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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 2005 Mar 18;102(13):4890–4895. doi: 10.1073/pnas.0501042102

Thyroid hormone can increase estrogen-mediated transcription from a consensus estrogen response element in neuroblastoma cells

Xing Zhao *, Heather Lorenc *, Heather Stephenson *, Yunjiao Joy Wang *, Dawn Witherspoon *, Benita Katzenellenbogen †, Donald Pfaff ‡, Nandini Vasudevan *,§
PMCID: PMC555723  PMID: 15778291

Abstract

Thyroid hormones (T) and estrogens (E) are nuclear receptor ligands with at least two molecular mechanisms of action: (i) relatively slow genomic effects, such as the regulation of transcription by cognate T receptors (TR) and E receptors (ER); and (ii) relatively rapid nongenomic effects, such as kinase activation and calcium release initiated at the membrane by putative membrane receptors. Genomic and nongenomic effects were thought to be disparate and independent. However, in a previous study using a two-pulse paradigm in neuroblastoma cells, we showed that E acting at the membrane could potentiate transcription from an E-driven reporter gene in the nucleus. Because both T and E can have important effects on mood and cognition, it is possible that the two hormones can act synergistically. In this study, we demonstrate that early actions of T via TRα1 and TRβ1 can potentiate E-mediated transcription (genomic effects) from a consensus E response element (ERE)-driven reporter gene in transiently transfected neuroblastoma cells. Such potentiation was reduced by inhibition of mitogen-activated protein kinase. Using phosphomutants of ERα, we also show that probable mitogen-activated protein kinase phosphorylation sites on the ERα, the serines at position 167 and 118, are important in TRβ1-mediated potentiation of ERα-induced transactivation. We suggest that crosstalk between T and E includes potential interactions through both nuclear and membrane-initiated molecular mechanisms of hormone signaling.

Keywords: crosstalk, nuclear receptors, phosphorylation, synergy

Thyroid hormones (T) are important in the regulation of neural differentiation, neural development, and mood modulation. Most of the effects of T are mediated by T receptors (TRs). TRs belong to the nuclear receptor superfamily, whose members act as ligand-dependent transcription factors (1). Such genomic transcriptional effects usually require 1 h to many hours to be manifest. Different isoforms of the TR, TRα1 and TRα2, are derived from the TRα gene, whereas TRβ1 and TRβ2 are from a separate TRβ gene (2, 3). In contrast, T also have rapid effects (seconds to minutes), which are mediated through putative membrane receptors (ref. 4 and references therein). Previously, we have investigated the contribution of rapid nongenomic actions of estrogen (E) to slower genomic transcriptional actions of E in neuroblastoma cells. Cells transiently transfected with E receptor (ER)α and an E response element (ERE)-based reporter gene were exposed to two pulses of hormones. The first pulse of 20 min used a membrane limited estradiol conjugate [17β-estradiol linked to BSA (E-BSA)] to promote the nongenomic actions of E. The second pulse (1-h duration), separated from the first pulse by an interpulse hormone-free interval of 2 h, used 10-9 M 17β-estradiol and was designed to promote transcriptional actions from a consensus ERE. Using this two-pulse paradigm, we demonstrated that initial membrane actions of E were essential and sufficient to potentiate transcription from the consensus ERE in neuroblastoma cells (5).

In MCF-7 breast carcinoma cells, the membrane impermeant agarose-T4 applied for 15 min increased cell proliferation (6), suggesting that nongenomic actions of T can mimic 17β-estradiol in breast cancer cells (6). Triiodothyronine (T3)-liganded TRβ1 could also enhance liganded ERα-mediated transcription from an oxytocin receptor promoter in the neuroblastoma cell line, SK-N-BE(2)C (7). Could this transcriptional potentiation be due to nongenomic actions of T? Among the different TR isoforms, we investigated the role of TRα1 and TRβ1, because these are (i) ligand-binding TR isoforms unlike the TRα2 isoform and (ii) more ubiquitously distributed in different tissues, unlike TRβ2, which has a restricted distribution in the pituitary (8). In this study, we have adopted this two-pulse paradigm to test the hypothesis that early actions of 10-8 M T3 can potentiate transcription by 10-9 M17β-estradiol from a consensus ERE in neuroblastoma cells. We demonstrate that either TRβ1 or TRα1 increases 17β-estradiol-mediated transcription upon short administration of 10-8 M T3. TRβ1-mediated potentiation requires mitogen-activated protein-extracellular signal-regulated kinase kinase (MEK) activation and ERα phosphorylation.

Materials and Methods

Plasmids, Constructs, and Chemicals. The pGL2-TATA-Inr-Luc construct, a gift of Donald McDonnell (Duke University, Durham, NC), has three consensus tandem EREs upstream of the luciferase reporter (9). The pSG-hERα, a gift of Pierre Chambon (Institut National de la Santé et de la Recherche Médicale) (10, 11), and the TRα1 and TRβ1 plasmids in pCDNAI/Amp, a gift of William Chin (Lilly Research Laboratories, Indianapolis) have been described (12). The ERα phosphorylation mutants in the pCMV vector have been described (13). The 17β-estradiol 6-(carboxymethyl) oxime/BSA (E2-6-BSA; E-BSA) (Sigma) was dissolved in distilled water and filtered according to Stevis et al. (14) to remove free 17β-estradiol. The final concentration of E in the E-BSA (corrected for the molar ratio of 17β-estradiol/BSA) and 17β-estradiol (E2) (Sigma) (in ethanol) in the experiments was 10-9 M. To achieve physiologic free concentrations of T3 in a complex cell culture system, we have used a slightly higher concentration of total T3, i.e., 10-8 M T3, in experiments unless otherwise detailed. The inhibitors, obtained from Calbiochem, were dissolved either in water or DMSO, as appropriate.

Cell Culture and Transfections. SK-N-BE(2) C cells were plated in Ham's F12/MEM (1:1) (Cellgro, Kansas City, MO) supplemented with 10% FBS (Bioreclamation)/100 units/ml penicillin/50 μg/ml streptomycin in six-well plates (Falcon) at a density of 0.3 × 106 cells per well. Forty-eight hours after plating, the cells were transfected at ≈50% confluence by using the Effectene reagent (Qiagen, Valencia, CA) according to the manufacturer's instructions. Cells were cotransfected with pGL2-TATA-Inr-Luc (200 ng)/pSG-hERα (80 ng)/pCDNA-TRα1 or pCDNA-TRβ1 (80 ng)/pSV-βgal (40 ng)/pBSKII+ to a total of 400 ng per well. For experiments with ERα phosphorylation mutants, cells were transfected with either wild-type ERα or the mutant ERα (80 ng). Twenty-four hours after transfection, the cells were washed free of the media, and phenol-red free Ham's F-12/MEM (1:1), supplemented with 5% charcoal dextran-stripped FBS (Valley Bio-medical, Winchester, VA) and antibiotics, was added. We then initiated a hormone regimen of two pulses. At the end of the first 20-min pulse, the media were removed from cells, and the cells were washed twice with Dulbecco's PBS (D-PBS) and fresh hormone-free media added for the duration of the 2-h interpulse interval, after which the second pulse (1 h) commenced. Hormones and inhibitors were added at the concentrations shown in Figs. 1, 2, 3, 4, 5. At the end of the second pulse, the cells were washed again with D-PBS, and fresh phenol-red free media were added for another 16 h. There is no transactivation from the ERE without 17β-estradiol or transfected ERα (unpublished data). The cells were lysed with Glo Lysis Buffer (Promega), and lysate from each well was used for both luciferase and β-gal assays according to the manufacturer's instructions. The β-gal assays from each sample were used to normalize lysate preparation and transfection efficiency. Results (means ± SEM) from duplicate or triplicate experiments (n = at least three per treatment group in each experiment) are plotted (prism software, GraphPad, San Diego) as fold induction over that obtained in the control group (ethanol added in both pulses). Statistical analysis was done by using one-way ANOVA followed by the Student-Newman-Keuls post hoc test (prism software) to compare between treatment groups. A P value of <0.05 was taken as significant.

Fig. 1.

Fig. 1.

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T3 (10-7 M), given for 20 min in the first pulse, could potentiate transcription mediated by 17β-estradiol (10-9 M) in the second pulse in cells transfected with TRβ1(A) and TRα1(B). Neuroblastoma cells were transiently transfected as detailed in Materials and Methods. A two-pulse paradigm was then initiated with hormones and ethanol added for 20 min in the first pulse and for 1 h in the second pulse. Twenty-four hours after the first pulse, each sample was lysed, and β-gal and luciferase assays were performed. Results were analyzed by using one-way ANOVA. Positive control: E-BSA or 17β-estradiol (E) (10-9 M; 20-min first pulse) followed by 17β-estradiol (10-9 M; 1-h second pulse). Results (n = 4-8 per treatment group): *, P < 0.05 compared with ethanol-treated samples (bar 1). a, P < 0.05, compare with target and positive control groups (bars 5-7) and <0.05, compare with ethanol-treated samples.

Fig. 2.

Fig. 2.

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Different concentrations of T3 potentiate transcription mediated by ERα via TRα1 (A) and TRβ1 (B). Transient transfections were performed as detailed in Materials and Methods. Results (fold over control) were analyzed by using one-way ANOVA followed by the Student-Newman-Keuls test to compare among treatment groups. Results (n = 3-5 per treatment group): *, P < 0.05, compare with controls (bars 1 and 2). a, P < 0.05, compare with ethanol-treated control.

Fig. 3.

Fig. 3.

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Inhibitors to kinases and calcium affect T3-potentiation of ERα transactivation via TRα1 (white bars) or TRβ1 (black bars). Results (fold over control) were analyzed by using one-way ANOVA followed by the Student-Newman-Keuls test to compare between treatment groups. Results (n = 5-8 per treatment group): I1, 75 μM Rp-cAMPs (PKA); I2, 10 μM chelerythrine (PKC); I3, 10 μM 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetate-acetoxymethyl ester (Ca+2); I4, 50 μM U0126 (MAPK). *, P < 0.05, compare with control (bars 1-4); ^, P < 0.05, compare with T3 in the first pulse followed by 17β-estradiol in the second pulse. a, P < 0.05, compare with ethanol-treated samples and target groups (bars 5-8).

Fig. 4.

Fig. 4.

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Inhibitors to MEK decrease T3-mediated potentiation of transcription via TRβ1 only when added in the first pulse with T3. Results (fold over control) were analyzed by using one-way ANOVA followed by the Student-Newman-Keuls test to compare between treatment groups. Results (n = 3-5 per treatment group): I4, 100 nM U0126; I5, 5 μM PD 98059. *, P < 0.05, compare with control (bars 1 and 2). a, P < 0.05, compare with ethanol; ^, P < 0.05, compare with T3 in the first pulse followed by 17β-estradiol in the second pulse (bar 3).

Fig. 5.

Fig. 5.

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Phosphorylation mutants of the ERα abrogate T3-mediated potentiation of transcription via TRβ1. Cells were transfected with wild-type ERα or ERα S118A (A), ERα S167A (B), or ERα S294A (C). All cells were subject to a two-pulse paradigm as detailed in the tables. Results were analyzed by using two-way ANOVA to compare between treatment groups. (A) n = 6 per treatment group; a, P < 0.05, compare with control treatment (ethanol treatment) and <0.05, compare with T3 in the first pulse followed by 17β-estradiol in the second pulse. *, P < 0.05, compare with control groups (bars 1-4); ^, P < 0.05, compare with mutant in the same treatment group. (B) n = 5-6 per treatment group; a, P < 0.05, compare with control treatment (ethanol treatment) and <0.05, compare with T3 in the first pulse followed by 17β-estradiol in the second pulse. *, P < 0.05, compare with control groups (bars 1-4) ^, P < 0.05, compare with mutant in the same treatment group. (C) n = 5-6 per treatment group; a, P < 0.05, compare with control treatment (ethanol treatment) and <0.05, compare with T3 in the first pulse followed by 17β-estradiol in the second pulse. *, P < 0.05, compare with control groups (bars 1-4); ^, P < 0.05, compare with mutant in the same treatment group.

Results

To achieve complete control of ER and TR expression, we transfected ERα and TR into SK-N-BE(2)C cells, a neuroblastoma cell line, with no endogenous ER and TR. This transfected cell line has been used as a model for E action in the brain (15-17). We have previously designed (5) a two-pulse paradigm to demonstrate that rapid nongenomic effects of E can potentiate the transcriptional effects of E. Using that paradigm, we investigated whether a pulsatile application of T3 can potentiate liganded ERα-mediated transcription from a consensus ERE in the presence of transfected TRα1 or TRβ1. T3 was added in the first pulse (20 min), and 10-9 M 17β-estradiol was added in the 1-h second pulse, with the pulses separated by a 2-h hormone-free interval.

T3 (10-7 M), via TRα1 (Fig. 1A) or TRβ1 (Fig. 1B), potentiated ERα-mediated transcription from a consensus ERE-driven luciferase gene compared with a single 17β-estradiol pulse, similar to the potentiation caused by E-BSA and 17β-estradiol added in the first pulse. Neither E-BSA nor T3 given in a single pulse had any effect on transcription. Potentiation was greatest at 10-7 M for TRα1 (Fig. 2A) and TRβ1 (Fig. 2B). Because both TRα1 and TRβ1 potentiate transcription at 10-8 M T3, this concentration was chosen for future experiments.

Because E-BSA appears to potentiate transcription via rapid signal transduction cascades, we hypothesized that T may act similarly. Hence, we used inhibitors to PKA [Rp-cAMPS, inhibitor (I)1], PKC (chelerythrine, I2), MEK (U0126, I4), and a chelator of calcium [1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetate-acetoxymethyl ester, I3] either in the first pulse along with T3 or in the second pulse with 17β-estradiol (Fig. 3) in cells transfected with either TRα1 (white bars) or TRβ1 (black bars). None of the inhibitors or the calcium chelator had any effect on potentiation mediated by TRα1 (white bars). However, the MEK inhibitor inhibited TRβ-mediated potentiation only when added in the first pulse (bar 20 in Fig. 3), suggesting that MEK was involved in the T3 effect mediated by TRβ1. The inactive MEK inhibitor analog, U0124 (data not shown), had no effect on TRβ1 potentiation. To confirm the role of MEK, we used a second MEK inhibitor, PD 98059 (I5) (Fig. 4). The higher transcription obtained with this compound (bars 10-12 in Fig. 4) could be due to estrogenic contamination (18). However, despite this potentially confounding effect and similar to the effect seen with 100 nM U0126 (bars 5 and 6 in Fig. 4), addition of PD 98059 in the first pulse along with 10-8 M T3 inhibited ERα-mediated transcription. Hence, we chose to examine the role of mitogen-activated protein kinase (MAPK) and TRβ1 in T3 potentiation of E-driven ERα-mediated transcription.

Because of the importance of MEK activation, we hypothesized that a MAPK target that increases transcription might be the ERα itself. To test this, cells were transfected with either mutant phospho-deficient ERα or wild-type ERα and subjected to a two-pulse paradigm, as noted (Fig. 5). ERα proteins from the wild-type and mutant plasmid promoters were at equivalent levels. The serine at position 118 is phosphorylated by MAPK both in vivo and in vitro (ref. 19 and references therein). Fig. 5A shows that when the serine at position 118 is mutated to alanine (S118A), potentiation by T3-liganded TRβ1 was reduced. However, when E-BSA was used in the first pulse, such a mutant did not abrogate E-BSA-mediated potentiation, demonstrating that phosphorylation of this amino acid is specifically important in liganded TRβ1 signaling to ERα-mediated transcription. On the other hand, the S167A mutant blocked both E-BSA and T3-mediated potentiation (Fig. 5B) and serves as a common functional phosphorylation site in the ERα for cognate (E) ligands and for crosstalk with T3. Finally, although the S294A mutant abrogates E-BSA-mediated potentiation, it does not affect the T3 potentiation of ERα-mediated transcription (Fig. 5C), showing specificity for the signal from the cognate membrane-impermeant ligand. The S118A and S294A mutants also decrease basal transcription from the consensus ERE initiated by T3 (bar 6 in Fig. 5A) and E-BSA, respectively (bar 8 in Fig. 5C). These three different phosphorylation mutants demonstrate that T3 specifically modulates transcription from a consensus ERE via phosphorylation at the MAPK sites at serines 118 and 167 in ERα.

Discussion

Nongenomic effects of T have been demonstrated by using both T3 and T4 (4, 20, 21, ¶). In glial cells, T4 and reverse T3, but not T3 itself, cause a transition from soluble actin to F-actin (22). T4 increases actin polymerization and subsequent integrin anchorage in astrocytes, increasing granule cell migration toward the cerebellum (23, 24). T4 is more potent than T3 in PKC activation in erythroid cells (25) and MAPK activation in HeLa and CV-1 cells (26). Membrane-impermeant T4-agarose could replicate this T4-mediated MAPK activation, suggesting that T4 initiated a signal transduction cascade at the membrane. On the other hand, T3 was more active than T4 in stimulating the Na+/H antiporter via the PKC pathway in rat myoblasts (27) and in evoking action potentials (28), suggesting that the potency of T varies according to cell type. In this study, we have used the genomically more active form of T, T3. Although the unavailability of the membrane-limited T compound from commercial sources for this study makes it difficult to unequivocally assert that the T3 actions in this study are membrane-limited, limited exposure (20 min) of the cells to hormone and the importance of MAPK activation to transcription make it probable. Recently, an integrin receptor at the membrane has been shown to function in MAPK activation by T. However, it is also conceivable that T3 may activate MAPK transcriptionally.

On a reporter gene driven by a single ERE in CV-1 cells, transiently transfected with both ERα and TRβ1, coapplication of 10-7 M 17β-estradiol and 10-6 M T3 for 48 h did not affect the level of transactivation seen with 17β-estradiol alone (29). Compared with continuous administration of both these hormones, preliminary administration of T3 followed by 17β-estradiol resulted in increased E transcription in neuroblastoma cells. This could be because of differences in cell lines or enhancers driving the reporter gene (three EREs vs. a single ERE in the previous study) or the method of hormonal administration. Pulsatile administration of estradiol has also been shown to be as effective as continuous administration in promoting cell proliferation (30) and gene transactivation (31) in MCF-7 cells and sex behavior in female rodents (32, 33). Both TRα1 and TRβ1 potentiate ERα-mediated transcription in response to T3, suggesting that these isoforms could function in a parallel manner in the CNS.

Signal Transduction from the Membrane to the Nucleus. How does limited exposure of neural cells to T3 increase transcription from the ERE? Because transcription is enhanced only in the presence of liganded TRβ1 and ERα, E and T must interact via their cognate receptors, possibly through several mechanisms. In PR1 lactotroph cells, T3 selectively stabilized 17β-estradiol-liganded ERα by prevention of proteasome-mediated proteolysis and consequently inhibited activation from a consensus ERE but not from the endogenous prolactin gene (34). In human fibroblasts, T3 rapidly activates phosphatidylinositol 3-kinase and Akt via TRβ1 (35). T4 also increased MAPK translocation from the cytoplasm to the nucleus (20, 26), whereas T3 could increase transport of the TRβ1 into the nucleus (36). In MCF-7 cells, agarose-T4 for 15 min resulted in ERα phosphorylation on serine 118. A MAPK inhibitor blocked T4-mediated ERα phosphorylation, demonstrating that MAPK activation preceded ERα phosphorylation (6). Therefore, the interaction between nongenomic actions of T, i.e., MAPK activation and genomic transcriptional actions of E, could be via a common target, the ERα. Initially, we demonstrated that MEK activation is important in T3-mediated potentiation of transcription from the consensus ERE. Hence, we next investigated the most parsimonious explanation, the functional relevance of ERα phosphorylation by T3. Phosphorylation increases the ability of ER to recruit coactivators and regulates dimerization (37-39).

ERα Phosphorylation by T. ERα is phosphorylated on serine residues in response to 17β-estradiol and growth factors. The major sites of serine phosphorylation on the ERα are serine residues at positions 104/106, 118, 167 (ref. 19 and refs. therein), and 305 (13). The stoichiometry and the sites of ERα phosphorylation, however, vary depending on the cell type, presumably because of the differences in kinase and phosphatase activities. Based on MAPK specificity for select residues, i.e., serines at 167 and 118, we studied the functional importance of ERα mutants that had a serine→alanine mutation at these sites (13). In vivo, MAPK-mediated phosphorylation (40) of serine 167 occurs via the ribosomal S6 kinase (41). In vitro, S167 is phosphorylated by AKT and casein kinase II (42-44). In a previous study (unpublished work), we have shown that this mutant is effective in decreasing ERα transactivation mediated by E-BSA, and hence this regimen (EBSA in the first pulse followed by 17β-estradiol in the second pulse) is used as a positive control. In this study, we show that the S167A ERα phosphomutant could also decrease the T3 potentiation of transactivation by ERα. Migliaccio et al. (45-47) have reported that specifically in breast and prostate cell lines, estradiol activates MAPK via c-src, which in turn phosphorylates the ERα at S118, although this has been disputed by other studies (48, 49). Similar to the results on the S167A mutant, this S118A mutant was selectively effective in abrogating T3-mediated potentiation of ERα transcription. These mutants demonstrate that both sites (serine at positions 118 and 167) that are MAPK targets in other cells are also functionally significant in ERα transactivation in this neuroblastoma cell line. We used a third phosphomutant, the ERα S294A, as a negative control, because it was shown to be unimportant in 17β-estradiol-mediated ERα phosphorylation in COS cells (13), despite being a consensus site for proline-directed protein kinase. Although this site was not important in T3 potentiation of ERα transcription, it was important for E-BSA-mediated potentiation, suggesting that the E-mediated phosphorylation of this site in the ERα may be cell-specific.

Physiological Relevance of T and E Synergy in the Brain. In male Sprague-Dawley rats, hypothyroidism produces a general inattention to the environment (50). Supporting the role of TRs in affective disorders, mice lacking TRα1 show symptoms of increased anxiety (51). Postmenopausal women show heightened irritability and depression (52-54). Both T and E can therefore synergize to affect mood, anxiety, and cognition (55-59).

This study demonstrates the interaction not only between two hormones but also between two different mechanisms of hormone action, which are relevant to neuroendocrine action.

Acknowledgments

We thank Dr. Donald McDonnell for the reporter gene, Dr. Pierre Chambon for the ERα expression plasmids, and Dr. William Chin for the TR plasmids. This work is supported by National Institutes of Health Grant CA18119 (to B.K.).

Abbreviations: T, thyroid hormone; TR, T receptor; E, estrogen; ER, E receptor; E-BSA, 17β-estradiol linked to BSA; T3, triiodothyronine; MEK, mitogen-activated protein-extracellular signal-regulated kinase kinase; ERE, E response element; In, inhibitor n; MAPK, mitogen-activated protein kinase.

Footnotes

Davis, P. J., Davis, F. B., Lin, H. Y. & Bergh, J., FASEB 2004 Summer Research Conference, July 31-Aug. 5, 2004, Tucson, AZ.

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