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Proc Natl Acad Sci U S A. Feb 15, 2005; 102(7): 2632–2636.
Published online Feb 7, 2005. doi:  10.1073/pnas.0409854102
PMCID: PMC548976

Rapid nitric oxide-mediated S-nitrosylation of estrogen receptor: Regulation of estrogen-dependent gene transcription


Nitric oxide (NO) and estrogen receptor (ER) are both important mediators of signal transduction in cardiovascular and reproductive tissues. In this study, we evaluated NO-mediated S-nitrosylation of ER and assessed the effect of this structural modification on transcription-related functions of ER. We have found selective inhibitory effects of NO on specific binding of ER to specific estrogen-responsive elements (ERE) that can be reversed in the presence of the reducing agent, DTT, thus suggesting that S-nitrosylation of thiolate–zinc centers may occur within the ER molecule. Furthermore, we examined inhibitory effects of NO on ER-dependent transcriptional activity by using an ERE-driven reporter gene system. By monitoring biophysical changes in the structure of NO-treated or untreated human recombinant ERα,we obtained evidence for the formation of S-nitrosothiols in the ER molecule. In addition, we have detected specific S-nitrosylation of cysteine residues within the ER molecule by immunodetection of S-nitrosocysteine moieties in ER. Collectively, these findings suggest an important physiological role for NO in modification of human ER structure by S-nitrosylation, an effect that leads, in turn, to impaired DNA-binding activity of ER and subsequent blockade of estrogen-dependent gene transcription. Thus, NO-induced S-nitrosylation of ER can occur at cysteine residues that coordinate Zn2+ within the two major DNA-binding Zn-finger domains of ER, resulting in selective inhibition of DNA-binding at specific ERE. This cross-communication between NO and ER may favor activation of rapid (nongenomic) signaling pathways and subsequent modulation of downstream genomic activity.

Keywords: nuclear receptors, steroid hormone receptors

It is widely reported that estrogen exerts a protective effect on the cardiovascular system. The incidence of cardiovascular disease differs significantly between men and women, in part because of differences in risk factors and hormones (1). Until recently, the atheroprotective effects of estrogen were attributed mainly to hormonal effects on serum lipid concentration and modification (2). However, new roles for estrogens are emerging that may contribute to beneficial effects in the cardiovascular system. Estrogens stimulate vasodilatation and inhibit the response of blood vessels to injury and development of atherosclerosis. Many of these estrogen-dependent cardiovascular-related effects occur rapidly after administration of estrogen and are not dependent on gene expression; such actions are commonly referred to as “nongenomic” effects. In contrast, long-term actions of estrogens that elicit cell proliferation and inhibit the response to vascular injury require gene expression and are usually designated as “genomic” functions.

It has been shown that a membrane-associated form of estrogen receptor (ER) mediates rapid estrogen-dependent nongenomic functions (3). Moreover, a subpopulation of ERα has been localized to endothelial cell caveolae where they are coupled to endothelial nitric oxide (NO) synthase in a functional signaling module (4). Engagement of membrane ER results in rapid endothelial NO release through a phospatidylinositol-3-OH kinase–Akt-dependent pathway (5). As the antiatherogenic properties of NO emerge, it has been proposed that the cardiovascular protective effect of estrogen is mediated through augmentation of endothelial NO generation (6). Either endogenously produced NO or the use of NO donors exerts pleiotropic physiological and pathophysiological effects including smooth-muscle relaxation, cellular proliferation, apoptosis, neurotoxicity, cell differentiation, immunomodulation, and regulation of gene expression. NO has been shown to interact with cysteine residues to form nitrosothiol adducts, thus altering the activity of proteins. The reversible regulation of protein function by S-nitrosylation has led to the proposal that nitrosothiols might function as significant posttranslational modifications, analogous to those created by phosphorylation or acetylation (710).

The ER contains two (Cys)4-liganded zinc fingers with high homology to other members of the nuclear receptor superfamily, and it is similarly redox-sensitive. This finding is consistent with the observation that the transcriptional activity and DNA-binding capacity of ER are modulated by the action of oxidation agents and redox effector proteins such as thioredoxin (11, 12).

However, molecular events involving NO-related rapid functions of ER remain elusive. We hypothesize that NO-mediated S-nitrosylation of ER can occur at cysteine residues that coordinate Zn2+ within the two major DNA-binding Zn-finger domains of ER, resulting in selective inhibition of DNA-binding at specific estrogen-responsive elements (EREs). This action may favor rapid (“nongenomic”) activation signaling pathways and/or alter genomic activity of ER. Here, we aim to determine the role of NO in ER-mediated rapid signaling and in gene transcription, characteristic of cardioprotective functions. The findings indicate that ER undergoes S-nitrosylation on exposure to NO, resulting in significant alterations in binding of ER to specific EREs in DNA and subsequent modulation of ER-dependent transcription.

Materials and Methods

Cell Culture and Reagents. MCF-7 human breast cancer cells, highly enriched in ER, and COS-7 monkey kidney fibroblast cells, ER-negative, were obtained from the American Type Culture Collection (Manassas, VA). Cell cultures were maintained as monolayers on plastic dishes in RPMI medium 1640 (MediaTech, Herndon, VA) supplemented with 10% heat-inactivated FBS (Gemini Bio-Products, Calabasas, CA), 1% lr-glutamine (Life Technologies), 1% pyruvate (Life Technologies), and 1% nonessential amino acids (Life Technologies) and incubated at 37°C and 5% CO2. For every experimental condition, cells were cultured in 1% FBS 24 h before treatments. For estrogen-free conditions, medium was changed 48 h before experiments to phenol-red free RPMI medium 1640 with 1% dextran-coated, charcoal-treated FBS (25). DEA/NONOate (diethylamine NONOate, t1/2 ≈ 2.5 min) and DETA/NONOate (diethylenetriamine NONOate, t1/2 ≈ 500 min) were purchased from Cayman Chemical (Ann Arbor, MI).

Nuclear Extract Preparation. Nuclear protein extracts from different experimental conditions were isolated as described (13). Briefly, cultured cells (1 × 106) treated under selected conditions were washed twice with ice-cold DPBS (MediaTech). P-40 lysis buffer (10 mM Tris·HCl, pH 7.4/10 mM NaCl/3 mM MgCl2/0.5% Nonidet P-40/0.1 mM EDTA) was added to the top of the washed cells and incubated on ice for 5 min. Lysed cells were collected by gentle pipetting three to four times and transferred to a microcentrifuge tube. Nuclear pellets in selected experiments were generated by two consecutive centrifugation and washing steps at 300 × g. Nuclear pellets were lysed in buffer C (20 mM Hepes, pH 7.9/25% glycerol/0.42 M NaCl/1.5 mM MgCl2/0.1 mM EDTA/0.5 mM PMSF/0.5 mM DTT). Total nuclear protein concentrations were determined by using the method of Bradford (14).

EMSA. Nuclear protein extracts (2 μg) were assayed for DNA interaction by EMSA as described with modifications (13). The double-stranded ERE consensus binding sequence (5′-TAA TAG GTC ACA GTG ACC TGA TTC C-3′) oligonucleotide was radiolabeled with [γ32P]ATP (ICN Pharmaceuticals) by incubation with 10 units of T4 polynucleotide kinase (New England Biolabs) and further purified by using QIAquick nucleotide removal kit (Qiagen, Valencia, CA). After the DNA-binding reaction, samples were resolved on 4–15% Tris·HCl polyacrylamide minigels (Bio-Rad), and the gels were dried and autoradiographed. Specificity of the DNA-binding reaction was determined by competition assays performed with a 100-fold excess of unlabeled ERE. The relative concentration of specific ER shifted bands were then assessed by densitometric analysis of the digitized autoradiographic images using the public domain nih image software (http://rsb.info.nih.gov/nih-image).

Transfections and ERE-CAT Reporter Gene System. A reporter plasmid containing a palindromic ERE and the chloramphenicol acetyltransferase (CAT) gene was used in these studies and is termed ERE-CAT (15). MCF-7 cells were prepared and transfected by using established procedures (15). CAT protein was quantitated in cell extracts by using a nonradioactive enzyme-linked immunosorbant assay (5 Prime–3 Prime, Boulder, CO), with ≈50 pg of CAT protein per ml of cell extract found to be the lower limit of detection. CAT reporter activity was normalized for the protein content in each sample. Transfection efficiency was established for all samples by cotransfection with pCMV-βgal construct and monitoring gene expression by established procedures (25).

Immunodetection of S-Nitrosocysteine. Cells were maintained in estrogen-free conditions 48 h before each experimental treatment. All procedures were performed under nonreducing conditions. MCF-7 cells were incubated 30 min in the presence of the NO donor DEA/NONOate at 0.1 mM, 0.5 mM, and 10 nM estradiol-17β and 100 nM ICI 182780. Cells were homogenized and equal amounts of total protein were immunoprecipitated overnight by using anti-S-nitrosocysteine antibody (EMD Biosciences, San Diego). Samples were then resolved by SDS/4–20% PAGE under nonreducing conditions and transferred to a nitrocellulose membrane for immunodetection with anti-ER antibody GR-17 (Oncogene) and secondary peroxidase-conjugated anti-mouse IgG antibody (Amersham Pharmacia). Relative intensity of the specific bands were detected by using an established ECL-chemiluminescent detection system (Amersham Pharmacia).

Statistical Analysis. The experimental values were expressed as the mean ± SEM for the number of separate experiments indicated in each case. One-way ANOVA was used to compare variances within and among groups. Bartlett's tests were used to establish the homogeneity of variance based on the differences among SDs. Whenever needed, post hoc unpaired multiple comparison tests (Bonferroni's test) and the Student t test were used for comparison between two groups. Significant differences were considered for those probabilities <5% (P < 0.05).


NO Inhibits ER-Binding Activity to ERE. We first evaluated the effect of NO on modulation of the DNA-binding activity of ER to its cognate ERE. Two micrograms of nuclear protein extracts were prepared from MCF-7 human breast cancer cells and then exposed to 10 or 100 μM DEA/NONOate for 2 h at room temperature in the presence or absence of 1 mM DTT. Thereafter, treated and untreated nuclear extracts were incubated in the presence of a radiolabeled, double-stranded ERE consensus-binding sequence probe and analyzed by EMSA. The specificity of the DNA-binding activity for ER was determined by competition assays performed with a 100-fold excess of cold probe, as well as by use of a control mutated probe and by utilization of a supershift assay performed with specific anti-ER antibody.

As shown in Fig. 1, nuclear extract from ER-rich MCF-7 cells exhibited a concentration-dependent inhibition of ER-binding activity to ERE (Fig. 1 A, lanes 6 and 7) when compared with the untreated control (Fig. 1 A, lane 1). The specificity of ER-binding activity was determined by competition assay by using a 100-fold excess of unlabeled ERE oligonucleotide (Fig. 1 A, lane 2), unlabeled mutated ERE oligonucleotide (Fig. 1 A, lane 3), or supershifting using a rabbit ER polyclonal antibody and its competition with immunogenic peptide (Fig. 1 A, lanes 4 and 5). The impaired ER-binding activity elicited by treatment with 10 and 100 μM DEA/NO was completely reversed to normal levels in the presence of 1 mM DTT (Fig. 1B, lanes 6 and 7), whereas specific competitor and control treatments remained unchanged. Relative densitometric units were determined for the ER-specific shifted bands and plotted to provide a semiquantitative assessment. These results suggest that reduction of ER binding with a specific ERE may be subject to redox regulation by NO, which may occur through S-nitrosothiol modification of critical cysteine residues with consequent disruption of the structural conformation that allows ER to bind ERE.

Fig. 1.
NO inhibits binding of ER to ERE. Nuclear protein extracts from ER-expressing MCF-7 breast tumor cells where exposed to different concentration of the NO donor DEA/NONOate in the absence (A) or presence (B) of DTT (1 mM) and then assessed by EMSA. Specific ...

NO Blocks ER-Mediated Genomic Function. NO has been shown to selectively inhibit 17β-estradiol (E2)-induced gene expression without affecting nongenomic functions in HeLa cells (16). To determine the role of NO in inhibition of the genomic (transcriptional) response of ER, MCF-7 and COS-7 cells were transiently transfected with a reporter gene system containing an ERE and the TK minimal promoter driving the expression of the CAT gene. Cells were incubated in the presence or absence of increasing concentrations of the NO donor, DETA/NONOate (0.1 and 0.5 mM), and 1 nM E2. Transcriptional activation was then determined, based on the expression of CAT by these cells after 18 h of treatment, by using the established CAT-ELISA assay system. Equal amounts of protein were analyzed in duplicate for CAT activity, and data were collected from at least three independent experiments.

As shown in Fig. 2A, MCF-7 cells were transiently transfected with the ERE-CAT reporter vector for 24 h before treatment with E2 and NO donors. After 18 h of incubation, E2-dependent activation was significantly inhibited in the presence of 100 and 500 μM of NO donor (Fig. 2 A, center and right bars). To confirm these findings, we transiently cotransfected ER-negative COS-7 cells with a vector containing the coding region for ERα (pCDNA3-ERα) and the ERE-based reporter vector. After treatment as described for MCF-7 cells, E2-dependent transcriptional activation was significantly inhibited in a concentration-dependent manner by treating with 100 and 500 μM DETA/NONOate (Fig. 2B, center and right bars). These results further suggest a significant role of NO in modulating the transcriptional activity of ER.

Fig. 2.
Transcriptional activity of ER in the presence of NO. (A) Transiently transfected ER-expressing MCF-7 cells with the ERE/thymidine kinase (TK)-driven, CAT-based reporter vector were cultured in the presence of increasing concentrations of the NO donor, ...

NO Promotes S-Nitrosothiol Formation Within ER: S-Nitrosylation of ER. The DNA-binding and transactivating functions of many transcription factors are redox sensitive, and most of these factors appear to be regulated by oxidation of critical cysteine residues within their DNA-binding or other functional domains. With reports that 8 of 13 cysteine residues located in two zinc-thiolate centers are essential for maintaining ER dimerization and DNA binding activities, the ER is an ideal target for NO-mediated S-nitrosylation of these critically exposed thiol groups. To determine whether ER can be S-nitrosylated on exposure to NO, purified human recombinant ERα was assessed by use of biophysical methods in the presence or absence of 1 mM DEA/NONOate, for incubation periods of 30 min to 2 h at 37°C. The formation of S-nitrosothiols upon reaction of ER with NO was monitored by observing the absorbance changes in the region of 300–400 nm by using UV-visible spectrophotometry. As shown in Fig. 3, 24 pmoles of purified recombinant ERα were treated under aerobic conditions in the presence or absence of 1 mM DEA/NONOate at pH 7.0 in phosphate buffer. Absorbance changes between 195 and 600 nm were monitored immediately (green line), 30 min (blue thin line), and 2 h (purple thick line) after exposure to NO. The distinct peak in the region 330–350 nm, indicating formation of S-nitrosothiol, was observed after a time-dependent correlation in the presence of NO. These results suggest the specific S-nitrosyl modification of thiol-containing residues within ERα by NO. Furthermore, these findings confirm the potential role of NO in modifying the structural conformation of ER. This action of NO may lead to impaired DNA-binding and transcriptional activity of the estrogen receptor.

Fig. 3.
Specific formation of S-nitrosothiol groups within ERα in the presence of NO. Under aerobic conditions, purified recombinant ERα was incubated in the presence or absence of a 1 mM concentration of the NO donor, DEA/NONOate. Absorbance ...

NO-Dependent Formation of S-Nitrosocysteine Within ER. The most likely targets for S-nitrosothiol modifications within the ER molecule are the cysteine residues located in two Zn-finger structures comprising the ER DNA-binding domain. To assess S-nitrosothiol modification of cysteine residues in ER, we used anti-S-nitrosocysteine antibody for specific immunoprecipitation. For this assay, we prepared total protein extracts from MCF-7 cells that were treated in the absence or presence of the NO donor DEA/NONOate at 0.1 mM and 0.5 mM, and with or without 10 nM E2. In further control experiments, the pure antiestrogen, ICI 182,780, was tested in the presence of estradiol. Immunodetection was then conducted by using anti-ERα antibody. As shown in Fig. 4, untreated control cells expressed a low background level of S-nitrocysteine residues in ERα molecules. Furthermore, after treatment with the receptor ligand, estradiol-17β, a significant increase in the concentration of S-nitrosylated cysteine residues in ER was observed. This E2-dependent S-nitrosocysteine generation was abrogated by the use of the specific ER-antagonist, ICI 182,780, suggesting an ER-dependent endogenous generation of NO with ensuing S-nitrosylation of ER. Moreover, treatment of MCF-7 cells in the presence of the short half-life NO donor, DEA/NONOate (0.5 mM), resulted in a significant accumulation of S-nitrocysteine in ER molecules.

Fig. 4.
NO-dependent formation of S-nitrosocysteine within ER. Total protein extract from MCF-7 cells was incubated in the absence or presence of 10 nM E2 and 0.01 mM or 0.5 mM DEA/NONOate, and with or without 100 nM ICI 182,780. The samples were then immunoprecipitated ...


Rapid actions of estrogen in vascular cells appear to play a major role in mediating cardioprotective properties of the steroid hormone (17). More than two decades ago, Pietras and Szego identified a plasma membrane-associated ER that was shown to respond rapidly to E2 (3, 18). The action of E2 at the membrane likely results from binding of this sex steroid to ERs that, in turn, acutely activate downstream signaling systems. Signal transduction may occur, in part, as the result of E2 activation of G proteins coupled to endothelial NO synthase through Gαi (19). Furthermore, engagement of membrane estrogen receptors results in rapid endothelial NO release through a phospatidylinositol-3-OH kinase–Akt-dependent pathway (5).

Here, we have demonstrated that NO significantly inhibits DNA-binding of ER with its cognate ERE. Furthermore, this effect of NO on DNA-binding activity of ER correlates with inhibition of the delayed gene transcriptional activity of the hormone. Finally, evidence showing S-nitrosothiol modification of ER is presented. These findings support the notion that critically exposed cysteine (Cys) residues are important in modulating ER transcriptional function without compromising the rapid (nongenomic) activity of ER (16).

It has been shown that NO inhibits DNA-binding activity of the 4×[His-2-Cys-2]-zinc-finger transcription repressor YY1 (20). The presence of nine Cys residues in the DNA binding domain of ERα makes ERα especially susceptible to NO-mediated chemical modification. Eight of nine Cys residues occur in two zinc–thiolate centers and appear to be essential for ERα dimerization and DNA binding (21), whereas another four Cys residues are present in the ligand-binding domain (22). It was suggested that preferential oxidation of Zn-finger 2 in the DNA-binding domain of ERα prevents dimerization and, in turn, DNA binding (11).

The EMSA results reported here demonstrate that NO can inhibit DNA-binding of ER to its cognate ERE in the absence of the reducing agent DTT (see Fig. 1 A, lanes 6 and 7). These results suggest the possible modification of thiol-containing residues such as Cys present in the (Cys)4 Zn-finger of ER by the oxidative action of NO.

It has been shown that NO selectively inhibits E2-induced gene expression without affecting nongenomic events in HeLa cells (16). Here, we used an ERE-CAT transcriptional reporter system to show significant inhibition of E2-mediated transcriptional activity of ER by NO. By monitoring biophysical changes in the structure of NO-treated or untreated human recombinant ERα, we also provided evidence for the formation of S-nitrosothiols in the ER molecule. In addition to protein phosphorylation and acetylation, S-nitrosylation may also prove to be critical in regulating vital cellular functions. Moreover, immunodetection of S-nitrosocysteine residues in ER molecules exposed either to E2-dependent endogenous generation of NO or to exogenous NO-donor provide strong support for the notion that specific modification of thiol-containing residues such as cysteine, predominantly in the ER DNA-binding domain, does occur. These findings add to other emerging data indicating that thiol-containing residues in ER, both inside and outside the receptor DNA-binding domain, may undergo important alterations, such as nitrosylation and palmitoylation, to regulate the biologic activity of ER in vivo (16, 23, 24).

Estrogen-mediated biogeneration of NO is one of the key features that appears integral to the cardioprotective role of these steroid hormones. This process then seems to modulate, in turn, the bioactivity of ER, possibly shifting the receptor from its major role as a transcription factor toward more rapid (nongenomic) functions such as the synthesis and activation of vasoactive peptides, cell matrix interactions, alterations in platelet adhesiveness, and inhibition of vascular smooth muscle cell migration (Fig. 5). Based on these findings, it may be possible in the future to design more selective cardioprotective ligands for interaction with ERs in cardiovascular tissues, thus enhancing patient survival and quality of life.

Fig. 5.
Rapid NO-mediated S-nitrosylation of ER: A model for regulation of estrogen-dependent gene transcription. Binding of estradiol (E2) by plasma membrane-associated ER results in rapid activation of a complex signaling cascade, leading to activation of endothelial ...


We thank Mr. Samuel Olson for valuable laboratory assistance. This work was supported by an educational grant from NicOx S.A. (to H.J.G.), U.S. Army Grant DAMD17-03-1-0381, California Breast Cancer Research Program Grant 5JB-0105, the Stiles Program in Integrative Oncology, and National Institutes of Health Grants HL40922 and HL35014 (to L.J.I.).


Author contributions: H.J.G., D.C.M.-G., R.J.P., and L.J.I. designed research; H.J.G. and D.C.M.-G. performed research; H.J.G. and D.C.M.-G. contributed new reagents/analytic tools; H.J.G., D.C.M.-G., and R.J.P. analyzed data; and H.J.G. and R.J.P. wrote the paper.

Abbreviations: ER, estrogen receptor; ERE, estrogen response element; CAT, chloramphenicol acetyltransferase; E2, 17β-estradiol.


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