Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01178 (oxytocin)
 15,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An understanding of the functional significance of the newly identified estrogen receptor (ER beta) in the brain will require definition of its expression pattern and relationship to ER alpha. Using an antibody generated against the C-terminus of rat ER beta, we report the presence of ER beta immunoreactivity in the lateral septum, medial amygdala, hippocampus and paraventricular nucleus (PVN) of ovariectomized rats. Double labelling studies in the PVN revealed that approximately 35% of oxytocin neurons located principally in the medial and lateral parvocellular divisions of the caudal PVN were immunoreactive for ER beta while vasopressin, somatostatin and magnocellular oxytocin neurons exhibited no ER beta staining with this antibody. No ER alpha immunoreactive cells were identified in the caudal PVN. These observations provide direct evidence for the differential expression of ER sub-types within neurons and indicate that ER beta may be of physiological significance in the regulation of hypothalamic parvocellular oxytocin neurons by estrogen.
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PMID:Differential expression of estrogen receptor alpha and beta immunoreactivity by oxytocin neurons of rat paraventricular nucleus. 941 30

Evidence exists for the localization of the newly identified estrogen receptor beta (ERbeta) within the rat paraventricular nucleus (PVN) and supraoptic nucleus (SON), regions which lack ERalpha. Presently, we investigate whether ERbeta-like-immunoreactivity (-ir) is found within cells of several major neuropeptide systems of these regions. Young adult Sprague-Dawley rats were ovariectomized (OVX), and 1 week later half of the animals received estradiol-17beta (E). Dual-label immunocytochemistry was performed on adjacent sections by using an ERbeta antibody, followed by an antibody to either oxytocin (OT), arginine-vasopressin (AVP), or corticotropin releasing hormone. Nuclear ERbeta-ir was identified within SON and retrochiasmatic SON, and in specific PVN subnuclei: medial parvicellular part, ventral and dorsal zones, dorsal and lateral parvicellular parts, and in the posterior magnocellular part, medial and lateral zones. However, the ERbeta-ir within magnocellular areas was noticeably less intense. OT-/ERbeta-ir colocalization was confirmed in neurons of the parvicellular subnuclei, in both OVX and OVX+E brains ( approximately 50% of OT and 25% of ERbeta-labeled cells between bregma -1.78 and -2.00). In contrast, few PVN parvicellular neurons contained both AVP- and ERbeta-ir. As well, very little overlap was observed in the distribution of cells containing corticotropin releasing hormone- or ERbeta-ir. In the SON, most nuclear ERbeta-ir colocalized with AVP-ir, whereas few OT-/ERbeta-ir dual-labeled cells were observed. These findings suggest that estrogen can directly modulate specific OT and AVP systems through an ERbeta-mediated mechanism, in a tissue-specific manner.
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PMID:Differential colocalization of estrogen receptor beta (ERbeta) with oxytocin and vasopressin in the paraventricular and supraoptic nuclei of the female rat brain: an immunocytochemical study. 950 Dec 54

Estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) are differentially distributed in the brain and likely mediate different estrogen-dependent processes. ERbeta is abundant in the bed nucleus of the stria terminalis, medial preoptic nucleus, paraventricular nucleus of the hypothalamus and the amygdala of the rat. In the paraventricular nucleus, which is devoid of ERalpha, ERbeta is colocalized with the neuropeptides, oxytocin and vasopressin, suggesting a potential functional role for ERbeta in the regulation of these peptides. We examined the regulation of ERbeta mRNA expression in the rat brain by 17beta-estradiol and the phytoestrogen, coumestrol. 17beta-Estradiol treatment decreased ERbeta mRNA in situ hybridization signal by 44.5% in the paraventricular nucleus of the hypothalamus (PVN), but had no effect in the bed nucleus of the stria terminalis (BnST) or the medial preoptic nucleus (MPA). In contrast, dietary exposure to coumestrol increased ERbeta mRNA signal by 47.5% in the PVN but had no effect in the BnST or the MPA. These data demonstrate that like ERalpha, ERbeta is down regulated by estrogen in a region specific manner in the rat brain. Furthermore, exposure to coumestrol may modulate ERbeta-dependent processes by acting as an anti-estrogen at ERbeta. This data contradicts results from cell transfection assays which suggest an estrogenic activity of coumestrol on ERbeta, indicating that the mode of action may be tissue specific, or that metabolism of dietary coumestrol may alter its effects. Because the highest concentrations of phytoestrogens are found in legumes, vegetables and grains, they are most prevalent in vegetarian and traditional Asian diets. Understanding the neuroendocrine effects of phytoestrogens is particularly important now that they are being marketed as a natural alternative to estrogen replacement therapy and sold in highly concentrated pills and powders.
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PMID:Regulation of estrogen receptor beta mRNA in the brain: opposite effects of 17beta-estradiol and the phytoestrogen, coumestrol. 1010 Dec 43

The sex steroids and the peptide hormone oxytocin are both ancient modulators of the reproductive system of most metazoan species responsible for tissue differentiation and acute events respectively. In vivo experimentation implies estrogenic control of both the oxytocin (OT) gene and that for its receptor (OTR). Yet neither gene promoter appears able to bind classic estrogen-dependent nuclear receptors (ER) in vitro. The literature is confused by some transfected cell culture experiments which suggest that the human and rat OT gene promoter can be regulated by both ER alpha and ER beta through a major hormone response element at -160 bp upstream of the transcription start site. These findings depended, however, upon the presence of a high molar excess of the nuclear estrogen receptor. The current consensus suggests that the sex steroids are acting indirectly on both the OT and OTR genes, possibly involving intermediate transcription factors or cofactors. They may also act upon the OTR at the cell membrane, though more study is needed before the few current observations can be generalized. Due to the OT system being so ancient and fundamental to all aspects of reproduction, it is likely that the mechanisms by which the sex steroids influence this system are going to be of general importance to many other basic aspects of reproductive control.
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PMID:The role of sex steroids in the oxytocin hormone system. 1041 24

It has previously been demonstrated that 19-nor contraceptive progestins undergo in vivo and in vitro enzyme-mediated A-ring double bond hydrogenation. Bioconversion of 19-nor progestins to their corresponding tetrahydro derivatives results in the loss of progestational activity and acquisition of estrogenic activities and binding to the ER. Herein, we report subtype-selective differences in ligand binding and transcriptional potency of nonphenolic synthetic 19-nor derivatives between ER alpha and ER beta. In this study, we have examined both ER- and PR-mediated transcriptional activity of a number of A-ring chemically reduced derivatives of norethisterone and Gestodene. Double bond hydrogenation decreased the transcriptional potency of norethisterone and Gestodene through both PR isoforms with a 100- to 1,000-fold difference, respectively. In terms of the effects of norethisterone and Gestodene and their corresponding 5 alpha-dihydro (5 alpha-norethisterone and 5 alpha-Gestodene), or 3 alpha,5 alpha-tetrahydro or 3 beta,5 alpha-tetrahydro derivatives (3 alpha,5 alpha-norethisterone/3 alpha,5 alpha-Gestodene and 3 beta,5 alpha-norethisterone/3beta,5 alpha-Gestodene, respectively) on estrogen-mediated transcriptional regulation, the 3 beta,5 alpha-tetrahydro derivatives of both norethisterone and Gestodene showed the highest induction when HeLa cells were transiently transfected with an expression vector for ER alpha. This activity could be inhibited with tamoxifen. These compounds did not activate gene transcription via ER beta, and none of them showed antagonistic activities through either ER subtype. The 3 beta,5 alpha-tetrahydro derivatives of both norethisterone and Gestodene were active in other cells in addition to HeLa cells and activated reporter expression through the oxytocin promoter. In summary, two ER alpha selective agonists have been identified. These compounds, with ER alpha vs. ER beta selective agonist activity, may be useful in evaluating the distinct role of these receptors as well as in providing useful insights into ER action.
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PMID:A-ring reduced metabolites of 19-nor synthetic progestins as subtype selective agonists for ER alpha. 1151 55

Estrogen receptor beta (ERbeta) activates transcription by binding to estrogen response elements (EREs) and coactivator proteins that act as bridging proteins between the receptor and the basal transcription machinery. Although the imperfect vitellogenin B1, pS2, and oxytocin (OT) EREs each differ from the consensus vitellogenin A2 ERE sequence by a single base pair, ERbeta activates transcription of reporter plasmids containing A2, pS2, B1, and OT EREs to different extents. To explain how these differences in transactivation might occur, we have examined the interaction of ERbeta with these EREs and monitored recruitment of the coactivators amplified in breast cancer (AIB1) and transcription intermediary factor 2 (TIF2). Protease sensitivity, antibody interaction, and DNA pull-down assays demonstrated that ERbeta undergoes ERE-dependent changes in conformation resulting in differential recruitment of AIB1 and TIF2 to the DNA-bound receptor. Overexpression of TIF2 or AIB1 in transient transfection assays differentially enhanced ERbeta-mediated transcription of reporter plasmids containing the A2, pS2, B1, and OT EREs. Our studies demonstrate that individual ERE sequences induce changes in conformation of the DNA-bound receptor and influence coactivator recruitment. DNA-induced modulation of receptor conformation may contribute to the ability of ERbeta to differentially activate transcription of genes containing divergent ERE sequences.
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PMID:Estrogen response elements alter coactivator recruitment through allosteric modulation of estrogen receptor beta conformation. 1157 41

Several strategies have been described for the primary culture of human myometrial cells. However, primary cultures of myometrial cells have a limited life span, making continual tissue acquisition and cell isolation necessary. Recent studies have demonstrated that cell culture life span is related to chromosomal telomere length, and cellular senescence results from progressive telomere shortening and the lack of telomerase expression. Transfection of cells with expression vectors containing the human telomerase reverse transcriptase (hTERT) maintains telomere length and effectively gives normal cells an unlimited life span in culture. In addition, hTERT extends the life span of cultured cells far beyond normal senescence without causing neoplastic transformation. In the present study, we developed a cell line from hTERT-infected myometrial cells (hTERT-HM). Cells were isolated from myometrial tissue obtained from women undergoing hysterectomy, and retroviral infection was used to express the catalytic subunit of telomerase in myometrial cells. Cells expressing hTERT have been in continuous culture for >10 mo, whereas the control culture senesced after approximately 2 mo. Telomerase activity was monitored in cells with a polymerase chain reaction-based telomerase activity assay. Telomerase-expressing cells contained mRNA for alpha smooth muscle actin, smoothelin, oxytocin receptor, and estrogen receptor alpha, but the estrogen receptor beta receptor was lost. Immunoblotting analysis identified the expression of calponin, caldesmon, alpha smooth muscle actin, and oxytocin receptor. Although estrogen receptor expression was below the level of detection with immunoblotting, transfection experiments performed with reporter constructs driven by estrogen response elements demonstrated estrogen responsiveness in the hTERT-HM. In addition, treatment of hTERT-HM with oxytocin caused a concentration-dependent increase in intracellular calcium levels, confirming the presence of functional oxytocin receptors. Myometrial cells immortalized with hTERT retained markers of differentiation that are observed in primary cultures of smooth muscle cells. The expression of various smooth muscle/myometrium cell markers suggests that these cells may be an appropriate model system to study certain aspects of human myometrial function.
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PMID:Telomerase immortalization of human myometrial cells. 1213 89

Oxytocin is an important modulator of female reproductive functions including parturition, lactation and maternal behavior, while vasopressin regulates water balance and acts as a neurotransmitter. For decades, it has been suggested that estrogen regulates the production and/or release of oxytocin and vasopressin in the rodent brain. Although several studies demonstrated that estrogen can modulate vasopressin mRNA levels in regions known to contain estrogen receptor (ER), such as the bed nucleus of the stria terminalis and medial amygdala, data from the paraventricular and supraoptic nuclei were inconclusive. Since early immunohistochemical and in situ hybridization studies revealed few, if any, ER containing cells in these hypothalamic nuclei, it was thought that oxytocin and vasopressin were not directly regulated by estrogen. The discovery of a second ER (ER-beta) in the late 1990s suggested that estrogen could act in many brain regions heretofore not considered targets for estrogen action. Initial in situ hybridization studies revealed a wide distribution of ER-beta mRNA in the rat brain including neurons of the supraoptic nucleus and the parvocellular and magnocellular divisions of the paraventricular nucleus. Subsequent double-label in situ hybridization/immunocytochemistry studies showed that ER-beta mRNA was present in oxytocin and vasopressin neurons, with the degree of colocalization being both neuropeptide and region specific. In an attempt to demonstrate that ER-beta mRNA was translated into a biologically active protein, a series of in vivo binding studies were conducted in rats with 125I-estrogen. These data revealed the presence of nuclear estrogen binding sites in neurons of the magnocellular system indicating that ER-beta mRNA was translated into protein. Concurrent studies in mice found that the distribution of ER-beta mRNA and 125I-estrogen binding was similar to rats, although there were some notable differences. For example, ER-beta mRNA and binding were not detected in the mouse supraoptic nucleus and although ER-beta was the principle ER in the paraventricular nucleus, ER-alpha was also present. The prevalence of ERs in the mouse paraventricular nucleus was further investigated using ER-alpha and ER-beta knockout mice for in vivo binding studies with 125I-estrogen. The results of these studies showed that ER-beta was the predominant ER in the paraventricular nucleus and confirmed the presence of ER-beta in other brain regions. Moreover, our group recently generated and characterized several polyclonal antisera raised against the C-terminus of ER-beta. Through the use of these antisera, we have confirmed the presence of ER-beta in the rat paraventricular and supraoptic nuclei and shown that ER-beta is colocalized, in part, with oxytocin and vasopressin. To assess the ability of estrogen to modulate the expression of oxytocin mRNA, ovariectomized rats were treated with vehicle or estradiol and the brains processed for in situ hybridization. The results of these studies revealed that estradiol down-regulated oxytocin mRNA in the rat paraventricular nucleus within 6 h of treatment. Together these data and the observation that some of the oxytocin and vasopressin neurons contain ER-beta suggest that estrogen, acting through ER-beta, may directly regulate oxytocin gene expression. However, since the paraventricular nucleus has many subdivisions with different projections and the degree of colocalization of ER-beta with oxytocin/vasopressin varies among subdivisions, the effects of estrogen treatment on gene expression requires further study to ascertain the role of estrogen action in this neuronal systems.
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PMID:Estrogen modulates oxytocin gene expression in regions of the rat supraoptic and paraventricular nuclei that contain estrogen receptor-beta. 1243 23

Estrogen receptor (ER)-beta, unlike ER-alpha, is localized in the hypothalamic paraventricular nucleus (PVN) which also contains neuropeptide synthesizing neurons, such as oxytocin (OT), arginine vasopressin (AVP) and corticotropin-releasing hormone (CRH). Although it is known that some ER-beta containing neurons co-express OT and AVP, but not CRH, in the PVN, it is not yet determined whether ER-beta activation may indeed play a role in estrogenic regulation on syntheses of these neuropeptides. In the present study, we tested this hypothesis by comparing the effects of estrogen on the levels of OT, AVP and CRH messenger RNA (mRNA) between ER-beta knockout (betaERKO) and wild type (WT) control male mice. Mice were gonadectomized and implanted with either a pellet containing estradiol benzoate (2.5-5.0 microg/day) or a placebo pellet for 21 days. In situ hybridization histochemistry revealed that estrogen treatment resulted in a significant increase in OT transcripts (151.6+/-6.0%) and a decrease in AVP transcripts (77.8+/-5.2%) in the PVN of WT mice, compared to the placebo control group. This estrogenic regulation of OT and AVP mRNA levels in the PVN was completely abolished in betaERKO mice. Similar genotype differences in the effects of estrogen on the numbers of OT- and AVP-containing cells were found in immunocytochemical studies performed in a separate set of mice. On the other hand, the expression of CRH mRNA in the PVN was not affected by estrogen treatment in either WT or betaERKO mice. Furthermore, estrogen did not cause any changes in the levels of OT or AVP mRNA, regardless of genotype, in the supraoptic nucleus where, unlike in rats, ER-beta containing neurons are rarely found in mice. Finally, estrogen significantly increased OT mRNA levels in both betaERKO and WT in the medial preoptic area, which contains both ER-alpha and ER-beta. These results suggest that ER-beta activation may play a critical role in estrogenic regulation of OT and AVP gene expression in the PVN.
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PMID:Estrogen receptor-beta regulates transcript levels for oxytocin and arginine vasopressin in the hypothalamic paraventricular nucleus of male mice. 1253 18

The functional significance of the novel estrogen receptor beta in brain areas that exclusively contain the ERbeta receptor subtype such as the paraventricular (PVN) and the supraoptic (SON) nuclei of the hypothalamus is not yet fully understood. The present study attempts to characterize the peptidergic nature of the ERbeta-containing neuronal population in the PVN and the SON using the double in situ histochemistry method in the female rat. Using this method, the ERbeta mRNA coexpressions with the novel opioid neuropeptide (orphanin FQ and its receptor ORL1) mRNA in addition to the previously reported neuropeptide (arginine vasopressin-AVP, oxytocin-OXY, corticotropin releasing hormone-CRH, enkephalin-ENK) mRNAs were assessed. In the PVN, roughly half of the ERbeta expression was colocalized with the prepro-orphanin FQ mRNA, which was comparable to the colocalization observed between the ERbeta and AVP mRNAs in the same region. In addition, there was 20% overlap between the ERbeta and ORL1 receptor mRNAs, and 10% overlap between the ERbeta and OXY mRNAs in the PVN. By contrast, the coexpression between the prepro-orphanin FQ and ERbeta mRNAs was less striking in the SON. Potential interactions between the ERbeta and the well-characterized AVP-OXY neurosecretory system as well as the novel OFQ-ORL1 opioid neuropeptide system may provide new leads for the functional significance of ERbeta, specifically in stress/autonomic responses.
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PMID:Colocalization of estrogen beta-receptor messenger RNA with orphanin FQ, vasopressin and oxytocin in the rat hypothalamic paraventricular and supraoptic nuclei. 1269 Apr 47


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