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School of Biological Sciences, University of Liverpool, Liverpool, L69 3BX, United Kingdom
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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However, more recent evidence has suggested that the ER, in particular, may be activated in a ligand-independent manner by a variety of agents that include several growth factors (9, 10, 11), the neurotransmitter dopamine (12), and cAMP (13, 14). The expression of a variety of estrogen-responsive genes has been shown to be stimulated by these agents by a mechanism that is inhibited by the presence of the pure antiestrogen, ICI 164384 (9, 11, 13). Because ICI 164384 acts by binding to the ER (15), this is taken as evidence that transcriptional activation by these alternative agents involves the ER. Stimulation by epidermal growth factor (EGF) of the expression of estrogen-responsive reporter gene constructs in HeLa cells, which do not express endogenous ER, has been shown to be dependent upon coexpression of ER (9). In addition, it has been shown that the estrogen-like effects of EGF upon the mouse uterus do not occur in ER-deficient transgenic mice (10).
We now present evidence that the activation of the human ER by EGF and by cAMP involves mechanisms distinct from that of estradiol and distinguishable from each other. Furthermore, the transactivation effect of EGF is not dependent upon estradiol effects upon receptor activity.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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, the product of HE15 consists of the A/B and C
domains and therefore retains AF-1, but not AF-2, transactivation
function. The HEG19 product consists of domains C, D, and E/F and
therefore has ligand-binding activity and retains AF-2 but not AF-1
transactivation function. We investigated the ability of these ER
constructs to stimulate the expression of chloramphenicol
acetyltransferase (CAT) reporter gene constructs, in response to
estradiol, EGF, and elevated cAMP. The relative contributions of AF-1
and AF-2 to overall transcriptional activation are reported to be
promoter specific (6, 7, 8), and we therefore used three reporter
constructs, each with a different promoter structure (Fig. 1b).
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). CT causes irreversible stimulation of adenylate
cyclase, and IBMX inhibits cAMP phosphodiesterase; together they cause
a major increase in intracellular cAMP (13). Cotransfection of the full
length ER (HEG0) with the reporter gene enables all three agents to
stimulate CAT expression (Fig. 2). EGF alone causes an increase in CAT
expression that is less than that seen with estradiol; however,
simultaneous treatment of the cells with EGF and estradiol results in a
response that is the sum of the two separate responses. CT/IBMX alone
causes only a weak stimulation of reporter gene activity but has a
synergistic effect when combined with estradiol. The Gly->Val mutation
in HE0 has been reported to prevent the ligand-independent activation
of the ER by dopamine (12). However, we found that HE0 is able to
support a pattern of response to estradiol, EGF, and CT/IBMX, alone and
in combination, similar to that seen in the presence of the wild type
receptor. The pattern of response to the inducers is similar for the
different reporter gene constructs, although the scale of the increase
varies.
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). The scale of increase produced by EGF with HE15
(e.g. 2ERE.TATA, 5.6 ± 0.8-fold increase) is
equivalent to that seen with the complete receptor (2ERE.TATA, 4.8
± 0.7-fold increase). The product of HE15 does not possess a
hormone-binding site and is therefore unresponsive to both estradiol
and ICI 164384. HEG19 can respond to estradiol, but there is no further
increase seen when EGF is combined with the hormone.
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). The pattern
of response to CT/IBMX, alone or in combination with estradiol or with
ICI 164384, in the presence of HEG19 is similar to that seen with HEG0.
The response to estradiol in the presence of HEG19 is reduced
(e.g. ERE.VIT, 6.1-fold increase) compared with that seen
with HEG0 (11.1-fold increase), but CT/IBMX in combination with
estradiol still produces a synergistic response with ERE.VIT and
2ERE.TATA reporters, although the ERE.TK response is merely
additive (data not presented). Cells transfected with HEG19 were
rigorously depleted of estrogen before they were treated with
CT/IBMX, making it unlikely that the response seen in the absence of
exogenous estradiol involves an interaction between cAMP and
ligand-occupied receptor.
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). In addition, the response to EGF is now inhibited
by ICI 164384, indicating that the two truncated receptors interact
with each other. Phosphorylation of Ser118 has been shown
to be necessary for full activation of AF-1 (18) and to occur via
mitogen-activated protein kinase in EGF-stimulated cells (19, 20). The
HE457 mutant ER cannot be phosphorylated at this residue and does not
support stimulation of the ERE.VIT or 2ERE.TATA reporter genes by EGF,
although their responsiveness to estradiol and to increased cAMP is
retained (Fig. 5b).
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). Interestingly, the
response of the reporter gene to estradiol or to EGF is unaffected by
either of these protein kinase inhibitors. The involvement of PKA in
the activation of the ER by cAMP is supported by the results shown in
Fig. 7. HeLa cells were cotransfected with the ERE.VIT
reporter gene, with the HEG0 ER expression vector and, as indicated,
with an expression vector coding for either the 
- or the ß-isoform
of the human PKA catalytic subunit (23). Overexpression of PKA alone
had no detectable effect upon reporter gene expression but, in the
presence of estradiol, there was a nearly 4-fold increase in the
response above that seen with estradiol alone. Both PKA and PKAß
produced a synergistic increase, equivalent to that seen upon elevation
of cellular cAMP levels with CT/IBMX. The effects of PKA upon ERE.VIT
expression were abolished by the presence of ICI 164384, indicating
their requirement for ER.
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). Neither reporter gene showed a
significant response to EGF alone, although the CAT activity with EGF +
estradiol (ERE.VIT, 121 ± 4%; ERE.TK, 125 ± 5%) was
marginally higher than that with estradiol alone. Both reporter genes
responded to CT/IBMX, but only ERE.VIT showed a synergistic response
when CT/IBMX was combined with estradiol (CT/IBMX, 2-fold increase;
estradiol, 14-fold increase; estradiol + CT/IBMX 36-fold increase).
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), i.e.
induction by EGF but not by estradiol or CT/IBMX. However, ERE.TK
responded to EGF and failed to respond to estradiol, but also showed a
clear response to CT/IBMX. ERE.VIT and ERE.TK, in the presence of
HEG19, reproduced the pattern of responses to the three inducers that
was seen in HeLa cells, i.e. induction by estradiol and by
CT/IBMX, but only ERE.TK showed a synergistic response to their
simultaneous presence.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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This latter conclusion is supported by our experiments using truncated
versions of the ER, which demonstrate that EGF and cAMP require
different regions of the receptor to achieve their effects upon
transcription. The fact that EGF can cause stimulation of transcription
in the absence of the carboxyl-terminal AF-2 transactivation domain
suggests that its effects are mediated via AF-1. EGF can stimulate
reporter gene transcription via HE15, a truncated version of the ER
that completely lacks the ligand-binding domain of the receptor,
clearly establishing that EGF does not simply enhance the action of
estradiol, but is able to activate the ER de novo. On the
other hand, elevated cellular cAMP levels, produced by treating cells
with CT/IBMX, appear to act by increasing the transactivation activity
of AF-2, located in the carboxyl-terminal half (E domain) of the
receptor. In this connection it is interesting to note that the only
difference we observed between the activity of the wild type receptor
(HEG0) and the receptor with a point mutation in the E domain (HE0) is
that the latter showed a diminished response to CT/IBMX (Fig. 2
).
Because the HEG19 construct retains the ligand-binding domain of the
receptor, we cannot determine whether or not the cAMP effect requires
the occupation of the LBD by an agonistic ligand. The fact that
stimulation of transcription by CT/IBMX can be seen in cells that have
been rigorously depleted of estrogen makes this unlikely.
The role played by phosphorylation of the ER in the ability of the
receptor to stimulate transcription is unclear. The ER protein is
phosphorylated at a basal level in the absence of estradiol, and
numerous reports (e.g. Refs. 18, 25, and 26) have shown that
the level of phosphorylation is increased upon hormone binding. The
identity of the amino acids phosphorylated, their relative levels of
phosphorylation, and the functional consequences of their
phosphorylation are, however, the subjects of conflicting reports (18, 25, 26, 27). Nevertheless, the fact that ER phosphorylation is also
increased, at apparently identical sites, by antiestrogen binding (18, 25) indicates that ligand-induced transactivation activity of the
receptor is not determined solely by its level of phosphorylation. The
evidence we present here supports the idea that ligand-independent
activation of the ER requires phosphorylation of the receptor protein
at sites that differ with the identity of the activator.
Ser118, which is situated within the AF-1 domain (28), has
been identified as a major site of ligand-stimulated phosphorylation
(18, 26) and has also been shown to be phosphorylated by
mitogen-activated protein kinase in response to EGF stimulation of
cells (19, 20). Conversion of this residue to a nonphosphorylatable
alanine (HE457) abolishes activation of the ER by EGF (Fig. 5b).
However, HE457 is still activated, albeit to a reduced extent, by
estradiol and by elevated cAMP. Elevation of cellular cAMP has been
reported to stimulate ER phosphorylation at a site(s) outside the A/B
domain and distinct from those responsive to ligand binding (25). We
show that inhibition of cAMP-stimulated protein kinase (PKA), by
treating cells with the specific inhibitor H-89, prevents stimulation
of reporter gene activity by CT/IBMX and, most strikingly, prevents the
synergism between estradiol and CT/IBMX (Fig. 6). The involvement of
PKA in the activation of ER by elevated cAMP is also supported by our
observation that increasing kinase activity by overexpression of the
PKA catalytic subunit duplicates the synergistic response to estradiol
seen with CT/IBMX treatment (Fig. 7). This stimulation of reporter gene
expression by elevated PKA level was prevented by the antiestrogen, ICI
164384, indicating the requirement for ER.
ICI 164384 is termed a "pure" antiestrogen (15) because, unlike
non-steroid antiestrogens such as tamoxifen, it does not exhibit any
agonist activity but inhibits both the AF-1 and the AF-2
transactivation functions of the receptor (29). The mechanism by which
ICI 164384 occupation of the ligand-binding domain, in the
carboxy-terminal half of the receptor, may interfere with the activity
of the amino-terminal AF-1 function is unclear. Our experiments (Fig. 5a), in which both truncated versions of the ER (HE15+HEG19) were
simultaneously expressed in HeLa cells, show that the AF-1 domain and
the ligand-binding domain do not need to be situated in the same
molecule for inhibition to occur. ICI 164384 was able to inhibit the
action of EGF, previously shown to operate by stimulating AF-1 but not
AF-2, indicating that the two truncated receptors interacted with each
other rather than acting independently. The mechanism of this
intermolecular interaction is unclear. Both HE15 and HEG19 possess
DNA-binding domains so that they may be capable of binding to the ERE
as a heterodimer, and the association of HEG19, in an inactive
configuration, with HE15 may inactivate HE15 also.
Both AF-1 and AF-2 contribute to the overall transactivation activity
of the ligand-occupied ER, but the nature of their contributions
differs. Truncated receptors have shown that AF-1 can exhibit
transactivation in the absence of estrogen binding to the ER whereas
AF-2 activity is dependent upon hormone binding (6, 7). We have now
demonstrated that AF-1 activity, although ligand-independent, is not
constitutive but may be indirectly regulated by signal molecules that
bind to plasma membrane receptors. The relative contributions of AF-1
and AF-2 to gene activation are markedly influenced both by the
structure of the target gene promoter and by the cell type containing
the target gene (6, 7, 8). Differences in their extent of response were
observed between the reporter genes, although the pattern of response
to the inducers was similar for all three reporter gene constructs.
However, it is difficult to detect any consistent pattern in the
relative responsiveness of the reporter genes. In general, the ERE.VIT
reporter gene, which has the largest number of copies of the ERE and
the most complex promoter, gave the largest response, but there were
exceptions to this, e.g. with HEG19 in COS-1 cells (Fig. 9).
We assume that these differences between promoters arise from
differences in requirements for possible intermediary factors and
differences in the availability of these molecules in different cell
types (30). We compared the responses of the ERE.VIT and ERE.TK
reporter genes in COS-1 cells with those in HeLa cells. The only
significant difference between the results with the two cell lines was
that ERE.TK was able to respond to CT/IBMX in the presence of HE15, in
COS-1 cells. Apparently, in the presence of certain promoters and in a
cooperative cellular context, cAMP may also work through AF-1. A
potential PKA phosphorylation site does exist within the HE15 sequence
at Ser236 (25).
Our results show that the ER can be stimulated to activate transcription by EGF and cAMP as well as by binding estradiol. Transcriptional activation by estradiol is believed to involve both the AF-1 and AF-2 transactivation functions. Our experiments indicate that, at least in certain promoter/cell type contexts, EGF and cAMP effects each involve only one transactivation function: AF-1 for EGF and AF-2 for cAMP. The fact that addition of either EGF or CT/IBMX in the presence of a saturating concentration of estradiol results in a further increase in reporter gene expression indicates that there are basic differences between the mechanisms of ligand-independent and ligand-dependent activation. We have presented evidence that specific protein kinases are involved in the mechanisms triggered by the two non-ligand activators of the ER. It is increasingly recognized that the many intracellular signal transduction pathways in eukaryotic cells do not operate independently of each other but that cross-talk between pathways is possible and potentially important. It appears that the ER provides a site for the integration of three well recognized signal transduction pathways, i.e. those of steroid hormones, cAMP, and tyrosine kinase receptors.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The ER plasmids, reporter constructs, and PKA plasmids were obtained
from the laboratories in which they were constructed. ER derivatives,
HE0 (4), HEG0, HEG19 (17), and HE457 (18) are contained within the
eukaryotic expression vector pSG5, and HE15 is contained in pKCR2 (4).
pCEV and pCßEV consist of cDNAs coding for the - and
ß-isoforms of the PKA catalytic subunit, contained within the Zem3
vector in which transcription is driven by the mouse metallothionein
promoter (23). ERE.VIT is derived from the Xenopus laevis
vitellogenin B1 gene (31). 2ERE.TATA is an entirely synthetic
enhancer/promoter sequence (31). ERE.TK (pERE BLCAT) consists of a
consensus ERE linked to the promoter sequence (nucleotides -105 to
+51) of the herpes simplex virus, thymidine kinase gene (6).
Cell Culture and Transient Transfections
HeLa cells and COS-1 cells were obtained from the European
Collection of Animal Cell Culture (Porton Down, U.K). Both cell lines
were cultured in MEM medium (GIBCO BRL) containing 100 µg/ml
penicillin (GIBCO), 100 µg/ml streptomycin (GIBCO), and 10%
(vol/vol) FCS (GIBCO). Cells were depleted of estrogen by culture for 6
days in phenol red-free RPMI 1640 medium (GIBCO), supplemented with 5%
(vol/vol) dextran/charcoal-treated NBCS (32). Cells were further
cultured for 1 day in medium supplemented with 1% (vol/vol)
dextran/charcoal-treated NBCS followed by 1 day in serum-free medium
[phenol red-free RPMI 1640 supplemented with: 10 µg/ml transferin;
10 ng/ml sodium selenite; 1% (wt/vol) glutamine; 0.2% (wt/vol) BSA].
Cells were then harvested and seeded, in multiwell plates, at a density
of 2 x 105 cells per 35-mm well, in serum-free
medium. After 24 h, cells were transfected with DNA \[300 ng ER
plasmid (HEG0, HE0, HE15, HEG19 or HE457), 1000 ng each of 2ERE.TATA,
ERE.VIT, or ERE.TK plasmid, 20 ng pCEV or pCßEV plasmid, 700 ng
pSV-ß-galactosidase plasmid (Promega, Madison, WI)\] using the
LipofectAMINE reagent (Life Technologies, Gaithersburg, MD) according
to the manufacturer’s protocol. After 5 h an equal volume of
serum-free medium was added to each well. After a further 19 h the
medium was changed for fresh serum-free medium containing the inducing
agents: 10-8 M estradiol (E); 100 ng/ml EGF; 1
µg/ml CT, 10-4 M IBMX; 10-6
M ICI 164384 (ICI); or without addition (C). For
transfections involving the pCEV and pCßEV vectors, the culture
medium was supplemented with 80 µM ZnSO4.
Cells were incubated for 24 h and then were harvested and CAT
(liquid scintillation method) and ß-galactosidase activities were
assayed in whole cell extracts using assay kits (Promega) according to
the manufacturer’s protocols. CAT activity results were normalized
relative to the ß-galactosidase activity, to correct for differences
in efficiency of transfection, and are expressed as a percentage of the
estradiol-induced level, as indicated. Results are the mean ±
SD of at least three separate experiments.
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ACKNOWLEDGMENTS |
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EV and pCßEV;
D. J. Shapiro for the gift of ERE.VIT and 2ERE.TATA; M. G. Parker for
the gift of ERE.TK; and A. E. Wakeling for the gift of ICI 164384. |
FOOTNOTES |
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This work was supported by the Association for International Cancer Research.
Received for publication July 19, 1996. Accepted for publication March 11, 1997.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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R. K. Tyagi, Y. Lavrovsky, S. C. Ahn, C. S. Song, B. Chatterjee, and A. K. Roy Dynamics of Intracellular Movement and Nucleocytoplasmic Recycling of the Ligand-Activated Androgen Receptor in Living Cells Mol. Endocrinol., August 1, 2000; 14(8): 1162 - 1174. [Abstract] [Full Text]
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E. M. Resnick, D. A. Schreihofer, A. Periasamy, and M. A. Shupnik Truncated Estrogen Receptor Product-1 Suppresses Estrogen Receptor Transactivation by Dimerization with Estrogen Receptors alpha and beta J. Biol. Chem., March 15, 2000; 275(10): 7158 - 7166. [Abstract] [Full Text] [PDF]
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L. Dong, W. Wang, F. Wang, M. Stoner, J. C. Reed, M. Harigai, I. Samudio, M. P. Kladde, C. Vyhlidal, and S. Safe Mechanisms of Transcriptional Activation of bcl-2 Gene Expression by 17beta -Estradiol in Breast Cancer Cells J. Biol. Chem., November 5, 1999; 274(45): 32099 - 32107. [Abstract] [Full Text] [PDF]
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S. C. Sharma, J. W. Clemens, M. D. Pisarska, and J. S. Richards Expression and Function of Estrogen Receptor Subtypes in Granulosa Cells: Regulation by Estradiol and Forskolin Endocrinology, September 1, 1999; 140(9): 4320 - 4334. [Abstract] [Full Text]
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M. D. Sadar Androgen-independent Induction of Prostate-specific Antigen Gene Expression via Cross-talk between the Androgen Receptor and Protein Kinase A Signal Transduction Pathways J. Biol. Chem., March 19, 1999; 274(12): 7777 - 7783. [Abstract] [Full Text] [PDF]
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 D. Chen, P. E. Pace, R. C. Coombes, and S. Ali Phosphorylation of Human Estrogen Receptor alpha by Protein Kinase A Regulates Dimerization Mol. Cell. Biol., February 1, 1999; 19(2): 1002 - 1015. [Abstract] [Full Text] [PDF]
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J. W. Clemens, R. L. Robker, W. L. Kraus, B. S. Katzenellenbogen, and J. S. Richards Hormone Induction of Progesterone Receptor (PR) Messenger Ribonucleic Acid and Activation of PR Promoter Regions in Ovarian Granulosa Cells: Evidence for a Role of Cyclic Adenosine 3',5'-Monophosphate but Not Estradiol Mol. Endocrinol., August 1, 1998; 12(8): 1201 - 1214. [Abstract] [Full Text]
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M. A. Ansonoff and A. M. Etgen Estradiol Elevates Protein Kinase C Catalytic Activity in the Preoptic Area of Female Rats Endocrinology, July 1, 1998; 139(7): 3050 - 3056. [Abstract] [Full Text] [PDF]
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A. L. Jacob and J. Lund Mutations in the Activation Function-2 Core Domain of Steroidogenic Factor-1 Dominantly Suppresses PKA-dependent Transactivation of the Bovine CYP17 Gene J. Biol. Chem., May 29, 1998; 273(22): 13391 - 13394. [Abstract] [Full Text] [PDF]
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 D. M. Tanenbaum, Y. Wang, S. P. Williams, and P. B. Sigler Crystallographic comparison of the estrogen and progesterone receptor's ligand binding domains PNAS, May 26, 1998; 95(11): 5998 - 6003. [Abstract] [Full Text] [PDF]
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R. M. Lavinsky, K. Jepsen, T. Heinzel, J. Torchia, T.-M. Mullen, R. Schiff, A. L. Del-Rio, M. Ricote, S. Ngo, J. Gemsch, et al. Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes PNAS, March 17, 1998; 95(6): 2920 - 2925. [Abstract] [Full Text] [PDF]
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R. S. Piotrowicz, L. Ding, P. Maher, and E. G. Levin Inhibition of Cell Migration by 24-kDa Fibroblast Growth Factor-2 Is Dependent upon the Estrogen Receptor J. Biol. Chem., February 2, 2001; 276(6): 3963 - 3970. [Abstract] [Full Text] [PDF]
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E. Castro-Rivera, I. Samudio, and S. Safe Estrogen Regulation of Cyclin D1 Gene Expression in ZR-75 Breast Cancer Cells Involves Multiple Enhancer Elements J. Biol. Chem., August 10, 2001; 276(33): 30853 - 30861. [Abstract] [Full Text] [PDF]
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J. M. Hall, J. F. Couse, and K. S. Korach The Multifaceted Mechanisms of Estradiol and Estrogen Receptor Signaling J. Biol. Chem., September 28, 2001; 276(40): 36869 - 36872. [Full Text] [PDF]
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