of the rat are more than 95% homologous and
they are both expressed specifically in liver, no known counterpart to
them has been identified in humans to date.
The chicken ER
gene is transcribed from at least five different
promoters known as A1, A2, B, C, and D (36, 37). Exons A1
and B are homologous to exons A and B of the human ER
gene. Exon C
is not homologous directly to human C but to a region of human ER
located in the intron between exons B and C. The A2 promoter is located
in the region of the translational start site of the main open reading
frame, and the transcribed mRNA encodes a protein variant missing 41
amino acids at the N terminus. The smaller ER
protein is
predominantly expressed in liver (37).
Finally, it has been known for several years that two ER
protein
isoforms exist in rainbow trout (38). However, the origin
of these two isoforms has been elucidated only recently. The rainbow
trout ER
gene is transcribed from two different promoters, and the
resulting mRNAs encode ER
proteins of 65 kDa and 71 kDa; the latter
isoform possesses an additional 45 amino acids at its N terminus
(39).
We can conclude that chicken, mouse, rat, and rainbow trout ER
genes are also complex transcription units with multiple promoters and
upstream exons. All upstream exons are again spliced to an acceptor
splice site located in the first translated exon. This splice site is
highly conserved between species, although the sequences of upstream
exons are less homologous.
TISSUE-SPECIFIC PROMOTER UTILIZATION
The purpose and function of multiple promoters in the ER
gene
has been questioned since the discovery of the first alternative
promoter. Probably one of the most obvious implications is a potential
for a tissue-specific regulation of particular promoters and thus
regulation of expression of mRNA variants in tissues. Indeed, Grandien
et al. (26) showed that both human ER
promoters A and C are used in MCF7 cells but only promoter A is used in
ZR-75-1 cells. Another report from the same laboratory describes an
increased utilization of the promoter A in comparison to decreased
transcription from the promoter B in tumor-derived cell lines as
opposed to normal breast and uterine tissue (40).
Differential use of promoter C in normal and cancerous breast tissue
was also demonstrated (41). Later, Grandien also described
the liver-specific mRNA variant "E2-E1" (28)
(originally called "C" by the author) showing the existence of the
promoter E, which is used predominantly in liver as confirmed by others
(30). However, as we have already mentioned, rat exon C
and mouse exon H are exclusively expressed in the liver of rat and
mouse and are highly conserved between both species (32, 35), and yet these are not homologous to the human
liver-specific exon E. Several other publications show tissue-
specific expression of ER
mRNA variants in the human, mouse,
chicken, rat, rainbow trout, and even Japanese monkey (30, 32, 33, 34, 36, 37, 39, 42, 43, 44).
MULTIPLE PROMOTERS AND REGULATION OF ER
EXPRESSION
Several attempts to characterize promoters of ER
yielded a
handful of enhancer elements and transcription factors involved in
regulation of promoters in several cell lines (31, 45, 46, 47, 48, 49, 50, 51). Also auto-regulation of some ER
promoters by
estrogen has been observed (36, 43, 52, 53, 54). Most ER
promoters have no TATA, CCAAT box, or GC box sequences or, if present,
these do not match consensus sequences very well. Consequently,
multiple transcription start sites have been identified for most
upstream exons. Furthermore, ER
promoters are rather weak when
compared with other promoters, e.g. human A, F, and T
promoters are 100- to 1,000-fold weaker than the human
glyceraldehyde-3-phosphate dehydrogenase promoter in transient
transfection assays (our unpublished data). The low
transcriptional activity of the ER
promoters ensures that only low
levels of protein are expressed in the cell. This raises the question
of why there are multiple promoters rather than one that would be
tightly regulated? Several explanations are possible: 1) different
tissues use different promoters and/or 2) different promoters are used
in different stages of development and/or 3) transcripts produced from
various promoters undergo different alternative splicing resulting in
transcripts encoding various protein isoforms. We should also note that
if we consider a hypothetical system with only one promoter, then the
levels of various transcription activators and/or repressors need to be
regulated in a tissue-specific or developmental stage-specific manner
to ensure appropriate spatiotemporal expression of the target protein.
This could be achieved, for example, by control of transcription by
other factor and/or by regulating differential stabilities of mRNAs
encoding these factors or by the various stabilities of the factors
themselves. Such a system is perhaps even more complicated than the
reality found in nature with multiple promoters for ER
gene. An
increasing number of genes for which multiple promoters are being
described might support this view. Another interesting feature of the
ER
gene is its size. Large distances between promoters might be
needed to allow epigenetic regulation of promoters, as gene silencing
usually involves large genomic regions (for review see e.g.
Ref. 55).
The tissue-specific utilization of ER
promoters has been well
demonstrated as we have described. However, the relative quantification
of levels of ER
mRNA variants (28, 30, 32, 36, 37)
shows that some promoters are used, albeit to different extents, in all
the tissues tested and perhaps, surprisingly, also in tissues for which
a specific promoter had been described. We can speculate that the
promoters that are active in all tissues result in basal levels of
ER
mRNA and the tissue-specific promoters refine the level of ER
expression according to the requirements of the cell. This would
presume that ubiquitously active promoters might share the same
regulatory elements; however no data supporting or rejecting this
hypothesis are available today. Perhaps a genetic approach using
conditional and selective knockout technology might help to elucidate
the role of individual promoters in development and
differentiation.
A lack of data also accompanies the question of the developmental
regulation of ER
promoters. Kato et al. (42)
reported that levels of mRNA variants in rat brain change during
embryonic development. However, no more data addressing the regulation
of different promoters during development have been published. The
recent characterization of multiple ER
variants in the mouse
(32) renders this issue more amenable to
investigation.
As indicated above, another possible explanation for multiple promoters
is that it permits the variation of the alternative splicing of
transcripts produced from different promoters. Splicing of upstream
exons to the acceptor splice site in the first coding exon results in
multiple transcripts encoding the same full-length protein. These mRNA
variants differ only in their 5'-UTRs. It is known that regulatory
elements and short open reading frames in the 5'-UTR can control the
translation of mRNA (for review see Ref. 56). Most
upstream exons contain short open reading frames. Our data show that
these can significantly reduce translation of the mRNA (our
unpublished data). ER
5'-UTRs may further tighten the
regulation of ER
expression achieved by selective promoter usage.
However, it has been recently demonstrated that human exon F can be
spliced directly to the second coding exon in approximately 10% of
transcripts from F promoter in MCF7 cells. The resulting mRNA encodes
an ER
protein variant that lacks the N-terminal domain containing
the trans-activation function 1 (AF-1). This protein isoform
was detected in MCF7 cells (57). The same transcript is
also present in human osteoblasts; however, in this case it is
expressed to the same level as the full-length ER
protein
(58). The different relative levels of the
F-exon1 and F-exon2 transcripts indicate that this
alternative splicing might be regulated in a
tissue-specific manner. It is thus possible that utilization of
some promoters can lead to the alternative splicing of upstream exons
to different coding exons downstream of translational start sites and
thereby lead to the expression of ER
protein variants lacking
various amounts of the N terminus. We have also observed that most
upstream exons in mouse ER
can be spliced to the second or even
third coding exon, but the putative shorter protein isoforms encoded by
these transcripts have not been detected (our unpublished data).
Also, many alternatively spliced mRNA transcripts with a deletion of
one or more coding exons or truncation in the coding region have been
observed, especially in breast cancer tissue (for review see Refs.
59 and 60). However, a correlation between
the particular promoter usage and splicing pattern has not been
clearly demonstrated (61). Further investigation
addressing the question of possible tissue-specific regulation of
this alternative splicing and its consequences on a protein level is
necessary.
We have shown in this review that ER
is a large and complex
transcription unit. Although a significant amount of data on the
function and regulation of ER
in various species has been generated,
many questions, especially regarding the function of multiple
promoters, remain unanswered. We hope that this review
will help to stimulate new thoughts and
ideas to clarify these issues.
Sources of used sequences are listed in Table 1
.
ACKNOWLEDGMENTS
We would like to thank members of our laboratory for helpful
comments and discussions.
FOOTNOTES
This work was partially supported by European Community Grant
QLK6-1999-02108.
Abbreviations: UTR, Untranslated region.
Received for publication July 9, 2001.
Accepted for publication August 3, 2001.
REFERENCES
-
Henderson BE, Ross R, Bernstein L 1988 Estrogen as a
cause of human cancer: The Richard and Linda Rosenthal Foundation Award
Lecture. Cancer Res 48:246253[Medline]
-
Horowitz MC 1993 Cytokines and estrogen in bone:
anti-osteoporotic effects. Science 260:626627[Medline]
-
Jensen EV, Jacobson HI 1962 Basic guides to the mechanism of
estrogen action. Recent Prog Horm Res 18:387414
-
Jensen EV, DeSombre ER 1972 Mechanism of action of the female
sex hormones. Annu Rev Biochem 41:203230[CrossRef][Medline]
-
Green S, Walter P, Kumar V, Krust A, Bornert JM, Argos P,
Chambon P 1986 Human estrogen receptor cDNA: sequence, expression and
homology to v-erbA. Nature 320:134139[Medline]
-
Nuclear Receptors Nomenclature Committee 1999 A unified
nomenclature system for the nuclear receptor superfamily. Cell 97:161163[Medline]
-
Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA 1996 Cloning of a novel receptor expressed in rat prostate and ovary.
Proc Natl Acad Sci USA 93:59255930[Abstract/Free Full Text]
-
Evans RM 1988 The steroid and thyroid hormone receptor
superfamily. Science 240:889895[Medline]
-
Beato M 1989 Gene regulation by steroid hormones. Cell 56:335344[Medline]
-
Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schütz
G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM 1995 The nuclear receptor superfamily: the second decade. Cell 83:835839[Medline]
-
Beato M, Herrlich P, Schütz G 1995 Steroid hormone
receptors: many actors in search of a plot. Cell 83:851857[Medline]
-
Bourguet W, Germain P, Gronemeyer H 2000 Nuclear receptor
ligand-binding domains: three-dimensional structures, molecular
interactions and pharmacological implications. Trends Pharmacol Sci 21:381388[CrossRef][Medline]
-
Glass CK, Rosenfeld MG 2000 The coregulator exchange in
transcriptional functions of nuclear receptors. Genes Dev 14:121141[Free Full Text]
-
Aranda A, Pascual A 2001 Nuclear hormone receptors and gene
expression. Physiol Rev 81:12691304[Abstract/Free Full Text]
-
Greene GL, Gilna P, Waterfield M, Baker A, Hort Y, Shine J 1986 Sequence and expression of human estrogen receptor complementary
DNA. Science 231:11501154[Medline]
-
Ponglikitmongkol M, Green S, Chambon P 1988 Genomic
organization of the human oestrogen receptor gene. EMBO J 7:33853388[Abstract]
-
Walter P, Green S, Greene G, Krust A, Bornert JM, Jeltsch JM,
Staub A, Jensen E, Scrace G, Waterfield M, 1985 Cloning of the human
estrogen receptor cDNA. Proc Natl Acad Sci USA 82:78897893[Abstract]
-
Gosden JR, Middleton PG, Rout D 1986 Localization of the human
oestrogen receptor gene to chromosome 6q24q27 by in situ
hybridization. Cytogenet Cell Genet 43:218220[Medline]
-
Krust A, Green S, Argos P, Kumar V, Walter P, Bornert JM,
Chambon P 1986 The chicken oestrogen receptor sequence: homology with
v-erbA and the human oestrogen and glucocorticoid receptors. EMBO J 5:891897[Abstract]
-
Koike S, Sakai M, Muramatsu M 1987 Molecular cloning and
characterization of rat estrogen receptor cDNA. Nucleic Acids Res 15:24992513[Abstract]
-
White R, Lees JA, Needham M, Ham J, Parker MG 1987 Structural
organization and expression of the mouse estrogen receptor. Mol
Endocrinol 1:735744[Abstract]
-
Hodin RA, Lazar MA, Wintman BI, Darling DS, Koenig RJ, Larsen
PR, Moore DD, Chin WW 1989 Identification of a thyroid
hormone receptor that is pituitary-specific. Science 244:7679[Medline]
-
Kastner P, Krust A, Turcotte B, Stropp U, Tora L, Gronemeyer
H, Chambon P 1990 Two distinct estrogen-regulated promoters generate
transcripts encoding the two functionally different human progesterone
receptor forms A and B. EMBO J 9:16031614[Abstract]
-
Keaveney M, Klug J, Dawson MT, Nestor PV, Neilan JG, Forde RC,
Gannon F 1991 Evidence for a previously unidentified upstream exon in
the human oestrogen receptor gene. J Mol Endocrinol 6:111115[Abstract]
-
Piva R, Gambari R, Zorzato F, Kumar L, del Senno L 1992 Analysis of upstream sequences of the human estrogen receptor gene.
Biochem Biophys Res Commun 183:9961002[Medline]
-
Grandien KF, Berkenstam A, Nilsson S, Gustafsson JA 1993 Localization of DNase I hypersensitive sites in the human oestrogen
receptor gene correlates with the transcriptional activity of two
differentially used promoters. J Mol Endocrinol 10:269277[Abstract]
-
Piva R, Bianchi N, Aguiari GL, Gambari R, del Senno L 1993 Sequencing of an RNA transcript of the human estrogen receptor gene:
evidence for a new transcriptional event. J Steroid Biochem Mol Biol 46:531538[CrossRef][Medline]
-
Grandien K 1996 Determination of transcription start sites in
the human estrogen receptor gene and identification of a novel,
tissue-specific, estrogen receptor-mRNA isoform. Mol Cell Endocrinol 116:207212[CrossRef][Medline]
-
Thompson DA, McPherson LA, Carmeci C, deConinck EC, Weigel RJ 1997 Identification of two estrogen receptor transcripts with novel 5'
exons isolated from a MCF7 cDNA library. J Steroid Biochem Mol Biol 62:143153[CrossRef][Medline]
-
Flouriot G, Griffin C, Kenealy M-R, Sonntag-Buck V, Gannon F 1998 Differentially expressed messenger RNA isoforms of the human
estrogen receptor-
gene are generated by alternative splicing and
promoter usage. Mol Endocrinol 12:19391954[Abstract/Free Full Text]
-
Schuur ER, McPherson LA, Yang GP, Weigel RJ 2001 Genomic
structure of the promoters of the human estrogen receptor-
gene
demonstrate changes in chromatin structure induced by AP2
. J
Biol Chem 276:1551915526[Abstract/Free Full Text]
-
Kos M, OBrien S, Flouriot G, Gannon F 2000 Tissue-specific
expression of multiple mRNA variants of the mouse estrogen receptor
gene. FEBS Lett 477:1520[CrossRef][Medline]
-
Hirata S, Koh H, Yamada-Mouri N, Hoshi K, Kato J 1996 The
untranslated exon "exon 0S" of the rat estrogen receptor (ER) gene.
FEBS Lett 394:371373[CrossRef][Medline]
-
Hirata S, Koh H, Yamada-Mouri N, Kato J 1996 The novel
untranslated first "exon 0N" of the rat estrogen receptor gene.
Biochem Biophys Res Commun 225:849854[CrossRef][Medline]
-
Freyschuss B, Grandien K 1996 The 5' flank of the rat estrogen
receptor gene: structural characterization and evidence for tissue- and
species-specific promoter utilization. J Mol Endocrinol 17:197206[Abstract]
-
Griffin C, Flouriot G, Sonntag-Buck V, Nestor PV, Gannon F 1998 Identification of novel chicken estrogen receptor-
messenger ribonucleic acid isoforms generated by alternative splicing
and promoter usage. Endocrinology 139:46144625[Abstract/Free Full Text]
-
Griffin C, Flouriot G, Sonntag-Buck V, Gannon F 1999 Two
functionally different protein isoforms are produced from the chicken
estrogen receptor-
gene. Mol Endocrinol 13:15711587[Abstract/Free Full Text]
-
Pakdel F, Petit F, Anglade I, Kah O, Delaunay F, Bailhache
T, Valotaire Y 1994 Overexpression of rainbow trout estrogen receptor
domains in Escherichia coli: characterization and
utilization in the production of antibodies for immunoblotting and
immunocytochemistry. Mol Cell Endocrinol 104:8193[CrossRef][Medline]
-
Pakdel F, Metivier R, Flouriot G, Valotaire Y 2000 Two
estrogen receptor (ER) isoforms with different estrogen dependencies
are generated from the trout ER gene. Endocrinology 141:571580[Abstract/Free Full Text]
-
Grandien K, Backdahl M, Ljunggren O, Gustafsson JA, Berkenstam
A 1995 Estrogen target tissue determines alternative promoter
utilization of the human estrogen receptor gene in osteoblasts and
tumor cell lines. Endocrinology 136:22232229[Abstract]
-
Weigel RJ, Crooks DL, Iglehart JD, deConinck EC 1995 Quantitative analysis of the transcritional start sites of estrogen
receptor in breast carcinoma. Cell Growth Differ 6:707711[Abstract]
-
Kato J, Hirata S, Koh T, Yamada-Mouri N, Hoshi K, Okinaga S 1998 The multiple untranslated first exons and promoters system of the
oestrogen receptor gene in the brain and peripheral tissues of the rat
and monkey and the developing rat cerebral cortex. J Steroid Biochem
Mol Biol 65:281293[CrossRef][Medline]
-
Donaghue C, Westley BR, May FE 1999 Selective promoter usage
of the human estrogen receptor-
gene and its regulation by estrogen.
Mol Endocrinol 13:19341950[Abstract/Free Full Text]
-
Osterlund MK, Grandien K, Keller E, Hurd YL 2000 The human
brain has distinct regional expression patterns of estrogen receptor
mRNA isoforms derived from alternative promoters. J Neurochem 75:13901397[CrossRef][Medline]
-
deConinck EC, McPherson LA, Weigel RJ 1995 Transcriptional
regulation of estrogen receptor in breast carcinomas. Mol Cell Biol 15:21912196[Abstract]
-
McPherson LA, Baichwal VR, Weigel RJ 1997 Identification of
ERF-1 as a member of the AP2 transcription factor family. Proc Natl
Acad Sci USA 94:43424347[Abstract/Free Full Text]
-
Tang Z, Treilleux I, Brown M 1997 A transcriptional enhancer
required for the differential expression of the human estrogen receptor
in breast cancers. Mol Cell Biol 17:12741280[Abstract]
-
Cohn CS, Sullivan JA, Kiefer T, Hill SM 1999 Identification of
an enhancer element in the estrogen receptor upstream region:
implications for regulation of ER transcription in breast cancer. Mol
Cell Endocrinol 158:2536[CrossRef][Medline]
-
McPherson LA, Weigel RJ 1999 AP2
and AP2
: a comparison
of binding site specificity and trans-activation of the estrogen
receptor promoter and single site promoter constructs. Nucleic Acids
Res 27:40404049[Abstract/Free Full Text]
-
Tanimoto K, Eguchi H, Yoshida T, Hajiro-Nakanishi K, Hayashi S 1999 Regulation of estrogen receptor
gene mediated by promoter B
responsible for its enhanced expression in human breast cancer. Nucleic
Acids Res 27:903909[Abstract/Free Full Text]
-
Penolazzi L, Lambertini E, Aguiari G, del Senno L, Piva R 2000 Cis element "decoy" against the upstream promoter of the human
estrogen receptor gene. Biochim Biophys Acta 1492:560567[Medline]
-
Castles CG, Oesterreich S, Hansen R, Fuqua SAW 1997 Auto-regulation of the estrogen receptor promoter. J Steroid
Biochem Mol Biol 62:155163[CrossRef][Medline]
-
Pakdel F, Le Guellec C, Vaillant C, Le Roux MG, Valotaire Y 1989 Identification and estrogen induction of two estrogen receptors
(ER) messenger ribonucleic acids in the rainbow trout liver: sequence
homology with other ERs. Mol Endocrinol 3:4451[Abstract]
-
Treilleux I, Peloux N, Brown M, Sergeant A 1997 Human estrogen
receptor (ER) gene promoter-P1: estradiol independent activity and
estradiol inducibility in ER+ and
ER- cells. Mol Endocrinol 11:13191331[Abstract/Free Full Text]
-
Wolffe AP, Matzke MA 1999 Epigenetics: regulation through
repression. Science 286:481486[Abstract/Free Full Text]
-
Gray NK, Wickens M 1998 Control of translation initiation in
animals. Annu Rev Cell Dev Biol 14:399458[CrossRef][Medline]
-
Flouriot G, Brand H, Denger S, Metivier R, Kos M, Reid G,
Sonntag-Buck V, Gannon F 2000 Identification of a new isoform of the
human estrogen receptor-
(hER-
) that is encoded by distinct
transcripts and that is able to repress hER-
activation function 1.
EMBO J 19:46884700[Abstract/Free Full Text]
-
Denger S, Reid G, Ko
M, Flouriot G, Parsch D,
Brand H, Korach KS, Sonntag-Buck V, Gannon F 2001 ER
gene expression in human primary osteoblasts: evidence for the
expression of two receptor proteins. Mol Endocrinol 15:20642077[Abstract/Free Full Text]
-
Pfeffer U 1996 Estrogen receptor mRNA variants. Do they have a
physiological role? Ann NY Acad Sci 784:304312[Medline]
-
Zhang QX, Hilsenbeck SG, Fuqua SA, Borg A 1996 Multiple
splicing variants of the estrogen receptor are present in individual
human breast tumors. J Steroid Biochem Mol Biol 59:251260[CrossRef][Medline]
-
Fasco MJ 1998 Estrogen receptor mRNA splice variants produced
from the distal and proximal promoter transcripts. Mol Cell Endocrinol 138:5159[CrossRef][Medline]