Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gonadotropin releasing hormone is a hypothalamic decapeptide that stimulates the release of gonadotropic hormones from the anterior pituitary gland. Therapeutically, the human pituitary GnRH receptor is the target of agonists used in the suppression of prostate cancer. Here we report the isolation of a cDNA representing this receptor. It encodes a protein with a transmembrane topology similar with that of other G protein-coupled, 7-transmembrane receptors. Binding studies of the cloned receptor demonstrate high affinity and pharmacological properties similar with the native human pituitary GnRH receptor. Northern blot and reverse transcriptase/PCR analysis revealed that its mRNA is expressed in pituitary, ovary, testis, breast, and prostate but not in liver and spleen. Availability of a human GnRH receptor cDNA should permit the design of improved analogs for therapeutic applications.
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PMID:Cloning, sequencing, and expression of human gonadotropin releasing hormone (GnRH) receptor. 133 90

Inhibition of the growth of hormone related human tumor cells in vitro by GnRH agonists and antagonists suggests a direct effect on cell growth and proliferation, and this effect may be achieved through its receptors present in tumor cells. However, the nature of the GnRH receptors present in these tumors is controversial. To determine the molecular characteristics of GnRH receptors in such tumors, we used the reverse transcriptase/polymerase chain reaction (RT/PCR) technique to clone these receptors. Primers were selected from the human pituitary GnRH receptor cDNA sequence to amplify the open reading frame and parts of its 5' and 3'-untranslated sequences. Nucleotide sequencing of the GnRH receptor cDNAs from a breast tumor cell line (MCF-7) and from an ovarian tumor showed identity with that of the human pituitary GnRH receptor which binds GnRH with high affinity. GnRH receptor mRNA was found to be expressed in human pituitary, breast, breast tumor, ovary, ovarian tumor, prostate, prostate tumor and in breast tumor cell lines (MCF-7 and MDA-MB 468) and prostate tumor cell lines (PC-3 and LNCaP). These findings demonstrate that a mRNA representing the pituitary form of the GnRH receptor (which shows high affinity binding with GnRH) is also expressed in certain normal tissues and in hormone related human tumors and tumor cell lines derived from them.
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PMID:The nucleotide sequences of human GnRH receptors in breast and ovarian tumors are identical with that found in pituitary. 753 32

Recent evidence indicates that the GnRH receptor (GnRH-R) gene is expressed in a number of tissues besides the anterior pituitary gland, suggesting that GnRH may serve other functions in addition to its role as a hypothalamic releasing factor. In particular, high levels of GnRH-R transcripts have been detected in rat and human ovarian granulosa cells. To better understand the role of the GnRH-R in the ovary under physiological conditions and to determine which follicles are potentially responsive to the actions of GnRH, we used in situ hybridization histochemistry and quantitative reverse transcriptase-polymerase chain reaction for measurement of ovarian GnRH-R messenger RNA (mRNA) expression during the rat ovulatory cycle. Reverse transcriptase-polymerase chain reaction analyses revealed that total ovarian GnRH-R mRNA levels were elevated significantly at 1800 h on proestrus and again at 0900 and 1800 h on estrus compared to metestrus 0900 h levels. In situ hybridization analysis of GnRH-R gene expression at different stages of follicular maturation revealed significant variation in GnRH-R mRNA levels with respect to the degree of follicular development as well as the estrous cycle stage. GnRH-R gene expression was greatest in the granulosa cells of Graafian and atretic follicles, with lower levels of expression present in preantral and small antral follicles and corpora lutea. GnRH-R mRNA levels in atretic follicles showed substantial variation across the 4-day rat estrous cycle, with mRNA levels increasing 3-fold on the day of proestrus coincident with the preovulatory gonadotropin surges. A second peak of expression in atretic follicles was observed on the morning of estrus. Levels of GnRH-R gene expression in corpora lutea also varied significantly during the estrous cycle, with gene expression increasing 3-fold between the morning of metestrus and the afternoon of proestrus. These results demonstrate that the level and localization of ovarian GnRH-R mRNAs change significantly during the rat ovulatory cycle. The finding that atretic follicles exhibit the greatest degree of GnRH-R gene expression is consistent with a role for GnRH in the induction of follicular atresia.
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PMID:Gonadotropin-releasing hormone receptor messenger ribonucleic acid expression in the ovary during the rat estrous cycle. 766 63

GnRH regulates gonadotropin biosynthesis and release in the anterior pituitary via specific receptors. Although extrapituitary expression and action of GnRH have been shown in some species, in the human it is not clear whether GnRH has a peripheral action. In this study we sought to determine whether the human ovary expresses GnRH receptor (GnRHR) messenger ribonucleic acid (mRNA). Ovarian tissues from 11 women (32-61 yr old) and granulosa-lutein (GL) cells purified from follicular aspirates of 51 women undergoing oocyte retrieval for in vitro fertilization were analyzed by ribonuclease protection assay and reverse transcriptase-polymerase chain reaction (RT-PCR). Human pituitaries, lymphocytes, and placenta were also studied. Measurable levels of GnRHR mRNA were found by ribonuclease protection assay in 2 of 10 ovaries, in 2 of 4 GL cells preparations from women whose ovarian hyperstimulation involved a GnRH agonist, in GL cells from 3 women whose ovarian hyperstimulation involved a GnRH antagonist, and in human pituitaries. Relative to the total amount of RNA analyzed, the level of GnRHR mRNA was about 200-fold lower in the ovary than in the pituitary. A sequence of 314 basepairs of GnRHR mRNA was amplified by RT-PCR in the pituitary, in 9 of 10 ovaries, and in 4 of 5 GL cell preparations. No message could be amplified in human lymphocytes, and placental specimens showed a weak signal. The relative GnRHR mRNA levels in GL cells from 13 women analyzed by quantitative RT-PCR showed a wide range of individual differences. These results suggest that GnRHR mRNA is expressed in GL cells and the human ovary across different functional stages, implying that multiple ovarian compartments may express GnRH receptors. The administration of GnRH analogs may have a further direct action on the human ovary.
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PMID:Gonadotropin-releasing hormone receptor gene expression in human ovary and granulosa-lutein cells. 785 1

While gonadotropin-releasing hormone (GnRH), GnRH-like, or GnRH receptor (GnRH-R) have been reported to exist in several tissues other than brain or anterior pituitary, there is no report concerning GnRH or GnRH-R gene expression in the normal mammary gland. In order to define the production of GnRH as well as GnRH-R in the mammary gland at the molecular level we examined their gene expression in various functional stages of the mouse mammary gland using the reverse transcriptase-polymerase chain reaction (RT-PCR). GnRH mRNA transcripts were found in mouse mammary glands of mid-pregnant, lactating, and 3, 6, 9 days post-lactational mice, whereas GnRH-R mRNA transcripts were not detected in mammary glands of any functional stage. These results suggest a possible biological role of GnRH in mammary gland.
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PMID:Detection of messenger RNA for gonadotropin-releasing hormone (GnRH) but not for GnRH receptors in mouse mammary glands. 786 75

The alpha T3-1 cell line, an immortalized gonadotroph cell line, expresses high levels of the gonadotrophin-releasing hormone (GnRH) receptor. Sustained exposure of these cells to the GnRH receptor agonist des-Gly10-[D-Ala6]luteinizing hormone-releasing hormone ethylamide resulted in a substantial down-regulation of cellular levels of a combination of the alpha subunits of the phospholipase C-beta 1-linked G proteins Gq and G11, as assessed by immunoblotting with an antiserum able to identify these two proteins equally. This effect was dependent upon the concentration of agonist used (EC50 = 4 nM) and on the time of the treatment (t1/2 = 6 hr) when a maximally effective concentration of agonist (1 microM) was used. Comparison of agonist regulation of inositol phosphate generation and Gq alpha/G11 alpha down-regulation demonstrated that effects on inositol phosphate production were approximately 3-fold more potent. In contrast to Gq alpha/G11 alpha, membrane-associated levels of Gs alpha and G12 alpha, the G proteins that transduce stimulatory and inhibitory regulation, respectively, of adenylyl cyclase, were not altered by agonist treatment. Analysis of mRNA by reverse transcriptase/polymerase chain reaction indicated the coexpression by alpha T3-1 cells of mRNA corresponding to both Gq alpha and G11 alpha. Immunoblotting with antisera selective for either Gq alpha or G11 alpha confirmed their coexpression. Resolution of membranes from untreated and agonist-treated alpha T3-1 cells under sodium dodecyl sulfate-polyacrylamide gel electrophoresis conditions able to separate Gq alpha from G11 alpha indicated that G11 alpha was more prevalent than Gq alpha at steady state but that agonist treatment regulated cellular levels of both of these G proteins in a nonselective manner. Sustained activation of protein kinase C with phorbol myristate acetate was unable to mimic agonist regulation of cellular Gq alpha/G11 alpha levels, as was treatment of alpha T3-1 cells with the selective protein kinase C inhibitor chelerythrine. These data suggest that the GnRH receptor is able to interact functionally with both Gq alpha and G11 alpha in alpha T3-1 cells and that sustained exposure to a GnRH receptor agonist selectively regulates the cellular levels of the G proteins that interact with the receptor.
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PMID:The gonadotrophin-releasing hormone receptor of alpha T3-1 pituitary cells regulates cellular levels of both of the phosphoinositidase C-linked G proteins, Gq alpha and G11 alpha, equally. 805 44

An important question in the pathogenesis and regulation of human gonadotroph adenomas is whether heterogeneous gonadotropin responses to gonadotropin-releasing hormone (GnRH) are due to dysregulation of GnRH receptor biosynthesis and/or cell-signaling pathways. We investigated gonadotropin responsiveness to pulsatile GnRH in 13 gonadotroph adenomas. All tumors had evidence of follicle-stimulating hormone (FSH) beta and alpha subunit biosynthesis using reverse transcriptase/polymerase chain reaction (RTPCR) techniques. Four tumors significantly increased gonadotropin and/or free subunit secretion during pulsatile 10(-8) M GnRH administration. The GnRH antagonist Antide (10(-6) to 10(-8) M) blocked secretory increases in all GnRH-responsive tumors. Gonadotropin and/or free subunit secretion increased after 60 mM KCl, confirming that GnRH nonresponsiveness was not due to intracellular gonadotropin depletion. We hypothesized that GnRH nonresponsiveness in these tumors may be due to GnRH receptor (GnRH-Rc) biosynthetic defects. RTPCR analyses detected GnRH-Rc transcripts only in responsive tumors and normal human pituitary. This is the first demonstration of a cell-surface receptor biosynthetic defect in human pituitary tumors. We conclude (a) one third of gonadotroph tumors respond to pulsatile GnRH in vitro, (b) GnRH-Rc mRNA is detected in human gonadotroph adenomas and predicts GnRH responsiveness, and (c) GnRH-Rc biosynthetic defects may underlie GnRH nonresponsiveness in gonadotroph tumors.
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PMID:Gonadotropin-releasing hormone receptor mRNA expression by human pituitary tumors in vitro. 820 Sep 67

Receptors for gonadotropin releasing hormone (GnRH), located in the cell membranes of adeno-hypophysial gonadotropes, mediate the action of GnRH to stimulate the secretion of the gonadotropic hormones (LH and FSH). In the present studies, we have isolated a GnRH receptor cDNA from bovine pituitary, determined its primary structure, and studied the regulation of its gene expression. The cDNA is composed of 1326 nucleotides and encodes a protein containing 328 amino acids. The GnRH receptor of cattle, like that in humans and mice, is a seven transmembrane receptor and has structural characteristics homologous with the family of G protein-coupled receptors. It exhibits 91% identity at the amino acid level with the human and 86% identity with mouse and rat receptors. Northern blot analysis of the RNA from bovine pituitary, probed with 32P-labeled bovine GnRH receptor cDNA, revealed the presence of four different transcripts (5.0, 3.5, 2.5 and 1.5 kb) in the pituitary of which the 5.0 kb form was most abundant. Using the reverse transcriptase/PCR technique, we detected expression of GnRH receptor mRNA in the pituitary but not in any other extrapituitary tissues such as the hypothalamus, hippocampus, testis, corpus luteum, ovary (containing follicles), myoendometrium, adrenal, kidney, liver and spleen. Higher levels of GnRH receptor mRNA were found in the pituitaries of steers than in cohort bulls, suggesting regulation of GnRH receptor gene expression by testicular steroids.
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PMID:Molecular cloning, sequencing, and characterizing the bovine receptor for gonadotropin releasing hormone (GnRH). 830 35

The number of gonadotropin-releasing hormone (GnRH) receptors on pituitary gonadotropes varies substantially during the rat estrous cycle and may modulate pituitary responsiveness to GnRH. The present studies were undertaken to determine to what extent these changes in GnRH receptor number reflect a change in GnRH receptor mRNA expression in the anterior pituitary gland. Using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), pituitary GnRH receptor mRNA levels were measured at various timepoints throughout the rat estrous cycle. There was a three-fold increase in GnRH receptor mRNA levels on the afternoon of proestrus (PRO) when compared to levels observed on the morning of metestrus (MET). This rise preceded the onset of the LH surge by 6h (1200h). GnRH receptor mRNA levels remained elevated through 2100h PRO, after which they dropped dramatically, and by 2400h PRO were not significantly different from levels observed at 0900h MET. A two-fold increase in GnRH receptor mRNA expression was also observed during the early stages of the estrous cycle (0900h to 1800h MET), and this increase was sustained until 1800h on diestrus, at which time mRNA levels decreased to levels observed at 0900h MET. These results demonstrate that pituitary GnRH receptor mRNAs are dynamically regulated during the rat estrous cycle, with receptor mRNA expression being greatest on the afternoon of PRO, the time of the estrous cycle at which gonadotropes are most sensitive to GnRH stimulation.
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PMID:Dynamic regulation of gonadotropin-releasing hormone receptor mRNA levels in the anterior pituitary gland during the rat estrous cycle. 840 35

Recently, cloning of the gonadotropin-releasing hormone (GnRH) receptor from the human breast tumor cell line (MCF-7) and from an ovarian tumor, and its expression in various other human tumors, tumor cell lines and reproductive organs have been reported (Kakar et al., Mol. Cell. Endocrinol., 106 (1994) 145-149). In the present studies, we investigated the expression of GnRH and GnRH receptor mRNAs in normal human non-reproductive tissues. Using reverse transcriptase-polymerase chain reaction (RT-PCR) techniques and specific oligonucleotide primers derived from the placental GnRH cDNA sequence, PCR products of the expected size were obtained from human liver, heart, skeletal muscle, kidney, placenta, and pituitary. The authenticity of the PCR products was confirmed by Southern blot analysis with an internal oligonucleotide primer as probe. Similarly, using specific oligonucleotide primers for the GnRH receptor selected from the human pituitary GnRH receptor cDNA sequence, PCR products of the expected size were amplified from human liver, heart, skeletal muscle, kidney, placenta, and pituitary, and these strongly hybridized with the human GnRH receptor cDNA on Southern blot. Cloning and nucleotide sequencing of the PCR products for the GnRH and GnRH receptor from heart revealed identical sequences when compared to the human placental GnRH and pituitary GnRH receptor cDNAs, respectively. These data demonstrate for the first time the existence of GnRH and GnRH receptor mRNAs in normal human non-reproductive tissues and suggest that GnRH and its receptor may play an important role in the regulation of cellular functions in an autocrine or paracrine manner, in addition to regulating the secretion of gonadotropins from the anterior pituitary.
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PMID:Expression of gonadotropin-releasing hormone and gonadotropin-releasing hormone receptor mRNAs in various non-reproductive human tissues. 852 6


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