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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined the expression and regulation of the two estrogen receptor (ER alpha and ER beta) genes in the rat ovary, using Northern blotting, RT-PCR, and in situ hybridization histochemistry. Northern blotting results show that the ovary expresses both ER alpha and ER beta genes as single (approximately 6.5-kb) and multiple (ranging from approximately 1.0-kb to approximately 10.0-kb) transcripts, respectively. ER alpha mRNA is expressed at a level lower than ER beta mRNA in immature rat ovaries. This relationship appears unchanged between sexually mature adult rats and immature rats. In sexually mature adult rats undergoing endogenous hormonal changes, whole ovarian content of ER beta mRNA, as determined by RT-PCR, remained more or less constant with the exception of the evening of proestrus when ER beta mRNA levels were decreased. Examination of ER beta mRNA expression at the cellular level, by in situ hybridization, showed that ER beta mRNA is expressed preferentially in granulosa cells of small, growing, and preovulatory follicles, although weak expression of ER beta mRNA was observed in a subset of corpora lutea, and that the decrease in ER beta mRNA during proestrous evening is attributable, at least in part, to down-regulation of ER beta mRNA in the preovulatory follicles. This type of expression and regulation was not typical for ER alpha mRNA in the ovary. Although whole ovarian content of ER alpha mRNA was clearly detected by RT-PCR, no apparent modulation of ER alpha mRNA levels was observed during the estrous cycle. Examination of ER alpha mRNA expression at the cellular level, by in situ hybridization, showed that ER alpha mRNA is expressed at a low level throughout the ovary with no particular cellular localization. To further examine the potential role of the preovulatory pituitary gonadotropins in regulating ER beta mRNA expression in the ovary, we used immature rats treated with gonadotropins. In rats undergoing exogenous hormonal challenges, whole ovarian content of ER beta mRNA, as determined by RT-PCR, remained more or less unchanged after an injection of PMSG. In contrast, a subsequent injection of human CG (hCG) resulted in a substantial decrease in whole ovarian content of ER beta mRNA. In situ hybridization for ER beta mRNA shows that small, growing, and preovulatory follicles express ER beta mRNA in the granulosa cells. The preovulatory follicles contain ER beta mRNA at a level lower than that observed for small and growing follicles. In addition, there is an abrupt decrease in ER beta mRNA expression in the preovulatory follicles after hCG injection. The inhibitory effect of hCG on ER beta mRNA expression was also observed in cultured granulosa cells. Moreover, agents stimulating LH/CG receptor-associated intracellular signaling pathways (forskolin and a phorbol ester) readily mimicked the effect of hCG in down-regulating ER beta mRNA in cultured granulosa cells. Taken together, our results demonstrate that 1) the ovary expresses both ER alpha and ER beta genes, although ER beta is the predominant form of estrogen receptor in the ovary, 2) ER beta mRNA is localized predominantly to the granulosa cells of small, growing, and preovulatory follicles, and 3) the preovulatory LH surge down-regulates ER beta mRNA. These results clearly implicate the physiological importance of ER beta in female reproductive functions.
Mol Endocrinol 1997 Feb
PMID:Estrogen receptor-beta mRNA expression in rat ovary: down-regulation by gonadotropins. 901 64

Estrogen receptor beta (ER beta) is a novel steroid receptor that is expressed in rat prostate and ovary. We have cloned the mouse homolog of ER beta and mapped the gene, designated Estrb, to the central region of chromosome 12. The cDNA encodes a protein of 485 amino acids that shares, respectively, 97% and 60% identity with the DNA- and ligand-binding domains of mouse (m) ER alpha. Mouse ER beta bind to an inverted repeat spaced by three nucleotides in a gel mobility shift assay and transactivates promoters containing synthetic or natural estrogen response elements in an estradiol (E2)-dependent manner. Scatchard analysis indicates that mER beta has slightly lower affinity for E2 [dissociation constant (Kd) = 0.5 nM] when compared with mER alpha (Kd = 0.2 nM). Antiestrogens, including 4-hydroxytamoxifen (OHT), ICI 182,780, and a novel compound, EM-800, inhibit E2-dependent transactivation efficiently. However, while OHT displays partial agonistic activity with ER alpha on a basal promoter linked to estrogen response elements in Cos-1 cells, this effect is not observed with mER beta. Cotransfection of mER beta and H-RasV12 causes enhanced activation in the presence of E2. Mutagenesis of a serine residue (position 60), located within a mitogen-activated protein kinase consensus phosphorylation site abolishes the stimulatory effect of Ras, suggesting that the activity of mER beta is also regulated by the mitogen-activated protein kinase pathway. Surprisingly, the coactivator SRC-1 up-regulates mER beta transactivation both in the absence and presence of E2, and in vitro interaction between SRC-1 and the ER beta ligand-binding domain is enhanced by E2. Moreover, the ligand-independent stimulatory effect of SRC-1 on ER beta transcriptional activity is abolished by ICI 182,780, but not by OHT. Our results demonstrate that while ER beta shares many of the functional characteristics of ER alpha, the molecular mechanisms regulating the transcriptional activity of mER beta may be distinct from those of ER alpha.
Mol Endocrinol 1997 Mar
PMID:Cloning, chromosomal localization, and functional analysis of the murine estrogen receptor beta. 905 81

The recent discovery that an additional estrogen receptor subtype is present in various rat tissues has advanced our understanding of the mechanisms underlying estrogen signaling. Here we report on the cloning of the cDNA encoding the mouse homolog of estrogen receptor-beta (ER beta) and the functional characterization of mouse ER beta protein. ER beta is shown to have overlapping DNA-binding specificity with that of the estrogen receptor-alpha (ER alpha) and activates transcription of reporter gene constructs containing estrogen-response elements in transient transfections in response to estradiol. Using a mammalian two-hybrid system, the formation of heterodimers of the ER beta and ER alpha subtypes was demonstrated. Furthermore, ER beta and ER alpha form heterodimeric complexes with retained DNA-binding ability and specificity in vitro. In addition, DNA binding by the ER beta/ER alpha heterodimer appears to be dependent on both subtype proteins. Taken together these results suggest the existence of two previously unrecognized pathways of estrogen signaling; I, via ER beta in cells exclusively expressing this subtype, and II, via the formation of heterodimers in cells expressing both receptor subtypes.
Mol Endocrinol 1997 Sep
PMID:Mouse estrogen receptor beta forms estrogen response element-binding heterodimers with estrogen receptor alpha. 928 64

Recently a second estrogen receptor termed estrogen receptor beta (ERbeta) has been cloned and characterized, and shown to be expressed at the highest levels in ovarian granulosa cells and prostatic epithelium. In the course of amplifying a region of the ligand-binding domain of the rat ERbeta cDNA we identified a second, larger transcript which appears to arise through differential splicing. The second isoform has 54 nucleotides inserted after position 1372 encoding 18 additional amino acids. Both isoforms are expressed at similar relative abundance in a range of tissues.
Mol Cell Endocrinol 1997 Sep 19
PMID:Identification of a splice variant of the rat estrogen receptor beta gene. 932 61

In the present study, estrogen receptor (ER)alpha and ER beta genes were found to be differentially expressed in discrete subregions of the rat amygdaloid complex. The amygdala nuclei showing predominant ER alpha mRNA expression included the posterolateral cortical nucleus, amygdala hippocampal area, and lateral dorsolateral nucleus, whereas the amygdala areas with predominant ER beta mRNA expression were the medial anterodorsal and central nuclei. Both ER alpha and ER beta mRNAs were highly expressed in the medial posterodorsal nucleus. In addition to the discrete anatomical expression patterns, there appeared to be a differential regulation by estradiol of the ER alpha and ER beta mRNAs. Two weeks of estradiol (170 microgram total) treatment decreased ER alpha mRNA expression levels in the arcuate, ventromedial hypothalamus, and posterolateral cortical amygdala nucleus, but increased ER beta mRNA in the arcuate. In the medial amygdala nuclei, only ER beta mRNA levels were altered (reduced) by estradiol treatment. These results suggest that estrogen can modulate behaviors and functions mediated by the amygdala and hypothalamus via differentially regulated ER subtypes.
Brain Res Mol Brain Res 1998 Feb
PMID:Differential distribution and regulation of estrogen receptor-alpha and -beta mRNA within the female rat brain. 952 77

The existence of two rather than one estrogen receptor, today characterized as estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta), indicates that the mechanism of action of 17beta-estradiol and related synthetic drugs is more complex than previously thought. Because the homology of amino acid residues in the ligand-binding domain (LBD) of ERbeta is high compared with those amino acid residues in ERalpha LBD, previously shown to line the ligand binding cavity or to make direct contacts with ligands, it is not surprising that many ligands have a similar affinity for both receptor subtypes. We report that 17alpha-ethynyl, 17beta-estradiol, for example, has an ERalpha-selective agonist potency and that 16beta,17alpha-epiestriol has an ERbeta-selective agonist potency. We also report that genistein has an ERbeta-selective affinity and potency but an ERalpha-selective efficacy. Furthermore, we show that tamoxifen, 4-OH-tamoxifen, raloxifene, and ICI 164,384 have an ERalpha-selective partial agonist/antagonist function but a pure antagonist effect through ERbeta. In addition, raloxifene displayed an ERalpha-selective antagonist potency, in agreement with its ERalpha-selective affinity. However, although ICI 164,384 showed an ERbeta-selective affinity, it had a similar potency to antagonize the effect of 17beta-estradiol in the ERalpha- and ERbeta-specific reporter cell lines, respectively. In conclusion, our data indicate that the ligand binding cavity of ERbeta is probably more different from that of ERalpha than can be anticipated from the primary sequences of the two ER subtypes and that it will be possible to develop receptor-specific ligands that may form the basis of novel pharmaceuticals with better in vivo efficacy and side effect profile than current available drugs.
Mol Pharmacol 1998 Jul
PMID:Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists. 965 95

Estrogen receptor (ER)-beta mRNA splice variants have been identified in human breast tumors as well as normal human and mouse ovarian, uterine and mammary tissues. In both species transcripts deleted in exons 5 or 6, or 5 + 6 have been characterized by RT-PCR followed by cloning and sequencing. In mouse tissues an ER-beta transcript containing 54 nucleotides inserted in frame between exons 5 and 6 was identified. Interestingly, no equivalent of the mouse inserted transcript was detected in any of the four human tissues analyzed.
Mol Cell Endocrinol 1998 Mar 16
PMID:Estrogen receptor-beta mRNA variants in human and murine tissues. 968 28

In vivo autoradiographic studies have shown that neurons in the estrogen receptor-alpha knockout (ERKO) mouse brain are capable of concentrating radiolabeled estrogen. In one region of the ERKO hypothalamus that binds estrogen, the preoptic area, we have also shown that a variety of estrogenic compounds modulate the expression of progesterone receptor. Recently, a second estrogen receptor (ER-beta) was isolated from the rat prostate. In situ hybridization studies have demonstrated that ER-beta mRNA is present in the rat brain as well as the preoptic area of the ERKO mouse brain. Interestingly, ER-beta mRNA was also detected in regions of the brain where the classical ER is sparse or absent, including the cerebral cortex and hippocampus. Together, the results of these studies suggest the presence and functionality of a non-classical estrogen receptor in the ERKO brain and provided evidence that this receptor may be ER-beta. Moreover, the localization of ER-beta mRNA in many new brain regions, including those associated with learning and memory, may provide new insight about the anatomical substrate for estrogen action in the brain.
Mol Psychiatry 1998 Jul
PMID:Estrogen action in the estrogen receptor alpha-knockout mouse: is this due to ER-beta? 970 37

A novel human estrogen receptor beta (hERbeta) was cloned from human testis mRNA, ovary and thymus cDNA utilizing PCR and 5' RACE methods. The 5' end of hERbeta contained an additional open reading frame, in-frame and upstream of the published clones. hERbeta encodes a protein of 530 amino acids with an approximate molecular weight of 63 kDa and is larger than the previously reported rat, mouse and human protein. To determine the functional role of additional N-terminal amino acids, we compared the transcription functions of receptor lacking (hERbetaT) and receptor containing (hERbetaL) this N-terminal extension. hERbetaL is more active than hERbetaT in transactivating ERE-based reporter genes. hERbetaL, but not hERbetaT, attenuated cytokine mediated NFkappaB activation. Taken together, the additional N-terminal amino acids appear to play a role in modulating estrogen responsive gene expression in vitro.
J Steroid Biochem Mol Biol 1998 Nov
PMID:A novel human estrogen receptor beta: identification and functional analysis of additional N-terminal amino acids. 987 82

The biosynthesis of estrogens is catalyzed by an enzyme known as aromatase (aromatase cytochrome P450; P450 arom; the product of the CYP19 gene). In recent years a number of patients have been described suffering from aromatase deficiency due to mutations in the CYP19 gene, resulting in the synthesis of a non-functional gene product and a resulting failure to synthesize estrogens. Males with this condition have sustained linear growth into adulthood resulting from failure of epiphyseal closure. Osteopenia and reduced bone mineral density and bone age are also characteristic. Lack of circulating estrogens is accompanied by elevated testosterone and gonadotropins. One of the men had macroorchidism with testicular volumes in excess of 25 ml (Morishima et al. J. Clin. Endocrinol. Metab. 80, 3689, 1995). Semen analysis was not performed on this patient, but it is of note that the one patient described with estrogen insensitivity due to a mutation in the estrogen receptor had a normal sperm count, although motility was decreased (Smith et al., New England J. Med. 331. 1056, 1994). By contrast, the other man with aromatase deficiency had testicular volumes of only 8 ml per testes, and was infertile. Sperm analysis revealed a count of 1 million/ml with 100% immotile sperm (Carani et al. New England J. Med. 337, 91, 1997). However, his clinical picture is confused by the fact that another male sibling has azoospermia, but has no CYP19 mutation, suggesting that the infertility problem may be due to a second genetic condition in this consanguineous family. Recently mice have been generated in which the aromatase (CYP19) gene and the gene encoding the estrogen receptor-alpha have been inactivated by targeted disruption (ArKO and ERKO mice, respectively). Male ERKO mice are infertile with atrophy of the testes and seminiferous tubule dysmorphogenesis resulting in decreased spermatogenesis and inacive sperm. By contrast the ArKO mice are initially fertile and sire litters of normal size ad frequency, however with advancing age the number of litters sired decreases relative to those of wild type litter ates. In contrast to the ERKO mice, light microscopic analysis of the testes of the ArKO mice reveals no gross morphological abnormalties and the testes are of normal size. Following recent observations that the estrogen receptor-beta isoform is highly expressed in seminiferous epthelium, spermatids and spermatocytes, it is conceivable that the relatively high levels of estrogens present in the ERKO mice can act through the ER-beta to cause infertility by a direct action on the testes. In this context it is well known that administration of high levels of estrogen to men results in infertility. It is apparent that studies of human and mouse models with disruptions of aromatase and the estrogen receptor have as yet failed to clarify the role of estrogens in male fertility and testicular function. Development of an ER-beta knockout mouse, or else a double, or even triple, knockout model, may be required in order to resolve these issues.
Mol Cell Endocrinol 1998 Oct 25
PMID:Genetic mutations resulting in estrogen insufficiency in the male. 992 99


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