Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q02556 (DNA-binding domain)
 6,431 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel estrogen receptor (hereinafter referred to as ER beta) was cloned using degenerate PCR primers. A comparison of the amino acid sequence of ER beta with the "classical' ER (ER alpha) shows a high degree of conservation of the DNA-binding domain (96%), and of the ligand-binding domain (58%). In contrast, the A/B domain, the hinge region and the F-domain are not conserved. Northern blot analysis revealed that ER beta is expressed in human thymus, spleen, ovary and testis. Transient transfections of an ER beta expression construct together with an ERE-based reporter construct in CHO cells clearly demonstrated transactivation of ER beta by 17 beta-estradiol. In addition, the ER alpha antagonist ICI-164384 is a potent antagonist for ER beta as well. Interestingly, the level of transactivation by 17 beta-estradiol is higher for ER alpha than for ER beta, which may reflect suboptimal conditions for ER beta at the level of the ligand, responsive element or cellular context.
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PMID:ER beta: identification and characterization of a novel human estrogen receptor. 876 13

Several studies have shown that estrogen is important for the differentiation of midbrain dopaminergic neurons. This is supported by the previous demonstration of estrogen synthesis in the perinatal ventral midbrain. The present study attempts to characterize the expression pattern of nuclear estrogen receptors (ER-alpha/beta) mRNAs in the ventral rat midbrain during development. By applying primers specific for the hormone-binding domain, ER-alpha mRNA was detected from embryonic day (E) 14 until postnatal day (P) 20, whereas considerable levels of ER-beta mRNA were found from P3 to P20. In contrast, primers spanning the DNA-binding domain demonstrated the presence of transcripts for ER-alpha as well as ER-beta after birth. These findings indicate that both ERs are expressed in the developing midbrain. The presence of ER-alpha transcripts devoid of the DNA-binding region is discussed in the context of 'non-genomic' estrogen signaling possibly by membrane receptors.
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PMID:Ontogenetic expression and splicing of estrogen receptor-alpha and beta mRNA in the rat midbrain. 1055 75

In 1996 Kuiper et al. have cloned a novel member of the nuclear receptor superfamily. The cDNA of clone 29 was isolated from a rat prostate cDNA library. The new receptor was highly homologus to the rat estrogen receptor protein, particularly in the DNA-binding domain. New protein consists of 485 amino acid residues and its molecular weight is 54.2 kDa. Like other steroid receptors, ER beta has six regions, A-F. A novel receptor is expressed in the secretory epithelial cells of the prostate and also in the granulosa cells of the ovary. Differences in the ligand-binding properties and transactivation function on target genes may exist. The tissue distribution and relative level of ER alpha and beta expression seems to be quite different, i.e. moderate to high expression in uterus, testis, pituitary, ovary, kidney, and adrenal for ER alpha and prostate, ovary, lung, bladder, brain, uterus and testis for ER beta. The differences between the receptors subtypes in relative ligand binding affinity and tissue distribution could contribute to the selective action of ER aginists and antagonists in different tissues. These new findings bring up many questions. The most intriguing is how has this second ER eluded investigators for so many years? Perhaps a limited number of estrogen target tissues were screened. The biological significance of the existence of two different ERs is at this moment unclear. Perhaps the existence of two ERs subtypes provides an explanation for the selective actions of estrogens in different target tissues.
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PMID:[Novel estrogen receptor: a chance for more specific and safe endocrinological treatment?]. 1076 6

To characterize the specificity of synthetic compounds for nuclear receptors, we established stable cell lines expressing the luciferase gene and different wild-type or chimaeric receptors. MCF-7 cells, which express the oestrogen receptor alpha (ER alpha), and HeLa cells, which do not express the oestrogen receptor, were transfected with a plasmid containing the luciferase gene downstream from a minimum promoter (beta-globin) and an oestrogen-responsive element, generating the MELN and the HELN cell lines, respectively. MELN cells enabled the detection of compounds that bind to the ER alpha or interfere with its pathway. HELN cells were used to establish stable transfectants expressing different nuclear receptors containing the DNA-binding domain of the oestrogen receptors. We thus established ER alpha or ER beta reporter cell lines by transfecting ER alpha or ER beta expression plasmids, and also retinoic acid receptor alpha, beta or gamma reporter cell lines by transfecting the chimaeric RAR gene, in which the DNA-binding domain was replaced by the ER alpha DNA-binding domain.
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PMID:Reporter cell lines are useful tools for monitoring biological activity of nuclear receptor ligands. 1131 41

Estrogen receptor-alpha (ER alpha) is a ligand-activated transcription factor and a member of the nuclear receptor superfamily. The classic mechanism of ER alpha action is associated with estrogen-induced formation of a nuclear ER alpha homodimer, binding to 5'-regulatory estrogen response elements (EREs) in target gene promoters, interaction with other nuclear proteins, and general transcription factors to activate gene expression. ER alpha also interacts with Sp1 protein to transactivate genes through binding Sp1(N)xERE or Sp1(N)xERE half-site (1/2) motifs where both ER alpha and Sp1 bind DNA elements. Activation through Sp1(N)xERE1/2 requires interactions of both proteins with their cognate DNA elements as well as additional nuclear factors to form a functional ER alpha/Sp1-DNA complex. Recent studies also show that ER alpha and Sp1 physically interact and ER alpha preferentially binds to the C-terminal DNA-binding domain of Sp1 protein. Moreover, ER alpha/Sp1 can activate transcription from a consensus GC-rich Sp1 binding site in transient transfection studies in MCF-7 human breast cancer cells, and this response is also observed with ER alpha variants that do not contain the DNA-binding domain. Several genes that are induced by estrogens in MCF-7 cells are activated through one or more GC-rich sites in their regulatory regions and these include the cathepsin D, E2F1, bcl-2, c-fos, adenosine deaminase, insulinlike growth factor binding protein 4, and retinoic acid receptor alpha 1 genes. ER alpha/Sp1 and ER beta/Sp1 action is dependent on ligand structure and cell context and ER beta/Sp1 is primarily associated with decreased ligand-dependent gene expression. ER alpha/Sp1, like ER alpha/AP1, represents a pathway for hormone activation of genes in which the receptor does not bind DNA, and results of ongoing studies suggest that ER alpha/Sp1 plays an important role in transcriptional activation of multiple growth regulatory genes in breast cancer cells.
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PMID:Transcriptional activation of genes by 17 beta-estradiol through estrogen receptor-Sp1 interactions. 1134

A chemokine, monocyte chemoattractant protein 1 (MCP-1), attracts macrophages. The production of MCP-1 is enhanced in keratinocytes of psoriatic lesions, which may contribute to macrophage infiltration into the lesions. It is known that estrogen regulates the course of psoriasis. We examined in vitro effects of 17beta-estradiol (E2) on MCP-1 production by human keratinocytes. E2 inhibited constitutive and 12-O-tetradecanoylphorbol-13-acetate-induced MCP-1 secretion, mRNA expression, and promoter activity in keratinocytes, and these effects of E2 were counteracted by estrogen receptor antagonist ICI 182 780. GC-rich Sp1 element and activator protein 1 (AP-1) element on MCP-1 promoter were required for constitutive and 12-O-tetradecanoylphorbol-13-acetate-induced transcription, respectively, and involved in transrepression by E2. E2 inhibited constitutive Sp1 and 12-O-tetradecanoylphorbol-13-acetate-induced AP-1 transcriptional activities whereas it did not inhibit DNA binding of Sp1 or AP-1 c-Fos/c-Jun. E2 inhibited Sp1 and AP-1 transcriptional activities and MCP-1 promoter activity in estrogen receptor beta (ERbeta) transfected SKBR3 cells. Deletion of the A/B region or mutation of activation function 2 in ERbeta abrogated E2-dependent transcriptional inhibition by ERbeta whereas mutation of DNA-binding domain retained the inhibitory effects. Transfection of ERbeta enhanced the inhibitory effects of E2 on Sp1 and AP-1 transcriptional activities and MCP-1 promoter activities in nontransfected keratinocytes. Coimmunoprecipitation studies showed an E2-dependent association of ERbeta with Sp1 or AP-1 in ERbeta-transfected keratinocytes. These results suggest that E2-bound ERbeta may inhibit MCP-1 gene expression by inhibiting Sp1 and AP-1 transcriptional activities in keratinocytes. A/B region and intact activation function 2 of ERbeta may be responsible for the effects of E2.
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PMID:17Beta-estradiol inhibits MCP-1 production in human keratinocytes. 1278 35

The status of the 66-kDa human estrogen receptor-alpha (hER-alpha66) is a critical determinant in the assessment of the prognosis and in the design of treatment strategies of human breast cancer. Recently, we cloned the cDNA of an alternatively spliced variant of hER-alpha66, termed hER-alpha36; the predicted protein lacks both transcriptional activation domains of hER-alpha66 but retains its DNA-binding domain, partial dimerization, and ligand-binding domains and three potential myristoylation sites located near the N terminus. These findings thus predict that hER-alpha36 functions very differently from hER-alpha66 in response to estrogen signaling. We now demonstrate that hER-alpha36 inhibits the estrogen-dependent and estrogen-independent transactivation activities of hER-alpha66 and hER-beta. We further demonstrate that hER-alpha36 is predominantly associated with the plasma membrane where it transduces both estrogen- and antiestrogen-dependent activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway and stimulates cell growth. We conclude that hER-alpha36 is a predominantly membrane-based, unique alternatively spliced variant of hER-alpha66 that acts as a dominant-negative effector of both estrogen-dependent and estrogen-independent transactivation functions signaled through hER-alpha66 and ER-beta; it also transduces membrane-initiated estrogen-dependent activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase mitogenic signaling pathway. The estrogen and antiestrogen signaling pathways mediated by hER-alpha36 provide an alternative explanation for why some human breast cancers are resistant to and others are worsened by antiestrogen therapy; the data suggest that hER-alpha36 also may be an important marker to direct therapy in human breast cancers, and perhaps hER-alpha36 also may transduce estrogen-dependent signaling in other estrogen target tissues.
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PMID:A variant of estrogen receptor-{alpha}, hER-{alpha}36: transduction of estrogen- and antiestrogen-dependent membrane-initiated mitogenic signaling. 1675 86

In all vertebrates, estrogen action is mediated by cognate nuclear receptors. In this study, we cloned the different transcripts of the estrogen receptor beta (ERbeta) gene of the common sole, Solea solea. 5'-RLM-RACE (RNA Ligase-Mediated 5'-Rapid Amplification of cDNA Ends) and 3'-RACE analyses revealed three isoforms of different length, called Long, Intermediate and Short isoforms, consisting of 2212, 1531 and 1207 b, respectively. The Long isoform is characterised by an open reading frame (ORF) encoding 589aa, with an estimated molecular weight of 65kDa. Phylogenetic analysis established that it belongs to the teleost ERbeta1 or ERbetaa cluster. The Intermediate isoform encodes a 490-aa protein, which lacks the first 99aa of the Long isoform, but still retains a complete DNA-binding domain (DBD). In the Short variant (363aa-long), all the N-terminal region, down to the two zinc fingers included, is missing, thus crippling DBD. ERbeta transcription was analysed by semiquantitative RT-PCR with specific primers, common to the Long and Intermediate isoforms, in various sole tissues, such as brain, gills, muscle, stomach, intestine, spleen, head kidney, kidney, liver and gonads. This analysis revealed that ERbeta displays a widespread or ubiquitous pattern of transcription, with the highest levels being found in the gonads and liver.
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PMID:Characterisation of three variants of estrogen receptor beta mRNA in the common sole, Solea solea L. (Teleostei). 1733 5

Estrogens have numerous effects on the brain, both in adulthood and during development. These actions of estrogen are mediated by two distinct estrogen receptor (ER) systems, ER alpha (ERalpha) and ER beta (ERbeta). In brain, ERalpha plays a critical role in regulating reproductive neuroendocrine function and behavior, however, a definitive role for ERbeta in any neurobiological function has been slow in forthcoming. Clues to the function of ERbeta in the central nervous system can be gleaned from the neuroanatomical distribution of ERbeta and the phenotypes of neurons that express ERbeta. ERbeta immunoreactivity has been found in populations of GnRH, CRH, vasopressin, oxytocin and prolactin containing neurons in the hypothalamus. Utilizing subtype-selective estrogen receptor agonists can help determine the roles for ERbeta in non-reproductive behaviors in rat models. ERbeta-selective agonists exert potent anxiolytic activity when animals were tested in a number of behavioral paradigms. Consistent with this, ERbeta-selective agonists also inhibited the ACTH and corticosterone response to stress. In contrast, ERalpha selective agonists were found to be anxiogenic and correspondingly increased the hormonal stress response. Taken together, our studies implicate ERbeta as an important modulator of some non-reproductive neurobiological systems. The molecular and neuroanatomical targets of estrogen that are mediated by ERbeta remain to be determined. A number of splice variants of ERbeta mRNA have been reported in brain tissue. Imaging of eGFP labeled chimeric receptor proteins transfected into cell lines shows that ERbeta splice variation can alter trafficking patterns and function. The originally described ERbeta (herein termed ERbeta1) is characterized by possessing a high affinity for estradiol. Similar to ERalpha, it is localized in the nucleus and is trafficked to nuclear sites termed "hyperspeckles" following ligand binding. In contrast, ERbeta2 contains an 18 amino acid insert within the ligand-binding domain and as a result can be best described as a low affinity form of ERbeta. A delta3 (delta3) variant of ERbeta has a deletion of the 3rd exon (coding for the second half of the DNA-binding domain) and as a result does not bind an estrogen response element in DNA. delta3 variants are trafficked to a unique low abundance and larger nuclear site following ligand binding. A delta4 (delta4) variant lacks exon 4 and as a result is localized to the cytoplasm. The amount of individual splice variant mRNAs varies depending upon brain region. Examination of neuropeptide promoter regulation by ERbeta splice variants demonstrates that ERbeta functions as a constitutively active transcription factor. Moreover, it appears that splice variation of ERbeta alters its ability to regulate transcription in a promoter-dependent and ligand-dependent fashion.
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PMID:Estrogen receptor beta in the brain: from form to function. 1766 59

A major focus in the current discovery of drugs targeting nuclear receptors (NRs) is identifying drugs with reduced side effects by improving selectivity, not only from other receptors but also by selective modulation of the NR of interest. Cellular assays not only provide valuable information on functional activity, potency, and selectivity but also are ideally suited for differentiating partial agonists and antagonists. The ability to partially activate a receptor is believed to be closely tied to the ability to selectively modulate the NR, resulting in expression of a subset of the normally regulated genes. To this end, the authors have built a complete panel of cell-based steroid hormone receptor assays for the androgen receptor, estrogen receptor alpha, estrogen receptor beta, glucocorticoid receptor, mineralocorticoid receptor, and progesterone receptor by stably engineering a Gal4 DNA-binding domain/nuclear receptor ligand-binding domain fusion protein into an upstream activation sequence beta-lactamase reporter cell line. Each assay was validated with known agonists and antagonists for correct pharmacology and high-throughput compatibility. To demonstrate the utility of these assays, the authors profiled 35 pharmacologically relevant compounds in a dose-response format against the panel in both agonist and antagonist modes. The results demonstrated that selective estrogen receptor modulators can be identified and differentiated, as well as mixed and partial agonists and antagonists easily detected in the appropriate assays. Importantly, a comparison of the chimeric assays with full-length reporter gene assay data from the literature shows a good degree of correlation in terms of selectivity and pharmacology of important ligands. Taken together, these steroid hormone receptor assays provide good selectivity, sensitivity, and appropriate pharmacology for high-throughput screening and selectivity profiling of modulators of steroid hormone receptors.
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PMID:Compound profiling using a panel of steroid hormone receptor cell-based assays. 1875 90


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