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Metabolic Research Unit (R.M.U., C.M.A., P.W., P.J.K.), Department of Pathology (R.M.U.), School of Medicine, University of California at San Francisco, San Francisco, California 94143
Address all correspondence and requests for reprints to: Peter J. Kushner, Metabolic Research Unit, HSW Room 1141, University of California, San Francisco, San Francisco, California 94143-0540. E-mail: kushner{at}itsa.ucsf.edu
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Abstract |
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. The
ER/GR/AP-1 response element interaction was present, not only in a cell
line originally derived from a uterine cervical adenocarcinoma (HeLa),
but also in a cell line derived from the hypothalamus (GT1–1). Lastly,
both progesterone receptor types A and B also interacted with the ER at
the AP-1 site. These data indicate that opposing steroid influences can
be mediated at the level of transcription through the AP-1 site and
suggest that the integration of hormone action at this response element
may underlie some of the opposing actions of estrogens and
glucocorticoids or progestins on physiological responses. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Steroids act by binding to cognate receptors. The steroid-receptor complex then binds DNA at a hormone response element and activates gene transcription. For estrogens and glucocorticoids to counteract each other at the level of transcription, a given cell would have to express both receptors (ER and GR). In the uterus, there is evidence that ER and GR coexist in the endometrium (10). In the brain, maps of ER and GR immunoreactivity and messenger RNA (mRNA) localization suggest colocalization in certain cerebral nuclei, such as the paraventricular nucleus of the hypothalamus, the hypothalamic arcuate nucleus, and the central nucleus of the amygdala (11, 12). In bone, ER and GR have been found in cultured osteoblast-like cells (13). ER also has been demonstrated in osteoclasts (6), and data suggest that Dex regulates metabolism in these cells (14), raising the possibility that osteoclasts contain functional GR, as well. Lastly, numerous breast tumor cell lines have been demonstrated to have both ER and GR (15). Therefore, there is potential for ER/GR interactions at the level of transcription in numerous cell lines and tissue types.
The mechanism by which the ER and GR interact at the level of transcription must involve a process distinct from steroid receptor/hormone response element interactions. These interactions are highly specific, as dictated by differences in the DNA-binding regions of the ER and GR and in the sequence specificity of their cognate response elements (16, 17). An alternate explanation could involve interactions between steroid receptors and other transcription factors. The ER, GR, and other nuclear hormone receptors have been shown to alter transcription through the AP-1 response element that is bound by the transcription factors Jun and Fos. In fact, estrogens and glucocorticoids have opposing effects at this response element: estrogens stimulate AP-1-activated transcription (18, 19), whereas glucocorticoids inhibit it (20). Therefore, it might be possible for estrogens and glucocorticoids to influence each other’s ability to modulate transcription through the AP-1 site.
Given these common tissue targets, the presence of ER and GR in cell types contained within them, and the large number of genes regulated by members of the AP-1 family, we sought to determine whether the AP-1 response element could functionally integrate the transcriptional effects of estrogens and glucocorticoids. We characterized this interaction in cells originally derived from a uterine cervical adenocarcinoma (HeLa) and in a hypothalamic cell line (GT1–1) (21). We also tested the possibility that ER and progesterone receptor (PR) types A and B (PR-A and -B) might interact at the AP-1 response element.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cells
All cells were maintained in DME medium without phenol red. The
medium is supplemented by serum (Sigma), which we test for low
estrogenic activity before use. Charcoal- and heat-treated (55 C
x 1/2 h) serum was used in the GT1–1 and in all PR experiments. In
these experiments, cells were treated with media containing
charcoal-treated serum the night before transfection.
Transfection
Cells were transfected by electroporation, as previously
described (19). Briefly, 1–2 million cells from just confluent plates
were used for each cuvette. Cells were electroporated at .24 kV in
electroporation buffer. The electroporated cells were resuspended in
medium, which was then divided into six well plates. The efficiency of
transfection was monitored by cotransfection with either a ßhCG
reporter driven by an actin promoter (22) or by cotransfection with
pJ3LacZ. CAT or luciferase activity was then corrected by
dividing by hCG levels or ß-galactosidase activity. Five micrograms
of collagenase reporter plasmid and 1 µg of GR expression vector were
used in all experiments unless otherwise indicated.
Cell treatments
Cells were treated either immediately or up to 6 h after
transfection. They were then harvested at approximately 40 h after
plating. Dex, estradiol, and R5020 all were used at 10-7
M. Tamoxifen was used at 5 x 10-6
M. Phorbol 12-myristate 13-acetate (PMA; Sigma) was
suspended in dimethylsulfoxide, and cells were treated at
10-7 M; tumor necrosis factor- (TNF-;
R&D Systems, Minneapolis, MN) was resuspended in 0.1% BSA, and cells
were treated at 10 ng/ml.
CAT, luciferase, hCG, and ß-galactosidase assays
CAT, luciferase, and hCG assays were performed as described (19, 22). A commercial luminescent assay (Tropix, Bedford, MA) was used for
ß-galactosidase measurements.
Data analysis
In most figures, data has been expressed relatively to permit
statistical analysis of data from separate experiments. The relative
number, fold induction or percent stimulation, was averaged from two to
five experiments, as indicated in the figure legends. SD
was calculated for each averaged point, except for the reference, which
was set to 1 (fold induction) or 100% (percent stimulation). Fold
induction was calculated as the ratio of a steroid treatment to the No
Steroid treatment point. Percent stimulation was calculated as percent
of estradiol treatment. In some figures, representative data are shown
instead of averaged data. This permits evaluation of the effect of a
cotransfected plasmid or AP-1 activator treatment on transcription in
the absence of steroid treatment. In all cases, the data represented
has been repeated in 3 or more similar experiments.
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Results |
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HeLa cells were transfected with ER (HE0) and the truncated collagenase
promoter (Coll73-LUC) (Fig. 1A
), then treated with Dex,
estradiol, or Dex + estradiol. As previously reported, Dex inhibited,
and estradiol stimulated, transcription through this promoter. When
both steroids were added, GR blocked estradiol-stimulated transcription
(Fig. 1B). A similar ER/GR interaction occurs with both HE0 and HEG0,
which encodes the wild-type receptor (data not shown).
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) (19, 20, and
references therein). The minor steroid effects seen in Fig. 1C are not
reproducible (data not shown). Steroid effects also were attenuated
when HeLa cells were transfected with Coll73-CAT deleted of the AP-1
response element (Coll60-LUC) (19, 20, and data not shown). Dex then is
able to block estradiol stimulation of transcriptional activation
mediated by the AP-1 response element.
ER and GR functionally compete at the AP-1 response element
The above finding that Dex could block estradiol stimulation of
transcriptional activity at the AP-1 site suggested that the ER and GR
might functionally compete at this response element. We sought to
determine whether this was the case. We transfected HeLa cells with
increasing amounts of ER in the presence of a constant amount of
cotransfected GR (1 µg). At high levels of transfected ER, Dex was
unable to inhibit the estradiol response (Fig. 2, A and
B). We then transfected increasing amounts of GR in the presence of a
constant, high level of cotransfected ER. In the presence of endogenous
levels of GR, Dex was unable to inhibit estradiol stimulation. Dex
inhibition was restored by cotransfecting 1 µg or more of GR and
became more pronounced at higher levels of GR (Fig. 2, C and D; and
data not shown). Taken together, these data and the data presented in
Fig. 1 indicate that ER and GR transcriptional actions functionally
compete through the AP-1 response element. The competitive nature of
this interaction predicts that the net outcome of estrogen and
glucocorticoid transcriptional activity at the AP-1 response element
will depend on the ratio of ER to GR in a given cell. High levels of ER
would result in stimulation, and high levels of GR would result in
inhibition. Intermediate levels of each would result in an intermediate
effect. In some cases, a given proportion of ER:GR might result in the
cancellation of any estrogen or glucocorticoid effects at all.
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pathway is characterized by tamoxifen-induced transcriptional
activation and a requirement for the ER DNA-binding domain. Dex
inhibited tamoxifen activation (Fig. 3A). As seen with
estradiol, the degree of Dex inhibition diminished in the presence of
high levels of cotransfected ER (Fig. 3A). A C-terminally deleted ER
(HE15) serves as a model of tamoxifen activation. It lacks the
activation function in the C-terminus and activates transcription
through the activation function in the N-terminal domain. Therefore, it
is constitutively active at Coll73 (19). When we transfected cells with
increasing amounts of HE15 and treated with vehicle or Dex, Dex
inhibited the constitutive activity of HE15 (Fig. 3B). Again, the
interaction was functionally competitive; overexpression of HE15 (Fig. 3B) overcame Dex-mediated inhibition.
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). Because Dex inhibited tamoxifen stimulation, the
constitutive activity of the ER deleted of its C-terminal domain, and
estradiol-activated ER deleted of its DNA-binding domain (Figs. 3 and 4), we infer that glucocorticoids can inhibit both and ß pathways
of ER stimulation.
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We evaluated steroid responses in the presence of increasing amounts of
transfected c-Jun or c-Fos expression vectors. As previously
demonstrated, c-Jun increased estradiol transcriptional activation at
Coll73 (Fig. 5A) (19). At levels of cotransfected c-Jun
that resulted in slightly increased AP-1 activated transcription,
estradiol stimulation was potentiated. At levels of cotransfected c-Jun
that resulted in marked stimulation of AP-1 activated transcription,
further estradiol stimulation of AP-1 activation was no longer present.
Dex treatment alone restricted transcriptional activity to low levels
at all amounts of transfected c-Jun. In the presence of both Dex and
estradiol, the levels of transcription were close to those seen when
cells were treated with Dex alone. Cotransfected c-Fos potentiated
c-Jun stimulation of estradiol-mediated transcriptional activation
(Fig. 5B) (19). In distinction to transfection with c-Jun alone,
transfection with c-Fos alone failed to alter steroid responses.
Cotransfection of Jun B and D (0.1–3.0 µg) had minimal effects on
the pattern of steroid responses (data not shown). Therefore,
individual AP-1 family members seem to have different effects on the
profile of steroid responses at the AP-1 site.
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(TNF-) both activate c-Jun. However, they do so through different
pathways, which ultimately target different c-Jun phosphorylation sites
(37, 38). To determine whether glucocorticoid and/or estrogen effects
at the AP-1 response element would be altered in the presence of these
activators, HeLa cells were treated with estradiol and/or Dex in the
presence or absence of either PMA (10-7 M) or
TNF- (10 ng/ml). These doses resulted in maximal AP-1 activation for
each agent (data not shown). PMA treatment in the absence of steroids
resulted in a 10-fold stimulation of transcriptional activity (Fig. 6A, note difference in the scale of the No PMA and PMA
axes). The pattern of steroid effects was maintained in the presence of
PMA (Fig. 6A). In distinction, estradiol stimulation no longer was
apparent in the presence of TNF-, although Dex inhibition was
maintained (Fig. 6B). The loss of estradiol stimulation was not a
result of altering the functional activity of ER. Cells simultaneously
transfected with both Coll73-LUC and ERE-Coll60-CAT failed to show
diminished activity of ER at an ERE (data not shown). Therefore, though
both of these agents activate c-Jun, they each have different effects
on estradiol responses at the AP-1 response element.
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): estradiol stimulated, and
Dex inhibited, both basal and estradiol-stimulated transcription (Fig. 7). Like HeLa cells (Fig. 1C), GT1–1 cells transfected
with a collagenase reporter bearing a mutated AP-1 response element
(Coll517 mAP-1) failed to show steroid responses when compared with
Coll517 (data not shown). These data suggest that in the appropriate
state of c-Jun expression, ER and GR may competitively interact to
modulate expression of genes activated through the AP-1 response
element in neurons (see Discussion).
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). As
before, estradiol treatment stimulated transcription. Treatment with
both steroids resulted in a loss of RU5020 inhibition. PR-A behavior
was then evaluated in a different cell line. In the presence of
transfected PR-A, R5020 inhibited the estradiol response in CV-1 cells,
monkey kidney cells which lack endogenous GR (Fig. 8B). Further,
cotransfection of increasing amounts of c-Jun resulted in a pattern
similar to that seen in HeLa cells (compare Fig. 5A to 8B): the
transfecting of increased amounts of c-Jun lead to increased estradiol
stimulation, whereas RU5020 inhibition of estradiol was maintained at
low levels. As in the case of the GR, PR-A responses were not seen in
the presence of the collagenase reporter bearing the mutated AP-1 site
(Coll517 vs. Coll517 mAP-1, data not shown). These data
indicate that, like ER and GR, ER and PR influence each other’s
transcriptional activation properties at the AP-1 response element.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The data presented here support the hypothesis that opposing effects of estrogens and glucocorticoids or progestins can be mediated at the level of transcription. It has been reported previously that the ER, GR, and PR compete for unidentified factors involved in transcriptional regulation at hormone response elements (41). Here, we show that estrogen and glucocorticoid or PRs influence each other’s activity at an element through which they individually regulate transcription: the AP-1 site. This does not preclude that steroid interactions occur through other mechanisms, some of which may include other nuclear transcription factors.
The potential implications of these results are several fold. First,
although a cell may be capable of mounting an estrogen or
glucocorticoid response at the AP-1 response element, whether the
response will actually occur will depend on the relative levels of each
receptor. Estrogen stimulation of AP-1-regulated genes may be blunted
in the presence of glucocorticoids. Conversely, glucocorticoid
inhibition could be overcome by estrogen activation. Second, the
steroid response will be modulated by the levels and composition of the
AP-1 protein complex in the cell. Transfected c-Jun and c-Fos
differentially altered the estrogen and glucocorticoid pattern of
transcription. Lastly, the steroid responses also will be modified by
the activation state of the cell. Certain activators of AP-1 may
modulate a steroid response, e.g. TNF- modulation of
estrogen stimulation, whereas others may not.
There are several candidate genes for which such an ER/GR/or ER/PR/AP-1 response element interaction might be important. In the uterus, estradiol treatment increases the level of IGF-1 mRNA, and the increase is attenuated by prior administration of Dex (42). Our data from HeLa cells, a cell line originally derived from a uterine cervical adenocarcinoma, may suggest that genes expressed in the uterus have the cellular machinery to integrate ER and GR or PR responses through the AP-1 response element. The ER/PR interaction would be particularly important to pursue in uterine tissues, given the number of physiological estrogen/progestin interactions in that organ. For example, the high estrogen levels of the menstrual follicular phase are associated with proliferation of the endometrial epithelium. The transition from the proliferative to the secretory phase is associated with increased levels of progesterone. It is possible that genes associated with this transition could be jointly regulated by estrogen and progesterone at an AP-1 site.
In the nervous system, estrogens and glucocorticoids regulate the synthesis of numerous neuropeptides, including VP, POMC, and GnRH (43, 44, 45). Because we have shown that the ER/GR/AP-1 response element interaction is present in a hypothalamic cell line, it is possible that neurons that express these genes could have the cellular machinery to integrate estrogen and glucocorticoid or progestin effects at AP-1 sites. In particular, GT1 cells synthesize GnRH, and we and others have evidence that they contain functional endogenous ER (data not shown) (46). Further, GT1 cells contain endogenous GR, which apparently functions to down-regulate GnRH transcription in GT1 cell lines, in response to Dex (39). We suggest that GnRH, which contains an AP-1 response element in its promoter (47), could be regulated by estrogens and glucocorticoids in this manner.
The data presented here demonstrate that the AP-1 response element integrates the transcriptional properties of the ER with three other members of the nuclear receptor transcription factor family, the GR and PR-A and PR-B. Multiple receptors in this family have been shown to act at an AP-1 site (22, 48, 49, 50, 51). Therefore, the potential exists for the AP-1 response element to integrate the effect of the ER with other members of the family, as well as to integrate the effects of other superfamily members with each other. Such integration might occur at Jun/Jun, Jun/Fos AP-1 complexes, or through shared coactivators. For example, the CREB-Binding Protein (CBP) is a coactivator for AP-1 (52). In turn, CBP has been shown to interact with several members of the steroid receptor superfamily, as well as with members of the steroid receptor coactivator family (53). Therefore, the functional interaction of the steroid receptors described at the AP-1 site could be mediated, not only through AP-1 protein complexes, but also through a number of coactivator proteins involved in transducing steroid receptor signals to the basal transcriptional machinery.
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Acknowledgments |
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Footnotes |
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Received November 1, 1996.
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 P. E. Gallagher, P. Li, J. R. Lenhart, M. C. Chappell, and K. B. Brosnihan Estrogen Regulation of Angiotensin-Converting Enzyme mRNA Hypertension, January 1, 1999; 33(1): 323 - 328. [Abstract] [Full Text] [PDF]
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C. M. Klinge, B. F. Silver, M. D. Driscoll, G. Sathya, R. A. Bambara, and R. Hilf Chicken Ovalbumin Upstream Promoter-Transcription Factor Interacts with Estrogen Receptor, Binds to Estrogen Response Elements and Half-Sites, and Inhibits Estrogen-induced Gene Expression J. Biol. Chem., December 12, 1997; 272(50): 31465 - 31474. [Abstract] [Full Text] [PDF]
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L. F. Su, R. Knoblauch, and M. J. Garabedian Rho GTPases as Modulators of the Estrogen Receptor Transcriptional Response J. Biol. Chem., January 26, 2001; 276(5): 3231 - 3237. [Abstract] [Full Text] [PDF]
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 J. Teng, Z.-Y. Wang, and D. E. Bjorling Estrogen-induced proliferation of urothelial cells is modulated by nerve growth factor Am J Physiol Renal Physiol, June 1, 2002; 282(6): F1075 - F1083. [Abstract] [Full Text] [PDF]
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