Estradiol and Selective Estrogen Receptor Modulators Differentially Regulate Target Genes with Estrogen Receptors α and β

Tee, Meng Kian; Rogatsky, Inez; Tzagarakis-Foster, Christina; Čvoro, Aleksandra; An, Jinping; Christy, Robert J.; Yamamoto, Keith R.; Leitman, Dale C.

doi:10.1091/mbc.e03-06-0360

Cited by 200 publications

(141 citation statements)

References 45 publications

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“…Most notably, ER ligands such as estradiol, tamoxifen, and raloxifene display distinct functions in different cell types, and induce dramatically different gene expression profiles in a single cell type (Shang and Brown 2002;Jordan 2004;Kian Tee et al 2004). Although these results are striking, the chemical structures of these ER ligands are significantly different, thus complicating inferences of potential relationships between chemical structure and biological response.…”

Section: Discussionmentioning

confidence: 99%

“…It is now apparent, however, that ligand activities are strongly context dependent. For example, selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, are agonist-like or antagonist-like in different tissues, and modulate distinct subsets of ER target genes in a given cell type (Shang and Brown 2002;Jordan 2004;Kian Tee et al 2004); selective ligands for FXR have also been reported (Downes et al 2003). Accordingly, the definitions of agonist and antagonist are relative to particular phenotypes or specific subsets of target genes, and therefore it is likely that any ligand could act as either agonist or antagonist depending on the context.…”

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confidence: 99%

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Novel arylpyrazole compounds selectively modulate glucocorticoid receptor regulatory activity

Wang¹,

Shah²,

Pantoja³

et al. 2006

Genes Dev.

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The activities of intracellular receptors are regulated by their cognate ligands. Here we show that a series of related arylpyrazole compounds, which specifically bind the glucocorticoid receptor (GR), selectively modulated GR-regulated biological functions in preadipocyte, preosteoblast, and lung epithelial cell lines. Indeed, when we monitored 17 endogenous GR target genes in one of these cell types, we found that distinct arylpyrazole compounds induced different expression patterns. We showed by chromatin immunoprecipitation that the arylpyrazole compounds regulated, in a gene-specific manner, either GR occupancy of the genomic glucocorticoid response element (GRE) or events after GR association, such as histone modification. Overall, our results establish that subtle differences in ligand chemistry can profoundly influence the transcriptional regulatory activity of GR, and that endogenous genes bearing natural GREs are especially sensitive detectors of these differences.[Keywords: Glucocorticoid receptor; glucocorticoid receptor ligand; arylpyrazole compounds; response element; chromatin immunoprecipitation] Supplemental material is available at http://www.genesdev.org.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Novel arylpyrazole compounds selectively modulate glucocorticoid receptor regulatory activity

Wang¹,

Shah²,

Pantoja³

et al. 2006

Genes Dev.

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“…For example, U2OS osteosarcoma cell lines transfected with inducible ERa or ERb and studied with an Affymetrix GeneChip tm array were found to have fewer than a quarter of their estraidiol-, raloxifeneand tamoxifen-regulated genes in common. 16 The differential function of the two ER genes is illustrated in the placenta, where ERb is expressed in syncytiotrophoblast, ERa in cytotrophoblast and where they appear to promote proliferation and differentiation, respectively. 17 Clinical measurement of ER protein has been a routine practice since the 1970s; however, as biomedical science has advanced, the methodology has changed over the years, with varying results.…”

Section: Discussionmentioning

confidence: 99%

Estrogen receptor β expression in vascular neoplasia: an analysis of 53 benign and malignant cases

et al. 2004

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The importance of estrogen in vascular neoplasia is suggested by a predilection for women and a tendency for rapid growth during pregnancy. Although early experiments using radioligand assays demonstrated estrogen receptor (ER) expression, these findings were not confirmed by subsequent immunohistochemical studies which were performed with antibodies raised against ERa. A newly discovered estrogen receptor subtype, ERb, has not been previously characterized in vascular lesions. In order to verify the expression of estrogen receptors in vascular neoplasms as well as to clarify the inconsistency between radioligand and early immunohistochemical studies, we examined a series of 53 benign and malignant vascular neoplasms for ERb expression. All of the subtypes of vascular neoplasia examined had nuclear expression of ERb. The majority of cases (94%) displayed 2 þ to 3 þ staining. The discrepancy between radioligand studies and previous immunohistochemical studies is attributable to the use of antibodies raised against ERa, which is not expressed in vascular lesions, and not ERb, which is broadly expressed in both benign and malignant vascular neoplasms. Although ERb may be of limited diagnostic use in vascular neoplasia due to its broad expression, the potential exists for a therapeutic approach using ER agonists. The role of estrogen in vascular neoplasia has long been suspected due to the observation that vascular neoplasms tend to grow rapidly during pregnancy and in adolescence. 1 These clinical observations were initially substantiated by early experiments in the 1980s using radioligand assays, which confirmed the presence of the estrogen receptor (ER) in vascular tumors; 2,3 however, with the advent of immunohistochemical techniques, subsequent studies performed in the 1990s with antibodies raised against the ER refuted these earlier data and it appeared that the newer technology had exposed the limitations of the older biochemical assays. [4][5][6][7] Recently, an additional ER subtype, estrogen receptor beta (ERb), 8 was identified and the previous ER against which the original antibodies were raised was renamed estrogen receptor alpha (ERa). Although ERa has been assessed immunohistochemically in vascular neoplasms and found to be absent, ERb has not been previously characterized in these entities. In order to verify the expression of ER in vascular tumors as well as to clarify the inconsistency between radioligand and early immunohistochemical studies, we examined a series of 53 benign and malignant vascular neoplasms for ERb expression. Materials and methodsIn all, 22 cases of angiosarcoma, three cases of Kaposi sarcoma, one case of epithelioid hemangioendothelioma, two cases of spindle-cell hemangioma, four cases of infantile hemangioendothelioma, 13 cases of hemangioma, seven cases of lymphangioma and one case of papillary endothelial hyperplasia were identified and retrieved from the paraffin archives of the University of Chicago. Formalin-fixed paraffin-embedded specimens were cut into 4-mm sections an...

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“…SERMs are ligands whose estrogenic properties vary from tissue to tissue depending on the isoform of ER utilized, as well as the coregulators recruited (Nagel et al, 2001;Katzenellenbogen and Katzenellenbogen, 2002;Kian Tee et al, 2004). Raloxifene is an SERM that has estrogenic-like effects in bone, but it is a high-affinity antagonist of ERa in other reproductive tissues (Buelke-Sam et al, 1998).…”

Section: Figurementioning

confidence: 99%

Effects of Ovarian Steroids and Raloxifene on Proteins that Synthesize, Transport, and Degrade Serotonin in the Raphe Region of Macaques

Smith

Henderson

Abell

et al. 2004

Neuropsychopharmacol

147

123

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In the monkey dorsal raphe, we reported that 1-month (mo) of estrogen replacement, with or without progesterone supplementation for 14 days, significantly increased tryptophan hydroxylase-1 (TPH-1) mRNA; decreased serotonin reuptake transporter (SERT) mRNA and decreased monoamine oxidase (MAO)-A mRNA, but had no effect on MAO-B mRNA. Here, we questioned what effect would 1 or 5 mo of ovarian hormones or the selective estrogen receptor modulator (SERM), raloxifene, have on TPH protein and phosphorylation, and on protein expression of SERT, MAO-A or MAO-B? Raloxifene antagonizes estrogen in breast or uterus, but estrogen-like activities in the brain have been reported. Cytoplasmic and membrane extracts of the dorsal raphe region were processed for Western blotting. TPH, phosphoserine, SERT, MAO-A, and MAO-B were detected with specific antibodies. The optical densities of the signals were measured with NIH image and analyzed by ANOVA. Both 1 and 5 mo of estrogen, with or without progesterone, and 5 mo of raloxifene significantly increased TPH protein. Administration for 5 mo of estrogen plus progesterone and raloxifene also increased TPH phosphorylation. Estrogen, with or without progesterone, for 1 mo had no effect on SERT protein. However, 5 mo of estrogen and 5 mo of raloxifene increased SERT protein. Estrogen alone or combined with progesterone for 1 mo caused a significant reduction in MAO-A. Yet, after 5 mo of the same treatments, MAO-A was not different from spayed controls. Estrogen alone had no effect on MAO-B. However, the addition of progesterone significantly increased MAO-B. Raloxifene for 5 mo had no effect on MAO-A or MAO-B. Thus, to various extents, estrogen, progesterone, and raloxifene may increase serotonin production and transport. The expression of the degradative enzymes suggests a complex combination of gene transcription, post-transcriptional processing, and substrate feedback mechanisms.

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Estradiol and Selective Estrogen Receptor Modulators Differentially Regulate Target Genes with Estrogen Receptors α and β

Cited by 200 publications

References 45 publications

Novel arylpyrazole compounds selectively modulate glucocorticoid receptor regulatory activity

Novel arylpyrazole compounds selectively modulate glucocorticoid receptor regulatory activity

Estrogen receptor β expression in vascular neoplasia: an analysis of 53 benign and malignant cases

Effects of Ovarian Steroids and Raloxifene on Proteins that Synthesize, Transport, and Degrade Serotonin in the Raphe Region of Macaques

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