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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 Sep 1;102(37):13153–13157. doi: 10.1073/pnas.0502782102

Estrogen down-regulation of the corepressor N-CoR: Mechanism and implications for estrogen derepression of N-CoR-regulated genes

Jonna Frasor *, Jeanne M Danes *, Cory C Funk †, Benita S Katzenellenbogen *,†,‡
PMCID: PMC1201577  PMID: 16141343

Abstract

The nuclear receptor corepressor N-CoR plays a crucial role in the repressive activity of diverse transcription factors, yet little is known about what regulates its cellular level. We have found that estrogen markedly down-regulates N-CoR protein levels in estrogen receptor (ER)-positive breast cancer cells without affecting N-CoR mRNA levels, whereas levels of the related corepressor SMRT are unaffected. This effect is attributable to estrogen up-regulation of the ubiquitin ligase Siah2, which is a rapid and primary transcriptional response mediated by the ER, and precedes the loss of N-CoR. Treatment with proteasomal inhibitor or with small interfering RNA against Siah2 prevented the down-regulation of N-CoR by estrogen. Furthermore, the expression of 24-hydroxylase, a gene repressed by unliganded vitamin D receptor through its interaction with N-CoR, was up-regulated by estrogen and required Siah2. Our results illustrate a mechanism by which the estrogen–ER complex markedly reduces the level of N-CoR through a process involving the up-regulation of Siah2 and the subsequent targeting of N-CoR for proteasomal degradation. These findings reveal that, although estrogen directly regulates the transcription of many genes, by regulating a gene such as Siah2 it can exert profound “secondary” effects on cellular activity through mechanisms such as targeting regulatory proteins for degradation. This estrogen-evoked down-regulation of N-CoR could have a global derepressive effect on genes whose repression depends on N-CoR and thereby have broad impact on the activity of transcription factors and nuclear receptors whose actions involve N-CoR.

Keywords: breast cancer, estrogen receptor, proteasome, Siah2

Cellular activity is precisely regulated by a finely tuned balance between coactivator and corepressor proteins that control transcriptional networks during development and in normal and cancerous states (1). The corepressors N-CoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptors) play crucial roles in transcriptional repression by multiple classes of transcription factors, including some nuclear hormone receptors. Repression by N-CoR and SMRT results from their association with large histone deacetylase complexes, which lead to histone deacetylation, altered chromatin structure, and decreased gene transcription (reviewed in ref. 2). Although few studies have demonstrated that N-CoR expression is regulated at the level of gene transcription, several examples of posttranslational regulation of N-CoR expression and activity have been described. Recent studies have shown that N-CoR interaction with transcription factors, such as NF-κB and estrogen receptor (ER), can be reduced through translocation of N-CoR out of the nucleus and into the cytoplasm (3–5). N-CoR has also been shown to be regulated by ubiquitin-mediated protein degradation through an interaction with the E3 ubiquitin ligase Siah2, a mammalian homolog of Drosophila seven in absentia (Sina), which leads to the ubiquitination and degradation of N-CoR by the 26S proteasome (6).

The majority of estrogen's effects on its numerous target tissues are mediated by its two receptors, ERα and ERβ, which act primarily as ligand-dependent transcription factors. Upon binding to its ligand, the ER associates with DNA either directly at estrogen response elements or through tethering to other transcription factors, leading to the recruitment of transcriptional coregulators and chromatin-modifying complexes and the regulation of gene expression (7). We and others (8–17) have used microarray gene expression profiling to identify estrogen target genes in breast cancer cells, where estrogen has been shown to stimulate proliferation and suppress apoptosis through the regulation of multiple genes. These studies have demonstrated that, as expected, estrogen up-regulates many cell-cycle regulators, growth factors, and antiapoptotic genes but also down-regulates a number of cell-cycle inhibitors and proapoptotic genes.

Estrogen also regulates the mRNA expression of important transcriptional regulators, both transcription factors and transcriptional coactivators and corepressors (12). Evidence supporting the idea that 17β-estradiol (E2) is capable of regulating the expression of coregulators has grown in the past few years. For example, this hormone has been shown to up-regulate mRNA levels for the corepressors RIP140 (12, 18), SHP (19), and SHARP (20) and also to down-regulate mRNA levels for the coactivators SRC-2 and SRC-3 (12, 21). In addition to the regulation of mRNA for some coregulators, the activity of these proteins can be modulated by hormone by changing the protein's state of phosphorylation, as observed for the coactivator SRC3/AIB1 (22). Estrogen can also regulate the activity of the corepressor REA (repressor of estrogen activity) through the up-regulation of its inhibitory binding partner, prothymosin α (23).

In examining the regulation of coregulators by E2, we found that E2 had no effect on N-CoR mRNA but that it markedly down-regulated N-CoR protein levels. In exploring these observations, we found that this down-regulation depends on the ability of estrogen to up-regulate the ubiquitin ligase Siah2, which targets N-CoR for proteasomal degradation. We show that this specific down-regulation of N-CoR, but not of the related corepressor SMRT, enables estrogen to derepress the expression of N-CoR-repressed genes and has the potential to impact numerous transcriptional pathways in which gene repression depends on N-CoR.

Materials and Methods

Cell Culture and Treatments. MCF-7 cells were cultured in MEM (Sigma) containing 5% calf serum (HyClone), and ZR75-1 cells were grown in RPMI medium 1640 (American Type Culture Collection) supplemented with 10% FCS. At least 4 days before the experiments, cells were transferred to phenol red-free medium containing 5% charcoal-dextran-treated serum. E2, 4-hydroxytamoxifen, MG132, cycloheximide, and actinomycin D were obtained from Sigma. ICI 182,780 was provided by Astra-Zeneca, and raloxifene was prepared in the laboratory of John A. Katzenellenbogen (University of Illinois at Urbana–Champaign, Urbana).

Real-Time Quantitative PCR. RNA extraction and real-time PCR using SYBR green fluorescence were carried out as previously described (12). The primers used in these studies were 5′-GGAATCGAAGCGACCACGT and 5′-ACTAAAGGCAAAACCGCAGC for N-CoR, 5′-CTATGGAGAAGGTGGCCTCG and 5′-CGTATGGTGCAGGGTCAGG for Siah2, 5′-GCCTGCTGCCAGATTCTCTG and 5′-GAACCCAACTTCATGCGGAA for 24-hydroxylase, and 5′-GTGTTCGACAATGGCAGCAT and 5′-GACACCCTCCAGGAAGCGA for 36B4. Fold changes were calculated by using the ΔΔCt method with 36B4 as an internal control. Data reported are the mean fold change ± SEM for three independent determinations.

Western Blotting. Whole-cell extracts were prepared by using RIPA buffer (1× PBS, 1% Nonidet, 0.5% sodium deoxycholate, 0.1% SDS, 10–6 M sodium orthovanadate, 10 μg/ml phenylmethylsulfonyl fluoride, and 30 μl/ml aprotinin). Fifteen to 100 μg of whole-cell extract proteins were separated on SDS/PAGE gels and transferred to nitrocellulose or polyvinylidene difluoride membranes. Western blotting was performed by using an N-CoR antibody directed against the C terminus (N-CoR 718) kindly provided by Mitchell Lazar (University of Pennsylvania, Philadelphia). The SMRT (1542/H7) and Siah2 (N-14) antibodies were obtained from Santa Cruz Biotechnology, and the β-actin antibody was from Sigma. Blots were incubated with the appropriate secondary antibodies, and signals were detected by using Pierce chemiluminescent substrates. Densitometry was performed with imagequant software from Molecular Dynamics/Amersham Pharmacia Biosciences.

Transfection of Small Interfering RNA (siRNA). RNA interference was carried out by using SMARTpool siRNA from Dharmacon (Lafayette, CO) designed against Siah2, or luciferase GL3 as a negative control. After at least 4 days of culture in phenol red-free MEM containing 5% charcoal-dextran-treated calf serum (CD-CS), 5 × 105 cells were seeded per well in six-well plates in the same medium but prepared without antibiotics. Twenty-four hours later, the medium was changed to OptiMEM (Invitrogen) and the cells in each well were transfected with 5 μl of siRNA (20 μM stock) and 10 μl of Lipofectamine 2000 (Invitrogen) diluted in 500 μl of OptiMEM. Eight hours later, the medium was removed and changed back to phenol red-free MEM with 5% CD-CS without antibiotics. The following day, cells were treated with control vehicle or hormone for the times indicated.

Results

To examine whether E2 could regulate expression of N-CoR in ER-positive breast cancer cells, MCF-7 cells were treated with E2 for various times, up to 48 h, and N-CoR mRNA and protein levels were examined. We found that the level of N-CoR protein was consistently and robustly decreased by E2 treatment, with an 80% loss of N-CoR protein occurring by 48 h (Fig. 1 A and B), but that the level of N-CoR mRNA was not altered by E2 (Fig. 1C). The down-regulation of N-CoR protein was specific for this corepressor because the level of a related corepressor, SMRT, was not affected by E2 treatment (Fig. 1B). We also examined the effects of the ER antagonist ICI 182,780 and the selective ER modulators 4-hydroxytamoxifen and raloxifene on N-CoR expression. Neither ICI 182,780 nor raloxifene had a major impact on N-CoR levels, although 4-hydroxytamoxifen slightly down-regulated N-CoR, but not as robustly as E2 (Fig. 1D). Furthermore, ICI 182,780, when administered at a 100-fold excess of E2, acted as an antagonist to reverse the inhibitory effect of E2 (Fig. 1D), indicating that E2 down-regulation of N-CoR is mediated by ER.

Fig. 1.

Fig. 1.

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E2 markedly reduces N-CoR protein in MCF-7 breast cancer cells. (A) MCF-7 cells were cultured in the presence of 10 nM E2 for various times, and N-CoR protein levels were examined by Western blotting. N-CoR protein was quantified by using imagequant software and normalized to β-actin levels. The untreated control was considered to be 100%. Data are the mean ± SEM from three independent experiments. (B) N-CoR and SMRT protein levels were monitored by Western blotting in MCF-7 cells treated with E2 for various times. β-Actin served as a loading control. (C) N-CoR mRNA levels were monitored by real-time PCR at various times after 10 nM E2 treatment. Values are the mean ± SEM from three independent experiments. (D) N-CoR protein levels were examined in MCF-7 cells treated with vehicle (V, 0.1% ethanol), 10 nM E2, 1 μM ICI 182,780 (I), 1 μM 4-hydroxytamoxifen (T), 1 μM raloxifene (R), or 10 nM E2 plus 1 μM ICI 182,780 (E2 + I) for 48 h.

Through gene expression profiling, we have observed that E2 up-regulates expression of Siah2 mRNA (12). Because previous work has indicated a role for Siah2 in the proteasomal degradation of N-CoR (6), we further characterized the regulation of Siah2 by E2. We first examined the time course of E2 up-regulation of Siah2 by real-time PCR and Western blotting and found that E2 rapidly induces both Siah2 mRNA and Siah2 protein in MCF-7 cells, with these up-regulations preceding the down-regulation of N-CoR protein (Fig. 2 A and B). This up-regulation was prevented by the antiestrogen ICI 182,780 and the selective ER modulators tamoxifen and raloxifene, indicating that E2 regulation of Siah2 mRNA is mediated by the ER (Fig. 2C). The RNA synthesis inhibitor actinomycin D, but not the protein synthesis inhibitor cycloheximide, blocked E2 up-regulation of Siah2 mRNA, suggesting that Siah2 is a primary estrogen response gene (Fig. 2D).

Fig. 2.

Fig. 2.

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E2 up-regulates Siah2 mRNA and protein in MCF-7 cells. (A) Siah2 mRNA levels were examined by real-time PCR in MCF-7 cells treated with 10 nM E2 for various times. (B) Siah2 protein levels were examined by Western blotting after treatment with E2. (C) Siah2 mRNA levels were examined in cells treated for 8 h with 10 nM E2 in the presence or absence of 1 μM ICI 182,780 (ICI), 4-hydroxytamoxifen (TOT), or raloxifene (Ral). (D) Siah2 mRNA levels were determined after a 4-h treatment with E2 in the presence of the RNA synthesis inhibitor actinomycin D (Act D, 5 μM) or the protein synthesis inhibitor cycloheximide (CHX, 10 μg/ml).

We next examined whether Siah2 mRNA was up-regulated by E2 in other breast cancer cell lines and found a similar regulation in the ER-positive cell line ZR75-1 (Fig. 3A), as well as in ER-positive T47D cells and in MDA-MB-231 cells stably transfected with ERα (data not shown). We also observed a loss of N-CoR protein in these cells upon estrogen treatment (Fig. 3B), further suggesting a link between E2 up-regulation of Siah2 and down-regulation of N-CoR protein.

Fig. 3.

Fig. 3.

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E2 up-regulates Siah2 mRNA and down-regulates N-CoR protein in ZR75-1 cells. ZR75-1 breast cancer cells were treated with vehicle or 10 nM E2 for 24 h, and Siah2 mRNA levels were examined by real-time PCR (A) or for 48 h, and N-CoR protein levels were examined by Western blot (B).

We next investigated the effect of E2 on N-CoR expression in MCF-7 cells in the presence or absence of the proteasome inhibitor MG132. The ability of E2 to down-regulate N-CoR expression was impaired in the presence of 20 μM MG132, indicating that E2 action on N-CoR levels requires proteasome activity (Fig. 4A). Furthermore, the levels of N-CoR in control (vehicle-treated) cells were substantially increased in the presence of MG132 alone, suggesting that proteasomal degradation of N-CoR is occurring in MCF-7 cells even in the absence of E2.

Fig. 4.

Fig. 4.

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E2 down-regulation of N-CoR depends on proteasome activity and Siah2. (A) MCF-7 cells were treated for 48 h with vehicle or 10 nM E2, the proteasome inhibitor MG132 (MG, 20 μM) was added for the final 16 h, and N-CoR protein levels were examined by Western blot. (B) MCF-7 cells were transfected with control siRNA or siRNA for Siah2, and Siah2 protein was examined by Western blot after 4 h of E2 treatment. (C) N-CoR protein levels were examined after transfection of MCF-7 cells with control or Siah2 siRNA and treatment with 10 nM E2 for 4 or 24 h.

To determine whether E2 down-regulation of N-CoR required Siah2 up-regulation, cells were transfected with siRNA directed against Siah2 and treated with E2 for different lengths of time. We observed that E2 up-regulation of Siah2 protein was consistently reduced by >80% in the presence of the siRNA against Siah2 as compared with the control GL3 siRNA (Fig. 4B). The decrease in N-CoR by E2 seen in the control siRNA samples was completely prevented by Siah2 siRNA (Fig. 4C), whereas the expression of β-actin, an internal control, was not affected by either siRNA or E2 treatment. These data indicate that E2 up-regulation of Siah2 expression is essential for the E2-induced proteasomal degradation of N-CoR protein.

To examine the impact of E2-induced down-regulation of N-CoR on the gene-regulatory activity of other transcription factors, we investigated the regulation of 24-hydroxylase, a gene thought to be repressed by unliganded vitamin D receptor (VDR) interacting with N-CoR through a vitamin D response element in the 24-hydroxylase promoter (24). As seen in Fig. 5A, 1,25-dihydroxyvitamin D3 (Vit D3) robustly and rapidly increased 24-hydroxylase mRNA levels in MCF-7 cells. Of note, we found that expression of this gene was also up-regulated by E2 and that this regulation was delayed and less marked than the effect of Vit D3 (Fig. 5A), which suggests that these two hormones are regulating the same gene through different mechanisms. In addition, we found that E2 could no longer up-regulate 24-hydroxylase in the presence of Siah2 siRNA (Fig. 5B), the proteasomal inhibitor MG132, or ICI 182,780 (Fig. 5C). In contrast, Siah2 siRNA, MG132, or ICI 182,780 had no effect on the up-regulation of 24-hydroxylase by Vit D3 (Fig. 5 B and C). These findings are consistent with the hypothesis that, by up-regulating Siah2, E2 down-regulates N-CoR protein, leading to a derepression of transcription through the unliganded VDR and thus an up-regulation of 24-hydroxylase. A model for this regulatory mechanism is presented in Fig. 6 and is discussed below.

Fig. 5.

Fig. 5.

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E2 up-regulation of 24-hydroxylase requires Siah2. (A) MCF-7 cells were treated with 10 nM E2 or 50 nM Vit D3 for up to 24 h, and 24-hydroxylase mRNA levels were examined by real-time PCR. (B) MCF-7 cells were transfected with control siRNA (–) or Siah2 siRNA (+) and then treated with E2 (+) or vehicle (–) for 24 h (Left) or with Vit D3 (+) or vehicle (–) for 3 h (Right). Real-time PCR was then carried out for 24-hydroxylase mRNA. (C) Cells were treated for 24 h with E2 (Left) or for 3 h with Vit D3 (Right) in the absence or presence of 20 μM MG132 (MG) or 1 μM ICI 182,780 (ICI). Real-time PCR was carried out for 24-hydroxylase.

Fig. 6.

Fig. 6.

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A model of estrogen's derepressive effects on gene transcription through the down-regulation of N-CoR. In the absence of Vit D3 or E2, the unliganded VDR/RXR heterodimer occupies the vitamin D response element (VDRE) and represses gene transcription through the recruitment of N-CoR (Repressed state). In the presence of E2, Siah2 gene transcription is stimulated through the E2-occupied ER complex leading to the degradation of N-CoR and the subsequent derepression of gene activity (steps 1 and 2) (derepressed state). In the presence of Vit D3, N-CoR dissociates from the complex and coactivators are recruited (steps 3–5), leading to the activation of transcription (activated state). In contrast to Vit D3, E2 is not capable of activating transcription through the VDRE, only of releasing the basal repression through the degradation of N-CoR.

Discussion

In this study, we find that the cellular protein levels of N-CoR, an important transcriptional corepressor, are robustly decreased by E2 and that this decrease is mediated by the up-regulation of Siah2, which then leads to the ubiquitin-mediated proteasomal degradation of N-CoR protein without any change in the level of N-CoR mRNA. This mode of corepressor regulation by estrogen could extend the scope of genes that are influenced by estrogen activity because of the numerous transcription factors through which N-CoR works to repress gene activity. We have illustrated this mode of regulation by the derepression by estrogen of the N-CoR repressed gene Vit D3 24-hydroxylase (Cyp24A1).

Although there appears to be considerable overlap in activity between the two human Siah proteins, Siah1 and Siah2, their regulation by E2 is very different, with E2 up-regulating only Siah2 (E. Chang and B.S.K., unpublished observations). The generation of double knockout animals for the mouse homologues of Siah, Siah1a and Siah2, has demonstrated an essential role in embryonic development, whereas the individual knockout phenotypes are less severe (25–28). Currently, little is known about the regulation of Siah, but it appears that hypoxia, Wnt 5a, and p53 are capable of up-regulating Siah mRNA and protein expression (28–30). Our work now shows that estrogen is capable of up-regulating Siah2 mRNA through the ER. This regulation appears to be a primary response to E2, because the regulation occurs rapidly and protein synthesis inhibition does not prevent the up-regulation.

We demonstrate that the estrogen-induced increase in Siah2 evokes a marked decrease in the N-CoR protein level. Our findings are consistent with the report by Zhang et al. (6), who showed that cell lines with higher levels of Siah2 have low levels of N-CoR, that cell lines with low levels of Siah2 have higher levels of N-CoR (6), and that N-CoR interaction with Siah2 directed the corepressor for degradation.

The down-regulation of N-CoR by estrogen could have important implications for gene expression on a broad scale, because N-CoR has been shown to repress transcription through many different transcription factors, including gene repression by the unliganded nuclear receptors for thyroid hormones, retinoids, and vitamin D (VDR). As our data suggest, the up-regulation of Siah2 and the consequent down-regulation of N-CoR are required for E2 up-regulation of the enzyme 24-hydroxylase. The lag and slower time course of the effect of estrogen on this gene compared with Vit D3, and the reduced magnitude compared with the effect of Vit D3 are consistent with the mechanism we have proposed (Fig. 6): The derepression involves degradation of N-CoR in response to the production of another protein, Siah2, whose synthesis is induced by estrogen (Fig. 6, step 1) as well as a protein degradation process (for N-CoR), which would have an inherent time lag (Fig. 6, step 2). The lower magnitude of the estrogen-induced response is also consistent with this being only a derepression process that would elevate gene activity only to the basal (derepressed) level. By contrast, the effect of Vit D3 was of larger magnitude and more rapid, reflecting the activation of a repressed gene (i.e., a combination of derepression plus activation) in which binding of the agonist ligand D3 (Fig. 6, step 3) brings about a release of N-CoR (Fig. 6, step 4) and its replacement by coactivators (Fig. 6, step 5), a process that is more rapid because it is presumed to involve only binding events rather than protein synthesis and degradation.

Our findings imply that genes such as 24-hydroxylase, under basal repression by N-CoR through its interaction with nuclear receptors, as well as other transcription factors, may be derepressed in the presence of estrogen. This mode of action would be particularly true for transcription factors preferentially using N-CoR over SMRT, because we found the corepressor SMRT not to be regulated by E2. One would expect that the degree to which gene activity would be elevated by this estrogen-mediated derepression process would depend on the magnitude of gene basal activity as well as the degree to which this is repressed by N-CoR.

The effects of estrogen in reducing N-CoR may be of particular relevance in the regulation of transcription in breast cancer cells. For example, the transcription factor heterodimer of Myc/Max is capable of stimulating transcription through E-box binding sites, often regulating genes that lead to cell proliferation and transformation. In contrast, the transcriptional repressor Mad can also heterodimerize with Max but represses transcription through E-box sequences. This repression requires Mad interaction with the N-CoR/Sin3 complex to repress transcription (31). In breast cancer cells, estrogen is well known to stimulate Myc expression, and, in our gene expression microarray analyses, we have found that E2 also down-regulates the repressor Mad4 (12). In conjunction with our data presented here, that E2 down-regulates N-CoR, we suggest that E2 may be capable of stimulating Myc activity through several mechanisms: up-regulating Myc itself and down-regulating two repressor components, Mad and N-CoR.

Also of potential importance in breast cancer is the possibility that down-regulating N-CoR may affect ER activity. N-CoR can interact with ER, but this interaction appears to be weak in the absence of ligand or with the agonist E2, whereas N-CoR can be recruited to the ER on specific target genes in the presence of antagonists such as tamoxifen, raloxifene, or ICI 182,780 (32, 33). Several lines of evidence suggest that the partial agonist/antagonist nature of tamoxifen is determined by the relative cellular levels of coactivators, such as SRC-1 and SRC-3, and corepressors such as N-CoR or SMRT. Increasing amounts of corepressors are capable of suppressing the partial agonist activity of tamoxifen (34, 35), whereas increasing the amount of coactivator (SRC-1) can enhance the agonist activity of tamoxifen on particular genes in breast cancer cells (33). We have found that tamoxifen blocks the E2-induced increase in Siah2 and the decrease in N-CoR such that N-CoR levels are sustained. Thus, tamoxifen would act through this pathway to sustain the component of tamoxifen's antagonism that relies on N-CoR.

In conclusion, our findings reported here indicate that estrogen, by up-regulating Siah2 and consequently down-regulating N-CoR, could have a global derepressive effect on genes whose repression depends on N-CoR. The findings also reveal that, although estrogen acts through the ER to often regulate gene transcription (as in the regulation of Siah2 mRNA), estrogen can also have additional profound “secondary” effects on cellular activity through alternative mechanisms, such as the targeting of important proteins (e.g., N-CoR) for degradation. This estrogen-stimulated down-regulation of N-CoR protein could have a broad impact as well on the activity of other transcription factors (beyond just nuclear receptors) whose actions involve N-CoR.

Acknowledgments

We thank Leanne Trapp for her invaluable technical assistance and Dr. Mitchell Lazar for generously providing antibody to N-CoR. This work was supported by National Institutes of Health Grant CA 18119 and a grant from the Breast Cancer Research Foundation. C.C.F. was supported by National Institutes of Health Training Grant T32-ES07326.

Author contributions: J.F. and B.S.K. designed research; J.F., J.M.D., and C.C.F. performed research; J.F., J.M.D., C.C.F., and B.S.K. analyzed data; and J.F. and B.S.K. wrote the paper.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: E2, 17β-estradiol; ER, estrogen receptor; VDR, vitamin D receptor; Vit D3, 1,25-dihydroxyvitamin D3; siRNA, small interfering RNA.

References

  • 1.McKenna, N. J. & O'Malley, B. W. (2002) Cell 108, 465–474. [DOI] [PubMed] [Google Scholar]
  • 2.Jepsen, K. & Rosenfeld, M. G. (2002) J. Cell Sci. 115, 689–698. [DOI] [PubMed] [Google Scholar]
  • 3.Baek, S. H., Ohgi, K. A., Rose, D. W., Koo, E. H., Glass, C. K. & Rosenfeld, M. G. (2002) Cell 110, 55–67. [DOI] [PubMed] [Google Scholar]
  • 4.Espinosa, L., Ingles-Esteve, J., Robert-Moreno, A. & Bigas, A. (2003) Mol. Biol. Cell 14, 491–502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Carroll, J. S., Lynch, D. K., Swarbrick, A., Renoir, J. M., Sarcevic, B., Daly, R. J., Musgrove, E. A. & Sutherland, R. L. (2003) Cancer Res. 63, 4322–4326. [PubMed] [Google Scholar]
  • 6.Zhang, J., Guenther, M. G., Carthew, R. W. & Lazar, M. A. (1998) Genes Dev. 12, 1775–1780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Hall, J. M. & Korach, K. S. (2002) J. Biol. Chem. 277, 44455–44461. [DOI] [PubMed] [Google Scholar]
  • 8.Soulez, M. & Parker, M. G. (2001) J. Mol. Endocrinol. 27, 259–274. [DOI] [PubMed] [Google Scholar]
  • 9.Omoto, Y. & Hayashi, S. (2002) Breast Cancer 9, 308–311. [DOI] [PubMed] [Google Scholar]
  • 10.Lobenhofer, E. K., Bennett, L., Cable, P. L., Li, L., Bushel, P. R. & Afshari, C. A. (2002) Mol. Endocrinol. 16, 1215–1229. [DOI] [PubMed] [Google Scholar]
  • 11.Inoue, A., Yoshida, N., Omoto, Y., Oguchi, S., Yamori, T., Kiyama, R. & Hayashi, S. (2002) J. Mol. Endocrinol. 29, 175–192. [DOI] [PubMed] [Google Scholar]
  • 12.Frasor, J., Danes, J. M., Komm, B., Chang, K. C., Lyttle, C. R. & Katzenellenbogen, B. S. (2003) Endocrinology 144, 4562–4574. [DOI] [PubMed] [Google Scholar]
  • 13.Frasor, J., Stossi, F., Danes, J. M., Komm, B., Lyttle, C. R. & Katzenellenbogen, B. S. (2004) Cancer Res. 64, 1522–1533. [DOI] [PubMed] [Google Scholar]
  • 14.Cunliffe, H. E., Ringner, M., Bilke, S., Walker, R. L., Cheung, J. M., Chen, Y. & Meltzer, P. S. (2003) Cancer Res. 63, 7158–7166. [PubMed] [Google Scholar]
  • 15.Hodges, L. C., Cook, J. D., Lobenhofer, E. K., Li, L., Bennett, L., Bushel, P. R., Aldaz, C. M., Afshari, C. A. & Walker, C. L. (2003) Mol. Cancer Res. 1, 300–311. [PubMed] [Google Scholar]
  • 16.Wang, D. Y., Fulthorpe, R., Liss, S. N. & Edwards, E. A. (2004) Mol. Endocrinol. 18, 402–411. [DOI] [PubMed] [Google Scholar]
  • 17.Cicatiello, L., Scafoglio, C., Altucci, L., Cancemi, M., Natoli, G., Facchiano, A., Iazzetti, G., Calogero, R., Biglia, N., De Bortoli, M., et al. (2004) J. Mol. Endocrinol. 32, 719–775. [DOI] [PubMed] [Google Scholar]
  • 18.Thenot, S., Charpin, M., Bonnet, S. & Cavailles, V. (1999) Mol. Cell. Endocrinol. 156, 85–93. [DOI] [PubMed] [Google Scholar]
  • 19.Lai, K., Harnish, D. C. & Evans, M. J. (2003) J. Biol. Chem. 278, 36418–36429. [DOI] [PubMed] [Google Scholar]
  • 20.Shi, Y., Downes, M., Xie, W., Kao, H. Y., Ordentlich, P., Tsai, C. C., Hon, M. & Evans, R. M. (2001) Genes Dev. 15, 1140–1151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Lauritsen, K. J., List, H. J., Reiter, R., Wellstein, A. & Riegel, A. T. (2002) Oncogene 21, 7147–7155. [DOI] [PubMed] [Google Scholar]
  • 22.Wu, R. C., Qin, J., Yi, P., Wong, J., Tsai, S. Y., Tsai, M. J. & O'Malley, B. W. (2004) Mol. Cell 15, 937–949. [DOI] [PubMed] [Google Scholar]
  • 23.Martini, P. G., Delage-Mourroux, R., Kraichely, D. M. & Katzenellenbogen, B. S. (2000) Mol. Cell. Biol. 20, 6224–6232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Dwivedi, P. P., Muscat, G. E., Bailey, P. J., Omdahl, J. L. & May, B. K. (1998) J. Mol. Endocrinol. 20, 327–335. [DOI] [PubMed] [Google Scholar]
  • 25.Dickins, R. A., Frew, I. J., House, C. M., O'Bryan, M. K., Holloway, A. J., Haviv, I., Traficante, N., de Kretser, D. M. & Bowtell, D. D. (2002) Mol. Cell. Biol. 22, 2294–2303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Frew, I. J., Hammond, V. E., Dickins, R. A., Quinn, J. M., Walkley, C. R., Sims, N. A., Schnall, R., Della, N. G., Holloway, A. J., Digby, M. R., et al. (2003) Mol. Cell. Biol. 23, 9150–9161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Frew, I. J., Sims, N. A., Quinn, J. M., Walkley, C. R., Purton, L. E., Bowtell, D. D. & Gillespie, M. T. (2004) J. Biol. Chem. 279, 29583–29588. [DOI] [PubMed] [Google Scholar]
  • 28.Nakayama, K., Frew, I. J., Hagensen, M., Skals, M., Habelhah, H., Bhoumik, A., Kadoya, T., Erdjument-Bromage, H., Tempst, P., Frappell, P. B., et al. (2004) Cell 117, 941–952. [DOI] [PubMed] [Google Scholar]
  • 29.Topol, L., Jiang, X., Choi, H., Garrett-Beal, L., Carolan, P. J. & Yang, Y. (2003) J. Cell Biol. 162, 899–908. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Fiucci, G., Beaucourt, S., Duflaut, D., Lespagnol, A., Stumptner-Cuvelette, P., Geant, A., Buchwalter, G., Tuynder, M., Susini, L., Lassalle, J. M., et al. (2004) Proc. Natl. Acad. Sci. USA 101, 3510–3515. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Heinzel, T., Lavinsky, R. M., Mullen, T. M., Soderstrom, M., Laherty, C. D., Torchia, J., Yang, W. M., Brard, G., Ngo, S. D., Davie, J. R., et al. (1997) Nature 387, 43–48. [DOI] [PubMed] [Google Scholar]
  • 32.Lavinsky, R. M., Jepsen, K., Heinzel, T., Torchia, J., Mullen, T. M., Schiff, R., Del-Rio, A. L., Ricote, M., Ngo, S., Gemsch, J., et al. (1998) Proc. Natl. Acad. Sci. USA 95, 2920–2925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Shang, Y. & Brown, M. (2002) Science 295, 2465–2468. [DOI] [PubMed] [Google Scholar]
  • 34.Jackson, T. A., Richer, J. K., Bain, D. L., Takimoto, G. S., Tung, L. & Horwitz, K. B. (1997) Mol. Endocrinol. 11, 693–705. [DOI] [PubMed] [Google Scholar]
  • 35.Smith, C. L., Nawaz, Z. & O'Malley, B. W. (1997) Mol. Endocrinol. 11, 657–666. [DOI] [PubMed] [Google Scholar]

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