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Query: UNIPROT:P01178 (oxytocin)
 15,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The factors regulating oxytocin expression have not yet been characterized in detail. Although direct control by ligand-dependent binding of nuclear hormone receptors to the oxytocin promoter has been suggested, the presence of these receptors in the tissues expressing oxytocin has not been shown consistently. We have analyzed nuclear proteins from preovulatory bovine granulosa cells and corpus luteum, tissues actively expressing the oxytocin gene, and describe here the characterization of a tissue-specific factor binding to the conserved element in the oxytocin promoter that has been implicated in the control of this gene. This factor is the bovine homologue of SF-1, an orphan receptor expressed specifically in steroidogenic tissues. It is suggested that SF-1 binds to the oxytocin promoter in vivo and is involved in control of oxytocin gene expression possibly by interaction with other factors.
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PMID:The orphan receptor SF-1 binds to the COUP-like element in the promoter of the actively transcribed oxytocin gene. 802 62

The orphan receptor chicken ovalbumin upstream promoter transcription factor I (COUP-TF I) fully prevented not only the activation of the oxytocin gene by retinoic acid and thyroid hormone but also completely repressed the estrogen-dependent stimulation in transfected P19 EC cells. DNase I footprinting showed that the COUP-TF I protein bound to the 5'-flanking region of the oxytocin gene at the site of the distal composite hormone response element, which mediates the responses to estrogen, retinoic acid, and thyroid hormone. Electrophoretic mobility shift assay using this composite hormone response element as probe showed that COUP-TF I and the estrogen receptor competed for binding but did not form a heterodimer. The binding by COUP-TF I was stronger than the binding of the estrogen receptor. Thus, the mechanism of repression involves occupancy of integrated binding sites. By mutagenesis of the composite hormone response element, the COUP-TF I binding site and the estrogen response element could be separated, resulting in functional dissociation of the repressive action of COUP-TF I and the induction by estrogen. The results show that repression of gene expression by COUP-TF I is not limited to receptors that act through heterodimerization but also extends to the homodimer-forming estrogen receptor in a context-dependent manner. This interaction between COUP-TF I and the estrogen receptor may provide a physiological mechanism of selective antagonism of gene regulation by estrogens.
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PMID:Repression of estrogen-dependent stimulation of the oxytocin gene by chicken ovalbumin upstream promoter transcription factor I. 819 42

In the oxytocin (OT) gene several regions can be discerned that have a function in regulating its expression. Firstly, in the proximal 5' flanking region regulatory elements have been discovered that are targets for transcription factors of the nuclear hormone receptor family. Through these elements the OT gene of rat and man is responsive to estrogens, thyroid hormones and retinoids. Furthermore, these elements can be employed by the nuclear hormone orphan receptor family for repressive or inductive actions. In the distal 5' flanking region the POU class III proteins Brn-1, Brn-2, Brn-4, that are expressed in magnocellular neurons, and Oct-6 are able to bind, but do not display a significant regulatory activity on the OT gene in heterologous expression systems. Secondly, the OT precursor harbours both the biologically active hormone and the protein neurophysin that is able to associate with the hormone. Heterologous expression of wild-type and mutant vasopressin cDNAs in peptidergic cell lines shows that the highly homologous vasopressin-associated neurophysin domain associates with the hormone domain within the prohormone. This intramolecular interaction between two prohormone domains serves an essential intracellular function, i.e. the proper sorting of the prohormone into the regulated secretory pathway.
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PMID:Functional domains in the oxytocin gene for regulation of expression and biosynthesis of gene products. 871 48

The bovine oxytocin gene is massively up-regulated during the early development of the corpus luteum. Oxytocin transcription is induced in a highly synchronous fashion in the granulosa cells of the dominant follicle at the time of ovulation. The possibility to isolate large numbers of differentiating granulosa-luteal cells from exactly defined stages of development allows the investigation of the factors controlling oxytocin expression in vivo by molecular and cell biology methods. Using primary cultures of bovine granulosa cells the synergistic activation of oxytocin transcription by the cAMP pathway and stimulation of IGF-I or insulin receptors could be established. Analysis of transcription factors isolated from the nuclei of bovine granulosa cells and corpus luteum led to the identification of the tissue-specific orphan receptor SF-1 binding to the promoter of the actively transcribed oxytocin gene. The luteinizing bovine granulosa cells provide the only easily accessible experimental system established so far in which the endogenous oxytocin gene is expressed. Although the link between increased cAMP level and receptor tyrosine kinase activation on the one hand and the induction of oxytocin transcription on the other has not been established yet, these experiments constitute one of the few direct approaches to investigate the complexity of events that regulate oxytocin expression in vivo.
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PMID:Regulation of oxytocin expression in the bovine corpus luteum. Orphan receptors and the oxytocin promoter. 871 54

We have previously shown that COUP-TFII and Ear-2, two members of the nuclear orphan receptor family, are able to repress oestrogen-stimulated transcriptional activity of the human oxytocin (OT) gene promoter by binding to a site that overlaps with the oestrogen response element (ERE) present in the 5' flanking region of the gene. Although most nuclear receptor-mediated transcriptional repression conforms with the paradigm of passive repression and involves competitive binding to an activator site, active repression, i.e. silencing of basal promoter activity, has been observed in a limited number of cases. Here we show by co-transfection experiments using COUP-TFII and Ear-2 expression vectors and reporter constructs containing OT gene promoter fragments linked to the chloramphenicol acetyltransferase gene that both COUP-TFII and Ear-2 are capable of silencing basal OT gene promoter activity by 54 and 75% respectively. 5' Deletion and footprint analyses revealed two areas of functionally important interaction sites: (1) a direct TGACC(T/C) repeat overlapping the ERE and (2) a more promoter-proximal area centred at - 90 containing three imperfect direct repeats (R1-R3) spaced by four nucleotides each. Mutagenesis of reporter constructs as well as electrophoretic mobility-shift assays demonstrated that each of the three proximal repeats R1-R3 contributed to orphan receptor binding and the silencing effect. Inasmuch as the orphan receptor-binding sites are not involved in mediating basal transcriptional activity of the OT gene promoter, the observed effects are best interpreted as active repression or promoter silencing. Moreover, since COUP-TFII and Ear-2 are both co-expressed in OT-expressing uterine epithelial cells, the novel transcriptional effects described here are likely to be of functional importance in the fine-tuning of uterine OT gene expression in vivo.
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PMID:The nuclear orphan receptors COUP-TFII and Ear-2 act as silencers of the human oxytocin gene promoter. 934 8

The mechanisms regulating the expression of the neuropeptide hormone gene oxytocin have not yet been elucidated in detail. The binding of the orphan receptor Ad4BP, the bovine homolog of steroidogenic factor-1 (SF-1), which is correlated with in vivo oxytocin transcription in the luteinizing granulosa cells of the bovine corpus luteum, is not sufficient to explain the transcriptional up-regulation in these cells. Therefore, we started experiments to identify other regions of the oxytocin locus that are involved in gene activation. The study presented here is the very first investigation of DNA methylation and chromatin structure in the distal promoter region of the bovine oxytocin gene. We show that this region is tissue-specifically hypomethylated in bovine granulosa cells. Upon stimulation of the cells with the adenylate cyclase-activator forskolin, a DNase I-hypersensitive site is induced in the distal promoter region. Additionally, we find binding of a monomeric nuclear orphan receptor directly within the region of inducible DNase I sensitivity; this factor is not identical to Ad4BP/SF-1. This study identifies a region in the bovine oxytocin distal promoter where tissue-specific changes in DNA methylation and chromatin structure correlate with high induction of oxytocin gene transcription, and suggests that the binding of transcription factors to this region may be important for the up-regulation of oxytocin gene expression.
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PMID:Alterations in the chromatin structure of the distal promoter region of the bovine oxytocin gene correlate with ovarian expression. 936 35

We have previously demonstrated that the oxytocin (OT) gene is expressed in the rat uterine epithelium and that its expression is upregulated in vivo and in vitro by estrogen. This hormonal regulation is mediated by a hormone response element (HRE) located in the OT gene promoter. Here we show that the same OT-HRE is also capable of interacting with two novel members of the orphan nuclear receptor family, rat COUP-TFII and Ear-2, and that this interaction antagonizes the estrogenic induction of the OT promoter. By Northern blot analysis and immunocytochemistry, using specific cDNA probes and antibodies, respectively, we demonstrate furthermore that both orphan receptors are expressed in uterine epithelial cells. Therefore, the present findings indicate that uterine OT gene expression is under stimulatory as well as inhibitory influences which are both mediated by the same HRE. More detailed analysis of the sequences necessary for estrogen receptor action and for orphan receptor action, using site-directed mutagenesis, revealed that the specific recognition sequences are overlapping but distinct: whereas the (imperfect) palindromic structure of the HRE constitutes the estrogen response element (ERE), orphan receptor action relies on an underlying direct TGACC repeat which forms part of the OT-HRE structure and overlaps with the estrogen response element.
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PMID:Nuclear orphan receptors COUP-TFII and Ear-2: presence in oxytocin-producing uterine cells and functional interaction with the oxytocin gene promoter. 960 16

A hypothalamic peptide that stimulates PRL release has recently been found as a ligand of an orphan receptor and named PRL-releasing peptide (PrRP). PrRP and its receptor were mainly detected in the hypothalamus and pituitary gland, respectively. Its characteristics suggested PrRP to be a novel hypophysiotropic peptide that stimulates the anterior pituitary PRL cell; however, this remained to be confirmed morphologically. We therefore performed an immunocytochemical study to locate PrRP in the rat brain using the region-specific monoclonal antibodies, P2L-1C and P2L-1T, which recognize the C-terminal and the internal sequence of PrRP, respectively. Our results clearly show that dense immunoreactive nerve fiber networks are present in the paraventricular hypothalamic nucleus, supraoptic nucleus, paratenial thalamic nucleus, basolateral amygdaloid nucleus, and bed nucleus of the stria terminalis. A small number of PrRP nerve fibers was also observed in the neural lobe of the hypophysis. However, no immunopositive fiber was observed in the external region of the median eminence, which is known to be the release site of the classical hypophysiotropic hormones. Also, the distribution of PrRP was not changed during the estrous cycle. We therefore concluded that PrRP probably differs from classical hypothalamic releasing hormones. We found the immunoreactive cell bodies to be mainly in the caudal portion of the dorsomedial hypothalamic nucleus and solitary nucleus. A double immunocytochemical procedure revealed that some PrRP-positive neurons showed synaptic contact with oxytocin-positive cell bodies in the paraventricular hypothalamic nucleus, which suggests that PrRP regulates the function of oxytocin neurons. This is the first report to demonstrate the localization of the novel hypothalamic peptide, PrRP, and we therefore suggest that it takes part in a variety of brain functions. However, it is not yet known how PrRP is transported to the pituitary gland, which is the site that contains the greatest concentration of receptors to this new peptide. Therefore, additional work will be required to resolve this discrepancy between ligand and receptor site location.
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PMID:Immunocytochemical localization of prolactin-releasing peptide in the rat brain. 1021 86

Although an increasing number of nuclear orphan receptors have recently been identified, the number of known naturally occurring genes that are directly regulated by orphan receptors is still small. We have shown previously that the gene encoding the neuropeptide oxytocin (OT) is negatively regulated by the orphan receptors chicken ovalbumin upstream transcription factor I (COUP-TFI) and II. Here we show that the mouse OT gene promoter is activated by RORalpha, a representative of the ROR/RZR orphan receptor subfamily. Using promoter/chloramphenicol acetyltransferase reporter constructs in heterologous transfection assays, we determined that RORalpha action induces a <6-fold increase in promoter activity. By 5' and 3' deletion analysis, DNase footprint analysis and electrophoretic mobility shift assays, we found that RORalpha action is mediated by two 14 bp regions centered at 160 and 180 nucleotides upstream of the transcriptional initiation site. Both sites contain significant sequence identities with an established ROR recognition sequence. Mutations in either or both of these sites reduce significantly RORalpha-induced activation of the OT promoter. In view of the strong transcriptional activation exerted by RORalpha on the OT gene promoter and the widespread distribution of different members of the ROR/RZR family, interactions between ROR/RZR isoforms and the OT gene may form part of the multifactorial regulatory mechanisms that control OT gene expression in different tissues.
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PMID:Activation of the mouse oxytocin promoter by the orphan receptor RORalpha. 1060 79

The prolactin-releasing peptide (PrRP) is a novel hypothalamic peptide that has been purified as a ligand of an orphan receptor which is expressed in pituitary cells, and is known to stimulate prolactin release both in vitro and in vivo. We previously determined the immunocytochemical localization of PrRP neurons in the rat brain and our results suggest that PrRP takes part in a variety of brain functions. Additionally, in rats we have demonstrated the synaptic contact of PrRP neurons with oxytocin cell bodies in the paraventricular hypothalamic nucleus (PVH) and supraoptic nucleus (SON). This observation indicates that PrRP may regulate oxytocin secretion. In the present study, we performed intra-cerebroventricular administration of PrRP to conscious rats, and examined the effect of PrRP on the plasma levels of oxytocin and vasopressin. Our results show that central administration of PrRP increased the plasma oxytocin and vasopressin levels in female rats, but in male rats only oxytocin was increased. These results suggest that the PrRP acts as a neuro-modulator of the function of magnocellular neurons, especially oxytocin neurons, in the brain.
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PMID:Central administration of prolactin-releasing peptide stimulates oxytocin release in rats. 1061 38


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