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)

In the present work, first we reviewed and completed our previous experiments on the antiproliferative effect of oxytocin (OT) in breast cancer cell lines. In vitro, OT 10 nM and 100 nM inhibited cell proliferation of MDA-MB231 (human breast carcinoma) and TS/A (mouse mammary carcinoma) cell lines. In vivo, OT significantly reduced the growth of TS/A mammary tumors. Both effects are mediated by specific receptors (OTR) distributed on cell surface. Second, using immunohistochemistry and RT-PCR we detected OTR and OTR mRNA in normal and pathological breast tissue. There is no correlation among OTR presence in breast carcinomas and the age of patients, tumor stage, estrogen receptor positivity, oncogene expression and proliferation rate of the same tumor. On the contrary, progesterone and OTR expression are correlated. These data confirm our previous evidence of a role of OT and OTR in normal and neoplastic breast cells.
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PMID:Oxytocin receptor within the breast: biological function and distribution. 970 81

Several lines of evidence support a role for oxytocin and vasopressin in complex social behaviors, including parental care, sex behavior, and aggression. Recent studies in a monogamous mammal, the prairie vole, suggest an additional role for both peptides in the formation of pair bonds. Central administration of oxytocin facilitates and administration of an oxytocin antagonist inhibits partner preference formation in female prairie voles. Conversely, vasopressin facilitates and a V1a receptor antagonist inhibits pair bonding in males. A potential cellular basis for these effects is the species-specific pattern of expression of oxytocin and V1a receptor in reward pathways of the prairie vole brain. At a molecular level, comparative sequencing of the oxytocin and V1a receptors reveals species differences in the promoter sequences that may guide regional expression in the brain. Transgenic mice created with the 5' flanking region of the prairie vole oxytocin receptor gene demonstrate that sequencing in this region influence the pattern of expression within the brain. The unique promoter sequences of the prairie vole OTR and V1a receptor genes and the resulting species-specific pattern of regional expression provide a potential molecular mechanism for the evolution of pair bonding behaviors and a cellular basis for monogamy.
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PMID:Oxytocin, vasopressin, and the neuroendocrine basis of pair bond formation. 1002 8

The dynamics of the receptors for oestrogen (ER), progesterone (PR) and oxytocin (OTR) in the marmoset uterus have been analysed throughout the entire cycle and early pregnancy. Uteri obtained during the early, mid/late and late proliferative phase, and the early, mid and late secretory phase and early pregnancy were examined by immunohistochemistry (OTR, ER, PR) and autoradiography (OTR). A massive upregulation of the ER in the cell nuclei of glandular epithelium and stromal cells during the mid proliferative phase was succeeded by a declining staining intensity and positively stained cell number in the secretory phase. PR immunoreactivity increased in the late proliferative phase and early secretory phase, mainly within the cell nuclei, and then declined in both intensity and cell number towards the mid to late secretory phase. Myometrium showed a similar staining pattern for the steroid receptors. OTR were expressed weakly in stroma throughout the entire cycle, increasing slightly in the secretory phase. Glandular epithelium showed positive staining only during the periovulatory period. Myometrial OTR expression was weak during the proliferative phase, increased towards the secretory phase, and was maximal in the late secretory phase. Myometrial tissue adjacent to endometrium was most strongly stained. A cyclic shift evidently occurred in the pattern of steroid receptors, perhaps reflecting the steroid environment or the luteinizing hormone increase associated with ovulation.
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PMID:Expression of the oxytocin receptor in relation to steroid receptors in the uterus of a primate model, the marmoset monkey. 1002 17

Oxytocin (OT) receptors (OTRs) have been demonstrated in a number of human breast tumors and tumor cells, but it was not clear whether the receptors were functional. We examined the regulation and function of OTR in a tumor cell line, Hs578T, derived from human breast. These cells expressed moderate levels of OTR when cultured in 10% FBS, as demonstrated by RT-PCR and binding analyses. Serum deprivation resulted in the loss of OTRs, with no effect on cell viability. Restoration of serum and addition of 1 microM dexamethasone (DEX) increased OTR levels by about 9-fold. Up-regulation was blocked by the addition of phospholipase C and PKC inhibitors. Serum/DEX treatment also increased steady state OTR messenger RNA levels. OT increased intracellular Ca2+ in a time- and dose-responsive manner, and the effects of OT were lost when OTRs were down-regulated by serum starvation. Serum/DEX up-regulation of OTR restored the responsiveness to OT. OT also stimulated ERK-2 (extracellular signal-regulated protein kinase) phosphorylation and PGE2 synthesis in Hs578T cells. In addition to showing that OTRs in the breast tumor cells are functional, these studies show that Hs578T cells can be used to study molecular regulation of OTR gene expression and intracellular signaling pathways stimulated by OT.
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PMID:Demonstration of functional oxytocin receptors in human breast Hs578T cells and their up-regulation through a protein kinase C-dependent pathway. 1021 79

Oxytocin (OT) receptors (OTRs) mediate reproductive functions, including the initiation of labor and milk ejection. OTR messenger RNA levels are highly regulated, reaching the greatest concentration in the uterus at the end of gestation, and in the mammary gland during lactation. Factors directly effecting changes in OTR gene expression in the mammary gland are not known, so the present studies were done to elucidate possible regulators by characterizing the human OTR gene promoter and 5'-flanking sequence. By analyzing expression of promoter-luciferase constructs, we localized a region between -85 and -65 that was required for both basal and serum-induced expression in a mammary tumor cell line (Hs578T) that expresses inducible, endogenous OTRs. This DNA region contains an ets family target sequence (5'-GGA-3'), and a CRE/AP-1-like motif. The specific Ets factor binding to the OTR promoter was identified, by electrophoretic mobility immunoshift assays, to be GABP alpha/beta. Co-transfection of a -85 OTR/luciferase construct with vectors expressing GABP alpha and GABP beta1 had only a modest effect on expression, but cotransfection with GABP alpha/beta- with c-Fos/c-Jun-expressing plasmids resulted in an increase of almost 10-fold in luciferase activity. Mutation of either the GABP- or CRE-like binding sites obliterated the induction. These findings are consistent with the involvement of protein kinase C activity in serum induction of the endogenous gene in Hs578T cells. We showed the requirement for GABP alpha/beta and c-Fos/c-Jun in endogenous OTR gene expression, using oligonucleotide GABP and AP-1 binding decoys to inhibit serum-induced increases in 125I-labeled OT antagonist binding to Hs578T cells. Our work is the first characterization of the proximal promoter region of the human OTR gene, and it sets the stage for studying regulation of OTR expression in breast cells.
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PMID:Identification of a GABP alpha/beta binding site involved in the induction of oxytocin receptor gene expression in human breast cells, potentiation by c-Fos/c-Jun. 1021 80

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

Oxytocin is a nonapeptide hormone (CYIQNCPLG-NH2, OT), controlling labor and lactation in mammalian females, via interactions with specific cellular membrane receptors (OTRs). The native hormone is cyclized via a 1-6 disulfide and its receptor belongs to the GTP-binding (G) protein-coupled receptor (GPCR) family, also known as heptahelical transmembrane (7TM) or serpentine receptors. Using a technique combining multiple sequence alignments with available experimental constraints, a reliable OTR model was built. Subsequently, the OTR complexes with a selective agonist [Thr4,Gly7]OT, a selective cyclohexapeptide antagonist L-366,948 and oxytocin itself were modeled and relaxed using a constrained simulated annealing (CSA) protocol. All three ligands seem to prefer similar modes of binding to the receptor, manifested by repeating receptor residues which directly interact with the ligands. Those involved in the three complexes are putative helices: TM3: R113, K116, Q119, M123; TM4: Q171, and TM5: I201 and T205. Most of them are the equivalent residues/positions to those found in our earlier studies, regarding related vasopressin V2 receptor/bioligand interactions.
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PMID:Molecular modeling of the oxytocin receptor/bioligand interactions. 1069 66

We examined the effect of neurons on oxytocin (OT) receptors (OTR) and OTR gene expression in cultured astrocytes. The addition of neuron-conditioned medium induced an increase of both OTR binding and OTR mRNA level. This effect was enhanced after the medium was boiled or acidified. As it is known that transforming growth factor-beta (TGF-beta) can be released from carrier proteins by acid or heat, TGF-beta1 and 2 were tested and found to induce an increase of OTR binding. Furthermore, TGF-beta antibody abolished the stimulatory effect of normal or acidified neuron-conditioned medium. Neurons added to cultured astrocytes without contact mimicked the stimulatory effect of the conditioned medium. In contrast, neurons added with contact, induced a decrease in OTR binding and an increase of mRNA level, whereas neuronal membranes induced a decrease of both OTR binding and mRNA levels. In conclusion, the present data demonstrate that in vitro, neurons are able to modulate astrocytic OTR expression at the level of both protein and mRNA. They stimulate this expression through their release of TGF-beta and inhibit it by the action of unknown membrane components.
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PMID:Neurons modulate oxytocin receptor expression in rat cultured astrocytes: involvement of TGF-beta and membrane components. 1175 14

The effects of the peptide hormone oxytocin (OT) are mediated by the oxytocin receptor, which is a member of the G-protein-coupled receptor family. Defining differences between the binding of agonists and antagonists to the OTR, at the molecular level, is of fundamental importance to understanding OTR activation and to rational drug design. Previous reports have indicated that the N-terminus of the OTR is required for OT binding. The aim of this study was to identify which individual residues within the N-terminal domain of the human OTR provided these OT binding epitopes. A series of truncated OTRs and mutant receptor constructs with systematic alanine substitution were characterized with respect to their pharmacological profile and intracellular signaling capability. Although a number of residues within the OTR will be required for optimal OT-OTR interaction, our data establish that Arg(34) within the N-terminal domain contributes to high-affinity OT binding. Removal of Arg(34) by truncation or substitution resulted in a 2000-fold decrease in OT affinity. In addition, we show that the arginyl at this locus is required for high-affinity binding of agonists in general. However, the importance of Arg(34) is restricted to agonist interaction with the OTR, as it was not required for binding peptide antagonist or non-peptide antagonist. It is noteworthy that the corresponding Arg in the related rat V(1a) vasopressin receptor is also required for high-affinity agonist binding. This study defines, at the molecular level, the role of the N-terminus of the OTR in high-affinity agonist binding and identifies a key residue for this function.
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PMID:Agonist-specific, high-affinity binding epitopes are contributed by an arginine in the N-terminus of the human oxytocin receptor. 1195 56

We recently discovered the existence of the oxytocin/oxytocin receptor (OT/OTR) system in the heart. Activation of cardiac OTR stimulates the release of atrial natriuretic peptide (ANP), which is involved in regulation of blood pressure and cell growth. Having observed elevated OT levels in the fetal and newborn heart at a stage of intense cardiomyocyte hyperplasia, we hypothesized a role for OT in cardiomyocyte differentiation. We used mouse P19 embryonic stem cells to substantiate this potential role. P19 cells give rise to the formation of cell derivatives of all germ layers. Treatment of P19 cell aggregates with dimethyl sulfoxide (DMSO) induces differentiation to cardiomyocytes. In this work, P19 cells were allowed to aggregate from day 0 to day 4 in the presence of 0.5% DMSO, 10(-7) M OT and/or 10(-7) M OT antagonist (OTA), and then cultured in the absence of these factors until day 14. OT alone stimulated the production of beating cell colonies in all 24 independently growing cultures by day 8 of the differentiation protocol, whereas the same result was obtained in cells induced by DMSO only after 12 days. Cells induced with OT exhibited increased ANP mRNA, had abundant mitochondria (i.e., they strongly absorbed rhodamine 123), and expressed sarcomeric myosin heavy chain and dihydropyridine receptor-alpha 1, confirming a cardiomyocyte phenotype. In addition, OT as well as DMSO increased OTR protein and OTR mRNA, and OTA completely inhibited the formation of cardiomyocytes in OT- and DMSO-supplemented cultures. These results suggest that the OT/OTR system plays an important role in cardiogenesis by promoting cardiomyocyte differentiation.
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PMID:Oxytocin induces differentiation of P19 embryonic stem cells to cardiomyocytes. 1209 24


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