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Sample records for adipokinetic hormone receptor

  1. Molecular identification of the insect adipokinetic hormone receptors

    DEFF Research Database (Denmark)

    Staubli, Frank; Jørgensen, Thomas J D; Cazzamali, Giuseppe

    2002-01-01

    The insect adipokinetic hormones (AKHs) are a large family of peptide hormones that are involved in the mobilization of sugar and lipids from the insect fat body during energy-requiring activities such as flight and locomotion, but that also contribute to hemolymph sugar homeostasis. Here, we have...

  2. Cloning and characterization of the adipokinetic hormone receptor from the cockroach Periplaneta americana

    DEFF Research Database (Denmark)

    Hansen, Karina K; Hauser, Frank; Cazzamali, Giuseppe

    2006-01-01

    Cockroaches have long been used as insect models to investigate the actions of biologically active neuropeptides. Here, we describe the cloning and functional expression in Chinese hamster ovary cells of an adipokinetic hormone (AKH) G protein-coupled receptor from the cockroach Periplaneta...

  3. Adipokinetic hormones and their G protein-coupled receptors emerged in Lophotrochozoa

    DEFF Research Database (Denmark)

    Li, Shizhong; Hauser, Frank; Skadborg, Signe K.

    2016-01-01

    Most multicellular animals belong to two evolutionary lineages, the Proto- and Deuterostomia, which diverged 640-760 million years (MYR) ago. Neuropeptide signaling is abundant in animals belonging to both lineages, but it is often unclear whether there exist evolutionary relationships between...... the neuropeptide systems used by proto- or deuterostomes. An exception, however, are members of the gonadotropin-releasing hormone (GnRH) receptor superfamily, which occur in both evolutionary lineages, where GnRHs are the ligands in Deuterostomia and GnRH-like peptides, adipokinetic hormone (AKH), corazonin......, and AKH/corazonin-related peptide (ACP) are the ligands in Protostomia. AKH is a well-studied insect neuropeptide that mobilizes lipids and carbohydrates from the insect fat body during flight. In our present paper, we show that AKH is not only widespread in insects, but also in other Ecdysozoa...

  4. Adipokinetic hormones and their G protein-coupled receptors emerged in Lophotrochozoa

    DEFF Research Database (Denmark)

    Li, Shizhong; Hauser, Frank; Skadborg, Signe K.;

    2016-01-01

    and in Lophotrochozoa. Furthermore, we have cloned and deorphanized two G protein-coupled receptors (GPCRs) from the oyster Crassostrea gigas (Mollusca) that are activated by low nanomolar concentrations of oyster AKH (pQVSFSTNWGSamide). Our discovery of functional AKH receptors in molluscs is especially significant...

  5. Adipokinetic hormone receptor gene identification and its role in triacylglycerol mobilization and sexual behavior in the oriental fruit fly (Bactrocera dorsalis).

    Science.gov (United States)

    Hou, Qiu-Li; Chen, Er-Hu; Jiang, Hong-Bo; Wei, Dan-Dan; Gui, Shun-Hua; Wang, Jin-Jun; Smagghe, Guy

    2017-09-15

    Energy homeostasis requires continuous compensation for fluctuations in energy expenditure and availability of food resources. In insects, energy mobilization is under control of the adipokinetic hormone (AKH) where it is regulating the nutritional status by supporting the mobilization of lipids. In this study, we characterized the gene coding for the AKH receptor (AKHR) and investigated its function in the oriental fruit fly (Bactrocera dorsalis) that is economically one of the most important pest insects of tropical and subtropical fruit. Bacdo-AKHR is a typical G protein-coupled receptor (GPCR) and phylogenetic analysis confirmed that Bacdo-AKHR is closely related to insect AKHRs from other species. When expressed in Chinese hamster ovary (CHO) cells, Bacdo-AKHR exhibited a high sensitivity and selectivity for AKH peptide (EC50 = 19.3 nM). Using qPCR, the developmental stage and tissue-specific expression profiles demonstrated that Bacdo-AKHR was highly expressed in both the larval and adult stages, and also specifically in the fat body and midgut of the adult with no difference in sex. To investigate the role of AKHR in B. dorsalis, RNAi assays were performed with dsRNA against Bacdo-AKHR in adult flies of both sexes and under starvation and feeding condition. As major results, the knockdown of this gene resulted in triacylglycerol (TAG) accumulation. With RNAi-males, we observed a severe decrease in their sexual courtship activity when starved, but there was a partial rescue in copulation when refed. Also in RNAi-males, the tethered-flight duration declined compared with the control group when starved, which is confirming the dependency on energy metabolism. In RNAi-females, the sexual behavior was not affected, but their fecundity was decreased. Our findings indicate an interesting role of AKHR in the sexual behavior of males specifically. The effects are associated with TAG accumulation, and we also reported that the conserved role of AKH-mediated system

  6. Locust corpora cardiaca contain an inactive adipokinetic hormone.

    Science.gov (United States)

    Siegert, K J

    1999-03-26

    A neuropeptide from the migratory locust, Locusta migratoria, has been identified as a novel member of the family of adipokinetic hormones (AKHs). The peptide is probably synthesised in the brain because it is the first AKH found in the storage lobe, whilst the three 'classic' Locusta AKHs are present in the glandular lobe of the corpora cardiaca. In locusts, the peptide has no biological activity usually associated with AKHs. There is only 36-56% sequence identity with the three Lom-AKHs, but 78% identity with the Drosophila melanogaster AKH, Drm-HrTH. The new peptide is active in the American cockroach, Periplaneta americana, and was provisionally named 'L. migratoria hypertrehalosaemic hormone', Lom-HrTH; its biological role in locusts remains to be established. The high degree of identity with Drm-HrTH suggests that Lom-HrTH is an ancient molecule.

  7. The adipokinetic hormone family in Chrysomeloidea: structural and functional considerations *

    Science.gov (United States)

    Gäde, Gerd; Marco, Heather G.

    2011-01-01

    Abstract The presented work is a hybrid of an overview and an original research paper on peptides belonging to the adipokinetic hormone (AKH) family that are present in the corpora cardiaca of Chrysomeloidea. First, we introduce the AKH/red pigment-concentrating hormone (RPCH) peptide family. Second, we collate the available primary sequence data on AKH peptides in Cerambycidae and Chrysomelidae, and we present new sequencing data (from previously unstudied species) obtained by liquid-chromatography coupled with ion trap electrospray ionisation mass spectrometry. Our expanded data set encompasses the primary structure of AKHs from seven species of Cerambycidae and three species of Chrysomelidae. All of these species synthesise the octapeptide code-named Peram-CAH-I (pGlu-Val-Asn-Phe-Ser-Pro-Asn-Trp amide). Whereas this is the sole AKH peptide in Cerambycidae, Chrysomelidae demonstrate a probable event of AKH gene duplication, thereby giving rise to an additional AKH. This second AKH peptide may be either Emppe-AKH (pGlu-Val-Asn-Phe-Thr-Pro-Asn-Trp amide) or Peram-CAH-II (pGlu-Leu-Thr-Phe-Thr-Pro-Asn-Trp amide). The peptide distribution and structural data suggest that both families are closely related and that Peram-CAH-I is the ancestral peptide. We hypothesise on the molecular evolution of Emppe-AKH and Peram-CAH-II from the ancestral peptide due to nonsynonymous missense single nucleotide polymorphism in the nucleotide coding sequence of prepro-AKH. Finally, we review the biological significance of the AKH peptides as hyperprolinaemic hormones in Chrysomeloidea, i.e. they cause an increase in the circulating concentration of proline. The mobilisation of proline has been demonstrated during flight in both cerambycid and chrysomelid beetles. PMID:22303105

  8. Hypertrehalosaemic and hyperlipaemic responses to adipokinetic hormone in fifth larval instar locusts, Locusta migratoria

    NARCIS (Netherlands)

    Horst, D.J. van der; Marrewijk, W.J.A. van; Broek, A.Th.M. van den; Beenakkers, A.M.Th.

    1984-01-01

    In fifth instar larvae of Locusta migratoria the haemolymph lipid concentration is elevated after injection of adipokinetic hormone (AKH). This hyperlipaemic response in larvae remains substantially lower than in adults; over 75% of the mobilized lipid consists of diacylglycerol. In addition, unlike

  9. Conformational study of insect adipokinetic hormones using NMR constrained molecular dynamics

    Science.gov (United States)

    Nair, Margie M.; Jackson, Graham E.; Gäde, Gerd

    2001-03-01

    Mem-CC (pGlu-Leu-Asn-Tyr-Ser-Pro-Asp-Trp-NH2), Tem-HrTH (pGlu-Leu-Asn-Phe-Ser-Pro-Asn-Trp-NH2) and Del-CC (pGlu-Leu-Asn-Phe-Ser-Pro-Asn-Trp-Gly-Asn-NH2) are adipokinetic hormones, isolated from the corpora cardiaca of different insect species. These hormones regulate energy metabolism during flight and so are intimately involved in an insect's mobility. Secondary structural elements of these peptides and the N7 analogue, [N7]-Mem-CC (pGlu-Leu-Asn-Tyr-Ser-Pro-Asn-Trp-NH2), have been determined in dimethylsulfoxide solution using NMR restrained molecular mechanic simulations. The neuropeptides were all found to have an extended structure for the first 4 residues and a β-turn between residues 4-8. For Tem-HrTH and Del-CC, asparagine (N7) which is postulated to be involved in receptor binding and/or activation, projects outward form the β-turn. Mem-CC does not have an asparagine at position 7 while, for [N7]-Mem-CC, the N7 sidechain folds inside the β-turn preventing its interaction with the receptor.

  10. Postembryonic proliferation of neuroendocrine cells expressing adipokinetic hormone peptides in the corpora cardiaca of the locust.

    Science.gov (United States)

    Kirschenbaum, S R; O'Shea, M

    1993-08-01

    Neuroendocrine glands that synthesize and secrete peptide hormones regulate the levels of these peptide messengers during development. In this article we describe a mechanism for regulating neuropeptide levels in the corpora cardiaca of the locust Schistocerca gregaria, a neuroendocrine gland structurally analogous to the vertebrate adenohypophysis. A set of five colocalized peptide hormones of the adipokinetic hormone family is synthesized in intrinsic neurosecretory cells in the corpora cardiaca. During postembryonic development there are progressive changes in the absolute and relative levels of these five peptide hormones. We show that the ability of the gland to increase peptide synthesis is due to a 100-fold increase in the number of cells which make up the gland. The gland grows by the addition of new cells derived from symmetrical division of undifferentiated precursor cells within the corpora cardiaca. We show, using double-label immunocytochemistry, that cells born in the glandular lobe mature into cells that express adipokinetic hormone peptides. The pattern of cell birth and peptide expression can account for the dramatic increase in postembryonic peptide levels.

  11. Structure elucidation and biological activity of an unusual adipokinetic hormone from corpora cardiaca of the butterfly, Vanessa cardui.

    Science.gov (United States)

    Köllisch, G V; Lorenz, M W; Kellner, R; Verhaert, P D; Hoffmann, K H

    2000-09-01

    A structurally unusual member of the adipokinetic hormone/red pigment-concentrating hormone peptide family was isolated from corpora cardiaca of the painted lady butterfly, Vanessa cardui. Its primary structure was assigned by Edman degradation and nano-electrospray-time-of-flight mass spectrometry as pQLTFTSSWGGK (Vac-AKH). Vac-AKH represents the first 11mer and the first nonamidated peptide in this family. The peptide shows significant adipokinetic activity in adult specimens of V. cardui. Injection of 10 pmol of synthetic Vac-AKH into 4-day-old decapitated males resulted in an approximately 150% increase of hemolymph lipids after 90 min. Half maximal adipokinetic activity was achieved with about 0. 1 pmol of Vac-AKH. During a 2-h incubation of corpora cardiaca/corpora allata complexes in medium containing 50 mM KCl, significant amounts of Vac-AKH were released from the glands.

  12. Role of adipokinetic hormone and adenosine in the anti-stress response in Drosophila melanogaster.

    Science.gov (United States)

    Zemanová, Milada; Stašková, Tereza; Kodrík, Dalibor

    2016-01-01

    The role of adipokinetic hormone (AKH) and adenosine in the anti-stress response was studied in Drosophila melanogaster larvae and adults carrying a mutation in the Akh gene (Akh(1)), the adenosine receptor gene (AdoR(1)), or in both of these genes (Akh(1) AdoR(1) double mutant). Stress was induced by starvation or by the addition of an oxidative stressor paraquat (PQ) to food. Mortality tests revealed that the Akh(1) mutant was the most resistant to starvation, while the AdoR(1) mutant was the most sensitive. Conversely, the Akh(1) AdoR(1) double mutant was more sensitive to PQ toxicity than either of the single mutants. Administration of PQ significantly increased the Drome-AKH level in w(1118) and AdoR(1) larvae; however, this was not accompanied by a simultaneous increase in Akh gene expression. In contrast, PQ significantly increased the expression of the glutathione S-transferase D1 (GstD1) gene. The presence of both a functional adenosine receptor and AKH seem to be important for the proper control of GstD1 gene expression under oxidative stress, however, the latter appears to play more dominant role. On the other hand, differences in glutathione S-transferase (GST) activity among the strains, and between untreated and PQ-treated groups were minimal. In addition, the glutathione level was significantly lower in all untreated AKH- or AdoR-deficient mutant flies as compared with the untreated control w(1118) flies and further declined following treatment with PQ. All oxidative stress characteristics modified by mutations in Akh gene were restored or even improved by 'rescue' mutation in flies which ectopically express Akh. Thus, the results of the present study demonstrate the important roles of AKH and adenosine in the anti-stress response elicited by PQ in a D. melanogaster model, and provide the first evidence for the involvement of adenosine in the anti-oxidative stress response in insects. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Evidence that locustatachykinin I is involved in release of adipokinetic hormone from locust corpora cardiaca.

    Science.gov (United States)

    Nässel, D R; Passier, P C; Elekes, K; Dircksen, H; Vullings, H G; Cantera, R

    1995-06-27

    The glandular cells of the corpus cardiacum of the locust Locusta migratoria, known to synthesize and release adipokinetic hormones (AKH), are contacted by axons immunoreactive to an antiserum raised against the locust neuropeptide locustatachykinin I (LomTK I). Electron-microscopical immunocytochemistry reveals LomTK immunoreactive axon terminals, containing granular vesicles, in close contact with the glandular cells cells. Release of AKH I from isolated corpora cardiaca of the locust has been monitored in an in vitro system where the amount of AKH I released into the incubation saline is determined by reversed phase high performance liquid chromatography with fluorometric detection. We could show that LomTK I induces release of AKH from corpora cardiaca in a dose-dependent manner when tested in a range of 10-200 microM. This is thus the first clear demonstration of a substance inducing release of AKH, correlated with the presence of the substance in fibers innervating the AKH-synthesizing glandular cells, in the insect corpora cardiaca.

  14. Localization and functional characterization of a novel adipokinetic hormone in the mollusk, Aplysia californica.

    Directory of Open Access Journals (Sweden)

    Joshua I Johnson

    Full Text Available Increasing evidence suggests that gonadotropin-releasing hormone (GnRH, corazonin, adipokinetic hormone (AKH, and red pigment-concentrating hormone all share common ancestry to form a GnRH superfamily. Despite the wide presence of these peptides in protostomes, their biological effects remain poorly characterized in many taxa. This study had three goals. First, we cloned the full-length sequence of a novel AKH, termed Aplysia-AKH, and examined its distribution in an opisthobranch mollusk, Aplysia californica. Second, we investigated in vivo biological effects of Aplysia-AKH. Lastly, we compared the effects of Aplysia-AKH to a related A. californica peptide, Aplysia-GnRH. Results suggest that Aplysia-AKH mRNA and peptide are localized exclusively in central tissues, with abdominal, cerebral, and pleural ganglia being the primary sites of Aplysia-AKH production. However, Aplysia-AKH-positive fibers were found in all central ganglia, suggesting diverse neuromodulatory roles. Injections of A. californica with Aplysia-AKH significantly inhibited feeding, reduced body mass, increased excretion of feces, and reduced gonadal mass and oocyte diameter. The in vivo effects of Aplysia-AKH differed substantially from Aplysia-GnRH. Overall, the distribution and biological effects of Aplysia-AKH suggest it has diverged functionally from Aplysia-GnRH over the course of evolution. Further, that both Aplysia-AKH and Aplysia-GnRH failed to activate reproduction suggest the critical role of GnRH as a reproductive activator may be a phenomenon unique to vertebrates.

  15. Localization and Functional Characterization of a Novel Adipokinetic Hormone in the Mollusk, Aplysia californica

    Science.gov (United States)

    Johnson, Joshua I.; Kavanaugh, Scott I.; Nguyen, Cindy; Tsai, Pei-San

    2014-01-01

    Increasing evidence suggests that gonadotropin-releasing hormone (GnRH), corazonin, adipokinetic hormone (AKH), and red pigment-concentrating hormone all share common ancestry to form a GnRH superfamily. Despite the wide presence of these peptides in protostomes, their biological effects remain poorly characterized in many taxa. This study had three goals. First, we cloned the full-length sequence of a novel AKH, termed Aplysia-AKH, and examined its distribution in an opisthobranch mollusk, Aplysia californica. Second, we investigated in vivo biological effects of Aplysia-AKH. Lastly, we compared the effects of Aplysia-AKH to a related A. californica peptide, Aplysia-GnRH. Results suggest that Aplysia-AKH mRNA and peptide are localized exclusively in central tissues, with abdominal, cerebral, and pleural ganglia being the primary sites of Aplysia-AKH production. However, Aplysia-AKH-positive fibers were found in all central ganglia, suggesting diverse neuromodulatory roles. Injections of A. californica with Aplysia-AKH significantly inhibited feeding, reduced body mass, increased excretion of feces, and reduced gonadal mass and oocyte diameter. The in vivo effects of Aplysia-AKH differed substantially from Aplysia-GnRH. Overall, the distribution and biological effects of Aplysia-AKH suggest it has diverged functionally from Aplysia-GnRH over the course of evolution. Further, that both Aplysia-AKH and Aplysia-GnRH failed to activate reproduction suggest the critical role of GnRH as a reproductive activator may be a phenomenon unique to vertebrates. PMID:25162698

  16. A possible role of SchistoFLRFamide in inhibition of adipokinetic hormone release from locust corpora cardiaca.

    Science.gov (United States)

    Vullings, H G; Ten Voorde, S E; Passier, P C; Diederen, J H; Van Der Horst, D J; Nässel, D R

    1998-12-01

    The distribution and actions of FMRFamide-related peptides (FaRPs) in the corpora cardiaca of the locust Locusta migratoria were studied. Antisera to FMRFamide and SchistoFLRFamide (PDVDHVFLRFamide) label neuronal processes that impinge on glandular cells in the glandular lobe of the corpora cardiaca known to produce adipokinetic hormones. Electron microscopic immunocytochemistry revealed that these FaRP-containing processes form synaptoid contacts with the glandular cells. Approximately 12% of the axon profiles present in the glandular part of the corpus cardiacum contained SchistoFLRFamide-immunoreactive material. Retrograde tracing of the axons in the nervus corporis cardiaci II with Lucifer yellow revealed 25-30 labelled neuronal cell bodies in each lateral part of the protocerebrum. About five of these in each hemisphere reacted with the SchistoFLRFamide-antiserum. Double-labelling immunocytochemistry showed that the FaRP-containing processes in the glandular lobe of the corpora cardiaca are distinct from neuronal processes, reacting with an antiserum to the neuropeptide locustatachykinin. The effect of the decapeptide SchistoFLRFamide and the tetrapeptide FMRFamide on the release of adipokinetic hormone I (AKH I) from the cells in the glandular part of the corpus cardiacum was studied in vitro. Neither the deca- nor the tetrapeptide had any effect on the spontaneous release of AKH I. Release of AKH I induced by the phosphodiesterase inhibitor IBMX, however, was reduced significantly by both peptides. These results point to an involvement of FaRPs as inhibitory modulators in the regulation of the release of adipokinetic hormone from the glandular cells.

  17. Novel members of the adipokinetic hormone family in beetles of the superfamily Scarabaeoidea.

    Science.gov (United States)

    Gäde, Gerd; Šimek, Petr; Marco, Heather G

    2016-12-01

    Eight beetle species of the superfamily Scarabaeoidea were investigated with respect to peptides belonging to the adipokinetic hormone (AKH) family in their neurohemal organs, the corpora cardiaca (CC). The following beetle families are represented: Scarabaeidae, Lucanidae, and Geotrupidae. AKH peptides were identified through a heterospecific trehalose-mobilizing bioassay and by sequence analyses, using liquid chromatography coupled to positive electrospray mass spectrometry (LC-ESI-MS) and analysis of the tandem MS(2) spectra obtained by collision-induced dissociation. All the beetle species have octapeptide AKHs; some have two AKHs, while others have only one. Novel AKH members were found in Euoniticellus intermedius and Circellium bacchus (family Scarabaeidae), as well as in Dorcus parallelipipedus (family Lucanidae). Two species of the family Geotrupidae and two species of the Scarabaeidae subfamily Cetoniinae contain one known AKH peptide, Melme-CC, while E. intermedius produces a novel peptide code named Euoin-AKH: pEINFTTGWamide. Two AKH peptides were each identified in CC of C. bacchus and D. parallelipipedus: the novel Cirba-AKH: pEFNFSAGWamide and the known peptide, Scade-CC-I in the former, and the novel Dorpa-AKH: pEVNYSPVW amide and the known peptide, Melme-CC in the latter. Kheper bonelli (subfamily Scarabaeinae) also has two AKHs, the known Scade-CC-I and Scade-CC-II. All the novel peptides were synthesized and the amino acid sequence assignments were unequivocally confirmed by co-elution of the synthetic peptides with their natural equivalent, and identical MS parameters of the two forms. The novel synthetic peptides are all active in inducing hypertrehalosemia in cockroaches.

  18. Primary structure of two neuropeptide hormones with adipokinetic and hypotrehalosemic activity isolated from the corpora cardiaca of horse flies (Diptera).

    Science.gov (United States)

    Jaffe, H; Raina, A K; Riley, C T; Fraser, B A; Nachman, R J; Vogel, V W; Zhang, Y S; Hayes, D K

    1989-01-01

    The primary structures of two neuropeptides, Tabanus atratus adipokinetic hormone (Taa-AKH) and Tabanus atratus hypotrehalosemic hormone (Taa-HoTH), from the corpora cardiaca of horse flies (Diptera: Tabanidae) have been determined. Amino acid sequences of Taa-AKH (less than Glu-Leu-Thr-Phe-Thr-Pro-Gly-Trp-NH2) and Taa-HoTH (less than Glu-Leu-Thr-Phe-Thr-Pro-Gly-Trp-Gly-Tyr-NH2) (where less than Glu = pyroglutamic acid) were determined by automated gas-phase Edman degradation of the peptides deblocked by pyroglutamate aminopeptidase and by fast atom bombardment mass spectrometry. The hormones were synthesized, and the natural and synthetic peptides exhibited identical chromatographic, spectroscopic, and biological properties. When assayed in adult face fly males, Taa-AKH and Taa-HoTH demonstrated hyperlipemic activity, in addition, Taa-HoTH also demonstrated a significant hypotrehalosemic activity. PMID:2813385

  19. Unique translational modification of an invertebrate neuropeptide: a phosphorylated member of the adipokinetic hormone peptide family

    Science.gov (United States)

    2005-01-01

    Separation of an extract of corpora cardiaca from the protea beetle, Trichostetha fascicularis, by single-step RP (reverse-phase)-HPLC and monitoring of tryptophan fluorescence resulted in two distinctive peaks, the material of which mobilized proline and carbohydrates in a bioassay performed using the beetle. Material from one of these peaks was; however, inactive in the classical bioassays of locusts and cockroaches that are used for detecting peptides belonging to the AKH (adipokinetic hormone) family. After enzymatically deblocking the N-terminal pyroglutamic acid (pGlu) residue in the peptide material and sequencing by Edman degradation, a partial sequence was obtained: (pGlu)-Ile-Asn-Met-Thr-Xaa-Gly-Trp. The complete sequence was deduced from ESI-MSn (electrospray ionization multi-stage-MS); position six was identified as a phosphothreonine residue and the C-terminus is amidated. The peptide, code-named Trifa-CC, was chemically synthesized and used in confirmatory experiments to show that the primary structure had been correctly assigned. To our knowledge, this is the first report of a phosphorylated invertebrate neuropeptide. Synthetic Trifa-CC co-elutes with the natural peptide, found in the gland of the protea beetle, after RP-HPLC. Moreover, the natural peptide can be dephosphorylated by alkaline phosphatase and the product of that reaction has the same retention time as a synthetic nonphosphorylated octapeptide which has the same sequence as Trifa-CC. Finally, synthetic Trifa-CC has hypertrehalosaemic and hyperprolinaemic biological activity in the protea beetle, but even high concentrations of synthetic Trifa-CC are inactive in locusts and cockroaches. Hence, the correct peptide structure has been assigned. Trifa-CC of the protea beetle is an unusual member of the AKH family that is unique in its post-translational modification. Since it increases the concentration of carbohydrates and proline in the haemolymph when injected into the protea beetle, and

  20. Hyperprolinaemia caused by novel members of the adipokinetic hormone/red pigment-concentrating hormone family of peptides isolated from corpora cardiaca of onitine beetles.

    Science.gov (United States)

    Gäde, G

    1997-01-01

    Two novel members of the adipokinetic hormone/red pigment-concentrating hormone family of peptides were identified in dung beetles of the genus Onitis using heterologous (measuring lipid and carbohydrate mobilization in locusts and cockroaches) and a homologous (measuring proline increase in the haemolymph) bioassay(s). Isolation of the peptides was achieved by single-step reverse-phase HPLC of corpora cardiaca extracts. The primary structure was elucidated by automated Edman degradation and by electrospray MS. Both peptides are blocked octapeptides containing three aromatic amino acids. Peptide 1, designated Ona-CC-I, is pGlu-Tyr-Asn-Phe-Ser-Thr-Gly-Trp-NH2, and peptide 2, designated Ona-CC-II, is pGlu-Phe-Asn-Tyr-Ser-Pro-Asp-Trp-NH2. The synthetic peptides were chromatographically indistinguishable from the natural compounds. They both had a hyperprolinaemic effect in the dung beetle. Moreover, flight experiments established that proline is an important fuel to power flight metabolism in Onitis species. Therefore, it is concluded that these novel and unique peptides are involved in regulating proline-based flight metabolism.

  1. Discovery of a novel insect neuropeptide signaling system closely related to the insect adipokinetic hormone and corazonin hormonal systems

    DEFF Research Database (Denmark)

    Hansen, Karina Kiilerich; Stafflinger, Elisabeth; Schneider, Martina

    2010-01-01

    that are structurally related to the AKHs but represent a different neuropeptide signaling system. We have previously cloned an orphan GPCR from the malaria mosquito Anopheles gambiae that was structurally intermediate between the A. gambiae AKH and corazonin GPCRs. Using functional expression of the receptor in cells...... receptors, this is a prominent example of receptor/ligand co-evolution, probably originating from receptor and ligand gene duplications followed by mutations and evolutionary selection, thereby yielding three independent hormonal systems. The ACP signaling system occurs in the mosquitoes A. gambiae, Aedes...

  2. Isolation and structure of a novel charged member of the red-pigment-concentrating hormone-adipokinetic hormone family of peptides isolated from the corpora cardiaca of the blowfly Phormia terraenovae (Diptera).

    Science.gov (United States)

    Gäde, G; Wilps, H; Kellner, R

    1990-01-01

    A hypertrehalosaemic neuropeptide from the corpora cardiaca of the blowfly Phormia terraenovae has been isolated by reversed-phase h.p.l.c., and its primary structure was determined by pulsed-liquid phase sequencing employing Edman chemistry after enzymically deblocking the N-terminal pyroglutamate residue. The C-terminus was also blocked, as indicated by the lack of digestion when the peptide was incubated with carboxypeptidase A. The octapeptide has the sequence pGlu-Leu-Thr-Phe-Ser-Pro-Asp-Trp-NH2 and is clearly defined as a novel member of the RPCH/AKH (red-pigment-concentrating hormone/adipokinetic hormone) family of peptides. It is the first charged member of this family to be found. The synthetic peptide causes an increase in the haemolymph carbohydrate concentration in a dose-dependent fashion in blowflies and therefore is named 'Phormia terraenovae hypertrehalosaemic hormone' (Pht-HrTH). In addition, receptors in the fat-body of the American cockroach (Periplaneta americana) recognize the peptide, resulting in carbohydrate elevation in the blood. However, fat-body receptors of the migratory locust (Locusta migratoria) do not recognize this charged molecule, and thus no lipid mobilization is observed in this species. PMID:2386478

  3. UCP4 expression changes in larval and pupal fat bodies of the beetle Zophobas atratus under adipokinetic hormone treatment.

    Science.gov (United States)

    Slocinska, Malgorzata; Antos-Krzeminska, Nina; Golebiowski, Marek; Kuczer, Mariola; Stepnowski, Piotr; Rosinski, Grzegorz; Jarmuszkiewicz, Wieslawa

    2013-09-01

    We investigated the influence of adipokinetic hormone (AKH), an insect neurohormone, on uncoupling protein 4 (ZaUCP4) expression and activity in larval and pupal fat body mitochondria of the beetle Zophobas atratus in relation to intermediary metabolism. Homologous Tenmo-AKH was administered to the beetle larvae and pupae as either a single dose or as two doses of 20pmol during a 24h interval. In the larval and pupal fat bodies, downregulation of ZaUCP4 expression at the mRNA and protein levels was observed 24h and 48h after AKH treatment, respectively. In both developmental stages, ZaUCP4 activity was lowered in fat body mitochondria 48h after AKH treatment. In the AKH-injected larvae, changes in ZaUCP4 expression were accompanied by the mobilization of carbohydrate reserves, no change in the concentration of total lipids and an increase in the free fatty acid level. In contrast, AKH had no effect on carbohydrate metabolism in the pupal fat body but induced lipid mobilization. It seems that AKH influences ZaUCP4 expression by triggering multiple events and that it has different physiological roles in controlling intermediary metabolism in the fat body of the beetle larvae and pupae. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. Several isoforms of locustatachykinins may be involved in cyclic AMP-mediated release of adipokinetic hormones from the locust Corpora cardiaca.

    Science.gov (United States)

    Nässel, D R; Vullings, H G; Passier, P C; Lundquist, C T; Schoofs, L; Diederen, J H; Van der Horst, D J

    1999-03-01

    Four locustatachykinins (LomTK I-IV) were identified in about equal amounts in extracts of corpora cardiaca of locusts, using reverse-phase high-performance liquid chromatography and radioimmunoassay with synthetic LomTK I-IV as standards. Brain extracts also contained the four isoforms in roughly equimolar concentrations. Retrograde tracing of the nervi corporis cardiaci II (NCC II) in vitro with Lucifer yellow in combination with LomTK immunocytochemistry revealed that about half of the secretomotor neurons in the lateral part of the protocerebrum projecting into the glandular lobe of the corpora cardiaca (CCG) contain LomTK-immunoreactive material. Since the four LomTKs are present in the CCG, these four or five neurons in each hemisphere are likely to contain colocalized LomTK I-IV. The role of two of the LomTKs in the regulation of the release of adipokinetic hormones (AKHs) from the adipokinetic cells in the CCG in the locust was investigated. Experiments performed in vitro showed that LomTK I and II induced release of AKH in a dose-dependent manner. These peptides also rapidly and transiently elevated the cyclic AMP-content of the CCG. The peak level of cyclic AMP occurred about 45 seconds after stimulation with LomTK. These results support the proposal that LomTKs are involved in controlling the release of the adipokinetic hormones and suggest that all LomTK isoforms may participate in this cyclic AMP-mediated event. Copyright 1999 Academic Press.

  5. Two novel tyrosine-containing peptides (Tyr(4)) of the adipokinetic hormone family in beetles of the families Coccinellidae and Silphidae.

    Science.gov (United States)

    Gäde, Gerd; Šimek, Petr; Marco, Heather G

    2015-11-01

    Novel members of the adipokinetic hormone family of peptides have been identified from the corpora cardiaca (CC) of two species of beetles representing two families, the Silphidae and the Coccinellidae. A crude CC extract (0.3 gland equivalents) of the burying beetle, Nicrophorus vespilloides, was active in mobilizing trehalose in a heterologous assay using the cockroach Periplaneta americana, whereas the CC extract (0.5 gland equivalents) of the ladybird beetle, Harmonia axyridis, exhibited no hypertrehalosemic activity. Primary sequences of one adipokinetic hormone from each species were elucidated by liquid chromatography coupled to electrospray mass spectrometry (LC-MS). The multiple MS(N) electrospray mass data revealed an octapeptide with an unusual tyrosine residue at position 4 for each species: pGlu-Leu-Thr-Tyr-Ser-Thr-Gly-Trp amide for N. vespilloides (code-named Nicve-AKH) and pGlu-Ile-Asn-Tyr-Ser-Thr-Gly-Trp amide for H. axyridis (code-named Harax-AKH). Assignment of the correct sequences was confirmed by synthesis of the peptides and co-elution in reversed-phase high-performance liquid chromatography with fluorescence detection or by LC-MS. Moreover, synthetic peptides were shown to be active in the heterologous cockroach assay system, but Harax-AKH only at a dose of 30 pmol, which explains the negative result with the crude CC extract. It appears that the tyrosine residue at position 4 can be used as a diagnostic feature for certain beetle adipokinetic peptides, because this feature has not been found in another order other than Coleoptera.

  6. Hormone receptors in breast cancer

    NARCIS (Netherlands)

    Suijkerbuijk, K. P M; van der Wall, E.; van Diest, P. J.

    2016-01-01

    Steroid hormone receptors are critical for the growth and development of breast tissue as well as of breast cancer. The importance of the role estrogens in breast cancer has been delineated for more than 100 years. The analysis of its expression has been used not only to classify breast cancers but

  7. Characterisation and pharmacological analysis of a crustacean G protein-coupled receptor: the red pigment-concentrating hormone receptor of Daphnia pulex.

    Science.gov (United States)

    Marco, Heather G; Verlinden, Heleen; Vanden Broeck, Jozef; Gäde, Gerd

    2017-07-31

    This is the first pharmacological characterisation of a neuropeptide G protein-coupled receptor (GPCR) in a crustacean. We cloned the ORF of the red pigment-concentrating hormone from a German strain of Daphnia pulex (Dappu-RPCH), as well as that of the cognate receptor (Dappu-RPCHR). Dappu-RPCHR has the hallmarks of the rhodopsin superfamily of GPCRs, and is more similar to insect adipokinetic hormone (AKH) receptor sequences than to receptor sequences for AKH/corazonin-like peptide or corazonin. We provide experimental evidence that Dappu-RPCH specifically activates the receptor (EC50 value of 65 pM) in a mammalian cell-based bioluminescence assay. We further characterised the properties of the ligands for the Dappu-RPCHR by investigating the activities of a variety of naturally-occurring peptides (insect AKH and crustacean RPCH peptides). The insect AKHs had lower EC50 values than the crustacean RPCHs. In addition, we tested a series of Dappu-RPCH analogues, where one residue at a time is systematically replaced by an alanine to learn about the relative importance of the termini and side chains for activation. Mainly amino acids in positions 1 to 4 and 8 of Dappu-RPCH appear responsible for effective activation of Dappu-RPCHR. The substitution of Phe4 in Dappu-RPCH had the most damaging effect on its agonistic activity.

  8. Nuclear hormone receptors in podocytes

    Directory of Open Access Journals (Sweden)

    Khurana Simran

    2012-09-01

    Full Text Available Abstract Nuclear receptors are a family of ligand-activated, DNA sequence-specific transcription factors that regulate various aspects of animal development, cell proliferation, differentiation, and homeostasis. The physiological roles of nuclear receptors and their ligands have been intensively studied in cancer and metabolic syndrome. However, their role in kidney diseases is still evolving, despite their ligands being used clinically to treat renal diseases for decades. This review will discuss the progress of our understanding of the role of nuclear receptors and their ligands in kidney physiology with emphasis on their roles in treating glomerular disorders and podocyte injury repair responses.

  9. Thyroid hormone receptors bind to defined regions of the growth hormone and placental lactogen genes.

    Science.gov (United States)

    Barlow, J W; Voz, M L; Eliard, P H; Mathy-Harter, M; De Nayer, P; Economidis, I V; Belayew, A; Martial, J A; Rousseau, G G

    1986-12-01

    The intracellular receptor for thyroid hormone is a protein found in chromatin. Since thyroid hormone stimulates transcription of the growth hormone gene through an unknown mechanism, the hypothesis that the thyroid hormone-receptor complex interacts with defined regions of this gene has been investigated in a cell-free system. Nuclear extracts from human lymphoblastoid IM-9 cells containing thyroid hormone receptors were incubated with L-3,5,3'-tri[125I]iodothyronine and calf thymus DNA-cellulose. Restriction fragments of the human growth hormone gene were added to determine their ability to inhibit labeled receptor binding to DNA-cellulose. These fragments encompassed nucleotide sequences from about three kilobase pairs upstream to about four kilobase pairs downstream from the transcription initiation site. The thyroid hormone-receptor complex bound preferentially to the 5'-flanking sequences of the growth hormone gene in a region between nucleotide coordinates -290 and -129. The receptor also bound to an analogous promoter region in the human placental lactogen gene, which has 92% nucleotide sequence homology with the growth hormone gene. These binding regions appear to be distinct from those that are recognized by the receptor for glucocorticoids, which stimulate growth hormone gene expression synergistically with thyroid hormone. The presence of thyroid hormone was required for binding of its receptor to the growth hormone gene promoter, suggesting that thyroid hormone renders the receptor capable of recognizing specific gene regions.

  10. Genetic features of thyroid hormone receptors

    Indian Academy of Sciences (India)

    Maha Rebaï; Imen Kallel; Ahmed Rebaï

    2012-12-01

    Thyroid hormone receptors (TR) are prototypes of nuclear transcription factors that regulate the expression of target genes. These receptors play an important role in many physiological processes. Moreover, a dysfunction of these proteins is often implicated in several human diseases and malignancies. Here we report genetic variations and alterations of the TRs that have been described in the literature as well as their potential role in the development of some human diseases including cancers. The functional effects of some mutations and polymorphisms in TRs on disease susceptibility, especially on cancer risk, are now established. Therefore, further investigations are needed in order to use these receptors as therapeutic targets or as biological markers to decide on appropriate forms of treatment.

  11. Expression of growth hormone and growth hormone receptor in fibroadenomas of the breast.

    Science.gov (United States)

    Lenicek, Tanja; Kasumović, Dino; Stajduhar, Emil; Dzombeta, Tihana; Jukić, Zoran; Kruslin, Bozo

    2013-06-01

    Fibroadenoma is the most prevalent benign breast tumor. It consists of epithelial and stromal components. In general, breast tumors are highly hormonally dependent and growth hormone by its physiology may have a possible oncogenic potential. Therefore, the aim of this study was to determine the expression of growth hormone and growth hormone receptor in epithelial and stromal components of fibroadenomas. Study group included 30 randomly chosen fibroadenomas from female patients aged between 18 and 69 years. The expression of growth hormone and growth hormone receptor was defined in both histologic components of fibroadenomas. Growth hormone was expressed in 96.7% of both epithelial and stromal components of fibroadenomas, with stronger expression in the stromal component. The same percentage of positive reaction (96.7%) was obtained in the epithelial component of fibroadenomas for growth hormone receptor expression. Only 6.7% of stromal components tested for growth hormone receptor were positive. The high expression of growth hormone and growth hormone receptor in fibroadenoma tissue indicates their possible role in the pathogenesis of this tumor. Follow up of patients with high expression of growth hormone and growth hormone receptor may be suggested.

  12. Nuclear hormone receptors put immunity on sterols.

    Science.gov (United States)

    Santori, Fabio R

    2015-10-01

    Nuclear hormone receptors (NHRs) are transcription factors regulated by small molecules. The functions of NHRs range from development of primary and secondary lymphoid organs, to regulation of differentiation and function of DCs, macrophages and T cells. The human genome has 48 classic (hormone and vitamin receptors) and nonclassic (all others) NHRs; 17 nonclassic receptors are orphans, meaning that the endogenous ligand is unknown. Understanding the function of orphan NHRs requires the identification of their natural ligands. The mevalonate pathway, including its sterol and nonsterol intermediates and derivatives, is a source of ligands for many classic and nonclassic NHRs. For example, cholesterol biosynthetic intermediates (CBIs) are natural ligands for RORγ/γt. CBIs are universal endogenous metabolites in mammalian cells, and to study NHRs that bind CBIs requires ligand-free reporters system in sterol auxotroph cells. Furthermore, RORγ/γt shows broad specificity to sterol lipids, suggesting that RORγ/γt is either a general sterol sensor or specificity is defined by an abundant endogenous ligand. Unlike other NHRs, which regulate specific metabolic pathways, there is no connection between the genetic programs induced by RORγ/γt and ligand biosynthesis. In this review, we summarize the roles of nonclassic NHRs and their potential ligands in the immune system.

  13. Adiposity, hormone replacement therapy use and breast cancer risk by age and hormone receptor status : a large prospective cohort study

    NARCIS (Netherlands)

    Ritte, Rebecca; Lukanova, Annekatrin; Berrino, Franco; Dossus, Laure; Tjonneland, Anne; Olsen, Anja; Overvad, Thure Filskov; Overvad, Kim; Clavel-Chapelon, Francoise; Fournier, Agnes; Fagherazzi, Guy; Rohrmann, Sabine; Teucher, Birgit; Boeing, Heiner; Aleksandrova, Krasimira; Trichopoulou, Antonia; Lagiou, Pagona; Trichopoulos, Dimitrios; Palli, Domenico; Sieri, Sabina; Panico, Salvatore; Tumino, Rosario; Vineis, Paolo; Ramon Quiros, Jose; Buckland, Genevieve; Sanchez, Maria-Jose; Amiano, Pilar; Chirlaque, Maria-Dolores; Ardanaz, Eva; Sund, Malin; Lenner, Per; Bueno-de-Mesquita, Bas; van Gils, Carla H.; Peeters, Petra H. M.; Krum-Hansen, Sanda; Gram, Inger Torhild; Lund, Eiliv; Khaw, Kay-Tee; Wareham, Nick; Allen, Naomi E.; Key, Timothy J.; Romieu, Isabelle; Rinaldi, Sabina; Siddiq, Afshan; Cox, David; Riboli, Elio; Kaaks, Rudolf

    2012-01-01

    Introduction: Associations of hormone-receptor positive breast cancer with excess adiposity are reasonably well characterized; however, uncertainty remains regarding the association of body mass index (BMI) with hormone-receptor negative malignancies, and possible interactions by hormone replacement

  14. Endocrine therapy use among elderly hormone receptor-pos...

    Data.gov (United States)

    U.S. Department of Health & Human Services — Clinical guidelines recommend that women with hormone-receptor positive breast cancer receive endocrine therapy (selective estrogen receptor modulators or aromatase...

  15. In vitro studies on hormone-stimulated lipid mobilization from fat body and interconversion of haemolymph lipoproteins of Locusta migratoria

    NARCIS (Netherlands)

    Horst, D.J. van der; Heusden, M.C. van; Beenakkers, A.M.Th.

    1984-01-01

    Both adipokinetic hormone and octopamine have a stimulating effect on lipid release from locust fat body in vitro, when incubated in diluted haemolymph. The presence of adipokinetic hormone results in the formation of the flight-specific haemolymph lipoprotein A⁺ accepting the increased amount of li

  16. Luteinizing hormone-releasing hormone receptor antagonist may reduce postmenopausal flushing

    NARCIS (Netherlands)

    Gastel, P. van; Zanden, M. van der; Telting, D.; Filius, M.; Bancsi, L.; Boer, H. de

    2012-01-01

    OBJECTIVE: Hormone therapy (HT) is the most effective treatment of postmenopausal (PMP) flushing; however, its use is often contraindicated. As an alternative option, we explored the efficacy of the luteinizing hormone-releasing hormone (LHRH) receptor antagonist cetrorelix in women with severe PMP

  17. Thyroid Hormone Receptor beta Mediates Acute Illness-Induced Alterations in Central Thyroid Hormone Metabolism

    NARCIS (Netherlands)

    A. Boelen; J. Kwakkel; O. Chassande; E. Fliers

    2009-01-01

    Acute illness in mice profoundly affects thyroid hormone metabolism in the hypothalamus and pituitary gland. It remains unknown whether the thyroid hormone receptor (TR)-beta is involved in these changes. In the present study, we investigated central thyroid hormone metabolism during lipopolysacchar

  18. Asp330 and Tyr331 in the C-terminal cysteine-rich region of the luteinizing hormone receptor are key residues in hormone-induced receptor activation

    NARCIS (Netherlands)

    M.W.P. Bruysters (Martijn); M. Verhoef-Post (Miriam); A.P.N. Themmen (Axel)

    2008-01-01

    textabstractThe luteinizing hormone (LH) receptor plays an essential role in male and female gonadal function. Together with the follicle-stimulating hormone (FSH) and thyroid stimulating hormone (TSH) receptors, the LH receptor forms the family of glycoprotein hormone receptors. All glycoprotein ho

  19. Steroid Hormone Receptor Signals as Prognosticators for Urothelial Tumor

    Directory of Open Access Journals (Sweden)

    Hiroki Ide

    2015-01-01

    Full Text Available There is a substantial amount of preclinical or clinical evidence suggesting that steroid hormone receptor-mediated signals play a critical role in urothelial tumorigenesis and tumor progression. These receptors include androgen receptor, estrogen receptors, glucocorticoid receptor, progesterone receptor, vitamin D receptor, retinoid receptors, peroxisome proliferator-activated receptors, and others including orphan receptors. In particular, studies using urothelial cancer tissue specimens have demonstrated that elevated or reduced expression of these receptors as well as alterations of their upstream or downstream pathways correlates with patient outcomes. This review summarizes and discusses available data suggesting that steroid hormone receptors and related signals serve as biomarkers for urothelial carcinoma and are able to predict tumor recurrence or progression.

  20. Multiple exportins influence thyroid hormone receptor localization.

    Science.gov (United States)

    Subramanian, Kelly S; Dziedzic, Rose C; Nelson, Hallie N; Stern, Mary E; Roggero, Vincent R; Bondzi, Cornelius; Allison, Lizabeth A

    2015-08-15

    The thyroid hormone receptor (TR) undergoes nucleocytoplasmic shuttling and regulates target genes involved in metabolism and development. Previously, we showed that TR follows a CRM1/calreticulin-mediated nuclear export pathway. However, two lines of evidence suggest TR also follows another pathway: export is only partially blocked by leptomycin B (LMB), a CRM1-specific inhibitor; and we identified nuclear export signals in TR that are LMB-resistant. To determine whether other exportins are involved in TR shuttling, we used RNA interference and fluorescence recovery after photobleaching shuttling assays in transfected cells. Knockdown of exportins 4, 5, and 7 altered TR shuttling dynamics, and when exportins 5 and 7 were overexpressed, TR distribution shifted toward the cytosol. To further assess the effects of exportin overexpression, we examined transactivation of a TR-responsive reporter gene. Our data indicate that multiple exportins influence TR localization, highlighting a fine balance of nuclear import, retention, and export that modulates TR function.

  1. Effects of retinoic acid on growth hormone-releasing hormone receptor, growth hormone secretagogue receptor gene expression and growth hormone secretion in rat anterior pituitary cells.

    Science.gov (United States)

    Maliza, Rita; Fujiwara, Ken; Tsukada, Takehiro; Azuma, Morio; Kikuchi, Motoshi; Yashiro, Takashi

    2016-06-30

    Retinoic acid (RA) is an important signaling molecule in embryonic development and adult tissue. The actions of RA are mediated by the nuclear receptors retinoic acid receptor (RAR) and retinoid X receptor (RXR), which regulate gene expression. RAR and RXR are widely expressed in the anterior pituitary gland. RA was reported to stimulate growth hormone (GH) gene expression in the anterior pituitary cells. However, current evidence is unclear on the role of RA in gene expression of growth hormone-releasing hormone receptor (Ghrh-r), growth hormone secretagogue receptor (Ghs-r) and somatostatin receptors (Sst-rs). Using isolated anterior pituitary cells of rats, we examined the effects of RA on gene expression of these receptors and GH release. Quantitative real-time PCR revealed that treatment with all-trans retinoic acid (ATRA; 10(-6) M) for 24 h increased gene expression levels of Ghrh-r and Ghs-r; however, expressions of Sst-r2 and Sst-r5 were unchanged. Combination treatment with the RAR-agonist Am80 and RXR-agonist PA024 mimicked the effects of ATRA on Ghrh-r and Ghs-r gene expressions. Exposure of isolated pituitary cells to ATRA had no effect on basal GH release. In contrast, ATRA increased growth hormone-releasing hormone (GHRH)- and ghrelin-stimulated GH release from cultured anterior pituitary cells. Our results suggest that expressions of Ghrh-r and Ghs-r are regulated by RA through the RAR-RXR receptor complex and that RA enhances the effects of GHRH and ghrelin on GH release from the anterior pituitary gland.

  2. Introduction to the general principles of hormone-receptor interactions.

    Science.gov (United States)

    Levey, G S; Robinson, A G

    1982-07-01

    This review presents a concise overview of the historical development of receptor theory and the molecular mechanisms of action of the three broad classes of hormones, steroids, tyrosine derivatives, and polypeptides. Key terms required for understanding the basic terminology and concepts currently utilized in membrane receptor research are defined. The basic information should enable the reader to critically assess and understand more detailed discussions of hormone-receptor interactions and their application to clinical medicine.

  3. Fast evolution of growth hormone receptor in primates and ruminants

    Institute of Scientific and Technical Information of China (English)

    HOU Zhenfang; LI Ying; ZHANG Yaping

    2005-01-01

    Pituitary growth hormone (GH) evolves very slowly in most of mammals, but the evolutionary rates appear to have increased markedly on two occasions during the evolution of primates and ruminants. To investigate the evolutionary pattern of growth hormone receptor (GHR), we sequenced the extracellular domain of GHR genes from four primate species. Our results suggested that GHR in mammal also shows an episodic evolutionary pattern, which is consistent with that observed in pituitary growth hormone. Further analysis suggested that this pattern of rapid evolution observed in primates and ruminants is likely the result of coevolution between pituitary growth hormone and its receptor.

  4. The reciprocal regulation of stress hormones and GABAA receptors

    Directory of Open Access Journals (Sweden)

    Istvan eMody

    2012-01-01

    Full Text Available Stress-derived steroid hormones regulate the expression and function of GABAA receptors (GABAARs. Changes in GABAAR subunit expression have been demonstrated under conditions of altered steroid hormone levels, such as stress, as well as following exogenous steroid hormone administration. In addition to the effects of stress-derived steroid hormones on GABAAR subunit expression, stress hormones can also be metabolized to neuroactive derivatives which can alter the function of GABAARs. Neurosteroids allosterically modulate GABAARs at concentrations comparable to those during stress. In addition to the actions of stress-derived steroid hormones on GABAARs, GABAARs reciprocally regulate the production of stress hormones. The stress response is mediated by the hypothalamic-pituitary-adrenal (HPA axis, the activity of which is governed by corticotropin releasing hormone (CRH neurons. The activity of CRH neurons is largely controlled by robust GABAergic inhibition. Recently, it has been demonstrated that CRH neurons are regulated by neurosteroid-sensitive, GABAAR δ subunit-containing receptors representing a novel feedback mechanism onto the HPA axis. Further, it has been demonstrated that neurosteroidogenesis and neurosteroid actions on GABAAR δ subunit-containing receptors on CRH neurons are necessary to mount the physiological response to stress. Here we review the literature describing the effects of steroid hormones on GABAARs as well as the importance of GABAARs in regulating the production of steroid hormones. This review incorporates what we currently know about changes in GABAARs following stress and the role in HPA axis regulation.

  5. Cloning of partial putative gonadotropin hormone receptor sequence from fish

    Indian Academy of Sciences (India)

    G Kumaresan; T Venugopal; A Vikas; T J Pandian; S M Athavan

    2000-03-01

    A search for the presence of mariner-like elements in the Labeo rohita genome by polymerase chain reaction led to the amplification of a partial DNA sequence coding for a putative transmembrane domain of gonadotropin hormone receptor. The amplified DNA sequence shows a high degree of homology to the available turkey and human luteinizing and follicle stimulating hormone receptor coding sequences. This is the first report on cloning such sequences of piscine origin.

  6. Thyroid Hormone Receptor alpha Modulates Lipopolysaccharide-Induced Changes in Peripheral Thyroid Hormone Metabolism

    NARCIS (Netherlands)

    J. Kwakkel; O. Chassande; H.C. van Beeren; E. Fliers; W.M. Wiersinga; A. Boelen

    2010-01-01

    Acute inflammation is characterized by low serum T-3 and T-4 levels accompanied by changes in liver type 1 deiodinase (D1), liver D3, muscle D2, and muscle D3 expression. It is unknown at present whether thyroid hormone receptor alpha (TR alpha) plays a role in altered peripheral thyroid hormone met

  7. Adrenergic receptor control mechanism for growth hormone secretion.

    Science.gov (United States)

    Blackard, W G; Heidingsfelder, S A

    1968-06-01

    The influence of catecholamines on growth hormone secretion has been difficult to establish previously, possibly because of the suppressive effect of the induced hyperglycemia on growth hormone concentrations. In this study, an adrenergic receptor control mechanism for human growth hormone (HGH) secretion was uncovered by studying the effects of alpha and beta receptor blockade on insulin-induced growth hormone elevations in volunteer subjects. Alpha adrenergic blockade with phentolamine during insulin hypoglycemia, 0.1 U/kg, inhibited growth hormon elevations to 30-50% of values in the same subjects during insulin hypoglycemia without adrenergic blockade. More complete inhibition by phentolamine could not be demonstrated at a lower dose of insulin (0.05 U/kg). Beta adrenergic blockade with propranolol during insulin hypoglycemia significantly enhanced HGH concentrations in paired experiments. The inhibiting effect of alpha adrenergic receptor blockade on HGH concentrations could not be attributed to differences in blood glucose or free fatty acid values; however, more prolonged hypoglycemia and lower plasma free fatty acid values may have been a factor in the greater HGH concentrations observed during beta blockade. In the absence of insulin induced hypoglycemia, neither alpha nor beta adrenergic receptor blockade had a detectable effect on HGH concentrations. Theophylline, an inhibitor of cyclic 3'5'-AMP phosphodiesterase activity, also failed to alter plasma HGH concentrations. These studies demonstrate a stimulatory effect of alpha receptors and a possible inhibitory effect of beta receptors on growth hormone secretion.

  8. Structural Basis for Antibody Discrimination between Two Hormones That Recognize the Parathyroid Hormone Receptor

    Energy Technology Data Exchange (ETDEWEB)

    McKinstry, William J.; Polekhina, Galina; Diefenbach-Jagger, Hannelore; Ho, Patricia W.M.; Sato, Koh; Onuma, Etsuro; Gillespie, Matthew T.; Martin, T. John; Parker, Michael W.; (SVIMR-A); (Chugai); (Melbourne)

    2009-08-18

    Parathyroid hormone-related protein (PTHrP) plays a vital role in the embryonic development of the skeleton and other tissues. When it is produced in excess by cancers it can cause hypercalcemia, and its local production by breast cancer cells has been implicated in the pathogenesis of bone metastasis formation in that disease. Antibodies have been developed that neutralize the action of PTHrP through its receptor, parathyroid hormone receptor 1, without influencing parathyroid hormone action through the same receptor. Such neutralizing antibodies against PTHrP are therapeutically effective in animal models of the humoral hypercalcemia of malignancy and of bone metastasis formation. We have determined the crystal structure of the complex between PTHrP (residues 1-108) and a neutralizing monoclonal anti-PTHrP antibody that reveals the only point of contact is an {alpha}-helical structure extending from residues 14-29. Another striking feature is that the same residues that interact with the antibody also interact with parathyroid hormone receptor 1, showing that the antibody and the receptor binding site on the hormone closely overlap. The structure explains how the antibody discriminates between the two hormones and provides information that could be used in the development of novel agonists and antagonists of their common receptor.

  9. Coherence between biosynthesis, storage, and release of adipokinetic hormones

    NARCIS (Netherlands)

    Harthoorn, Leunis Forrinus

    2002-01-01

    In insects, specific parts of the retrocerebral complex are essential for homeostatic control in response to changes in both internal and external environments. Neuroendocrine cells in the glandular part of the coprus cardiacum of Locusta migratoria represent the site of synthesis and release of thr

  10. Diverse growth hormone receptor gene mutations in Laron syndrome.

    OpenAIRE

    Berg, M.A.; Argente, J.; Chernausek, S; Gracia, R.; Guevara-Aguirre, J; Hopp, M; Pérez-Jurado, L; Rosenbloom, A; Toledo,S.P.; Francke, U.

    1993-01-01

    To better understand the molecular genetic basis and genetic epidemiology of Laron syndrome (growth-hormone insensitivity syndrome), we analyzed the growth-hormone receptor (GHR) genes of seven unrelated affected individuals from the United States, South America, Europe, and Africa. We amplified all nine GHR gene exons and splice junctions from these individuals by PCR and screened the products for mutations by using denaturing gradient gel electrophoresis (DGGE). We identified a single GHR g...

  11. Evolution of the AKH/corazonin/ACP/GnRH receptor superfamily and their ligands in the Protostomia

    DEFF Research Database (Denmark)

    Hauser, Frank; Grimmelikhuijzen, Cornelis

    2014-01-01

    In this review we trace the evolutionary connections between GnRH receptors from vertebrates and the receptors for adipokinetic hormone (AKH), AKH/corazonin-related peptide (ACP), and corazonin from arthropods. We conclude that these G protein-coupled receptors (GPCRs) are closely related and have...... limpet Lottia gigantea (pQIHFSPTWGSamide), the oyster Crassostrea gigas (pQVSFSTNWGSamide), and the freshwater pearl mussel Hyriopsis cumingii (pQISFSTNWGSamide). We also found AKHs in the tardigrade Hysibius dujardini (pQLSFTGWGHamide), the rotifer Brachionus calycifloros (p...

  12. Receptors for thyrotropin-releasing hormone, thyroid-stimulating hormone, and thyroid hormones in the macaque uterus: effects of long-term sex hormone treatment.

    Science.gov (United States)

    Hulchiy, Mariana; Zhang, Hua; Cline, J Mark; Hirschberg, Angelica Lindén; Sahlin, Lena

    2012-11-01

    Thyroid gland dysfunction is associated with menstrual cycle disturbances, infertility, and increased risk of miscarriage, but the mechanisms are poorly understood. However, little is known about the regulation of these receptors in the uterus. The aim of this study was to determine the effects of long-term treatment with steroid hormones on the expression, distribution, and regulation of the receptors for thyrotropin-releasing hormone (TRHR) and thyroid-stimulating hormone (TSHR), thyroid hormone receptor α1/α2 (THRα1/α2), and THRβ1 in the uterus of surgically menopausal monkeys. Eighty-eight cynomolgus macaques were ovariectomized and treated orally with conjugated equine estrogens (CEE; n = 20), a combination of CEE and medroxyprogesterone acetate (MPA; n = 20), or tibolone (n = 28) for 2 years. The control group (OvxC; n = 20) received no treatment. Immunohistochemistry was used to evaluate the protein expression and distribution of the receptors in luminal epithelium, glands, stroma, and myometrium of the uterus. Immunostaining of TRHR, TSHR, and THRs was detected in all uterine compartments. Epithelial immunostaining of TRHR was down-regulated in the CEE + MPA group, whereas in stroma, both TRHR and TSHR were increased by CEE + MPA treatment as compared with OvxC. TRHR immunoreactivity was up-regulated, but THRα and THRβ were down-regulated, in the myometrium of the CEE and CEE + MPA groups. The thyroid-stimulating hormone level was higher in the CEE and tibolone groups as compared with OvxC, but the level of free thyroxin did not differ between groups. All receptors involved in thyroid hormone function are expressed in monkey uterus, and they are all regulated by long-term steroid hormone treatment. These findings suggest that there is a possibility of direct actions of thyroid hormones, thyroid-stimulating hormone and thyrotropin-releasing hormone on uterine function.

  13. Model for growth hormone receptor activation based on subunit rotation within a receptor dimer

    Energy Technology Data Exchange (ETDEWEB)

    Brown, Richard J.; Adams, Julian J.; Pelekanos, Rebecca A.; Wan, Yu; McKinstry, William J.; Palethorpe, Kathryn; Seeber, Ruth M.; Monks, Thea A.; Eidne, Karin A.; Parker, Michael W.; Waters, Michael J. (UWA); (St. Vincent); (Queensland)

    2010-07-13

    Growth hormone is believed to activate the growth hormone receptor (GHR) by dimerizing two identical receptor subunits, leading to activation of JAK2 kinase associated with the cytoplasmic domain. However, we have reported previously that dimerization alone is insufficient to activate full-length GHR. By comparing the crystal structure of the liganded and unliganded human GHR extracellular domain, we show here that there is no substantial change in its conformation on ligand binding. However, the receptor can be activated by rotation without ligand by inserting a defined number of alanine residues within the transmembrane domain. Fluorescence resonance energy transfer (FRET), bioluminescence resonance energy transfer (BRET) and coimmunoprecipitation studies suggest that receptor subunits undergo specific transmembrane interactions independent of hormone binding. We propose an activation mechanism involving a relative rotation of subunits within a dimeric receptor as a result of asymmetric placement of the receptor-binding sites on the ligand.

  14. [Effects of steroid hormones on nicotinic acetylcholine receptor channel kinetics].

    Science.gov (United States)

    Nurowska, E; Dworakowska, B; Dołowy, K

    2000-01-01

    Classically steroid hormones acts through genomic mechanism. In the last period there is more evidence that some steroid hormones exert fast (in order of seconds) effects on membrane receptors. In the presented work we analysed the effects of some steroid hormones on muscle acetylcholine receptor (AChR) channel kinetics. We divided steroid hormone on two groups which exert different effects. The first group including hydrocortisone (HC), corticosterone (COR), dexamethasone decrease the mean open time increasing the number of openings in bursts. The effects do not depend on agonist concentration. Some effects of HC and COR are voltage-dependent. The mechanism of such voltage dependent action caused by steroids hormones that are uncharged molecules, is unknown. Some experiments suggest however that an agonist molecule is involved in the mechanism of steroid action. The second group consists of progesterone, some of its derivatives and deoxycorticosterone. For this group the most evident effect was decrease in the probability of openings without a decrease in the mean open time. The effect depends on agonist concentration, suggesting an involvement of an agonist molecule in the mechanism. For this hormones an involvement of an charged agonist molecule does not however induce a voltage dependency. Most probably two groups of steroids acts on different part of the AChR. The localization of a steroid action site can be crucial for inducing voltage dependency.

  15. Thyroid hormone receptors regulate adipogenesis and carcinogenesis via crosstalk signaling with peroxisome proliferator-activated receptors

    Science.gov (United States)

    Lu, Changxue; Cheng, Sheue-Yann

    2012-01-01

    Peroxisome proliferator-activated receptors (PPARs) and thyroid hormone receptors (TRs) are members of the nuclear receptor superfamily. They are ligand-dependent transcription factors that interact with their cognate hormone response elements in the promoters to regulate respective target gene expression to modulate cellular functions. While the transcription activity of each is regulated by their respective ligands, recent studies indicate that via multiple mechanisms PPARs and TRs crosstalk to affect diverse biological functions. Here, we review recent advances in the understanding of the molecular mechanisms and biological impact of crosstalk between these two important nuclear receptors, focusing on their roles in adipogenesis and carcinogenesis. PMID:19741045

  16. Thyroid hormone receptors regulate adipogenesis and carcinogenesis via crosstalk signaling with peroxisome proliferator-activated receptors.

    Science.gov (United States)

    Lu, Changxue; Cheng, Sheue-Yann

    2010-03-01

    Peroxisome proliferator-activated receptors (PPARs) and thyroid hormone receptors (TRs) are members of the nuclear receptor superfamily. They are ligand-dependent transcription factors that interact with their cognate hormone response elements in the promoters to regulate respective target gene expression to modulate cellular functions. While the transcription activity of each is regulated by their respective ligands, recent studies indicate that via multiple mechanisms PPARs and TRs crosstalk to affect diverse biological functions. Here, we review recent advances in the understanding of the molecular mechanisms and biological impact of crosstalk between these two important nuclear receptors, focusing on their roles in adipogenesis and carcinogenesis.

  17. Growth hormone action in rat insulinoma cells expressing truncated growth hormone receptors

    DEFF Research Database (Denmark)

    Møldrup, Annette; Allevato, G; Dyrberg, Thomas

    1991-01-01

    Transfection of the insulin-producing rat islet tumor cell line RIN-5AH with a full length cDNA of the rat hepatic growth hormone (GH) receptor (GH-R1-638) augments the GH-responsive insulin synthesis in these cells. Using this functional system we analyzed the effect of COOH-terminal truncation...

  18. Neither bovine somatotropin nor growth hormone-releasing factor alters expression of thyroid hormone receptors in liver and mammary tissues.

    Science.gov (United States)

    Capuco, A V; Binelli, M; Tucker, H A

    2011-10-01

    Physiological effects of thyroid hormones are mediated primarily by binding of triiodothyronine to specific nuclear receptors. Organ-specific changes in production of triiodothyronine from its prohormone, thyroxine, have been hypothesized to target the action of thyroid hormones on the mammary gland and play a role in mediating or augmenting a galactopoietic response to bovine somatotropin (bST). Additionally, tissue responsiveness to thyroid hormones may be altered by changes in the number or affinity of nuclear receptors for thyroid hormones. In the present study, effects of bST and bovine growth hormone-releasing factor (bGRF) on thyroid hormone receptors in liver and mammary gland were studied. Lactating Holstein cows received continuous infusions of bST or bGRF for 63 d or served as uninfused controls. Nuclei were isolated from harvested mammary and liver tissues and incubated with [(125)I]-triiodothyronine. Treatments did not alter the capacity or affinity of specific binding sites for triiodothyronine in liver or mammary nuclei. Evaluation of transcript abundance for thyroid hormone receptors showed that isoforms of thyroid hormone receptor or retinoid receptor (which may influence thyroid receptor action) expressed in the mammary gland were not altered by bST or bGRF treatment. Data do not support the hypothesis that administration of bST or bGRF alters sensitivity of mammary tissue by changing expression of thyroid hormone receptors.

  19. The Growth Hormone Secretagogue Receptor: Its Intracellular Signaling and Regulation

    Directory of Open Access Journals (Sweden)

    Yue Yin

    2014-03-01

    Full Text Available The growth hormone secretagogue receptor (GHSR, also known as the ghrelin receptor, is involved in mediating a wide variety of biological effects of ghrelin, including: stimulation of growth hormone release, increase of food intake and body weight, modulation of glucose and lipid metabolism, regulation of gastrointestinal motility and secretion, protection of neuronal and cardiovascular cells, and regulation of immune function. Dependent on the tissues and cells, activation of GHSR may trigger a diversity of signaling mechanisms and subsequent distinct physiological responses. Distinct regulation of GHSR occurs at levels of transcription, receptor interaction and internalization. Here we review the current understanding on the intracellular signaling pathways of GHSR and its modulation. An overview of the molecular structure of GHSR is presented first, followed by the discussion on its signaling mechanisms. Finally, potential mechanisms regulating GHSR are reviewed.

  20. Primary structure of a novel neuropeptide isolated from the corpora cardiaca of periodical cicadas having adipokinetic and hypertrehalosemic activities.

    Science.gov (United States)

    Raina, A; Pannell, L; Kochansky, J; Jaffe, H

    1995-09-01

    A new neuropeptide hormone was isolated from the corpora cardiaca of the periodical cicadas, Magicicada species. Primary structure of the peptide as determined by a combination of automated Edman degradation after enzymatic deblocking with pyroglutamate aminopeptidase and mass spectrometry is: pGlu-Val-Asn-Phe-Ser-Pro-Ser-Trp-Gly-Asn-NH2. Synthetic peptide assayed in the green stink bug Nezara viridula caused a 112% increase in hemolymph lipids at a dose of 0.625 pmol, and a 67% increase in hemolymph carbohydrates at a dose of 2.5 pmol. Based on these results we designate this peptide, a first from order Homoptera, as Magicicada species-adipokinetic hormone (Mcsp-AKH).

  1. Nanostructured sensors containing immobilized nuclear receptors for thyroid hormone detection.

    Science.gov (United States)

    Bendo, Luana; Casanova, Monise; Figueira, Ana Carolina M; Polikarpov, Igor; Zucolotto, Valtencir

    2014-05-01

    Thyroid hormone receptors (TRs) are members of the nuclear receptors (NRs) superfamily, being encoded by two genes: TRa and TRbeta. In this paper, the ligand-binding domain (LBD) of the TRbeta1 isoform was immobilized on the surface of nanostructured electrodes for TR detection. The platforms containing TRbeta1-LBD were applied to the detection of specific ligand agonists, including the natural hormones T3 (triiodothyronine) and T4 (thyroxine), and the synthetic agonists TRIAC (3,5,3'-triiodothyroacetic acid) and GC-1 [3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl phenoxy) acetic acid]. Detection was performed via impedance spectroscopy. The biosensors were capable of distinguishing between the thyroid hormones T3 and T4, and/or the analogues TRIAC and GC-1 at concentrations as low as 50 nM. The detection and separation of thyroid hormones and analogue ligands by impedance techniques represents an innovative tool in the field of nanomedicine because it allows the design of inexpensive devices for the rapid and real-time detection of distinct ligand/receptor systems.

  2. Expression of functional growth hormone receptor in a mouse L cell line infected with recombinant vaccinia virus

    NARCIS (Netherlands)

    Strous, G J; van Kerkhof, P; Verheijen, C; Rossen, J W; Liou, W; Slot, J W; Roelen, C A; Schwartz, A L

    1994-01-01

    The growth hormone receptor is a member of a large family of receptors including the receptors for prolactin and interleukins. Upon binding to one molecule of growth hormone two growth hormone receptor polypeptides dimerize. We have expressed the rabbit growth hormone receptor DNA in transfected mou

  3. Resistance to Thyroid Hormone due to defective thyroid receptor alpha

    OpenAIRE

    Moran, Carla; Chatterjee, Krishna

    2015-01-01

    This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.beem.2015.07.007 Thyroid hormones act via nuclear receptors (TRα1, TRβ1, TRβ2) with differing tissue distribution; the role of α2 protein, derived from the same gene locus as TRα1, is unclear. Resistance to thyroid hormone alpha (RTHα) is characterised by tissue-specific hypothyroidism associated with near-normal thyroid function tests. Clinical features include dysmorphic facies, ...

  4. Steroidal Hormone Receptor Expression in Male Breast Cancer

    Directory of Open Access Journals (Sweden)

    Fatemeh Homaei-Shandiz

    2014-01-01

    Full Text Available Introduction: The etiology of male breast cancer is unclear, but hormonal levels may play a role in development of this disease. It seems that the risk of male breast cancer related to increased lifelong exposure to estrogen or reduced androgen. The aim of this study was to investigate the expression of the steroid hormone receptors including estrogen receptor (ER and progesterone receptor (PR in Iranian cases with male breast cancer. Methods: This is a prospective review of 18 cases of male breast cancer in in Omid Hospital, Mashhad, North East of Iran, between October 2001 and October 2006. ER and PR were measured by immunohistochemistry. Clinicopathologic features and family history were obtained by interview. Data were analyzed with SPSS 13 using descriptive statistics.  Results: The median age was 63.2 year. All the cases were infiltrating ductal carcinoma. A high rate of expression of ER (88.8% and PR (66.6% was found in the studied cases. Conclusion: Cancers of the male breast are significantly more likely than cancers of the female breast to express hormonal receptors.

  5. Thyroid hormones and thyroid hormone receptors: Effects of thyromimetics on reverse cholesterol transport

    Institute of Scientific and Technical Information of China (English)

    Matteo; Pedrelli; Camilla; Pramfalk; Paolo; Parini

    2010-01-01

    Reverse cholesterol transport (RCT) is a complex process which transfers cholesterol from peripheral cells to the liver for subsequent elimination from the body via feces. Thyroid hormones (THs) affect growth, develop- ment, and metabolism in almost all tissues. THs exert their actions by binding to thyroid hormone receptors (TRs). There are two major subtypes of TRs, TRα and TRβ, and several isoforms (e.g. TRα1, TRα2, TRβ1, and TRβ2). Activation of TRα1 affects heart rate, whereas activation of TRβ1 has po...

  6. Immunohistochemical localization of sex hormone receptors in two Raillietina tapeworms.

    Science.gov (United States)

    Chen, L; Sun, Y M; Mu, L; Zeng, Y; Li, H Y; Yang, T H

    2017-03-08

    Sex hormone receptors play critical roles in development and reproduction. However, it is not known whether they exist in Raillietina tapeworms, and if they do, whether they have a similar function to that in vertebrates. We examined the immunohistochemical distributions of androgen receptors (ARs), estrogen receptors (ERs), and progesterone receptors (PRs) in the tissues of two tapeworm species: Raillietina echinobothrida and Raillietina tetragona. Immunopositive ARs were found in the entire reproductive system of R. echinobothrida, including the testes, ovaries, and oocysts, and weakly immunopositive ERs and PRs were found in the testes, ovaries, and oocysts. Immunopositive ARs were also found throughout the entire reproductive system of R. tetragona, including the testes, ovaries, and oocysts, and weakly immunopositive ERs were in the testes and oocysts; the PRs were distributed in an immunonegative manner. The results show that androgens and their receptors play critical roles in reproductive system development in the two tapeworms. The immunoreactivity and tissue localizations of the sex hormone receptors suggest that, in both species, they have similar functions as in vertebrates, and modulate reproduction.

  7. Sex Hormones and Their Receptors Regulate Liver Energy Homeostasis

    Directory of Open Access Journals (Sweden)

    Minqian Shen

    2015-01-01

    Full Text Available The liver is one of the most essential organs involved in the regulation of energy homeostasis. Hepatic steatosis, a major manifestation of metabolic syndrome, is associated with imbalance between lipid formation and breakdown, glucose production and catabolism, and cholesterol synthesis and secretion. Epidemiological studies show sex difference in the prevalence in fatty liver disease and suggest that sex hormones may play vital roles in regulating hepatic steatosis. In this review, we summarize current literature and discuss the role of estrogens and androgens and the mechanisms through which estrogen receptors and androgen receptors regulate lipid and glucose metabolism in the liver. In females, estradiol regulates liver metabolism via estrogen receptors by decreasing lipogenesis, gluconeogenesis, and fatty acid uptake, while enhancing lipolysis, cholesterol secretion, and glucose catabolism. In males, testosterone works via androgen receptors to increase insulin receptor expression and glycogen synthesis, decrease glucose uptake and lipogenesis, and promote cholesterol storage in the liver. These recent integrated concepts suggest that sex hormone receptors could be potential promising targets for the prevention of hepatic steatosis.

  8. Hormonal regulation of AMPA receptor trafficking and memory formation

    Directory of Open Access Journals (Sweden)

    Harmen J Krugers

    2009-10-01

    Full Text Available Humans and rodents retain memories for stressful events very well. The facilitated retention of these memories is normally very useful. However, in susceptible individuals a variety of pathological conditions may develop in which memories related to stressful events remain inappropriately present, such as in post-traumatic stress disorder. The memory enhancing effects of stress are mediated by hormones, such as norepinephrine and glucocorticoids which are released during stressful experiences. Here we review recently identified molecular mechanisms that underlie the effects of stress hormones on synaptic efficacy and learning and memory. We discuss AMPA receptors as major target for stress hormones and describe a model in which norepinephrine and glucocorticoids are able to strengthen and prolong different phases of stressful memories.

  9. Osteopontin negatively regulates parathyroid hormone receptor signaling in osteoblasts.

    Science.gov (United States)

    Ono, Noriaki; Nakashima, Kazuhisa; Rittling, Susan R; Schipani, Ernestina; Hayata, Tadayoshi; Soma, Kunimichi; Denhardt, David T; Kronenberg, Henry M; Ezura, Yoichi; Noda, Masaki

    2008-07-11

    Systemic hormonal control exerts its effect through the regulation of local target tissues, which in turn regulate upstream signals in a feedback loop. The parathyroid hormone (PTH) axis is a well defined hormonal signaling system that regulates calcium levels and bone metabolism. To understand the interplay between systemic and local signaling in bone, we examined the effects of deficiency of the bone matrix protein osteopontin (OPN) on the systemic effects of PTH specifically within osteoblastic cell lineages. Parathyroid hormone receptor (PPR) transgenic mice expressing a constitutively active form of the receptor (caPPR) specifically in cells of the osteoblast lineage have a high bone mass phenotype. In these mice, OPN deficiency further increased bone mass. This increase was associated with conversion of the major intertrabecular cell population from hematopoietic cells to stromal/osteoblastic cells and parallel elevations in histomorphometric and biochemical parameters of bone formation and resorption. Treatment with small interfering RNA (siRNA) for osteopontin enhanced H223R mutant caPPR-induced cAMP-response element (CRE) activity levels by about 10-fold. Thus, in addition to the well known calcemic feedback system for PTH, local feedback regulation by the bone matrix protein OPN also plays a significant role in the regulation of PTH actions.

  10. Estrogen and Progesterone hormone receptor expression in oral cavity cancer

    Science.gov (United States)

    Biegner, Thorsten; Teriete, Peter; Hoefert, Sebastian; Krimmel, Michael; Munz, Adelheid; Reinert, Siegmar

    2016-01-01

    Background Recent studies have shown an increase in the incidence of oral squamous cell carcinoma (OSCC) in younger patients. The hypothesis that tumors could be hormonally induced during pregnancy or in young female patients without the well-known risk factors alcohol or tobacco abuse seems to be plausible. Material and Methods Estrogen Receptor alpha (ERα) and Progesterone Receptor (PR) expression were analyzed in normal oral mucosa (n=5), oral precursor lesions (simple hyperplasia, n=11; squamous intraepithelial neoplasia, SIN I-III, n=35), and OSCC specimen. OSCCs were stratified in a young female (n=7) study cohort and older patients (n=46). In the young female study cohort three patients (n=3/7) developed OSCC during or shortly after pregnancy. Breast cancer tissues were used as positive control for ERα and PR expression. Results ERα expression was found in four oral precursor lesions (squamous intraepithelial neoplasia, SIN I-III, n=4/35, 11%) and in five OSCC specimen (n=5/46, 11%). The five ERα positive OSCC samples were older male patients. All patients within the young female study cohort were negatively stained for both ERα and PR. Conclusions ER expression could be regarded as a seldom risk factor for OSCC. PR expression seems to be not relevant for the development of OSCC. Key words:Oral squamous cell carcinoma, estrogen receptor, progesterone receptor, hormone receptor. PMID:27475696

  11. Genetic models for the study of luteinizing hormone receptor function

    Directory of Open Access Journals (Sweden)

    Prema eNarayan

    2015-09-01

    Full Text Available The luteinizing hormone/chorionic gonadotropin receptor, LHCGR, is essential for fertility in men and women. LHCGR binds luteinizing hormone (LH as well as the highly homologous chorionic gonadotropin (CG. Signaling from LHCGR is required for steroidogenesis and gametogenesis in males and females and for sexual differentiation in the male. The importance of LHCGR in reproductive physiology is underscored by the large number of naturally occurring inactivating and activating mutations in the receptor that result in reproductive disorders. Consequently, several genetically modified mouse models have been developed for the study of LHCGR function. They include targeted deletion of LH and LHCGR that mimic inactivating mutations in hormone and receptor, expression of a constitutively active mutant in LHCGR that mimics activating mutations associated with familial male-limited precocious puberty and transgenic models of LH and hCG overexpression. This review summarizes the salient findings from these models and their utility in understanding the physiological and pathological consequences of loss and gain of function in LHCGR signaling.

  12. Expression of luteinizing hormone receptors in the mouse penis.

    Science.gov (United States)

    Kokk, Kersti; Kuuslahti, Marianne; Keisala, Tiina; Purmonen, Sami; Kaipia, Antti; Tammela, Teuvo; Orro, Helen; Simovart, Helle-Evi; Pöllänen, Pasi

    2011-01-01

    The role of luteinizing hormone (LH) in the regulation of normal reproductive functions in males and females is quite well established. Besides the expression of LH receptors in the target cells in gonads, it has been found in several extragonadal organs. There is no information about the expression of LH receptors in the penis up to now. The aim of the present study is to investigate the expression of the LH receptor in the mouse penis to see if LH effects are possible in the penis. BALB/c mice were used as donors of normal penis and testis tissue. Immunocytochemistry, Western blotting, and quantitative reverse transcriptase polymerase chain reactions (RT-PCRs) were used for the detection of the LH receptor. Positive immunoreaction for LH receptors was present in the nuclei of urethral epithelium and endothelial cells of cavernous spaces in the corpus cavernosum and corpus spongiosum penis. Western blotting experiments demonstrated the presence of LH antigen at M(r) = 97.4 and 78 kd. Quantitative RT-PCRs confirmed the expression of LH receptor in the penis. Our results show that LH receptor is expressed in the body of the mouse penis; thus, it may directly regulate functions of penile tissue.

  13. Radioiodination of chicken luteinizing hormone without affecting receptor binding potency

    Energy Technology Data Exchange (ETDEWEB)

    Kikuchi, M.; Ishii, S. (Waseda Univ., Tokyo (Japan))

    1989-12-01

    By improving the currently used lactoperoxidase method, we were able to obtain radioiodinated chicken luteinizing hormone (LH) that shows high specific binding and low nonspecific binding to a crude plasma membrane fraction of testicular cells of the domestic fowl and the Japanese quail, and to the ovarian granulosa cells of the Japanese quail. The change we made from the original method consisted of (1) using chicken LH for radioiodination that was not only highly purified but also retained a high receptor binding potency; (2) controlling the level of incorporation of radioiodine into chicken LH molecules by employing a short reaction time and low temperature; and (3) fractionating radioiodinated chicken LH further by gel filtration using high-performance liquid chromatography. Specific radioactivity of the final {sup 125}I-labeled chicken LH preparation was 14 microCi/micrograms. When specific binding was 12-16%, nonspecific binding was as low as 2-4% in the gonadal receptors. {sup 125}I-Labeled chicken LH was displaced by chicken LH and ovine LH but not by chicken follicle-stimulating hormone. The equilibrium association constant of quail testicular receptor was 3.6 x 10(9) M-1. We concluded that chicken LH radioiodinated by the present method is useful for studies of avian LH receptors.

  14. Effects of sex and pregnancy hormones on growth hormone and prolactin receptor gene expression in insulin-producing cells

    DEFF Research Database (Denmark)

    Møldrup, Annette; Petersen, Elisabeth D.; Nielsen, Jens Høiriis

    1993-01-01

    of islet cells to these hormones is regulated on the receptor level, GH and PRL receptor gene expression was studied in pancreata from male rats and virgin, pregnant, and lactating female rats and in cultured islets and insulinoma cells (RIN-5AH) in response to various hormones. The mRNA levels were...... quantitated by ribonuclease protection assay, using probes specific for mRNA encoding, extracellular and intracellular domains of the GH receptor, and short and long forms of the PRL receptor, respectively. Specific transcripts for the GH receptor were present in pancreas, islets, and RIN-5AH cells...

  15. Sex Steroid Hormone Receptor Expression Affects Ovarian Cancer Survival

    DEFF Research Database (Denmark)

    Jönsson, Jenny-Maria; Skovbjerg Arildsen, Nicolai; Malander, Susanne;

    2015-01-01

    BACKGROUND AND AIMS: Although most ovarian cancers express estrogen (ER), progesterone (PR), and androgen (AR) receptors, they are currently not applied in clinical decision making. We explored the prognostic impact of sex steroid hormone receptor protein and mRNA expression on survival...... in epithelial ovarian cancer. METHODS: Immunohistochemical stainings for ERα, ERβ, PR, and AR were assessed in relation to survival in 118 serous and endometrioid ovarian cancers. Expression of the genes encoding the four receptors was studied in relation to prognosis in the molecular subtypes of ovarian cancer...... in ovarian cancer and support that tumors should be stratified based on molecular as well as histological subtypes in future studies investigating the role of endocrine treatment in ovarian cancer....

  16. Androgen receptor gene mutations in hormone-refractory prostate cancer.

    Science.gov (United States)

    Wallén, M J; Linja, M; Kaartinen, K; Schleutker, J; Visakorpi, T

    1999-12-01

    Prostate cancer is considered to be one of the most hormone-dependent human malignancies. As a key mediator of hormonal response, the androgen receptor (AR) is believed to have an important role in the progression of prostate cancer. Mutations in the coding region of the AR gene have been found in both untreated and hormone-refractory prostate cancer, but the frequency of such mutations at different stages of the disease is poorly documented and even contradictory results have been published. In the present study, the frequency of AR gene mutations was determined in 30 locally recurrent and two metastatic hormone-refractory prostate tumours using the polymerase chain reaction (PCR), non-radioactive single strand conformation polymorphism (SSCP), and sequencing. The length of the polymorphic CAG repeat, which is inversely correlated with the ability of the AR to activate transcription, was also analysed as well as the GGC repeat. Twelve samples were known to contain an AR gene amplification. Altogether, one point mutation (Gly(674)-->Ala) and one microsatellite mutation (CAG(20)-->CAG(18)) were found, both in cancers containing the AR gene amplification. The mean lengths of the polymorphic CAG and GGC repeats were similar to those observed in the normal population. These results favour the view that mutations in the AR gene are rare in hormone-refractory prostate cancer and do not play an important role, at least, in local relapse. Instead, the amplification and consequent overexpression of the wild-type AR gene seem to be the most common alteration involving the AR in hormone-refractory prostate cancer.

  17. Growth hormone-dependent phosphorylation of tyrosine 333 and/or 338 of the growth hormone receptor

    DEFF Research Database (Denmark)

    VanderKuur, J A; Wang, X; Zhang, L

    1995-01-01

    Many signaling pathways initiated by ligands that activate receptor tyrosine kinases have been shown to involve the binding of SH2 domain-containing proteins to specific phosphorylated tyrosines in the receptor. Although the receptor for growth hormone (GH) does not contain intrinsic tyrosine...

  18. Discovery & development of small molecule allosteric modulators of glycoprotein hormone receptors

    Directory of Open Access Journals (Sweden)

    Selvaraj G Nataraja

    2015-09-01

    Full Text Available Glycoprotein hormones, follicle-stimulating hormone (FSH, luteinizing hormone (LH, and thyroid stimulating hormone (TSH are heterodimeric proteins with a common subunit and hormone-specific subunit. These hormones are dominant regulators of reproduction and metabolic processes. Receptors for the glycoprotein hormones belong to the family of G-protein coupled receptors (GPCR. FSH receptor (FSHR and LH receptor (LHR are primarily expressed in somatic cells in ovary and testis to promote egg and sperm production in women & men respectively. TSH receptor (TSHR is expressed in thyroid cells and regulates the secretion of T3 & T4. Glycoprotein hormones bind to the large extracellular domain of the receptor and cause a conformational change in the receptor that leads to activation of more than one intracellular signaling pathway. Several small molecules have been described to activate/inhibit glycoprotein hormone receptors through allosteric sites of the receptor. Small molecule allosteric modulators have the potential to be administered orally to patients thus improving the convenience of treatment. It has been a challenge to develop a small molecule allosteric agonist for glycoprotein hormones that can mimic the agonistic effects of the large natural ligand to activate similar signaling pathways. However, in the past few years, there have been several promising reports describing distinct chemical series with improved potency in preclinical models. In parallel, proposal of new structural model for FSH receptor and in silico docking studies of small molecule ligands to glycoprotein hormone receptors provide a giant leap on the understanding of the mechanism of action of the natural ligands and new chemical entities on the receptors. This review will focus on the current status of small molecule allosteric modulators of glycoprotein hormone receptors, their effects on common signaling pathways in cells, their utility for clinical

  19. NCBI nr-aa BLAST: CBRC-CBRI-01-0008 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CBRI-01-0008 ref|NP_001076809.1| adipokinetic hormone receptor [Tribolium cast...aneum] gb|ABE02225.1| adipokinetic hormone receptor [Tribolium castaneum] gb|ABN79650.1| adipokinetic hormone receptor [Tribolium castaneum] NP_001076809.1 4e-46 34% ...

  20. NCBI nr-aa BLAST: CBRC-AGAM-02-0026 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-AGAM-02-0026 ref|NP_001076809.1| adipokinetic hormone receptor [Tribolium cast...aneum] gb|ABE02225.1| adipokinetic hormone receptor [Tribolium castaneum] gb|ABN79650.1| adipokinetic hormone receptor [Tribolium castaneum] NP_001076809.1 5e-71 44% ...

  1. NCBI nr-aa BLAST: CBRC-CBRE-01-1475 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CBRE-01-1475 ref|NP_001076809.1| adipokinetic hormone receptor [Tribolium cast...aneum] gb|ABE02225.1| adipokinetic hormone receptor [Tribolium castaneum] gb|ABN79650.1| adipokinetic hormone receptor [Tribolium castaneum] NP_001076809.1 2e-29 32% ...

  2. NCBI nr-aa BLAST: CBRC-AGAM-02-0058 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-AGAM-02-0058 ref|NP_001076809.1| adipokinetic hormone receptor [Tribolium cast...aneum] gb|ABE02225.1| adipokinetic hormone receptor [Tribolium castaneum] gb|ABN79650.1| adipokinetic hormone receptor [Tribolium castaneum] NP_001076809.1 1e-112 60% ...

  3. Adherence and discontinuation of oral hormonal therapy in patients with hormone receptor positive breast cancer.

    Science.gov (United States)

    Ayres, Lorena Rocha; Baldoni, André de Oliveira; Borges, Anna Paula de Sá; Pereira, Leonardo Régis Leira

    2014-02-01

    Oral treatment in women with breast cancer has been increasingly used. However, a potentially negative side of oral medication is poor patient adherence and/or discontinuation, which reduces the treatment effectiveness, accelerating progression of the disease and reducing the patient survival rate. To compare the rates of adherence and/or discontinuation and the methodologies used to assess these outcomes. It was conducted an integrative review of original articles published from 2000 to 2012, in which their primary outcome was to quantify medication adherence and/or discontinuation of oral hormonal therapy in patients with hormone receptor positive breast cancer. Original studies were searched in the PubMed/MEDLINE, Scopus, Embase and SciELO databases. The Medical Subject Heading was used to define descriptors. The descriptor "breast neoplasms" was used in all combinations. Each of the descriptors "medication adherence" and "patient compliance" were combined with each of the following descriptors "tamoxifen", "aromatase inhibitors", "selective estrogen receptor modulators", or the terms "letrozole", "anastrozole", and "exemestane". Twenty-four original articles were included. Our study showed a wide range of adherence and discontinuation rates, ranging from 45-95.7 and 12-73 %, respectively. Regarding the methodological development of the selected articles, a high prevalence (87.5 %) of prospective and/or retrospective longitudinal studies was found. In addition, there was a high prevalence of studies using a database (70.8 %). Among some of the studies, it was shown that patient adherence to hormonal therapy gradually reduces, while discontinuation increases during the treatment. It was observed a great diversity among rates of adherence and/or discontinuation of hormonal therapy for breast cancer, which may be due to a lack of methodology standardization. Therefore, adequate and validated methods to ensure reliability of the results and allow comparison in the

  4. Neither bST nor Growth Hormone Releasing Factor Alter Expression of Thyroid Hormone Receptors in Liver and Mammary Tissues

    Science.gov (United States)

    Physiological effects of thyroid hormones are mediated primarily by binding of triiodothyronine, to specific nuclear receptors. It has been hypothesized that organ-specific changes in production of triiodothyronine from its prohormone, thyroxine, target the action of thyroid hormones to the mammary...

  5. Molecular cloning, genomic organization, and developmental regulation of a novel receptor from Drosophila melanogaster structurally related to members of the thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone/choriogonadotropin receptor family from mammals

    DEFF Research Database (Denmark)

    Hauser, F; Nothacker, H P; Grimmelikhuijzen, C J

    1997-01-01

    Using oligonucleotide probes derived from consensus sequences for glycoprotein hormone receptors, we have cloned an 831-amino acid residue-long receptor from Drosophila melanogaster that shows a striking structural homology with members of the glycoprotein hormone (thyroid-stimulating hormone (TSH...... until after pupation. Adult male flies express high levels of receptor mRNA, but female flies express about 6 times less. The expression pattern in embryos and larvae suggests that the receptor is involved in insect development. This is the first report on the molecular cloning of a glycoprotein hormone...

  6. Evolution of minimal specificity and promiscuity in steroid hormone receptors.

    Directory of Open Access Journals (Sweden)

    Geeta N Eick

    Full Text Available Most proteins are regulated by physical interactions with other molecules; some are highly specific, but others interact with many partners. Despite much speculation, we know little about how and why specificity/promiscuity evolves in natural proteins. It is widely assumed that specific proteins evolved from more promiscuous ancient forms and that most proteins' specificity has been tuned to an optimal state by selection. Here we use ancestral protein reconstruction to trace the evolutionary history of ligand recognition in the steroid hormone receptors (SRs, a family of hormone-regulated animal transcription factors. We resurrected the deepest ancestral proteins in the SR family and characterized the structure-activity relationships by which they distinguished among ligands. We found that that the most ancient split in SR evolution involved a discrete switch from an ancient receptor for aromatized estrogens--including xenobiotics--to a derived receptor that recognized non-aromatized progestagens and corticosteroids. The family's history, viewed in relation to the evolution of their ligands, suggests that SRs evolved according to a principle of minimal specificity: at each point in time, receptors evolved ligand recognition criteria that were just specific enough to parse the set of endogenous substances to which they were exposed. By studying the atomic structures of resurrected SR proteins, we found that their promiscuity evolved because the ancestral binding cavity was larger than the primary ligand and contained excess hydrogen bonding capacity, allowing adventitious recognition of larger molecules with additional functional groups. Our findings provide an historical explanation for the sensitivity of modern SRs to natural and synthetic ligands--including endocrine-disrupting drugs and pollutants--and show that knowledge of history can contribute to ligand prediction. They suggest that SR promiscuity may reflect the limited power of

  7. Evolution of minimal specificity and promiscuity in steroid hormone receptors.

    Science.gov (United States)

    Eick, Geeta N; Colucci, Jennifer K; Harms, Michael J; Ortlund, Eric A; Thornton, Joseph W

    2012-01-01

    Most proteins are regulated by physical interactions with other molecules; some are highly specific, but others interact with many partners. Despite much speculation, we know little about how and why specificity/promiscuity evolves in natural proteins. It is widely assumed that specific proteins evolved from more promiscuous ancient forms and that most proteins' specificity has been tuned to an optimal state by selection. Here we use ancestral protein reconstruction to trace the evolutionary history of ligand recognition in the steroid hormone receptors (SRs), a family of hormone-regulated animal transcription factors. We resurrected the deepest ancestral proteins in the SR family and characterized the structure-activity relationships by which they distinguished among ligands. We found that that the most ancient split in SR evolution involved a discrete switch from an ancient receptor for aromatized estrogens--including xenobiotics--to a derived receptor that recognized non-aromatized progestagens and corticosteroids. The family's history, viewed in relation to the evolution of their ligands, suggests that SRs evolved according to a principle of minimal specificity: at each point in time, receptors evolved ligand recognition criteria that were just specific enough to parse the set of endogenous substances to which they were exposed. By studying the atomic structures of resurrected SR proteins, we found that their promiscuity evolved because the ancestral binding cavity was larger than the primary ligand and contained excess hydrogen bonding capacity, allowing adventitious recognition of larger molecules with additional functional groups. Our findings provide an historical explanation for the sensitivity of modern SRs to natural and synthetic ligands--including endocrine-disrupting drugs and pollutants--and show that knowledge of history can contribute to ligand prediction. They suggest that SR promiscuity may reflect the limited power of selection within real

  8. The androgen receptor in hormone-refractory prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Hai-Lei Mao; Zhi-Qi Zhu; Charlie Degui Chen

    2009-01-01

    Advanced prostate cancer is responsive to hormone therapy that interferes with androgen receptor (AR) signalling.However,the effect is short-lived,as nearly all tumours progress to a hormone-refractory (HR) state,a lethal stage of the disease.Intuitively,the AR should not be involved because hormone therapy that blocks or reduces AR activity is not effective in treating HR turnouts.However,there is still a consensus that AR plays an essential role in HR prostate cancer (HRPC) because AR signalling is still functional in HR tumours.AR signalling can be activated in HR turnouts through several mechanisms.First,activation of intracellular signal transduction pathways can sensitize the AR to castrate levels of androgens.Also,mutations in the AR can change AR ligand specificity,thereby allowing it to be activated by non-steroids or anti-androgens.Finally,overexpression of the wild-type AR sensitizes itself to low concentrations of androgens.Therefore,drugs targeting AR signalling could still be effective in treating HRPC.

  9. Influence of estrogen receptor alpha and progesterone receptor polymorphisms on the effects of hormone therapy on mammographic density.

    NARCIS (Netherlands)

    Duijnhoven, F.J.B. van; Peeters, P.H.; Warren, R.M.; Bingham, S.; Uitterlinden, A.G.; Noord, P.A.H. van; Monninkhof, E.M.; Grobbee, D.E.; Gils, C.H. van

    2006-01-01

    Postmenopausal hormone therapy increases mammographic density, a strong breast cancer risk factor, but effects vary across women. We investigated whether the effect of hormone therapy use is modified by polymorphisms in the estrogen receptor (ESR1) and progesterone receptor (PGR) genes in the Dutch

  10. Genomic organization of a receptor from sea anemones, structurally and evolutionary related to glycoprotein hormone receptors from mamals

    DEFF Research Database (Denmark)

    Vibede, N; Hauser, Frank; Williamson, M

    1998-01-01

    glycoprotein hormone receptors, indicating that the cnidarian and mammalian receptor genes are evolutionarily related. As with the mammalian receptor genes, the sea anemone receptor gene does not contain introns in the region coding for the transmembrane and intracellular domains. Southern blot analyses show...

  11. The thyroid hormone receptors modulate the skin response to retinoids.

    Directory of Open Access Journals (Sweden)

    Laura García-Serrano

    Full Text Available BACKGROUND: Retinoids play an important role in skin homeostasis and when administered topically cause skin hyperplasia, abnormal epidermal differentiation and inflammation. Thyroidal status in humans also influences skin morphology and function and we have recently shown that the thyroid hormone receptors (TRs are required for a normal proliferative response to 12-O-tetradecanolyphorbol-13-acetate (TPA in mice. METHODOLOGY/PRINCIPAL FINDINGS: We have compared the epidermal response of mice lacking the thyroid hormone receptor binding isoforms TRα1 and TRβ to retinoids and TPA. Reduced hyperplasia and a decreased number of proliferating cells in the basal layer in response to 9-cis-RA and TPA were found in the epidermis of TR-deficient mice. Nuclear levels of proteins important for cell proliferation were altered, and expression of keratins 5 and 6 was also reduced, concomitantly with the decreased number of epidermal cell layers. In control mice the retinoid (but not TPA induced parakeratosis and diminished expression of keratin 10 and loricrin, markers of early and terminal epidermal differentiation, respectively. This reduction was more accentuated in the TR deficient animals, whereas they did not present parakeratosis. Therefore, TRs modulate both the proliferative response to retinoids and their inhibitory effects on skin differentiation. Reduced proliferation, which was reversed upon thyroxine treatment, was also found in hypothyroid mice, demonstrating that thyroid hormone binding to TRs is required for the normal response to retinoids. In addition, the mRNA levels of the pro-inflammatory cytokines TNFα and IL-6 and the chemotactic proteins S1008A and S1008B were significantly elevated in the skin of TR knock-out mice after TPA or 9-cis-RA treatment and immune cell infiltration was also enhanced. CONCLUSIONS/SIGNIFICANCE: Since retinoids are commonly used for the treatment of skin disorders, these results demonstrating that TRs

  12. The Neuroendocrine Functions of the Parathyroid Hormone 2 Receptor

    Directory of Open Access Journals (Sweden)

    Arpad eDobolyi

    2012-10-01

    Full Text Available The G-protein coupled parathyroid hormone 2 receptor (PTH2R is concentrated in endocrine and limbic regions in the forebrain. Its endogenous ligand,tuberoinfundibular peptide of 39 residues (TIP39, is synthesized in only 2 brain regions, within the posterior thalamus and the lateral pons. TIP39-expressing neurons have a widespread projection pattern, which matches the PTH2R distribution in the brain. Neuroendocrine centers including the preoptic area, the periventricular, paraventricular, and arcuate nuclei contain the highest density of PTH2R-positive networks. The administration of TIP39 and an antagonist of the PTH2R as well as the investigation of mice that lack functional TIP39 and PTH2R revealed the involvement of the PTH2R in a variety of neural and neuroendocrine functions. TIP39 acting via the PTH2R modulates several aspects of the stress response. It evokes corticosterone release by activating corticotropin-releasing hormone-containing neurons in the hypothalamic paraventricular nucleus. Block of TIP39 signaling elevates the anxiety state of animals and their fear response, and increases stress-induced analgesia. TIP39 has also been suggested to affect the release of additional pituitary hormones including arginine vasopressin and growth hormone. A role of the TIP39-PTH2R system in thermoregulation was also identified. TIP39 may play a role in maintaining body temperature in a cold environment via descending excitatory pathways from the preoptic area. Anatomical and functional studies also implicated the TIP39-PTH2R system in nociceptive information processing. Finally, TIP39 induced in postpartum dams may play a role in the release of prolactin during lactation. Potential mechanisms leading to the activation of TIP39 neurons and how they influence the neuroendocrine system are also described. The unique TIP39-PTH2R neuromodulator system provides the possibility for developing drugs with a novel mechanism of action to control

  13. Anti-idiotypic antibody: A new strategy for the development of a growth hormone receptor antagonist.

    Science.gov (United States)

    Lan, Hainan; Zheng, Xin; Khan, Muhammad Akram; Li, Steven

    2015-11-01

    In general, traditional growth hormone receptor antagonist can be divided into two major classes: growth hormone (GH) analogues and anti-growth hormone receptor (GHR) antibodies. Herein, we tried to explore a new class of growth hormone receptor (GHR) antagonist that may have potential advantages over the traditional antagonists. For this, we developed a monoclonal anti-idiotypic antibody growth hormone, termed CG-86. A series of experiments were conducted to characterize and evaluate this antibody, and the results from a competitive receptor-binding assay, Enzyme Linked Immunosorbent Assays (ELISA) and epitope mapping demonstrate that CG-86 behaved as a typical Ab2β. Next, we examined its antagonistic activity using in vitro cell models, and the results showed that CG-86 could effectively inhibit growth hormone receptor-mediated signalling and effectively inhibit growth hormone-induced Ba/F3-GHR638 proliferation. In summary, these studies show that an anti-idiotypic antibody (CG-86) has promise as a novel growth hormone receptor antagonist. Furthermore, the current findings also suggest that anti-idiotypic antibody may represent a novel strategy to produce a new class of growth hormone receptor antagonist, and this strategy may be applied with other cytokines or growth factors. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Unsaturated fatty acids prevent desensitization of the human growth hormone secretagogue receptor by blocking its internalization

    NARCIS (Netherlands)

    P.J.D. Delhanty (Patric); A. Kerkwijk (Anke); M. Huisman (Martijn); B. van de Zande (Bedette); M. Verhoef-Post (Miriam); C. Gauna (Carlotta); L.J. Hofland (Leo); A.P.N. Themmen (Axel); A-J. van der Lely (Aart-Jan)

    2010-01-01

    textabstractThe composition of the plasma membrane affects the responsiveness of cells to metabolically important hormones such as insulin and vasoactive intestinal peptide. Ghrelin is a metabolically regulated hormone that activates the G protein-coupled receptor GH secretagogue receptor type 1a (G

  15. Evidence for association of the cloned liver growth hormone receptor with a tyrosine kinase

    DEFF Research Database (Denmark)

    Wang, X; Uhler, M D; Billestrup, N;

    1992-01-01

    The ability of the cloned liver growth hormone (GH) receptor, when expressed in mammalian cell lines, to copurify with tyrosine kinase activity and be tyrosyl phosphorylated was examined. 125I-human growth hormone-GH receptor complexes isolated from COS-7 cells transiently expressing high levels ...

  16. Direct and in vitro observation of growth hormone receptor molecules in A549 human lung epithelial cells by nanodiamond labeling

    Science.gov (United States)

    Cheng, C.-Y.; Perevedentseva, E.; Tu, J.-S.; Chung, P.-H.; Cheng, C.-L.; Liu, K.-K.; Chao, J.-I.; Chen, P.-H.; Chang, C.-C.

    2007-04-01

    This letter presents direct observation of growth hormone receptor in one single cancer cell using nanodiamond-growth hormone complex as a specific probe. The interaction of surface growth hormone receptor of A549 human lung epithelial cells with growth hormone was observed using nanodiamond's unique spectroscopic signal via confocal Raman mapping. The growth hormone molecules were covalent conjugated to 100nm diameter carboxylated nanodiamonds, which can be recognized specifically by the growth hormone receptors of A549 cell. The Raman spectroscopic signal of diamond provides direct and in vitro observation of growth hormone receptors in physiology condition in a single cell level.

  17. Reconstruction of HaSNPV with helicoverpa hormone receptor 3

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    In order to develop a more efficient virus for controlling the cotton bollworm Helicoverpa armigera,Helicoverpa hormone receptor 3 (HHR3), which is involved in the ecdysteroid regulatory pathway, was used to genetically modify wild HaSNPV. HaSNPV-HHR3 budded virus and occlusion body virus were constructed in three steps: preparation of pFastBacHaPhpP10-HHR3 donor plasmid, transposition of HHR3 into the HaBacHZ8 bacmid, and transfection of HzAM1 cells to get HaSNPV-HHR3 virus. HHR3was proved to be expressed in the HaSNPV-HHR3 virus infected HzAM1 cells by immunoblotting. Results of bioassay indicated that the body weight of the HaSNPV-HHR3 infected larvae was lower than the larvae infected with wild virus and uninfected normal larvae, which suggests that HaSNPV-HHR3 delayed larval growth.

  18. Diverse growth hormone receptor gene mutations in Laron syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Berg, M.A.; Francke, U. (Stanford Univ. School of Medicine, CA (United States)); Gracia, R.; Rosenbloom, A.; Toledo, S.P.A. (Univ. Autonoma, Madrid (Spain)); Chernausek, S. (Children' s Hospital Medical Center, Cincinnati, OH (United States)); Guevara-Aguirre, J. (Institute of Endocrinology, Metabolism, and Reproduction, Quito (Ecuador)); Hopp, M. (Univ. of Witwatersrand, Johannesburg (South Africa)); Rosenbloom, A.; Argente, J. (Univ. of Florida, Gainesville (United States)); Toledo, S.P.A. (Univ. of Sao Paulo (Brazil))

    1993-05-01

    To better understand the molecular genetic basis and genetic epidemiology of Laron syndrome (growth-hormone insensitivity syndrome), the authors analysed the growth-hormone receptor (GHR) genes of seven unrelated affected individuals from the United States, South America, Europe, and Africa. They amplified all nine GHR gene exons and splice junctions from these individuals by PCR and screened the products for mutations by using denaturing gradient gel electrophoresis (DGGE). They identified a single GHR gene fragment with abnormal DGGE results for each affected individual, sequenced this fragment, and, in each case, identified a mutation likely to cause Laron syndrome, including two nonsense mutations (R43X and R217X), two splice-junction mutations, (189-1 G to T and 71+1 G to A), and two frameshift mutations (46 del TT and 230 del TA or AT). Only one of these mutations, R43X, has been previously reported. Using haplotype analysis, they determined that this mutation, which involves a CpG dinucleotide hot spot, likely arose as a separate event in this case, relative to the two prior reports of R43X. Aside from R43X, the mutations identified are unique to patients from particular geographic regions. Ten GHR gene mutations have now been described in this disorder. The authors conclude that Laron syndrome is caused by diverse GHR gene mutations, including deletions, RNA processing defects, translational stop codons, and missense codons. All the identified mutations involve the extracellular domain of the receptor, and most are unique to particular families or geographic areas. 35 refs., 3 figs., 1 tab.

  19. Gene specific actions of thyroid hormone receptor subtypes.

    Directory of Open Access Journals (Sweden)

    Jean Z Lin

    Full Text Available There are two homologous thyroid hormone (TH receptors (TRs α and β, which are members of the nuclear hormone receptor (NR family. While TRs regulate different processes in vivo and other highly related NRs regulate distinct gene sets, initial studies of TR action revealed near complete overlaps in their actions at the level of individual genes. Here, we assessed the extent that TRα and TRβ differ in target gene regulation by comparing effects of equal levels of stably expressed exogenous TRs +/- T(3 in two cell backgrounds (HepG2 and HeLa. We find that hundreds of genes respond to T(3 or to unliganded TRs in both cell types, but were not able to detect verifiable examples of completely TR subtype-specific gene regulation. TR actions are, however, far from identical and we detect TR subtype-specific effects on global T(3 response kinetics in HepG2 cells and many examples of TR subtype specificity at the level of individual genes, including effects on magnitude of response to TR +/- T(3, TR regulation patterns and T(3 dose response. Cycloheximide (CHX treatment confirms that at least some differential effects involve verifiable direct TR target genes. TR subtype/gene-specific effects emerge in the context of widespread variation in target gene response and we suggest that gene-selective effects on mechanism of TR action highlight differences in TR subtype function that emerge in the environment of specific genes. We propose that differential TR actions could influence physiologic and pharmacologic responses to THs and selective TR modulators (STRMs.

  20. Dual activities of odorants on olfactory and nuclear hormone receptors.

    Science.gov (United States)

    Pick, Horst; Etter, Sylvain; Baud, Olivia; Schmauder, Ralf; Bordoli, Lorenza; Schwede, Torsten; Vogel, Horst

    2009-10-30

    We have screened an odorant compound library and discovered molecules acting as chemical signals that specifically activate both G-protein-coupled olfactory receptors (ORs) on the cell surface of olfactory sensory neurons and the human nuclear estrogen receptor alpha (ER) involved in transcriptional regulation of cellular differentiation and proliferation in a wide variety of tissues. Hence, these apparent dual active odorants induce distinct signal transduction pathways at different subcellular localizations, which affect both neuronal signaling, resulting in odor perception, and the ER-dependent transcriptional control of specific genes. We demonstrate these effects using fluorescence-based in vitro and cellular assays. Among these odorants, we have identified synthetic sandalwood compounds, an important class of molecules used in the fragrance industry. For one estrogenic odorant we have also identified the cognate OR. This prompted us to compare basic molecular recognition principles of odorants on the two structurally and apparent functionally non-related receptors using computational modeling in combination with functional assays. Faced with the increasing evidence that ORs may perform chemosensory functions in a number of tissues outside of the nasal olfactory epithelium, the unraveling of these molecular ligand-receptor interaction principles is of critical importance. In addition the evidence that certain olfactory sensory neurons naturally co-express ORs and ERs may provide a direct functional link between the olfactory and hormonal systems in humans. Our results are therefore useful for defining the structural and functional characteristics of ER-specific odorants and the role of odorant molecules in cellular processes other than olfaction.

  1. Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination.

    Science.gov (United States)

    Refetoff, Samuel; Dumitrescu, Alexandra M

    2007-06-01

    At least six major steps are required for secreted thyroid hormone (TH) to exert its action on target tissues. Mutations interfering with three of these steps have been so far identified. The first recognized defect, which causes resistance to TH, involves the TH receptor beta gene and has been given the acronym RTH. Occurring in approximately 1 per 40,000 newborns, more than 1000 affected subjects, from 339 families, have been identified. The gene defect remains unknown in 15% of subjects with RTH. Two novel syndromes causing reduced sensitivity to TH were recently identified. One, producing severe psychomotor defects in > 100 males from 26 families, is caused by mutations in the cell-membrane transporter of TH, MCT8; the second, affecting the intracellular metabolism of TH in four individuals from two families, is caused by mutations in the SECISBP2 gene, which is required for the synthesis of selenoproteins, including TH deiodinases.

  2. Sustained cyclic AMP production by parathyroid hormone receptor endocytosis.

    Science.gov (United States)

    Ferrandon, Sébastien; Feinstein, Timothy N; Castro, Marian; Wang, Bin; Bouley, Richard; Potts, John T; Gardella, Thomas J; Vilardaga, Jean-Pierre

    2009-10-01

    Cell signaling mediated by the G protein-coupled parathyroid hormone receptor type 1 (PTHR) is fundamental to bone and kidney physiology. It has been unclear how the two ligand systems--PTH, endocrine and homeostatic, and PTH-related peptide (PTHrP), paracrine--can effectively operate with only one receptor and trigger different durations of the cAMP responses. Here we analyze the ligand response by measuring the kinetics of activation and deactivation for each individual reaction step along the PTHR signaling cascade. We found that during the time frame of G protein coupling and cAMP production, PTHrP(1-36) action was restricted to the cell surface, whereas PTH(1-34) had moved to internalized compartments where it remained associated with the PTHR and Galpha(s), potentially as a persistent and active ternary complex. Such marked differences suggest a mechanism by which PTH and PTHrP induce differential responses, and these results indicate that the central tenet that cAMP production originates exclusively at the cell membrane must be revised.

  3. Interspecies comparison of renal cortical receptors for parathyroid hormone and parathyroid hormone-related protein

    Energy Technology Data Exchange (ETDEWEB)

    Orloff, J.J.; Goumas, D.; Wu, T.L.; Stewart, A.F. (West Haven Veterans Administration Medical Center, CT (USA))

    1991-03-01

    Parathyroid hormone (PTH) and PTH-related proteins (PTHrP) interact with a common receptor in rat bone cells and in canine renal membranes with similar affinity, but PTHrP are substantially less potent than PTH in stimulating adenylate cyclase in canine renal membranes; in contrast, PTH and PTHrP are equipotent in stimulating adenylate cyclase in rat bone cells. This discrepancy has been largely viewed as reflecting differences in the relative efficiency of signal transduction of PTHrP between bone and kidney assay systems. To test the alternative (but not mutually exclusive) hypothesis that these differences could reflect interspecies differences in PTH receptors, we have characterized the bioactivity of amino-terminal PTHrP and PTH in rat and human renal cortical membranes (RCM) and compared them to results we previously reported in canine RCM. The stability of PTH and PTHrP peptides under binding and adenylate cyclase assay conditions was greater than 80% for each species. Competitive inhibition of ({sup 125}I)(Tyr36)hPTHrP-(1-36)NH{sub 2} binding to rat RCM by bPTH-(1-34) and (Tyr36)hPTHrP-(1-36)NH{sub 2} yielded nearly identical binding dissociation constants (3.7 and 3.6 nM, respectively), and binding to human RCM demonstrated slightly greater potency for PTHrP (0.5 nM) than for PTH (0.9 nM). Similarly, adenylate cyclase stimulating activity was equivalent for the two peptides in rat RCM, but PTHrP was twofold more potent than PTH in human RCM. Covalent photoaffinity labeling of protease-protected rat RCM yielded an apparent 80 kD receptor protein, and cross-linking of human RCM labeled an 85 kD receptor, indistinguishable in size from the canine renal PTH receptor. We conclude that rat, canine, and human renal cortical PTH receptors exhibit species specificity.

  4. CHHBP: a newly identified receptor of crustacean hyperglycemic hormone.

    Science.gov (United States)

    Li, Ran; Tian, Jin-Ze; Zhuang, Cui-Heng; Zhang, Yi-Chen; Geng, Xu-Yun; Zhu, Li-Na; Sun, Jin-Sheng

    2016-04-15

    Crustacean hyperglycemic hormone (CHH) is a neurohormone found only in arthropods that plays a pivotal role in the regulation of hemolymph glucose levels, molting and stress responses. Although it was determined that a membrane guanylyl cyclase (GC) acts as the CHH receptor in the Y-organ during ecdysteroidogenesis, the identity of the CHH receptor in the hepatopancreas has not been established. In this study, we identified CHH binding protein (CHHBP), as a potential receptor by screening the annotated unigenes from the transcriptome of ITALIC! Eriocheir sinensis, after removal of the eyestalk. Analysis of the binding affinity between CHH and CHHBP provided direct evidence that CHH interacts with CHHBP in a specific binding mode. Subsequent analysis showed that CHHBP is expressed primarily in the hepatopancreas where it localizes to the cell membrane. In addition, real-time PCR analysis showed that ITALIC! CHHBPtranscript levels gradually increase in the hepatopancreas following eyestalk ablation. RNAi-mediated suppression of ITALIC! CHHBPexpression resulted in decreased glucose levels. Furthermore, the reduction of blood glucose induced by ITALIC! CHHBPRNAi reached the same level as that observed in the eyestalk ablation group, suggesting that CHHBP is involved in glucose metabolism regulated by CHH. In addition, compared with the control group, injection of CHH was unable to rescue the decreased glucose levels in ITALIC! CHHBPRNAi crabs. CHH induced transport of 2-NBDG to the outside of cells, with indispensable assistance from CHHBP. Taken together, these findings suggest that CHHBP acts as one type of the primary signal processor of CHH-mediated regulation of cellular glucose metabolism. © 2016. Published by The Company of Biologists Ltd.

  5. Thyroid hormones regulate fibroblast growth factor receptor signaling during chondrogenesis.

    Science.gov (United States)

    Barnard, Joanna C; Williams, Allan J; Rabier, Bénédicte; Chassande, Olivier; Samarut, Jacques; Cheng, Sheue-Yann; Bassett, J H Duncan; Williams, Graham R

    2005-12-01

    Childhood hypothyroidism causes growth arrest with delayed ossification and growth-plate dysgenesis, whereas thyrotoxicosis accelerates ossification and growth. Thyroid hormone (T(3)) regulates chondrocyte proliferation and is essential for hypertrophic differentiation. Fibroblast growth factors (FGFs) are also important regulators of chondrocyte proliferation and differentiation, and activating mutations of FGF receptor-3 (FGFR3) cause achondroplasia. We investigated the hypothesis that T(3) regulates chondrogenesis via FGFR3 in ATDC5 cells, which undergo a defined program of chondrogenesis. ATDC5 cells expressed two FGFR1, four FGFR2, and one FGFR3 mRNA splice variants throughout chondrogenesis, and expression of each isoform was stimulated by T(3) during the first 6-12 d of culture, when T(3) inhibited proliferation by 50%. FGFR3 expression was also increased in cells treated with T(3) for 21 d, when T(3) induced an earlier onset of hypertrophic differentiation and collagen X expression. FGFR3 expression was reduced in growth plates from T(3) receptor alpha-null mice, which exhibit skeletal hypothyroidism, but was increased in T(3) receptor beta(PV/PV) mice, which display skeletal thyrotoxicosis. These findings indicate that FGFR3 is a T(3)-target gene in chondrocytes. In further experiments, T(3) enhanced FGF2 and FGF18 activation of the MAPK-signaling pathway but inhibited their activation of signal transducer and activator of transcription-1. FGF9 did not activate MAPK or signal transducer and activator of transcription-1 pathways in the absence or presence of T(3). Thus, T(3) exerted differing effects on FGFR activation during chondrogenesis depending on which FGF ligand stimulated the FGFR and which downstream signaling pathway was activated. These studies identify novel interactions between T(3) and FGFs that regulate chondrocyte proliferation and differentiation during chondrogenesis.

  6. SIRTUIN 1 (SIRT1) AND STEROID HORMONE RECEPTOR ACTIVITY IN CANCER

    Science.gov (United States)

    Moore, R.L.; Dai, Y.; Faller, D.V.

    2013-01-01

    Sirtuins, which are class III NAD-dependent histone deacetylases (HDACs) that regulate a number of physiological processes, play important roles in the regulation of metabolism, aging, oncogenesis and cancer progression. More recently, a role for the sirtuins in the regulation of steroid hormone receptor signaling is emerging. In this mini-review, we will summarize current research into the regulation of estrogen, androgen, progesterone, mineralocorticoid and glucocorticoid signaling by sirtuins in cancer. Sirtuins can regulate steroid hormone signaling through a variety of molecular mechanisms, including acting as co-regulatory transcription factors, deacetylating histones in the promoters of genes with nuclear receptor binding sites, directly deacetylating steroid hormone nuclear receptors, and regulating pathways which modify steroid hormone receptors through phosphorylation. Furthermore, disruption of sirtuin activity may be an important step in the development of steroid hormone-refractory cancers. PMID:22159506

  7. Thyroid-Stimulating Hormone Receptor Antibodies in Pregnancy: Clinical Relevance

    Directory of Open Access Journals (Sweden)

    Ines Bucci

    2017-06-01

    Full Text Available Graves’ disease is the most common cause of thyrotoxicosis in women of childbearing age. Approximately 1% of pregnant women been treated before, or are being treated during pregnancy for Graves’ hyperthyroidism. In pregnancy, as in not pregnant state, thyroid-stimulating hormone (TSH receptor (TSHR antibodies (TRAbs are the pathogenetic hallmark of Graves’ disease. TRAbs are heterogeneous for molecular and functional properties and are subdivided into activating (TSAbs, blocking (TBAbs, or neutral (N-TRAbs depending on their effect on TSHR. The typical clinical features of Graves’ disease (goiter, hyperthyroidism, ophthalmopathy, dermopathy occur when TSAbs predominate. Graves’ disease shows some peculiarities in pregnancy. The TRAbs disturb the maternal as well as the fetal thyroid function given their ability to cross the placental barrier. The pregnancy-related immunosuppression reduces the levels of TRAbs in most cases although they persist in women with active disease as well as in women who received definitive therapy (radioiodine or surgery before pregnancy. Changes of functional properties from stimulating to blocking the TSHR could occur during gestation. Drug therapy is the treatment of choice for hyperthyroidism during gestation. Antithyroid drugs also cross the placenta and therefore decrease both the maternal and the fetal thyroid hormone production. The management of Graves’ disease in pregnancy should be aimed at maintaining euthyroidism in the mother as well as in the fetus. Maternal and fetal thyroid dysfunction (hyperthyroidism as well as hypothyroidism are in fact associated with several morbidities. Monitoring of the maternal thyroid function, TRAbs measurement, and fetal surveillance are the mainstay for the management of Graves’ disease in pregnancy. This review summarizes the biochemical, immunological, and therapeutic aspects of Graves’ disease in pregnancy focusing on the role of the TRAbs in maternal and

  8. Panbo-Red Pigment Concentration Hormone u \\kur{Porcellio scaber} (stínka obecná)

    OpenAIRE

    ZRALÁ, Jana

    2007-01-01

    The Panbo-RPCH, one member of the AKH/RPCH (Adipokinetic Hormone/Red Pigment Concentrating Hormone) family, has been isolated from the rought woodlouse, Porcellio scaber CNS. The HPLC, ELISA and LC/MS analyses were used for characterization of the molecule. The peptide enhances lipid mobilization when injected into the red bug Pyrrhocoris apterus body with maximum response of 10 pmol.

  9. Hormonal regulation in insects: facts, gaps, and future directions.

    Science.gov (United States)

    Gäde, G; Hoffmann, K H; Spring, J H

    1997-10-01

    There are two main classes of hormones in insects: 1) the true hormones produced by epithelial glands and belonging to the ecdysteroids or juvenile hormones and 2) the neuropeptide hormones produced by neurosecretory cells. Members of these classes regulate physiological, developmental, and behavioral events in insects. Detailed accounts are given on isolation, identification, structure-activity relationships, mode of action, biological function, biosynthesis, inactivation, metabolism, and feedback for hormones involved in 1) metabolic regulation such as the adipokinetic/hypertrehalosemic peptides and the diuretic and antidiuretic peptides; 2) stimulation or inhibition of muscle activity such as the myotropic peptides; 3) control of reproduction, growth, and development such as allatotropins, allatostatins, juvenile hormones, ecdysteroids, folliculostimulins and folliculostatins, ecdysis-triggering and eclosion hormones, pheromone biosynthesis activating neuropeptides, and diapause hormones; and 4) regulation of tanning and of color change. Because of the improvements in techniques for isolation and structure elucidation, there has been rapid progress in our knowledge of the chemistry of certain neuropeptide families. With the employment of molecular biological techniques, the genes of some neuropeptides have been successfully characterized. There are, however, areas that are still quite underdeveloped. These are, for example, 1) receptor studies, which are still in their infancy; 2) the hormonal status of certain sequenced peptides is not clarified; and 3) functional studies are lacking even for established hormones. The authors plead for a concerted effort to continue research in this field, which will also advance our knowledge into the use of insect hormones as safer and species-specific molecules for insect pest management.

  10. Characterization of the hormone-binding domain of the chicken c-erbA/thyroid hormone receptor protein

    DEFF Research Database (Denmark)

    Muñoz, A; Zenke, M; Gehring, U

    1988-01-01

    mutations present in the carboxy-terminal half of P75gag-v-erbA co-operate in abolishing hormone binding, and that the ligand-binding domain resides in a position analogous to that of steroid receptors. Furthermore, a point mutation that is located between the putative DNA and ligand-binding domains of P75......To identify and characterize the hormone-binding domain of the thyroid hormone receptor, we analyzed the ligand-binding capacities of proteins representing chimeras between the normal receptor and P75gag-v-erbA, the retrovirus-encoded form deficient in binding ligand. Our results show that several......gag-v-erbA and that renders it biologically inactive fails to affect hormone binding by the c-erbA protein. These results suggest that the mutation changed the ability of P75gag-v-erbA to affect transcription since it also had no effect on DNA binding. Our data also suggest that hormone...

  11. Dexamethasone increases growth hormone (GH)-releasing hormone (GRH) receptor mRNA levels in cultured rat anterior pituitary cells.

    Science.gov (United States)

    Tamaki, M; Sato, M; Matsubara, S; Wada, Y; Takahara, J

    1996-06-01

    To examine the effects of glucocorticoid (GC) on growth hormone (GH)-releasing hormone (GRH) receptor gene expression, a highly-sensitive and quantitative reverse-transcribed polymerase chain reaction (RT-PCR) method was used in this study. Rat anterior pituitary cells were isolated and cultured for 4 days. The cultured cells were treated with dexamethasone for 2, 6, and 24 h. GRH receptor mRNA levels were determined by competitive RT-PCR using a recombinant RNA as the competitor. Dexamethasone significantly increased GRH receptor mRNA levels at 5 nM after 6- and 24 h-incubations, and the maximal effect was found at 25 nM. The GC receptor-specific antagonist, RU 38486 completely eliminated the dexamethasone-induced enhancement of GRH receptor mRNA levels. Dexamethasone did not alter the mRNA levels of beta-actin and prolactin at 5 nM for 24 h, whereas GH mRNA levels were significantly increased by the same treatment. The GH response to GRH was significantly enhanced by the 24-h incubation with 5 nM dexamethasone. These findings suggest that GC stimulates GRH receptor gene expression through the ligand-activated GC receptors in the rat somatotrophs. The direct effects of GC on the GRH receptor gene could explain the enhancement of GRH-induced GH secretion.

  12. Optimizing subcutaneous injection of the gonadotropin-releasing hormone receptor antagonist degarelix.

    Science.gov (United States)

    Barkin, Jack; Burton, Shelley; Lambert, Carole

    2016-02-01

    The gonadotropin-releasing hormone (GnRH) receptor antagonist degarelix has several unique characteristics compared to luteinizing hormone-releasing hormone (LHRH) analogs used in the management of prostate cancer. Notable differences of GnRH receptor antagonists include no flare reaction, and a more rapid suppression of testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH) and prostate-specific antigen (PSA) compared to LHRH analogs. Despite emerging evidence supporting the use of GnRH receptor antagonists over the more widely used LHRH analogs in the management of prostate cancer, physicians may be reluctant to prescribe degarelix. They may be concerned about patient complaints about injection-site reactions (ISRs). The subcutaneous injection of degarelix has been associated with a higher rate of ISRs compared with the intramuscular injections of LHRH analogs. This "How I Do It" article describes techniques and strategies that have been developed by physicians and nurses to reduce the discomfort associated with the subcutaneous delivery of degarelix.

  13. Molecular cloning and properties of a full-length putative thyroid hormone receptor coactivator.

    Science.gov (United States)

    Takeshita, A; Yen, P M; Misiti, S; Cardona, G R; Liu, Y; Chin, W W

    1996-08-01

    Thyroid hormone receptors (TRs) are ligand-dependent transcription factors that regulate target gene transcription. The conserved carboxy-terminal region of the ligand-binding domain (AF-2) has been thought to play a critical role in mediating ligand-dependent transactivation by the interaction with coactivator(s). Using bacterially-expressed TR as a probe, far-Western-based expression cDNA library screening identified cDNAs that encode, in part, the recently reported partial steroid receptor coactivator-1 (SRC-1) sequence. Additional work, including 5' RACE, has characterized a full-length cDNA that encodes a approximately 160 kD protein as a putative thyroid hormone receptor coactivator (F-SRC-1). In vitro binding studies show that F-SRC-1 binds to a variety of nuclear hormone receptors in a ligand-dependent manner, along with TBP and TFIIB, suggesting that F-SRC-1 may play a role as a bridging molecule between nuclear hormone receptors and general transcription factors. Interestingly, AF-2 mutants also retain ligand-dependent interaction with F-SRC-1. Although F-SRC-1 recognizes the ligand-induced conformational changes of nuclear hormone receptors, our observations suggest that F-SRC-1 may bind directly with subregion(s) in nuclear hormone receptors other than the AF-2 region.

  14. Infertility in Female Mice with a Gain-of-Function Mutation in the Luteinizing Hormone Receptor Is Due to Irregular Estrous Cyclicity, Anovulation, Hormonal Alterations, and Polycystic Ovaries

    National Research Council Canada - National Science Library

    Hai, Lan; McGee, Stacey R; Rabideau, Amanda C; Paquet, Marilène; Narayan, Prema

    2015-01-01

    The luteinizing hormone receptor, LHCGR, is essential for fertility in males and females, and genetic mutations in the receptor have been identified that result in developmental and reproductive defects...

  15. Melanin concentrating hormone receptor 1 (MCHR1) antagonists - Still a viable approach for obesity treatment?

    DEFF Research Database (Denmark)

    Högberg, T.; Frimurer, T.M.; Sasmal, P.K.

    2012-01-01

    Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the melanin concentrating hormone (MCH) and its receptor 1. The development of MCHR1 antagonists are described with a specific perspective on different chemotypes...

  16. Molecular cloning and functional characterization of the diapause hormone receptor in the corn earworm Helicoverpa zea

    Science.gov (United States)

    The diapause hormone (DH) in the heliothine moth has shown its activity in termination of pupal diapause, while the orthology in the silkworm is known to induce embryonic diapause. In the current study, we cloned the diapause hormone receptor from the corn earworm Helicoverpa zea (HzDHr) and tested ...

  17. Identifying neuropeptide and protein hormone receptors in Drosophila melanogaster by exploiting genomic data

    DEFF Research Database (Denmark)

    Hauser, Frank; Williamson, Michael; Cazzamali, Giuseppe

    2006-01-01

    insect genome, that of the fruitfly Drosophila melanogaster, was sequenced in 2000, and about 200 GPCRs have been annnotated in this model insect. About 50 of these receptors were predicted to have neuropeptides or protein hormones as their ligands. Since 2000, the cDNAs of most of these candidate...... receptors have been cloned and for many receptors the endogenous ligand has been identified. In this review, we will give an update about the current knowledge of all Drosophila neuropeptide and protein hormone receptors, and discuss their phylogenetic relationships. Udgivelsesdato: 2006-Feb...

  18. (-) Arctigenin and (+) pinoresinol are antagonists of the human thyroid hormone receptor β.

    Science.gov (United States)

    Ogungbe, Ifedayo Victor; Crouch, Rebecca A; Demeritte, Teresa

    2014-11-24

    Lignans are important biologically active dietary polyphenolic compounds. Consumption of foods that are rich in lignans is associated with positive health effects. Using modeling tools to probe the ligand-binding pockets of molecular receptors, we found that lignans have high docking affinity for the human thyroid hormone receptor β. Follow-up experimental results show that lignans (-) arctigenin and (+) pinoresinol are antagonists of the human thyroid hormone receptor β. The modeled complexes show key plausible interactions between the two ligands and important amino acid residues of the receptor.

  19. (−) Arctigenin and (+) Pinoresinol Are Antagonists of the Human Thyroid Hormone Receptor β

    Science.gov (United States)

    2015-01-01

    Lignans are important biologically active dietary polyphenolic compounds. Consumption of foods that are rich in lignans is associated with positive health effects. Using modeling tools to probe the ligand-binding pockets of molecular receptors, we found that lignans have high docking affinity for the human thyroid hormone receptor β. Follow-up experimental results show that lignans (−) arctigenin and (+) pinoresinol are antagonists of the human thyroid hormone receptor β. The modeled complexes show key plausible interactions between the two ligands and important amino acid residues of the receptor. PMID:25383984

  20. Multiple Novel Signals Mediate Thyroid Hormone Receptor Nuclear Import and Export*

    OpenAIRE

    Mavinakere, Manohara S.; Powers, Jeremy M.; Subramanian, Kelly S.; Roggero, Vincent R.; Allison, Lizabeth A.

    2012-01-01

    Thyroid hormone receptor (TR) is a member of the nuclear receptor superfamily that shuttles between the cytosol and nucleus. The fine balance between nuclear import and export of TR has emerged as a critical control point for modulating thyroid hormone-responsive gene expression; however, sequence motifs of TR that mediate shuttling are not fully defined. Here, we characterized multiple signals that direct TR shuttling. Along with the known nuclear localization signal in the hinge domain, we ...

  1. Turn-on switch in parathyroid hormone receptor by a two-step parathyroid hormone binding mechanism.

    Science.gov (United States)

    Castro, Marián; Nikolaev, Viacheslav O; Palm, Dieter; Lohse, Martin J; Vilardaga, Jean-Pierre

    2005-11-01

    Parathyroid hormone (PTH) and its related receptor (PTHR) are essential regulators of calcium homeostasis and bone physiology. PTH activates PTHR by interacting with a ligand-binding site localized within the N-terminal extracellular domain (the N-domain) and the domain comprising the seven transmembrane helices and the connecting extracellular loops (the J-domain). PTH binding triggers a conformational switch in the receptor, leading to receptor activation and subsequent cellular responses. The process of receptor activation occurs rapidly, within approximately 1 s, but the binding event preceding receptor activation is not understood. By recording FRET between tetramethyl-rhodamine in PTH(1-34) and GFP in the N-domain of the receptor, we measured the binding event in real time in living cells. We show that the association time course between PTH(1-34) and PTHR involves a two-step binding process where the agonist initially binds the receptor with a fast time constant (tau approximately 140 ms) and then with slower kinetics (tau approximately 1 s). The fast and slow phases were assigned to hormone association to the receptor N- and J domains, respectively. Our data indicate that the slow binding step to the J-domain coincides with a conformational switch in the receptor, also monitored by FRET between the enhanced cyan fluorescent protein and the enhanced yellow fluorescent protein in the PTHR sensor, PTHR enhanced cyan fluorescent protein/enhanced yellow fluorescent protein (PTHR(CFP/YFP)). These data suggest that the conformational change that switches the receptor into its active state proceeds in a sequential manner, with the first rapid binding step event preceding receptor activation by PTH(1-34).

  2. Differential gene expression of growth hormone (GH)-releasing hormone (GRH) and GRH receptor in various rat tissues.

    Science.gov (United States)

    Matsubara, S; Sato, M; Mizobuchi, M; Niimi, M; Takahara, J

    1995-09-01

    Growth hormone (GH)-releasing hormone (GRH) acts on specific receptors in the anterior pituitary to stimulate the synthesis and release of GH. Recent reports suggest that GRH is also synthesized in extrahypothalamic tissues. To evaluate the potential roles of extrahypothalamic GRH, we studied the gene expression of GRH and GRH receptors in various rat tissues by reverse transcribed (RT)-polymerase chain reaction (PCR). Total RNA was extracted from twenty-three rat organs and RT-PCR was performed with GRH and GRH receptor primers. Highly-sensitive RT-PCR-Southern blotting showed that GRH and GRH receptor mRNA coexist in the widespread tissues (14 of 25 tissues). GRH mRNA was relatively abundant in the cerebral cortex, brain stem, testis, and placenta, while GRH receptor mRNA was abundant in renal medulla and renal pelvis. Northern blot hybridization using poly A+ RNA indicated that the transcript of GRH receptor gene found in the renal medulla was similar to the longer transcript (about 4 Kb) of pituitary GRH receptor in the size. These results suggest that GRH plays a potential role not only in the neuroendocrine axis, but also in the autocrine and paracrine systems in extrahypothalamic tissues.

  3. Identification of intracellular domains in the growth hormone receptor involved in signal transduction

    DEFF Research Database (Denmark)

    Billestrup, N; Allevato, G; Norstedt, G

    1994-01-01

    The growth hormone (GH) receptor belongs to the GH/prolactin/cytokine super-family of receptors. The signal transduction mechanism utilized by this class of receptors remains largely unknown. In order to identify functional domains in the intracellular region of the GH receptor we generated...... a number of GH receptor mutants and analyzed their function after transfection into various cell lines. A truncated GH receptor missing 184 amino acids at the C-terminus was unable to mediate GH effects on transcription of the Spi 2.1 and insulin genes. However, this mutant was fully active in mediating GH...

  4. Pentadecapeptide BPC 157 Enhances the Growth Hormone Receptor Expression in Tendon Fibroblasts

    Directory of Open Access Journals (Sweden)

    Chung-Hsun Chang

    2014-11-01

    Full Text Available BPC 157, a pentadecapeptide derived from human gastric juice, has been demonstrated to promote the healing of different tissues, including skin, muscle, bone, ligament and tendon in many animal studies. However, the underlying mechanism has not been fully clarified. The present study aimed to explore the effect of BPC 157 on tendon fibroblasts isolated from Achilles tendon of male Sprague-Dawley rat. From the result of cDNA microarray analysis, growth hormone receptor was revealed as one of the most abundantly up-regulated genes in tendon fibroblasts by BPC 157. BPC 157 dose- and time-dependently increased the expression of growth hormone receptor in tendon fibroblasts at both the mRNA and protein levels as measured by RT/real-time PCR and Western blot, respectively. The addition of growth hormone to BPC 157-treated tendon fibroblasts dose- and time-dependently increased the cell proliferation as determined by MTT assay and PCNA expression by RT/real-time PCR. Janus kinase 2, the downstream signal pathway of growth hormone receptor, was activated time-dependently by stimulating the BPC 157-treated tendon fibroblasts with growth hormone. In conclusion, the BPC 157-induced increase of growth hormone receptor in tendon fibroblasts may potentiate the proliferation-promoting effect of growth hormone and contribute to the healing of tendon.

  5. Gustatory perception and fat body energy metabolism are jointly affected by vitellogenin and juvenile hormone in honey bees.

    Directory of Open Access Journals (Sweden)

    Ying Wang

    2012-06-01

    Full Text Available Honey bees (Apis mellifera provide a system for studying social and food-related behavior. A caste of workers performs age-related tasks: young bees (nurses usually feed the brood and other adult bees inside the nest, while older bees (foragers forage outside for pollen, a protein/lipid source, or nectar, a carbohydrate source. The workers' transition from nursing to foraging and their foraging preferences correlate with differences in gustatory perception, metabolic gene expression, and endocrine physiology including the endocrine factors vitellogenin (Vg and juvenile hormone (JH. However, the understanding of connections among social behavior, energy metabolism, and endocrine factors is incomplete. We used RNA interference (RNAi to perturb the gene network of Vg and JH to learn more about these connections through effects on gustation, gene transcripts, and physiology. The RNAi perturbation was achieved by single and double knockdown of the genes ultraspiracle (usp and vg, which encode a putative JH receptor and Vg, respectively. The double knockdown enhanced gustatory perception and elevated hemolymph glucose, trehalose, and JH. We also observed transcriptional responses in insulin like peptide 1 (ilp1, the adipokinetic hormone receptor (AKHR, and cGMP-dependent protein kinase (PKG, or "foraging gene" Amfor. Our study demonstrates that the Vg-JH regulatory module controls changes in carbohydrate metabolism, but not lipid metabolism, when worker bees shift from nursing to foraging. The module is also placed upstream of ilp1, AKHR, and PKG for the first time. As insulin, adipokinetic hormone (AKH, and PKG pathways influence metabolism and gustation in many animals, we propose that honey bees have conserved pathways in carbohydrate metabolism and conserved connections between energy metabolism and gustatory perception. Thus, perhaps the bee can make general contributions to the understanding of food-related behavior and metabolic disorders.

  6. Structure determination of adipokinetic hormones using fast atom bombardment tandem mass spectrometry; An unknown adipokinetic hormone (AKH-III) from Locusta migratoria

    Energy Technology Data Exchange (ETDEWEB)

    Heerma, W.; Versluis, C.; Lankhof, H. (Utrecht University (Netherlands). Faculty of Chemistry, Department of Analytical Molecular Spectrometry); Oudejans, R.C.H.M.; Kooiman, F.P.; Beenakkers, A.M.T. (Utrecht University (Netherlands). Department of Experimental Zoology)

    1991-08-01

    Fast atom bombardment mass spectrometry combined with various tandem mass spectrometric techniques and accurate mass measurement were used to elucidate the structure of an unknown biologically active peptide isolated from Locusa migratoria. (author). 23 refs.; 6 figs.; 2 schemes.

  7. Hormone-receptor expression and ovarian cancer survival

    DEFF Research Database (Denmark)

    Sieh, Weiva; Köbel, Martin; Longacre, Teri A

    2013-01-01

    Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated ...

  8. Aberrant Monoaminergic System in Thyroid Hormone Receptor-β Deficient Mice as a Model of Attention-Deficit/Hyperactivity Disorder

    OpenAIRE

    Ookubo, Masanori; Sadamatsu, Miyuki; Yoshimura, Atsushi; SUZUKI, Satoru; Kato, Nobumasa; Kojima, Hideto; Yamada, Naoto; Kanai, Hirohiko

    2015-01-01

    Background: Thyroid hormone receptors are divided into 2 functional types: TRα and TRβ. Thyroid hormone receptors play pivotal roles in the developing brain, and disruption of thyroid hormone receptors can produce permanent behavioral abnormality in animal models and humans. Methods: Here we examined behavioralchanges, regional monoamine metabolism, and expression of epigenetic modulatory proteins, including acetylated histone H3 and histone deacetylase, in the developing brain of TRα-disrupt...

  9. The diversity of abnormal hormone receptors in adrenal Cushing's syndrome allows novel pharmacological therapies

    Directory of Open Access Journals (Sweden)

    Lacroix A.

    2000-01-01

    Full Text Available Recent studies from several groups have indicated that abnormal or ectopic expression and function of adrenal receptors for various hormones may regulate cortisol production in ACTH-independent hypercortisolism. Gastric inhibitory polypeptide (GIP-dependent Cushing's syndrome has been described in patients with either unilateral adenoma or bilateral macronodular adrenal hyperplasia; this syndrome results from the large adrenal overexpression of the GIP receptor without any activating mutation. We have conducted a systematic in vivo evaluation of patients with adrenal Cushing's syndrome in order to identify the presence of abnormal hormone receptors. In macronodular adrenal hyperplasia, we have identified, in addition to GIP-dependent Cushing's syndrome, other patients in whom cortisol production was regulated abnormally by vasopressin, ß-adrenergic receptor agonists, hCG/LH, or serotonin 5HT-4 receptor agonists. In patients with unilateral adrenal adenoma, the abnormal expression or function of GIP or vasopressin receptor has been found, but the presence of ectopic or abnormal hormone receptors appears to be less prevalent than in macronodular adrenal hyperplasia. The identification of the presence of an abnormal adrenal receptor offers the possibility of a new pharmacological approach to control hypercortisolism by suppressing the endogenous ligands or by using specific antagonists for the abnormal receptors.

  10. Thyroid hormone regulation of brain gene expression: role of thyroid hormone receptors

    OpenAIRE

    Gil-Ibáñez, Pilar

    2014-01-01

    Tesis doctoral inédita, leída en la Universidad Autónoma de Madrid. Facultad de Medicina. Departamento de Bioquímica. Fecha de lectura: 13 de junio, 2014 Thyroid hormones are important during development of the mammalian brain. They are involved in neuronal and glial cell differentiation and migration, axonal myelination, and synaptogenesis. The effects of thyroid hormones on brain development ...

  11. Impaired hair growth and wound healing in mice lacking thyroid hormone receptors.

    Science.gov (United States)

    Contreras-Jurado, Constanza; García-Serrano, Laura; Martínez-Fernández, Mónica; Ruiz-Llorente, Lidia; Paramio, Jesus M; Aranda, Ana

    2014-01-01

    Both clinical and experimental observations show that the skin is affected by the thyroidal status. In hypothyroid patients the epidermis is thin and alopecia is common, indicating that thyroidal status might influence not only skin proliferation but also hair growth. We demonstrate here that the thyroid hormone receptors (TRs) mediate these effects of the thyroid hormones on the skin. Mice lacking TRα1 and TRβ (the main thyroid hormone binding isoforms) display impaired hair cycling associated to a decrease in follicular hair cell proliferation. This was also observed in hypothyroid mice, indicating the important role of the hormone-bound receptors in hair growth. In contrast, the individual deletion of either TRα1 or TRβ did not impair hair cycling, revealing an overlapping or compensatory role of the receptors in follicular cell proliferation. In support of the role of the receptors in hair growth, TRα1/TRβ-deficient mice developed alopecia after serial depilation. These mice also presented a wound-healing defect, with retarded re-epithelialization and wound gaping, associated to impaired keratinocyte proliferation. These results reinforce the idea that the thyroid hormone nuclear receptors play an important role on skin homeostasis and suggest that they could be targets for the treatment of cutaneous pathologies.

  12. Structural and functional divergence of growth hormone-releasing hormone receptors in early sarcopterygians: lungfish and Xenopus.

    Directory of Open Access Journals (Sweden)

    Janice K V Tam

    Full Text Available The evolutionary trajectories of growth hormone-releasing hormone (GHRH receptor remain enigmatic since the discovery of physiologically functional GHRH-GHRH receptor (GHRHR in non-mammalian vertebrates in 2007. Interestingly, subsequent studies have described the identification of a GHRHR(2 in chicken in addition to the GHRHR and the closely related paralogous receptor, PACAP-related peptide (PRP receptor (PRPR. In this article, we provide information, for the first time, on the GHRHR in sarcopterygian fish and amphibians by the cloning and characterization of GHRHRs from lungfish (P. dolloi and X. laevis. Sequence alignment and phylogenetic analyses demonstrated structural resemblance of lungfish GHRHR to their mammalian orthologs, while the X. laevis GHRHR showed the highest homology to GHRHR(2 in zebrafish and chicken. Functionally, lungfish GHRHR displayed high affinity towards GHRH in triggering intracellular cAMP and calcium accumulation, while X. laevis GHRHR(2 was able to react with both endogenous GHRH and PRP. Tissue distribution analyses showed that both lungfish GHRHR and X. laevis GHRHR(2 had the highest expression in brain, and interestingly, X. laevis(GHRHR2 also had high abundance in the reproductive organs. These findings, together with previous reports, suggest that early in the Sarcopterygii lineage, GHRHR and PRPR have already established diverged and specific affinities towards their cognate ligands. GHRHR(2, which has only been found in xenopus, zebrafish and chicken hitherto, accommodates both GHRH and PRP.

  13. Introduction of exogenous growth hormone receptors augments growth hormone-responsive insulin biosynthesis in rat insulinoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Billestrup, N.; Moeldrup, A.; Serup, P.; Nielsen, J.H. (Hagedorn Research Lab., Gentofte (Denmark)); Mathews, L.S.; Norstedt, G. (Karolinska Inst., Huddinge (Sweden))

    1990-09-01

    The stimulation of insulin biosynthesis in the pancreatic insulinoma cell line RIN5-AH by growth hormone (GH) is initiated by GH binding to specific receptors. To determine whether the recently cloned rat hepatic GH receptor is able to mediate the insulinotropic effect of GH, the authors have transfected a GH receptor cDNA under the transcriptional control of the human metallothionein promoter into RIN5-AH cells. The transfected cells were found to exhibit an increased expression of GH receptors and to contain a specific GH receptor mRNA that was not expressed in the parent cell line. The expression of GH receptors in one clone (1.24) selected for detailed analysis was increased 2.6-fold compared to untransfected cells. The increased GH receptor expression was accompanied by an increased responsiveness to GH. Thus, the maximal GH-stimulated increase of insulin biosynthesis was 4.1-fold in 1.24 cells compared to 1.9-fold in the nontransfected RIN5-AH cells. The expression of the transfected receptor was stimulated 1.6- and 2.3-fold when cells were cultured in the presence of 25 or 50 {mu}M Zn{sup 2+} was associated with an increased magnitude of GH-stimulated insulin biosynthesis. A close stoichiometric relationship between the level of receptor expression and the level of GH-stimulated insulin biosynthesis was observed. They conclude from these results that the hepatic GH receptor is able to mediate the effect of GH on insulin biosynthesis in RIN5-AH cells.

  14. Novel growth hormone receptor gene mutation in a patient with Laron syndrome.

    Science.gov (United States)

    Arman, Ahmet; Yüksel, Bilgin; Coker, Ajda; Sarioz, Ozlem; Temiz, Fatih; Topaloglu, Ali Kemal

    2010-04-01

    Growth Hormone (GH) is a 22 kDa protein that has effects on growth and glucose and fat metabolisms. These effects are initiated by binding of growth hormone (GH) to growth hormone receptors (GHR) expressed in target cells. Mutations or deletions in the growth hormone receptor cause an autosomal disorder called Laron-type dwarfism (LS) characterized by high circulating levels of serum GH and low levels of insulin like growth factor-1 (IGF-1). We analyzed the GHR gene for genetic defect in seven patients identified as Laron type dwarfism. We identified two missense mutations (S40L and W104R), and four polymorphisms (S473S, L526I, G168G and exon 3 deletion). We are reporting a mutation (W104R) at exon 5 of GHR gene that is not previously reported, and it is a novel mutation.

  15. Structural Stereochemistry of Androstene Hormones Determines Interactions with Human Androgen, Estrogen, and Glucocorticoid Receptors

    Directory of Open Access Journals (Sweden)

    Thomas L. Shaak

    2013-01-01

    Full Text Available DHEA, 17α-AED, 17β-AED, and 17β-AET exhibit strong biological activity that has been attributed to androgenic, estrogenic, or antiglucocorticoid activity in vivo and in vitro. This study compared DHEA, 17α-AED, 17β-AED, and 17β-AET for their ability to activate the human AR, ER, and GR and determine the relative androgenicity, estrogenicity, and glucocorticoid activity. The results show that, at the receptor level, these androstene hormones are weak AR and even weaker ER activators. Direct androstene hormone activation of the human AR, ERα, and ERβ may not be essential for their biological function. Similarly, these hormones indirectly activated the human GR, only in the presence of high dexamethasone concentrations. These results underscore the major difference between androstene hormone interactions with these nuclear receptors and their biological effects.

  16. Hormones

    Science.gov (United States)

    Hormones are your body's chemical messengers. They travel in your bloodstream to tissues or organs. They work ... glands, which are special groups of cells, make hormones. The major endocrine glands are the pituitary, pineal, ...

  17. Analysis of Paired Primary-Metastatic Hormone-Receptor Positive Breast Tumors (HRPBC Uncovers Potential Novel Drivers of Hormonal Resistance.

    Directory of Open Access Journals (Sweden)

    Luis Manso

    Full Text Available We sought to identify genetic variants associated with disease relapse and failure to hormonal treatment in hormone-receptor positive breast cancer (HRPBC. We analyzed a series of HRPBC with distant relapse, by sequencing pairs (n = 11 of tumors (primary and metastases at >800X. Comparative genomic hybridization was performed as well. Top hits, based on the frequency of alteration and severity of the changes, were tested in the TCGA series. Genes determining the most parsimonious prognostic signature were studied for their functional role in vitro, by performing cell growth assays in hormonal-deprivation conditions, a setting that mimics treatment with aromatase inhibitors. Severe alterations were recurrently found in 18 genes in the pairs. However, only MYC, DNAH5, CSFR1, EPHA7, ARID1B, and KMT2C preserved an independent prognosis impact and/or showed a significantly different incidence of alterations between relapsed and non-relapsed cases in the TCGA series. The signature composed of MYC, KMT2C, and EPHA7 best discriminated the clinical course, (overall survival 90,7 vs. 144,5 months; p = 0.0001. Having an alteration in any of the genes of the signature implied a hazard ratio of death of 3.25 (p<0.0001, and early relapse during the adjuvant hormonal treatment. The presence of the D348N mutation in KMT2C and/or the T666I mutation in the kinase domain of EPHA7 conferred hormonal resistance in vitro. Novel inactivating mutations in KMT2C and EPHA7, which confer hormonal resistance, are linked to adverse clinical course in HRPBC.

  18. Prolonged signaling at the parathyroid hormone receptor by peptide ligands targeted to a specific receptor conformation.

    Science.gov (United States)

    Okazaki, Makoto; Ferrandon, Sebastien; Vilardaga, Jean-Pierre; Bouxsein, Mary L; Potts, John T; Gardella, Thomas J

    2008-10-28

    The parathyroid hormone receptor (PTHR) is a class B G protein-coupled receptor that plays critical roles in bone and mineral ion metabolism. Ligand binding to the PTHR involves interactions to both the amino-terminal extracellular (N) domain, and transmembrane/extracellular loop, or juxtamembrane (J) regions of the receptor. Recently, we found that PTH(1-34), but not PTH-related protein, PTHrP(1-36), or M-PTH(1-14) (M = Ala/Aib(1),Aib(3),Gln(10),Har(11),Ala(12),Trp(14),Arg(19)), binds to the PTHR in a largely GTPgammaS-resistant fashion, suggesting selective binding to a novel, high-affinity conformation (R(0)), distinct from the GTPgammaS-sensitive conformation (RG). We examined the effects in vitro and in vivo of introducing the M substitutions, which enhance interaction to the J domain, into PTH analogs extended C-terminally to incorporate residues involved in the N domain interaction. As compared with PTH(1-34), M-PTH(1-28) and M-PTH(1-34) bound to R(0) with higher affinity, produced more sustained cAMP responses in cells, formed more stable complexes with the PTHR in FRET and subcellular localization assays, and induced more prolonged calcemic and phosphate responses in mice. Moreover, after 2 weeks of daily injection in mice, M-PTH(1-34) induced larger increases in trabecular bone volume and greater increases in cortical bone turnover, than did PTH(1-34). Thus, the putative R(0) PTHR conformation can form highly stable complexes with certain PTH ligand analogs and thereby mediate surprisingly prolonged signaling responses in bone and/or kidney PTH target cells. Controlling, via ligand analog design, the selectivity with which a PTH ligand binds to R(0), versus RG, may be a strategy for optimizing signaling duration time, and hence therapeutic efficacy, of PTHR agonist ligands.

  19. EMR1, an unusual member in the family of hormone receptors with seven transmembrane segments.

    Science.gov (United States)

    Baud, V; Chissoe, S L; Viegas-Péquignot, E; Diriong, S; N'Guyen, V C; Roe, B A; Lipinski, M

    1995-03-20

    Proteins with seven transmembrane segments (7TM) define a superfamily of receptors (7TM receptors) sharing the same topology: an extracellular N-terminus, three extramembranous loops on either side of the plasma membrane, and a cytoplasmic C-terminal tail. Upon ligand binding, cytoplasmic portions of the activated receptor interact with heterotrimeric G-coupled proteins to induce various second messengers. A small group, recently recognized on the basis of homologous primary amino acid sequences, comprises receptors to hormones of the secretin/vasoactive intestinal peptide/glucagon family, parathyroid hormone and parathyroid hormone-related peptides, growth hormone-releasing factor, corticotropin-releasing factor, and calcitonin. A cDNA, extracted from a neuroectodermal cDNA library, was predicted to encode a new 886-amino-acid protein with three distinct domains. The C-terminal third contains the seven hydrophobic segments and characteristic residues that allow the protein to be readily aligned with the various hormone receptors in the family. Six egf-like modules, at the N-terminus of the predicted mature protein, are separated from the transmembrane segments by a serine/threonine-rich domain, a feature reminiscent of mucin-like, single-span, integral membrane glycoproteins with adhesive properties. Because of its unique characteristics, this putative egf module-containing, mucin-like hormone receptor has been named EMR1. Southern analysis of a panel of somatic cell hybrids and fluorescence in situ hybridization have assigned the EMR1 gene to human chromosome 19p13.3.

  20. Association of the thyroid stimulating hormone receptor gene (TSHR) with Graves' disease

    DEFF Research Database (Denmark)

    Brand, Oliver J; Barrett, Jeffrey C; Simmonds, Matthew J;

    2009-01-01

    Graves' disease (GD) is a common autoimmune disease (AID) that shares many of its susceptibility loci with other AIDs. The thyroid stimulating hormone receptor (TSHR) represents the primary autoantigen in GD, in which autoantibodies bind to the receptor and mimic its ligand, thyroid stimulating...... hormone, causing the characteristic clinical phenotype. Although early studies investigating the TSHR and GD proved inconclusive, more recently we provided convincing evidence for association of the TSHR region with disease. In the current study, we investigated a combined panel of 98 SNPs, including 70...

  1. CORAL: prediction of binding affinity and efficacy of thyroid hormone receptor ligands.

    Science.gov (United States)

    Toropova, A P; Toropov, A A; Benfenati, E

    2015-08-28

    Quantitative structure - activity relationships (QSARs) for binding affinity of thyroid hormone receptors based on attributes of molecular structure extracted from simplified molecular input-line entry systems (SMILES) are established using the CORAL software (http://www.insilico.eu/coral). The half maximal inhibitory concentration (IC50) is used as the measure of the binding affinity of thyroid hormone receptors. Molecular features which are statistically reliable promoters of increase and decrease for IC50 are suggested. The examples of modifications of molecular structure which lead to the increase or to the decrease of the endpoint are represented. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  2. Osteoprotegerin and breast cancer risk by hormone receptor subtype

    DEFF Research Database (Denmark)

    Fortner, Renée T; Sarink, Danja; Schock, Helena

    2017-01-01

    BACKGROUND: Circulating osteoprotegerin (OPG), a member of the receptor activator of nuclear factor kappa-B (RANK) axis, may influence breast cancer risk via its role as the decoy receptor for both the RANK ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Circul...

  3. Internalization and recycling of receptor-bound gonadotropin-releasing hormone agonist in pituitary gonadotropes

    Energy Technology Data Exchange (ETDEWEB)

    Schvartz, I.; Hazum, E.

    1987-12-15

    The fate of cell surface gonadotropin-releasing hormone (GnRH) receptors on pituitary cells was studied utilizing lysosomotropic agents and monensin. Labeling of pituitary cells with a photoreactive GnRH derivative, (azidobenzoyl-D-Lys6)GnRH, revealed a specific band of Mr = 60,000. When photoaffinity-labeled cells were exposed to trypsin immediately after completion of the binding, the radioactivity incorporated into the Mr = 60,000 band decreased, with a concomitant appearance of a proteolytic fragment (Mr = 45,000). This fragment reflects cell surface receptors. Following GnRH binding, the hormone-receptor complexes underwent internalization, partial degradation, and recycling. The process of hormone-receptor complex degradation was substantially prevented by lysosomotropic agents, such as chloroquine and methylamine, or the proton ionophore, monensin. Chloroquine and monensin, however, did not affect receptor recycling, since the tryptic fragment of Mr = 45,000 was evident after treatment with these agents. This suggests that recycling of GnRH receptors in gonadotropes occurs whether or not the internal environment is acidic. Based on these findings, we propose a model describing the intracellular pathway of GnRH receptors.

  4. EVALUATION OF STEROID HORMONES AND THEIR RECEPTORS IN DEVELOPMENT AND PROGRESSION OF RENAL CELL CARCINOMA

    Directory of Open Access Journals (Sweden)

    Nigel Bennett

    2014-06-01

    Full Text Available Steroid hormones and their receptors have important roles in normal kidney biology, and alterations in their expression and function help explain the differences in development of kidney diseases, such as nephrotic syndrome and chronic kidney disease. The distinct gender difference in incidence of renal cell carcinoma (RCC, with males having almost twice the incidence as females globally, also suggests a role for sex hormones or their receptors in RCC development and progression. There was a peak in interest in evaluating the roles of androgen and estrogen receptors in RCC pathogenesis in the late 20th century, with some positive outcomes for RCC therapy that targeted estrogen receptors, especially for metastatic disease. Since that time, however, there have been few studies that look at use of steroid hormone modulators for RCC, especially in the light of new therapies such as the tyrosine kinase inhibitors and new immune therapies, which are having some success for treatment of metastatic RCC. This review summarises past and current literature and attempts to stimulate renewed interest in research into the steroid hormones and their receptors, which might be used to effect, for example, in combination with the other newer targeted therapies for RCC.

  5. A new mutation in the thyroid hormone receptor gene of a Chinese family with resistance to thyroid hormone

    Institute of Scientific and Technical Information of China (English)

    DONG Qian; GONG Chun-xiu; GU Yi; SU Chang

    2011-01-01

    Background Resistance to thyroid hormone (RTH) is a dominant inherited syndrome of reduced tissue responsiveness to thyroid hormone. It is usually due to mutations located at the ligand-binding domain and adjacent hinge region of the thyroid hormone receptor β(TRβ). We report the clinical and laboratory characteristics and the genetic analysis of a patient with this rare disorder and his family members.Methods The clinical presentations and changes of thyroid function tests (TFTs) including magnetic resonance imaging (MRI) of pituitary and other laboratory tests were analysed. TFTs of his family's members were detected as well. Direct DNA sequencing of the TRβ gene was done for those with abnormal TFTs.Results The RTH child had goiter, irritability, aggressiveness, and sudoresis. His TFTs showed high levels of circulating free thyroid hormones (FT4 and FT3) and normal thyroid-stimulating hormone (TSH) concentrations. He felt worse when treated as hyperthyroidism (Grave disease) with thiamazole and his clinical presentations got improved obviously when treated as RTH with bromocriptine without obvious advert effect. We identified a novel missense mutation, A317D, located in exon 9 of the gene of this boy and his mother. His mother had not any clinical presentation, but having abnormal TFTs results.Conclusions This patient reported here was concordant with the criteria of RTH. The feature is dysfunction of hypothalamus-pituitary-thyroid axis. A novel mutation was found in the TRβ, A317D, of this family. This research verified the phenomena that there is a clinical heterogeneity within the same mutation of different RTH patients.

  6. Pattern of hormone receptors and human epidermal growth factor ...

    African Journals Online (AJOL)

    2015-02-05

    Feb 5, 2015 ... Key words: Breast cancer, human epidermal growth factor receptor 2/neu, immunohistochemistry, ... therapy.[6‑8] Of all these prognostic and predictive factors, ... one of the biggest private medical laboratories in Nigeria.

  7. Distinct growth hormone receptor signaling modes regulate skeletal muscle development and insulin sensitivity in mice

    OpenAIRE

    Mavalli, Mahendra D.; DiGirolamo, Douglas J; FAN, Yong; Riddle, Ryan C.; Kenneth S Campbell; van Groen, Thomas; Frank, Stuart J; Sperling, Mark A.; Esser, Karyn A.; Bamman, Marcas M.; Clemens, Thomas L.

    2010-01-01

    Skeletal muscle development, nutrient uptake, and nutrient utilization is largely coordinated by growth hormone (GH) and its downstream effectors, in particular, IGF-1. However, it is not clear which effects of GH on skeletal muscle are direct and which are secondary to GH-induced IGF-1 expression. Thus, we generated mice lacking either GH receptor (GHR) or IGF-1 receptor (IGF-1R) specifically in skeletal muscle. Both exhibited impaired skeletal muscle development characterized by reductions ...

  8. Human rhabdomyosarcoma cells express functional pituitary and gonadal sex hormone receptors: Therapeutic implications

    Science.gov (United States)

    PONIEWIERSKA-BARAN, AGATA; SCHNEIDER, GABRIELA; SUN, WENYUE; ABDELBASET-ISMAIL, AHMED; BARR, FREDERIC G.; RATAJCZAK, MARIUSZ Z.

    2016-01-01

    Evidence has accumulated that sex hormones play an important role in several types of cancer. Because they are also involved in skeletal muscle development and regeneration, we were therefore interested in their potential involvement in the pathogenesis of human rhabdomyosarcoma (RMS), a skeletal muscle tumor. In the present study, we employed eight RMS cell lines (three fusion positive and five fusion negative RMS cell lines) and mRNA samples obtained from RMS patients. The expression of sex hormone receptors was evaluated by RT-PCR and their functionality by chemotaxis, adhesion and direct cell proliferation assays. We report here for the first time that follicle-stimulating hormone (FSH) and luteinizing hormone (LH) receptors are expressed in established human RMS cell lines as well as in primary tumor samples isolated from RMS patients. We also report that human RMS cell lines responded both to pituitary and gonadal sex hormone stimulation by enhanced proliferation, chemotaxis, cell adhesion and phosphorylation of MAPKp42/44 and AKT. In summary, our results indicate that sex hormones are involved in the pathogenesis and progression of RMS, and therefore, their therapeutic application should be avoided in patients that have been diagnosed with RMS. PMID:26983595

  9. Photoaffinity labelling of the rat liver nuclear thyroid hormone receptor with (/sup 125/I)triiodothyronine

    Energy Technology Data Exchange (ETDEWEB)

    David-Inouye, Y.; Somack, R.; Nordeen, S.K.; Apriletti, J.W.; Baxter, J.D.; Eberhardt, N.L.

    1982-11-01

    (/sup 125/I)Triiodothyronine (T3) was used as a photoreactive probe for the thyroid hormone nuclear receptor in photoaffinity labelling experiments. Autoradiograms of photolysis products electrophoresed on either one or two-dimensional gels showed that (/sup 125/I)T3 covalently, but nonspecifically, labelled many proteins in the partially purified receptor preparations used. However, one of these proteins with an estimated molecular weight of 47,000 and an isoelectric point of approximately 6.2 +/- 0.5 pH units appears to be the thyroid hormone receptor, since, in contrast to the other proteins, its photoinduced labelling was blocked by concentrations of T3 and thyroxine (T4) similar to those that inhibit binding of (/sup 125/I)T3 by the receptor in equilibrium binding assays. In addition, the isoelectric point of the photolabelled protein agrees with that determined in separate equilibrium isoelectric focusing studies. These results indicate that (/sup 125/)T3 can serve as a photoreactive probe for the thyroid hormone nuclear receptor, and they suggest that this receptor is a single polypeptide chain of molecular weight 47,000 with an isoelectric point of 6.2 +/- 0.5 pH units.

  10. Photoaffinity labelling of the rat liver nuclear thyroid hormone receptor with (/sup 125/I)triiodothyronine

    Energy Technology Data Exchange (ETDEWEB)

    David-Inouye, Y. (Univ. of California, San Francisco); Somack, R; Nordeen, S.K.; Apriletti, J.W.; Baxter, J.D.; Eberhardt, N.L.

    1982-11-01

    (/sup 125/I)Triiodothyronine (T/sub 3/) was used as a photoreactive probe for the thyroid hormone nuclear receptor in photoaffinity labelling experiments. Autoradiograms of photolysis products electrophoresed on either one or two-dimensional gels showed that (/sup 125/I)T/sub 3/ covalently, but nonspecifically, labelled many proteins in the partially purified receptor preparations used. However, one of these proteins with an estimated molecular weight of 47,000 and an isoelectric point of approximately 6.2 +/- 0.5 pH units appears to be the thyroid hormone receptor, since, in contrast to the other proteins, its photoinduced labelling was blocked by concentrations of T/sub 3/ and thyroxine (T/sub 4/) similar to those that inhibit binding of (/sup 125/I)T/sub 3/ by the receptor in equilibrium binding assays. In addition, the isoelectric point of the photolabelled protein agrees with that determined in separate equilibrium isoelectric focusing studies. These results indicate that (/sup 125/I)T/sub 3/ can serve as a photoreactive probe for the thyroid hormone nuclear receptor, and they suggest that this receptor is a single polypeptide chain of molecular weight 47,000 with an isoelectric point of 6.2 +/- 0.5 pH units.

  11. Analysis of Agonist and Antagonist Effects on Thyroid Hormone Receptor Conformation by Hydrogen/Deuterium Exchange

    NARCIS (Netherlands)

    Figueira, A C M; Saidemberg, D M; Telles de Souza, Paulo; Martínez, L; Scanlan, T S; Baxter, J D; Skaf, M S; Palma, M S; Webb, P M; Polikarpov, I

    2011-01-01

    Thyroid hormone receptors (TRs) are ligand-gated transcription factors with critical roles in development and metabolism. Although x-ray structures of TR ligand-binding domains (LBDs) with agonists are available, comparable structures without ligand (apo-TR) or with antagonists are not. It remains i

  12. On the Denaturation Mechanisms of the Ligand Binding Domain of Thyroid Hormone Receptors

    NARCIS (Netherlands)

    Martínez, Leandro; Telles de Souza, P C; Garcia, Wanius; Batista, Fernanda A H; Portugal, Rodrigo V; Nascimento, Alessandro S; Nakahira, Marcel; Lima, Luis M T R; Polikarpov, Igor; Skaf, Munir S

    2010-01-01

    The ligand binding domain (LBD) of nuclear hormone receptors adopts a very compact, mostly alpha-helical structure that binds specific ligands with very high affinity. We use circular dichroism spectroscopy and high-temperature molecular dynamics Simulations to investigate unfolding of the LBDs of t

  13. Model of the complex of Parathyroid hormone-2 receptor and Tuberoinfundibular peptide of 39 residues

    Directory of Open Access Journals (Sweden)

    Persson Bengt

    2010-10-01

    Full Text Available Abstract Background We aim to propose interactions between the parathyroid hormone-2 receptor (PTH2R and its ligand the tuberoinfundibular peptide of 39 residues (TIP39 by constructing a homology model of their complex. The two related peptides parathyroid hormone (PTH and parathyroid hormone related protein (PTHrP are compared with the complex to examine their interactions. Findings In the model, the hydrophobic N-terminus of TIP39 is buried in a hydrophobic part of the central cavity between helices 3 and 7. Comparison of the peptide sequences indicates that the main discriminator between the agonistic peptides TIP39 and PTH and the inactive PTHrP is a tryptophan-phenylalanine replacement. The model indicates that the smaller phenylalanine in PTHrP does not completely occupy the binding site of the larger tryptophan residue in the other peptides. As only TIP39 causes internalisation of the receptor and the primary difference being an aspartic acid in position 7 of TIP39 that interacts with histidine 396 in the receptor, versus isoleucine/histidine residues in the related hormones, this might be a trigger interaction for the events that cause internalisation. Conclusions A model is constructed for the complex and a trigger interaction for full agonistic activation between aspartic acid 7 of TIP39 and histidine 396 in the receptor is proposed.

  14. Expression of the growth hormone receptor gene in insulin producing cells

    DEFF Research Database (Denmark)

    Møldrup, Annette; Billestrup, N; Nielsen, Jens Høiriis

    1990-01-01

    Growth hormone (GH) plays a dual role in glucose homeostasis. On the one hand, it exerts an insulin antagonistic effect on the peripheral tissue, on the other hand, it stimulates insulin biosynthesis and beta-cell proliferation. The expression of GH-receptors on the rat insulinoma cell line RIN-5AH...

  15. On the denaturation mechanisms of the ligand binding domain of thyroid hormone receptors

    NARCIS (Netherlands)

    Martínez, Leandro; Souza, Paulo C T; Garcia, Wanius; Batista, Fernanda A H; Portugal, Rodrigo V; Nascimento, Alessandro S; Nakahira, Marcel; Lima, Luis M T R; Polikarpov, Igor; Skaf, Munir S

    2010-01-01

    The ligand binding domain (LBD) of nuclear hormone receptors adopts a very compact, mostly alpha-helical structure that binds specific ligands with very high affinity. We use circular dichroism spectroscopy and high-temperature molecular dynamics simulations to investigate unfolding of the LBDs of t

  16. On the Denaturation Mechanisms of the Ligand Binding Domain of Thyroid Hormone Receptors

    NARCIS (Netherlands)

    Martínez, Leandro; Telles de Souza, P C; Garcia, Wanius; Batista, Fernanda A H; Portugal, Rodrigo V; Nascimento, Alessandro S; Nakahira, Marcel; Lima, Luis M T R; Polikarpov, Igor; Skaf, Munir S

    2010-01-01

    The ligand binding domain (LBD) of nuclear hormone receptors adopts a very compact, mostly alpha-helical structure that binds specific ligands with very high affinity. We use circular dichroism spectroscopy and high-temperature molecular dynamics Simulations to investigate unfolding of the LBDs of t

  17. Trialkyltin rexinoid-X receptor agonists selectively potentiate thyroid hormone induced programs of xenopus laevis metamorphosis

    NARCIS (Netherlands)

    Mengeling, Brenda J.; Murk, Albertinka J.; Furlow, J.D.

    2016-01-01

    The trialkyltins tributyltin (TBT) and triphenyltin (TPT) can function as rexinoid-X receptor (RXR) agonists. We recently showed that RXR agonists can alter thyroid hormone (TH) signaling in a mammalian pituitary TH-responsive reporter cell line, GH3.TRE-Luc. The prevalence of TBT and TPT in the

  18. Domains of the growth hormone receptor required for association and activation of JAK2 tyrosine kinase

    DEFF Research Database (Denmark)

    VanderKuur, J A; Wang, X; Zhang, L

    1994-01-01

    Growth hormone (GH) has recently been shown to activate the GH receptor (GHR)-associated tyrosine kinase JAK2. In the present study, regions of the GHR required for JAK2 association with GHR were identified. GH-dependent JAK2 association with GHR was detected in Chinese hamster ovary (CHO) cells...

  19. Analysis of Agonist and Antagonist Effects on Thyroid Hormone Receptor Conformation by Hydrogen/Deuterium Exchange

    NARCIS (Netherlands)

    Figueira, A C M; Saidemberg, D M; Telles de Souza, Paulo; Martínez, L; Scanlan, T S; Baxter, J D; Skaf, M S; Palma, M S; Webb, P M; Polikarpov, I

    Thyroid hormone receptors (TRs) are ligand-gated transcription factors with critical roles in development and metabolism. Although x-ray structures of TR ligand-binding domains (LBDs) with agonists are available, comparable structures without ligand (apo-TR) or with antagonists are not. It remains

  20. Growth Hormone Receptor Signaling Pathways and its Negative Regulation by SOCS2

    DEFF Research Database (Denmark)

    Fernández Pérez, Leandro; Flores-Morales, Amilcar; Guerra, Borja

    2016-01-01

    Growth hormone (GH) is a critical regulator of linear body growth during childhood but continues to have important metabolic actions throughout life. The GH receptor (GHR) is ubiquitously expressed, and deficiency of GHR signaling causes a dramatic impact on normal physiology during somatic devel...

  1. Genomics, transcriptomics, and peptidomics of Daphnia pulex neuropeptides and protein hormones

    DEFF Research Database (Denmark)

    Dircksen, Heinrich; Neupert, Susanne; Predel, Reinhard

    2011-01-01

    We report 43 novel genes in the water flea Daphnia pulex encoding 73 predicted neuropeptide and protein hormones as partly confirmed by RT-PCR. MALDI-TOF mass spectrometry identified 40 neuropeptides by mass matches and 30 neuropeptides by fragmentation sequencing. Single genes encode adipokinetic...

  2. Binding properties of solubilized gonadotropin-releasing hormone receptor: role of carboxylic groups

    Energy Technology Data Exchange (ETDEWEB)

    Hazum, E.

    1987-11-03

    The interaction of /sup 125/I-buserelin, a superactive agonist of gonadotropin-releasing hormone (GnRH), with solubilized GnRH receptor was studied. The highest specific binding of /sup 125/I-buserelin to solubilized GnRH receptor is evident at 4/sup 0/C, and equilibrium is reached after 2 h of incubation. The soluble receptor retained 100% of the original binding activity when kept at 4 or 22/sup 0/C for 60 min. Mono- and divalent cations inhibited, in a concentration-dependent manner, the binding of /sup 125/I-buserelin to solubilized GnRH receptor. Monovalent cations require higher concentrations than divalent cations to inhibit the binding. Since the order of potency with the divalent cations was identical with that of their association constants to dicarboxylic compounds, it is suggested that there are at least two carboxylic groups of the receptor that participate in the binding of the hormone. The carboxyl groups of sialic acid residues are not absolutely required for GnRH binding since the binding of /sup 125/I-buserelin to solubilized GnRH receptor was only slightly affected by pretreatment with neuraminidase and wheat germ agglutinin. The finding that polylysines stimulate luteinizing hormone (LH) release from pituitary cell cultures with the same efficacy as GnRH suggest that simple charge interactions can induce LH release. According to these results, the authors propose that the driving force for the formation of the hormone-receptor complex is an ionic interaction between the positively charged amino acid arginine in position 8 and the carboxyl groups in the binding site.

  3. Effectiveness and tolerability of fulvestrant in postmenopausal women with hormone receptor-positive breast cancer.

    Science.gov (United States)

    Jones, Stephen E; Pippen, John

    2005-04-01

    Fulvestrant, an estrogen receptor antagonist that downregulates the estrogen receptor but has no known agonist effects, has been evaluated in 2 randomized trials involving postmenopausal women with hormone receptor-positive, progressive advanced-stage breast cancer after disease progression with antiestrogen therapy. These phase III studies, from which data were reported separately and in a planned combined analysis, showed that fulvestrant 250 mg per month intramuscularly was at least as effective as anastrozole 1 mg per day orally with respect to the primary endpoint of time to progression as well as secondary efficacy endpoints, which included objective response, clinical benefit, and survival. Both trials showed that patients treated with fulvestrant had a significantly longer duration of response, and a retrospective analysis found that pretreatment with fulvestrant did not preclude response to third-line hormonal therapy. More recently, fulvestrant was shown to be active as first-line hormonal therapy for advanced-stage breast cancer, with overall efficacy similar to that of tamoxifen in patients with hormone receptor-positive disease. Fulvestrant has been well tolerated in comparative trials published to date, translating into low study withdrawal rates and maintenance of quality of life. The incidence of adverse events was similar between the treatment arms in both trials of fulvestrant versus anastrozole, but it was notably lower for fulvestrant relative to tamoxifen in the first-line setting. In light of the results of comparative phase III trials, fulvestrant is effective and well tolerated in the treatment of postmenopausal women with hormone receptor-positive advanced-stage breast cancer.

  4. Thyroid Hormone Receptors Predict Prognosis in BRCA1 Associated Breast Cancer in Opposing Ways.

    Directory of Open Access Journals (Sweden)

    Sabine Heublein

    Full Text Available Since BRCA1 associated breast cancers are frequently classified as hormone receptor negative or even triple negative, the application of endocrine therapies is rather limited in these patients. Like hormone receptors that bind to estrogen or progesterone, thyroid hormone receptors (TRs are members of the nuclear hormone receptor superfamily. TRs might be interesting biomarkers - especially in the absence of classical hormone receptors. The current study aimed to investigate whether TRs may be specifically expressed in BRCA1 associated cancer cases and whether they are of prognostic significance in these patients as compared to sporadic breast cancer cases. This study analyzed TRα and TRβ immunopositivity in BRCA1 associated (n = 38 and sporadic breast cancer (n = 86. Further, TRs were studied in MCF7 (BRCA1 wildtype and HCC3153 (BRCA1 mutated cells. TRβ positivity rate was significantly higher in BRCA1 associated as compared to sporadic breast cancers (p = 0.001. The latter observation remained to be significant when cases that had been matched for clinicopathological criteria were compared (p = 0.037. Regarding BRCA1 associated breast cancer cases TRβ positivity turned out to be a positive prognostic factor for five-year (p = 0.007 and overall survival (p = 0.026 while TRα positivity predicted reduced five-year survival (p = 0.030. Activation of TRβ resulted in down-modulation of CTNNB1 while TRα inhibition reduced cell viability in HCC3153. However, only BRCA1 wildtype MCF7 cells were capable of rapidly degrading TRα1 in response to T3 stimulation. Significantly, this study identified TRβ to be up-regulated in BRCA1 associated breast cancer and revealed TRs to be associated with patients' prognosis. TRs were also found to be expressed in triple negative BRCA1 associated breast cancer. Further studies need to be done in order to evaluate whether TRs may become interesting targets of endocrine therapeutic approaches, especially when

  5. Homologous and heterologous regulation of pituitary receptors for ghrelin and growth hormone-releasing hormone.

    Science.gov (United States)

    Luque, Raúl M; Kineman, Rhonda D; Park, Seungjoon; Peng, Xiao-Ding; Gracia-Navarro, Francisco; Castaño, Justo P; Malagon, María M

    2004-07-01

    Secretion of GH by pituitary somatotropes is primarily stimulated by the hypothalamic GHRH through the activation of a specific G protein-coupled receptor, GHRH receptor (GHRH-R). GH is also released in response to ghrelin, a peptide produced in the stomach, hypothalamus, and pituitary that activates somatotropes via a distinct G protein-coupled receptor, referred to as the GH secretagogue receptor (GHS-R). Here, we have analyzed the expression of both GHRH-R and GHS-R (by multiplex RT-PCR) in porcine pituitary cell cultures, after acute (4 h) treatment with GHRH or ghrelin as well as with other regulators of somatotropes (somatostatin, dexamethasone). Exposure of cultures to GHRH decreased GHRH-R mRNA content and also diminished GHS-R transcript levels. Likewise, ghrelin down-regulated both GHS-R and GHRH-R expression. Interestingly, administration of the activator of adenylate cyclase, forskolin, decreased GHRH-R mRNA levels but had no effect on GHS-R, thus suggesting a distinct contribution of the various intracellular signals operating in somatotropes to the regulation of the expression of these receptors. Accordingly, an atypical activator of adenylate cyclase in the pig somatotrope is low-dose (10(-13) m) somatostatin, which also suppressed GHRH-R mRNA levels without altering GHS-R expression. Finally, dexamethasone did not modify GHRH-R or GHS-R expression. In summary, our data show for the first time that ghrelin, as well as GHRH, mediates homologous and heterologous down-regulation of their own receptor synthesis. However, our results also indicate that the expression of porcine GHRH-R and GHS-R is regulated by distinct signals that may differ from those reported in other mammalian species.

  6. Expression of thyroid stimulating hormone receptor in differentiated thyroid carcinoma and its clinical significance

    Institute of Scientific and Technical Information of China (English)

    李清怀

    2013-01-01

    Objective To explore the expression of thyroid stimulating hormone (TSH) receptor in differentiated thyroid carcinoma and its clinical significance.Methods Seventy-four patients with differentiated thyroid carcinoma treated in our department from January 2009 to January 2011were selected as the observation group,and 28 patients with nodular goiter were selected as the control group.Expression of TSH receptor in the two groups were detected by immunohistochemistry.Results The positive rate of TSH receptor expression in the observation group was55.4 (41/74) ,significantly lower than that of the control

  7. Molecular identification of the first insect ecdysis triggering hormone receptors

    DEFF Research Database (Denmark)

    Iversen, Annette; Cazzamali, Giuseppe; Williamson, Michael

    2002-01-01

    The Drosophila Genome Project website (www.flybase.org) contains an annotated gene sequence (CG5911), coding for a G protein-coupled receptor. We cloned the cDNA corresponding to this sequence and found that the gene has not been correctly predicted. The corrected gene CG5911 has five introns and...

  8. Dimeric Arrangement of the Parathyroid Hormone Receptor and a Structural Mechanism for Ligand-induced Dissociation

    Energy Technology Data Exchange (ETDEWEB)

    Pioszak, Augen A.; Harikumar, Kaleeckal G.; Parker, Naomi R.; Miller, Laurence J.; Xu, H. Eric (Van Andel); (Mayo)

    2010-06-25

    The parathyroid hormone receptor (PTH1R) is a class B G protein-coupled receptor that is activated by parathyroid hormone (PTH) and PTH-related protein (PTHrP). Little is known about the oligomeric state of the receptor and its regulation by hormone. The crystal structure of the ligand-free PTH1R extracellular domain (ECD) reveals an unexpected dimer in which the C-terminal segment of both ECD protomers forms an {alpha}-helix that mimics PTH/PTHrP by occupying the peptide binding groove of the opposing protomer. ECD-mediated oligomerization of intact PTH1R was confirmed in living cells by bioluminescence and fluorescence resonance energy transfer experiments. As predicted by the structure, PTH binding disrupted receptor oligomerization. A receptor rendered monomeric by mutations in the ECD retained wild-type PTH binding and cAMP signaling ability. Our results are consistent with the hypothesis that PTH1R forms constitutive dimers that are dissociated by ligand binding and that monomeric PTH1R is capable of activating G protein.

  9. Targeting the Diuretic Hormone Receptor to Control the Cotton Leafworm, Spodoptera littoralis

    Science.gov (United States)

    Apone, Fabio; Ruggiero, Alessandra; Tortora, Assunta; Tito, Annalisa; Grimaldi, Maria Rosaria; Arciello, Stefania; Andrenacci, Davide; Lelio, Ilaria Di; Colucci, Gabriella

    2014-01-01

    The cotton leafworm, Spodoptera littoralis Boisduval (Lepidoptera: Noctuidae), is one of the most devastating pests of crops worldwide. Several types of treatments have been used against this pest, but many of them failed because of the rapid development of genetic resistance in the different insect populations. G protein coupled receptors have vital functions in most organisms, including insects; thus, they are appealing targets for species-specific pest control strategies. Among the insect G protein coupled receptors, the diuretic hormone receptors have several key roles in development and metabolism, but their importance in vivo and their potential role as targets of novel pest control strategies are largely unexplored. With the goal of using DHR genes as targets to control S. littoralis, we cloned a corticotropin-releasing factor-like binding receptor in this species and expressed the corresponding dsRNA in tobacco plants to knock down the receptor activity in vivo through RNA interference. We also expressed the receptor in mammalian cells to study its signaling pathways. The results indicate that this diuretic hormone receptor gene has vital roles in S. littoralis and represents an excellent molecular target to protect agriculturallyimportant plants from this pest. PMID:25368043

  10. Expression of a glycosylphosphatidylinositol-anchored ligand, growth hormone, blocks receptor signalling.

    Science.gov (United States)

    Guesdon, François; Kaabi, Yahia; Riley, Aiden H; Wilkinson, Ian R; Gray, Colin; James, David C; Artymiuk, Peter J; Sayers, Jon R; Ross, Richard J

    2012-12-01

    We have investigated the interaction between GH (growth hormone) and GHR (GH receptor). We previously demonstrated that a truncated GHR that possesses a transmembrane domain but no cytoplasmic domain blocks receptor signalling. Based on this observation we investigated the impact of tethering the receptor's extracellular domain to the cell surface using a native lipid GPI (glycosylphosphatidylinositol) anchor. We also investigated the effect of tethering GH, the ligand itself, to the cell surface and demonstrated that tethering either the ecGHR (extracellular domain of GHR) or the ligand itself to the cell membrane via a GPI anchor greatly attenuates signalling. To elucidate the mechanism for this antagonist activity, we used confocal microscopy to examine the fluorescently modified ligand and receptor. GH-GPI was expressed on the cell surface and formed inactive receptor complexes that failed to internalize and blocked receptor activation. In conclusion, contrary to expectation, tethering an agonist to the cell surface can generate an inactive hormone receptor complex that fails to internalize.

  11. Five gonadotrophin-releasing hormone receptors in a teleost fish: isolation, tissue distribution and phylogenetic relationships.

    Science.gov (United States)

    Moncaut, Natalia; Somoza, Gustavo; Power, Deborah M; Canário, Adelino V M

    2005-06-01

    Gonadotrophin-releasing hormone (GnRH) is the main neurohormone controlling gonadotrophin release in all vertebrates, and in teleost fish also of growth hormone and possibly of other adenohypophyseal hormones. Over 20 GnRHs have been identified in vertebrates and protochoordates and shown to bind cognate G-protein couple receptors (GnRHR). We have searched the puffer fish, Fugu rubripes, genome sequencing database, identified five GnRHR genes and proceeded to isolate the corresponding complementary DNAs in European sea bass, Dicentrachus labrax. Phylogenetic analysis clusters the European sea bass, puffer fish and all other vertebrate receptors into two main lineages corresponding to the mammalian type I and II receptors. The fish receptors could be subdivided in two GnRHR1 (A and B) and three GnRHR2 (A, B and C) subtypes. Amino acid sequence identity within receptor subtypes varies between 70 and 90% but only 50-55% among the two main lineages in fish. All European sea bass receptor mRNAs are expressed in the anterior and mid brain, and all but one are expressed in the pituitary gland. There is differential expression of the receptors in peripheral tissues related to reproduction (gonads), chemical senses (eye and olfactory epithelium) and osmoregulation (kidney and gill). This is the first report showing five GnRH receptors in a vertebrate species and the gene expression patterns support the concept that GnRH and GnRHRs play highly diverse functional roles in the regulation of cellular functions, besides the "classical" role of pituitary function regulation.

  12. The Parathyroid Hormone Family of Ligands and Receptors

    Directory of Open Access Journals (Sweden)

    Damian G. D'Souza

    2015-07-01

    Full Text Available The PTH family of ligands and receptors have a wide range of vital functions from calcium homeostasis to tissue and bone development from the embryo to adult. This family has undergone whole genome duplication events predating vertebrate evolution, indicating more primitive and ancient functions other than skeletal development. The N-terminal region of the ligands, have been widely studied by biophysical and functional analysis, resulting in the discovery of key characteristics essential for ligand-receptor activation being elucidated. Multi-substituted amino acid analogs with differential binding affinities and either antagonistic or agonistic signalling potencies have been created based on these findings allowing for improvement on potential therapies affected by the PTH system in skeletal and embryonic development. The PTH family has diversely evolved to cover a wide range of pivotal pathways crucial to growth and development throughout all animal life.

  13. Nuclear hormone receptor co-repressors: Structure and function

    OpenAIRE

    2012-01-01

    Co-repressor proteins, such as SMRT and NCoR, mediate the repressive activity of unliganded nuclear receptors and other transcription factors. They appear to act as intrinsically disordered “hub proteins” that integrate the activities of a range of transcription factors with a number of histone modifying enzymes. Although these co-repressor proteins are challenging targets for structural studies due to their largely unstructured character, a number of structures have recently been determined ...

  14. Glucocorticoid hormone resistance during primate evolution: receptor-mediated mechanisms.

    Science.gov (United States)

    Chrousos, G P; Renquist, D; Brandon, D; Eil, C; Pugeat, M; Vigersky, R; Cutler, G B; Loriaux, D L; Lipsett, M B

    1982-03-01

    The concentrations of total and protein-unbound plasma cortisol of New World monkeys are higher than those of Old World primates and prosimians. The urinary free-cortisol excretion also is increased markedly. However, there is no physiologic evidence of increased cortisol effect. These findings suggest end-organ resistance to glucocorticoids. This was confirmed by showing that the hypothalamic-pituitary adrenal axis is resistant to suppression by dexamethasone. To study this phenomenon, glucocorticoid receptors were examined in circulating mononuclear leukocytes and cultured skin fibroblasts from both New and Old World species. The receptor content is the same in all species, but the New World monkeys have a markedly decreased binding affinity for dexamethasone. Thus, the resistance of these species to the action of cortisol is due to the decreased binding affinity of the glucocorticoid receptor. This presumed mutation must have occurred after the bifurcation of Old and New World primates (approximately 60 x 10(6) yr ago) and before the diversion of the New World primates from each other (approximately 15 x 10(6) yr ago).

  15. Estradiol potentiation of gonadotropin-releasing hormone responsiveness in the anterior pituitary is mediated by an increase in gonadotropin-releasing hormone receptors

    Energy Technology Data Exchange (ETDEWEB)

    Menon, M.; Peegel, H.; Katta, V.

    1985-02-15

    In order to investigate the mechanism by which 17 beta-estradiol potentiates the action of gonadotropin-releasing hormone on the anterior pituitary in vitro, cultured pituitary cells from immature female rats were used as the model system. Cultures exposed to estradiol at concentrations ranging from 10(-10) to 10(-6) mol/L exhibited a significant augmentation of luteinizing hormone release in response to a 4-hour gonadotropin-releasing hormone (10 mumol/L) challenge at a dose of 10(-9) mol/L compared to that of control cultures. The estradiol augmentation of luteinizing hormone release was also dependent on the duration of estradiol exposure. When these cultures were incubated with tritium-labeled L-leucine, an increase in incorporation of radiolabeled amino acid into total proteins greater than that in controls was observed. A parallel stimulatory effect of estradiol on iodine 125-labeled D-Ala6 gonadotropin-releasing hormone binding was observed. Cultures incubated with estradiol at different concentrations and various lengths of time showed a significant increase in gonadotropin-releasing hormone binding capacity and this increase was abrogated by cycloheximide. Analysis of the binding data showed that the increase in gonadotropin-releasing hormone binding activity was due to a change in the number of gonadotropin-releasing hormone binding sites rather than a change in the affinity. These results suggest that (1) estradiol treatment increases the number of pituitary receptors for gonadotropin-releasing hormone, (2) the augmentary effect of estradiol on luteinizing hormone release at the pituitary level might be mediated, at least in part, by the increase in the number of binding sites of gonadotropin-releasing hormone, and (3) new protein synthesis may be involved in estradiol-mediated gonadotropin-releasing hormone receptor induction.

  16. Development of GR/MR Chimeric Receptors and Their Response to Steroid Hormones

    Institute of Scientific and Technical Information of China (English)

    Huang Qiman; Yang Qunying; Elisabeth Martinez; Guo Sandui

    2000-01-01

    We have established an effective and reliable technique of developing GR/MR chimeric receptors by DNA homologous recombination. To develop the method we transformed several different E. coli strains with a linearized plasmid containing full length of mGR(mouse GR) and hormone binding domain(HBD) of rMR(rat MR), the linear DNA undergoes recombination due to the homology of the mGR and the rMR and recircularize , and propagation in E. coli. PCR was performed to screen correct construction in which fusion between GR and MR took place. The constructs were digested with appropriate restriction endonucleases to test probable fusion sites of GR and HBD of MR. Precise fusion sites of GR and MR for constructs AB1157 # 2 , AB1157 # 18, AB 1157 # 22, AB1157 # 32, CMK603 # 6 were verified by DNA sequencing. Trans fection of COS- 7 cells with the constructs and subsequent treatment of transfected COS-7 cells with steroid hormones were carried out, the results showed that the constructs gave response to tested hormones. The study suggested that the GR/MR chimeric receptors can give rise to fusion proteins and their interactive function between hormone and receptor.

  17. Rational Design of Potent Antagonists to the Human Growth Hormone Receptor

    Science.gov (United States)

    Fuh, Germaine; Cunningham, Brian C.; Fukunaga, Rikiro; Nagata, Shigekazu; Goeddel, David V.; Wells, James A.

    1992-06-01

    A hybrid receptor was constructed that contained the extracellular binding domain of the human growth hormone (hGH) receptor linked to the transmembrane and intracellular domains of the murine granulocyte colony-stimulating factor receptor. Addition of hGH to a myeloid leukemia cell line (FDC-P1) that expressed the hybrid receptor caused proliferation of these cells. The mechanism for signal transduction of the hybrid receptor required dimerization because monoclonal antibodies to the hGH receptor were agonists whereas their monovalent fragments were not. Receptor dimerization occurs sequentially-a receptor binds to site 1 on hGH, and then a second receptor molecule binds to site 2 on hGH. On the basis of this sequential mechanism, which may occur in many other cytokine receptors, inactive hGH analogs were designed that were potent antagonists to hGH-induced cell proliferation. Such antagonists could be useful for treating clinical conditions of hGH excess, such as acromegaly.

  18. Gastrointestinal hormones stimulate growth of Foregut Neuroendocrine Tumors by transactivating the EGF receptor.

    Science.gov (United States)

    Di Florio, Alessia; Sancho, Veronica; Moreno, Paola; Delle Fave, Gianfranco; Jensen, Robert T

    2013-03-01

    Foregut neuroendocrine tumors [NETs] usually pursuit a benign course, but some show aggressive behavior. The treatment of patients with advanced NETs is marginally effective and new approaches are needed. In other tumors, transactivation of the EGF receptor (EGFR) by growth factors, gastrointestinal (GI) hormones and lipids can stimulate growth, which has led to new treatments. Recent studies show a direct correlation between NET malignancy and EGFR expression, EGFR inhibition decreases basal NET growth and an autocrine growth effect exerted by GI hormones, for some NETs. To determine if GI hormones can stimulate NET growth by inducing transactivation of EGFR, we examined the ability of EGF, TGFα and various GI hormones to stimulate growth of the human foregut carcinoid,BON, the somatostatinoma QGP-1 and the rat islet tumor,Rin-14B-cell lines. The EGFR tyrosine-kinase inhibitor, AG1478 strongly inhibited EGF and the GI hormones stimulated cell growth, both in BON and QGP-1 cells. In all the three neuroendocrine cell lines studied, we found EGF, TGFα and the other growth-stimulating GI hormones increased Tyr(1068) EGFR phosphorylation. In BON cells, both the GI hormones neurotensin and a bombesin analogue caused a time- and dose-dependent increase in EGFR phosphorylation, which was strongly inhibited by AG1478. Moreover, we found this stimulated phosphorylation was dependent on Src kinases, PKCs, matrix metalloproteinase activation and the generation of reactive oxygen species. These results raise the possibility that disruption of this signaling cascade by either EGFR inhibition alone or combined with receptor antagonists may be a novel therapeutic approach for treatment of foregut NETs/PETs.

  19. Transcriptional activation by the thyroid hormone receptor through ligand-dependent receptor recruitment and chromatin remodelling

    DEFF Research Database (Denmark)

    Grøntved, Lars; Waterfall, Joshua J; Kim, Dong Wook

    2015-01-01

    -repressors and facilitates recruitment of co-activators to activate transcription. Here we show that in addition to hormone-independent TR occupancy, ChIP-seq against endogenous TR in mouse liver tissue demonstrates considerable hormone-induced TR recruitment to chromatin associated with chromatin remodelling and activated...

  20. Polymorphism of growth hormone receptor (GHR gene in Holstein Friesian dairy cattle

    Directory of Open Access Journals (Sweden)

    Restu Misrianti

    2011-12-01

    Full Text Available Growth hormone gene have a critical role in the regulation of lactation, mammary gland development and growth process through its interaction with a specific receptor. Growth hormone (GH is an anabolic hormone which is synthesized and secreted by somatotrop cell in pituitary anterior lobe, and interacts with a specific receptor on the surface of the target cells. Growth hormone receptor (GHR has been suggested as candidate gene for traits related to milk production in Bovidae. The purpose of this study was to identify genetic polymorphism of the Growth Hormone Receptor (GHR genes in Holstein Friesian (HF cattle. Total of 353 blood samples were collected from five populations belonging to Cikole Dairy Cattle Breeding Station (BPPT-SP Cikole (88 samples, Pasir Kemis (95 samples, Cilumber (98 samples, Cipelang Livestock Embryo Center (BET Cipelang (40 samples, Singosari National Artificial Insemination Centre (BBIB Singosari (32 samples and 17 frozen semen samples from Lembang Artificial Insemination Center (BIB Lembang. Genomic DNAs were extracted by a standard phenol-chloroform protocol and amplified by a polymerase chain reaction (PCR techniques then PCR products were genotyped by the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP methods. There were two allele dan three genotypes were found namely: allele A and G, Genotype AA, AG and GG repectively. Allele A frequency (0.70-0.82 relatively higher than allele G frequency (0.18-0.30. Chi square test show that on group of BET Cipelang, BIB Lembang and BBIB Singosari population were not significantly different (0.00-0.93, while on group of BET Cipelang, BIB Lembang dan BBIB Singosari population were significantly different (6.02-11.13. Degree of observed heterozygosity (Ho ranged from 0.13-0.42 and expected heterozygosity (He ranged from 0.29-0.42.

  1. Ancient origins of metazoan gonadotropin-releasing hormone and their receptors revealed by phylogenomic analyses.

    Science.gov (United States)

    Plachetzki, David C; Tsai, Pei-San; Kavanaugh, Scott I; Sower, Stacia A

    2016-08-01

    The discovery of genes related to gonadotropin-releasing hormones (GnRH) and their receptors from diverse species has driven important advances in comparative endocrinology. However, our view of the evolutionary histories and nomenclature of these gene families has become inconsistent as several different iterations of GnRH and receptor relationships have been proposed. Whole genome sequence data are now available for most of the major lineages of animals, and an exhaustive view of the phylogenies of GnRH and their receptors is now possible. In this paper, we leverage data from publically available whole genome sequences to present a new phylogenomic analysis of GnRH and GnRH receptors and the distant relatives of each across metazoan phylogeny. Our approach utilizes a phylogenomics pipeline that searches data from 36 whole genome sequences and conducts phylogenetic analyses of gene trees. We provide a comprehensive analysis of the major groupings of GnRH peptides, related hormones and their receptors and provide some suggestions for a new nomenclature. Our study provides a framework for understanding the functional diversification of this family of neuromodulatory peptides and their receptors.

  2. Expansion of microsatellite in the thyroid hormone receptor-alpha1 gene linked to increased receptor expression and less aggressive thyroid cancer

    DEFF Research Database (Denmark)

    Onda, Masamitsu; Li, Daisy; Suzuki, Shinichi

    2002-01-01

    involvement, distant metastasis, extrathyroidal invasion and tumor-node-metastasis (TNM) classification. RESULTS: A statistically significant correlation between the length of THRA1 and thyroid hormone receptor-alpha1 expression was observed in both cell lines and primary thyroid cancers. Thyroid tumors...... that displayed higher than average thyroid hormone receptor-alpha1 expression had expanded THRA1 microsatellites and were less aggressive as judged by TNM ranking. A statistically significant correlation was also found between low thyroid hormone receptor-alpha1 expression and more aggressive thyroid cancer...

  3. High expression of follicle stimulating hormone receptor in testicular tissue of idiopathic azoospermic patients with severe spermatogenic defects

    Institute of Scientific and Technical Information of China (English)

    Wang Liquan; Huang Hefeng; Jin Fan; Zhou Caiyun; Qian Yuli; Chen Jianhua

    2014-01-01

    Background Follicle stimulating hormone is necessary for normal reproduction in men.The biochemical actions of follicle stimulating hormone result from binding to the follicle stimulating hormone receptor in the plasma membrane of Sertoli cells.Here,we investigated the expression of the follicle stimulating hormone receptor in different testicular histological phenotypes of patients with idiopathic azoospermia.Methods Fifty-seven cases of idiopathic azoospermia were classified into three groups according to the results of testicular biopsy:patients with hypospermatogenesis,patients with maturation arrest,and patients with Sertoli cell-only syndrome.Thirteen azoospermic patients identified by testicular biopsy as being capable of completing spermatogenesis acted as the control group.Immunohistochemistry and real-time quantitative reverse-transcriptase polymerase chain reaction were performed in each case,and the serum hormone level was also measured in all patients.Results The serum follicle stimulating hormone level in patients with Sertoli cell-only syndrome was significantly higher than in patients with hypospermatogenesis,maturation arrest,and complete spermatogenesis (P<0.01).The serum follicle stimulating hormone level in patients with maturation arrest was significantly higher than in patients with hypospermatogenesis and complete spermatogenesis (P<0.05).There was no difference in serum follicle stimulating hormone levels in patients with hypospermatogenesis and complete spermatogenesis.The follicle stimulating hormone receptor expression level of testicular samples with Sertoli cell-only syndrome was significantly higher than in those with hypospermatogenesis,maturation arrest,and complete spermatogenesis (P<0.05),but no significant difference was observed among hypospermatogenesis,maturation arrest,and complete spermatogenesis testicular samples.Conclusions Different serum follicle stimulating hormone levels and follicle stimulating hormone receptor

  4. Characterization of luteinizing hormone and luteinizing hormone receptor and their indispensable role in the ovulatory process of the medaka.

    Directory of Open Access Journals (Sweden)

    Katsueki Ogiwara

    Full Text Available The molecular properties and roles of luteinizing hormone (Lh and its receptor (Lhcgrbb have not been studied for the medaka (Oryzias latipes, which is an excellent animal model for ovulation studies. Here, we characterized the medaka Lh/Lhcgrbb system, with attention to its involvement in the ovulatory process of this teleost fish. In the medaka ovary, follicle-stimulating hormone receptor mRNA was expressed in small and medium-sized follicles, while lhcgrbb mRNA was expressed in the follicle layers of all growing follicles. Experiments using HEK 293T cells expressing medaka Lhcgrbb in vitro revealed that gonadotropin from pregnant mare's serum and medaka recombinant Lh (rLh bound to the fish Lhcgrbb. The fish gonadotropin subunits Gtha, Fshb, and Lhb were essentially expressed at fairly constant levels in the pituitary of the fish during a 24-h spawning cycle. Using medaka rLh, we developed a follicle culture system that allowed us to follow the whole process of oocyte maturation and ovulation in vitro. This follicle culture method enabled us to determine that the Lh surge for the preovulatory follicle occurred in vivo between 19 and 15 h before ovulation. The present study also showed that oocyte maturation and ovulation were delayed several hours in vitro compared with in vivo. Treatment of large follicles with medaka rLh in vitro significantly increased the expression of Mmp15, which was previously demonstrated to be crucial for ovulation in the fish. These findings demonstrate that Lh/Lhcgrbb is critically involved in the induction of oocyte maturation and ovulation.

  5. Estrogen, vascular estrogen receptor and hormone therapy in postmenopausal vascular disease.

    Science.gov (United States)

    Khalil, Raouf A

    2013-12-15

    Cardiovascular disease (CVD) is less common in premenopausal women than men of the same age or postmenopausal women, suggesting vascular benefits of estrogen. Estrogen activates estrogen receptors ERα, ERβ and GPR30 in endothelium and vascular smooth muscle (VSM), which trigger downstream signaling pathways and lead to genomic and non-genomic vascular effects such as vasodilation, decreased VSM contraction and growth and reduced vascular remodeling. However, randomized clinical trials (RCTs), such as the Women's Health Initiative (WHI) and Heart and Estrogen/progestin Replacement Study (HERS), have shown little vascular benefits and even adverse events with menopausal hormone therapy (MHT), likely due to factors related to the MHT used, ER profile, and RCT design. Some MHT forms, dose, combinations or route of administration may have inadequate vascular effects. Age-related changes in ER amount, distribution, integrity and post-ER signaling could alter the vascular response to MHT. The subject's age, preexisting CVD, and hormone environment could also reduce the effects of MHT. Further evaluation of natural and synthetic estrogens, phytoestrogens, and selective estrogen-receptor modulators (SERMs), and the design of appropriate MHT combinations, dose, route and 'timing' could improve the effectiveness of conventional MHT and provide alternative therapies in the peri-menopausal period. Targeting ER using specific ER agonists, localized MHT delivery, and activation of specific post-ER signaling pathways could counter age-related changes in ER. Examination of the hormone environment and conditions associated with hormone imbalance such as polycystic ovary syndrome may reveal the causes of abnormal hormone-receptor interactions. Consideration of these factors in new RCTs such as the Kronos Early Estrogen Prevention Study (KEEPS) could enhance the vascular benefits of estrogen in postmenopausal CVD. Copyright © 2013 Elsevier Inc. All rights reserved.

  6. ELABELA: a hormone essential for heart development signals via the apelin receptor.

    Science.gov (United States)

    Chng, Serene C; Ho, Lena; Tian, Jing; Reversade, Bruno

    2013-12-23

    We report here the discovery and characterization of a gene, ELABELA (ELA), encoding a conserved hormone of 32 amino acids. Present in human embryonic stem cells, ELA is expressed at the onset of zebrafish zygotic transcription and is ubiquitous in the naive ectodermal cells of the embryo. Using zinc-finger-nuclease-mediated gene inactivation in zebrafish, we created an allelic series of ela mutants. ela null embryos have impaired endoderm differentiation potential marked by reduced gata5 and sox17 expression. Loss of Ela causes embryos to develop with a rudimentary heart or no heart at all, surprisingly phenocopying the loss of the apelin receptor (aplnr), which we show serves as Ela's cognate G protein-coupled receptor. Our results reveal the existence of a peptide hormone, ELA, which, together with APLNR, forms an essential signaling axis for early cardiovascular development.

  7. Normal morphology and hormone receptor expression in the male California sea lion (Zalophus californianus) genital tract.

    Science.gov (United States)

    Colegrove, Kathleen M; Gulland, Frances M D; Naydan, Diane K; Lowenstine, Linda J

    2009-11-01

    Histomorphology and estrogen alpha (ER alpha), and progesterone receptor (PR) expression were evaluated in free-ranging stranded male California sea lions (Zalophus californianus). Hormone receptor expression was evaluated using an immunohistochemical technique with monoclonal antibodies. Estrogen and PRs were identified in the efferent ductules, prostate gland, corpus cavernosa, corpus spongiosium, penile urethra, and in the epithelium and stroma of both the penis and prepuce. In some tissues, ER alpha expression was more intense in the stroma, emphasizing the importance of the stroma in hormone-mediated growth and differentiation of reproductive organs. To our knowledge, this is the first study to localize ER alpha and PR to the epithelium of the glans penis. The results of this investigation add to the general knowledge of male California sea lion reproduction and suggest that estrogens could have a role in the function of the male reproductive tract.

  8. [Rare abnormalities of parathyroid gland function and parathyroid hormone receptor action].

    Science.gov (United States)

    Krysiak, Robert; Bartecka, Anna; Okopień, Bogusław

    2014-01-01

    The parathyroid glands, located near or within the posterior surface of the thyroid gland and secreting parathyroid hormone, are essential organs for the regulation of calcium and phosphate metabolism. As they are necessary to sustain life and maintain homeostasis, undetected or misdiagnosed parathyroid disorders may pose a significant threat to health outcomes, as their presence may increase morbidity and mortality in affected individuals. The clinical picture of some disorders associated with abnormal parathyroid hormone secretion and receptor action is sometimes complicated by coexisting abnormalities, and in these cases establishing the correct diagnosis is challenging. The remarkable progress of recent years in the area of hormonal assessment, imaging procedures and molecular biology, has resulted in a great improvement in the identification, differentiation and treatment of various parathyroid disorders and has made it possible to identify several new clinical entities. In this paper, we discuss the present state-of-art on the etiopathogenesis, clinical manifestations, diagnosis and treatment of chosen rare abnormalities of parathyroid gland function and parathyroid hormone receptor action.

  9. CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-gamma.

    Science.gov (United States)

    Herzig, Stephan; Hedrick, Susan; Morantte, Ianessa; Koo, Seung-Hoi; Galimi, Francesco; Montminy, Marc

    2003-11-13

    Fasting triggers a series of hormonal cues that promote energy balance by inducing glucose output and lipid breakdown in the liver. In response to pancreatic glucagon and adrenal cortisol, the cAMP-responsive transcription factor CREB activates gluconeogenic and fatty acid oxidation programmes by stimulating expression of the nuclear hormone receptor coactivator PGC-1 (refs 2-5). In parallel, fasting also suppresses lipid storage and synthesis (lipogenic) pathways, but the underlying mechanism is unknown. Here we show that mice deficient in CREB activity have a fatty liver phenotype and display elevated expression of the nuclear hormone receptor PPAR-gamma, a key regulator of lipogenic genes. CREB inhibits hepatic PPAR-gamma expression in the fasted state by stimulating the expression of the Hairy Enhancer of Split (HES-1) gene, a transcriptional repressor that is shown here to be a mediator of fasting lipid metabolism in vivo. The coordinate induction of PGC-1 and repression of PPAR-gamma by CREB during fasting provides a molecular rationale for the antagonism between insulin and counter-regulatory hormones, and indicates a potential role for CREB antagonists as therapeutic agents in enhancing insulin sensitivity in the liver.

  10. Identification of intracellular domains in the growth hormone receptor involved in signal transduction

    Energy Technology Data Exchange (ETDEWEB)

    Billestrup, N.; Allevato, G.; Moldrup, A. [Hagedorn Research Lab., Gentofte (Denmark)] [and others

    1994-12-31

    The growth hormone (GH) receptor belongs to the GH/prolactin/cytokine super-family of receptors. The signal transduction mechanism utilized by this class of receptors remains largely unknown. In order to identify functional domains in the intracellular region of the GH receptor we generated a number of GH receptor mutants and analyzed their function after transfection into various cell lines. A truncated GH receptor missing 184 amino acids at the C-terminus was unable to medite GH effects on transcription of the Spi 2.1 and insulin genes. However, this mutant was fully active in mediating GH-stimulated metabolic effects such as protein synthesis and lipolysis. Furthermore, this mutant GH receptor internalized rapidly following GH binding. Another truncated GH receptor lacking all but five amino acids of the cytoplasmic domain could not mediate any effects of GH nor did it internalize. Deletion of the proline-rich region or changing the four prolines to alanines also resulted in a GH receptor deficient in signaling. Mutation of phenylalanine 346 to alanine resulted in a GH receptor which did not internalize rapidly; however, this mutant GH receptor was capable of mediating GH-stimulated transcription as well as metabolic effects. These results indicate that the intracellular part of the GH receptor can be divided into at least three functional domains: (1) for transcriptional activity, two domains are involved, one located in the C-terminal 184 amino acids and the other in the proline-rich domain; (2) for metabolic effects, a domain located in or near the proline-rich region is of importance; and (3) for internalization, phenylalanine 346 is necessary. 28 refs., 1 fig.

  11. A gate-latch-lock mechanism for hormone signalling by abscisic acid receptors

    Energy Technology Data Exchange (ETDEWEB)

    Melcher, Karsten; Ng, Ley-Moy; Zhou, X Edward; Soon, Fen-Fen; Xu, Yong; Suino-Powell, Kelly M; Park, Sang-Youl; Weiner, Joshua J; Fujii, Hiroaki; Chinnusamy, Viswanathan; Kovach, Amanda; Li, Jun; Wang, Yonghong; Li, Jiayang; Peterson, Francis C; Jensen, Davin R; Yong, Eu-Leong; Volkman, Brian F; Cutler, Sean R; Zhu, Jian-Kang; Xu, H Eric; (NU Sinapore); (Van Andel); (MCW); (UCR); (Chinese Aca. Sci.)

    2010-01-12

    Abscisic acid (ABA) is a ubiquitous hormone that regulates plant growth, development and responses to environmental stresses. Its action is mediated by the PYR/PYL/RCAR family of START proteins, but it remains unclear how these receptors bind ABA and, in turn, how hormone binding leads to inhibition of the downstream type 2C protein phosphatase (PP2C) effectors. Here we report crystal structures of apo and ABA-bound receptors as well as a ternary PYL2-ABA-PP2C complex. The apo receptors contain an open ligand-binding pocket flanked by a gate that closes in response to ABA by way of conformational changes in two highly conserved β-loops that serve as a gate and latch. Moreover, ABA-induced closure of the gate creates a surface that enables the receptor to dock into and competitively inhibit the PP2C active site. A conserved tryptophan in the PP2C inserts directly between the gate and latch, which functions to further lock the receptor in a closed conformation. Together, our results identify a conserved gate-latch-lock mechanism underlying ABA signalling.

  12. Expression of anti-Mullerian hormone receptor on the appendix testis in connection with urological disorders

    Institute of Scientific and Technical Information of China (English)

    Kornél Kistamás; Olga Ruzsnavszky; Andrea Telek; Lívia Kosztka; Ilona Kovács; Beatrix Dienes; László Csernoch

    2013-01-01

    The female internal sex organs develop from the paramesonephric (Mullerian) duct.In male embryos,the regression of the Mullerian duct is caused by the anti-Mullerian hormone (AMH),which plays an important role in the process of testicular descent.The physiological remnant of the Mullerian duct in males is the appendix testis (AT).In our previous study,we presented evidence for the decreased incidence of AT in cryptorchidism with intraoperative surgery.In this report,the expression of the anti-Mullerian hormone receptor type 2 (AMHR2),the specific receptor of AMH,on the AT was investigated in connection with different urological disorders,such as hernia inguinalis,torsion of AT,cysta epididymis,varicocele,hydrocele testis and various forms of undescended testis.The correlation between the age of the patients and the expression of the AMHR2 was also examined.Reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry were used to detect the receptor's mRNA and protein levels,respectively.We demonstrate that AMHR2 is expressed in the ATs.Additionally,the presence of this receptor was proven at the mRNA and protein levels.The expression pattern of the receptor correlated with neither the examined urological disorders nor the age of the patients;therefore,the function of the AT remains obscure.

  13. A gate-latch-lock mechanism for hormone signalling by abscisic acid receptors

    KAUST Repository

    Melcher, Karsten

    2009-12-03

    Abscisic acid (ABA) is a ubiquitous hormone that regulates plant growth, development and responses to environmental stresses. Its action is mediated by the PYR/PYL/RCAR family of START proteins, but it remains unclear how these receptors bind ABA and, in turn, how hormone binding leads to inhibition of the downstream type 2C protein phosphatase (PP2C) effectors. Here we report crystal structures of apo and ABA-bound receptors as well as a ternary PYL2-ABA-PP2C complex. The apo receptors contain an open ligand-binding pocket flanked by a gate that closes in response to ABA by way of conformational changes in two highly conserved ?-loops that serve as a gate and latch. Moreover, ABA-induced closure of the gate creates a surface that enables the receptor to dock into and competitively inhibit the PP2C active site. A conserved tryptophan in the PP2C inserts directly between the gate and latch, which functions to further lock the receptor in a closed conformation. Together, our results identify a conserved gate-latch-lock mechanism underlying ABA signalling. © 2009 Macmillan Publishers Limited. All rights reserved.

  14. Prostate-specific antigen and hormone receptor expression in male and female breast carcinoma

    Directory of Open Access Journals (Sweden)

    Cohen Cynthia

    2010-09-01

    Full Text Available Abstract Background Prostate carcinoma is among the most common solid tumors to secondarily involve the male breast. Prostate specific antigen (PSA and prostate-specific acid phosphatase (PSAP are expressed in benign and malignant prostatic tissue, and immunohistochemical staining for these markers is often used to confirm the prostatic origin of metastatic carcinoma. PSA expression has been reported in male and female breast carcinoma and in gynecomastia, raising concerns about the utility of PSA for differentiating prostate carcinoma metastasis to the male breast from primary breast carcinoma. This study examined the frequency of PSA, PSAP, and hormone receptor expression in male breast carcinoma (MBC, female breast carcinoma (FBC, and gynecomastia. Methods Immunohistochemical staining for PSA, PSAP, AR, ER, and PR was performed on tissue microarrays representing six cases of gynecomastia, thirty MBC, and fifty-six FBC. Results PSA was positive in two of fifty-six FBC (3.7%, focally positive in one of thirty MBC (3.3%, and negative in the five examined cases of gynecomastia. PSAP expression was absent in MBC, FBC, and gynecomastia. Hormone receptor expression was similar in males and females (AR 74.1% in MBC vs. 67.9% in FBC, p = 0.62; ER 85.2% vs. 68.5%, p = 0.18; and PR 51.9% vs. 48.2%, p = 0.82. Conclusions PSA and PSAP are useful markers to distinguish primary breast carcinoma from prostate carcinoma metastatic to the male breast. Although PSA expression appeared to correlate with hormone receptor expression, the incidence of PSA expression in our population was too low to draw significant conclusions about an association between PSA expression and hormone receptor status in breast lesions.

  15. A Naturally Occurring Isoform Inhibits Parathyroid Hormone Receptor Trafficking and Signaling

    OpenAIRE

    Alonso, Ver?nica; Ardura, Juan A; WANG Bin; Sneddon, W Bruce; Peter A Friedman

    2010-01-01

    Parathyroid hormone (PTH) regulates calcium homeostasis and bone remodeling through its cognitive receptor (PTHR). We describe here a PTHR isoform harboring an in-frame 42-bp deletion of exon 14 (?e14-PTHR) that encodes transmembrane domain 7. ?e14-PTHR was detected in human kidney and buccal epithelial cells. We characterized its topology, cellular localization, and signaling, as well as its interactions with PTHR. The C-terminus of the ?e14-PTHR is extracellular, and cell surface expression...

  16. Receptors of Hypothalamic-Pituitary-Ovarian-Axis Hormone in Uterine Myomas

    Directory of Open Access Journals (Sweden)

    Danuta Plewka

    2014-01-01

    Full Text Available In this study the expression of GnRH, FSH, LH, ER-α, ER-β, and PR receptors was examined in uterine myomas of women in reproductive and perimenopausal age. In cases of GnRH and tropic hormones a membranous and cytoplasmic immunohistochemical reaction was detected, in cases of ER-α and PR the reaction was located in cell nucleus, and in the case of ER-β it manifested also a cytoplasmic location. In some of the examined cases the expression was detected in endometrium, myocytes, and endothelium of blood vessels, in uterine glands and myoma cells. In myometrium the level of GnRH and LH receptors increases with age, whereas the level of progesterone and both estrogen receptors decreases. In myomas of women in reproductive age, independently of their size, expression of GnRH, FSH, and LH receptors was more pronounced than in myometrium. In women of perimenopausal age, independently of myoma size, expression of LH and estrogen α receptors was higher while expression of GnRH receptors was lower than in myometrium. FSH receptor expression was not observed. Expression of estrogen receptor β was not affected by age of the woman or size of myoma. Analysis of obtained results indicates on existing in small myomas local feedback axis between GnRH-LH-progesterone.

  17. Involvement of Ghrelin-Growth Hormone Secretagogue Receptor System in Pathoclinical Profiles of Digestive System Cancer

    Institute of Scientific and Technical Information of China (English)

    Zhigang WANG; Weigang WANG; Wencai QIU; Youben FAN; Jun ZHAO; Yu WANG; Qi ZHENG

    2007-01-01

    Ghrelin receptor has been shown to be expressed along the human gastrointestinal tract.Recent studies showed that ghrelin and a synthetic ghrelin receptor agonist improved weight gain and lean body mass retention in a rat model of cancer cachexia by acting on ghrelin receptor, that is, growth hormone secretagogue receptor (GHS-R). This study aims to explore the expression and the distribution of ghrelin receptor in human gastrointestinal tract cancers and to investigate the possible involvement of the ghrelin-GHS-R system in human digestive cancers. Surgical human digestive cancer specimens were obtained from various portions of the gastrointestinal tract from different patients. The expression of ghrelin receptor in these tissues was detected by tissue microarray technique. Our results showed that ghrelin receptor was expressed in cancers throughout the gastrointestinal tract, mainly in the cytoplasm of mucosal layer cells.Its expression level possibly correlated with organ type, histological grade, tumor-nodes-metastases stage,and nutrition status (weight loss) of the patients. For the first time, we identified the distribution of ghrelin receptor in digestive system cancers. Our results implied that the ghrelin-GHS-R system might be involved in the pathoclinical profiles of digestive cancers.

  18. Pumpkin seed extract: Cell growth inhibition of hyperplastic and cancer cells, independent of steroid hormone receptors.

    Science.gov (United States)

    Medjakovic, Svjetlana; Hobiger, Stefanie; Ardjomand-Woelkart, Karin; Bucar, Franz; Jungbauer, Alois

    2016-04-01

    Pumpkin seeds have been known in folk medicine as remedy for kidney, bladder and prostate disorders since centuries. Nevertheless, pumpkin research provides insufficient data to back up traditional beliefs of ethnomedical practice. The bioactivity of a hydro-ethanolic extract of pumpkin seeds from the Styrian pumpkin, Cucurbita pepo L. subsp. pepo var. styriaca, was investigated. As pumpkin seed extracts are standardized to cucurbitin, this compound was also tested. Transactivational activity was evaluated for human androgen receptor, estrogen receptor and progesterone receptor with in vitro yeast assays. Cell viability tests with prostate cancer cells, breast cancer cells, colorectal adenocarcinoma cells and a hyperplastic cell line from benign prostate hyperplasia tissue were performed. As model for non-hyperplastic cells, effects on cell viability were tested with a human dermal fibroblast cell line (HDF-5). No transactivational activity was found for human androgen receptor, estrogen receptor and progesterone receptor, for both, extract and cucurbitin. A cell growth inhibition of ~40-50% was observed for all cell lines, with the exception of HDF-5, which showed with ~20% much lower cell growth inhibition. Given the receptor status of some cell lines, a steroid-hormone receptor independent growth inhibiting effect can be assumed. The cell growth inhibition for fast growing cells together with the cell growth inhibition of prostate-, breast- and colon cancer cells corroborates the ethnomedical use of pumpkin seeds for a treatment of benign prostate hyperplasia. Moreover, due to the lack of androgenic activity, pumpkin seed applications can be regarded as safe for the prostate.

  19. Expression of luteinizing hormone/chorionic gonadotropin receptor in the rat pineal gland.

    Science.gov (United States)

    Itoh, Masanori T; Hosaka, Takeshi; Takahashi, Noriyuki; Ishizuka, Bunpei

    2006-08-01

    Luteinizing hormone (LH) influences the secretion of melatonin (N-acetyl-5-methoxytryptamine) from the pineal gland. The present study examined the possible presence of LH/chorionic gonadotropin (CG) receptor in the pineal gland of adult female rats. Reverse transcriptase-polymerase chain reaction analyses demonstrated that LH/CG receptor mRNA is expressed in the pineal gland. Western blotting showed that the pineal gland, like the ovary, contains an 80 kDa receptor protein. Immunohistochemistry revealed that LH/CG receptor, arylalkylamine N-acetyltransferase (a regulatory enzyme in melatonin biosynthesis) and serotonin (a melatonin precursor) are localized primarily to the same cells of the pineal gland. We further found that the levels of pineal LH/CG receptor protein in normal cycling female rats change significantly during the estrous cycle, being lowest at early metestrus. These results demonstrate that LH/CG receptor is expressed in the pineal gland, primarily in melatonin-synthesizing cells, namely pinealocytes. Furthermore, it is suggested that LH influences pineal melatonin secretion through binding to this receptor. In addition, LH/CG receptor levels in the pineal gland are regulated during the estrous cycle under normal physiological conditions.

  20. Sex Hormones and Cardiometabolic Health: Role of Estrogen and Estrogen Receptors.

    Science.gov (United States)

    Clegg, Deborah; Hevener, Andrea L; Moreau, Kerrie L; Morselli, Eugenia; Criollo, Alfredo; Van Pelt, Rachael E; Vieira-Potter, Victoria J

    2017-02-17

    With increased life expectancy, women will spend over three decades of life post-menopause. The menopausal transition increases susceptibility to metabolic diseases such as obesity, diabetes, cardiovascular disease, and cancer. Thus, it is more important than ever to develop effective hormonal treatment strategies to protect aging women. Understanding the role of estrogens, and their biological actions mediated by estrogen receptors (ERs), in the regulation of cardiometabolic health is of paramount importance to discover novel targeted therapeutics. In this brief review, we provide a detailed overview of the literature, from basic science findings to human clinical trial evidence, supporting a protective role of estrogens and their receptors, specifically ERα, in maintenance of cardiometabolic health. In so doing, we provide a concise mechanistic discussion of some of the major tissue-specific roles of estrogens signaling through ERα. Taken together, evidence suggests that targeted, perhaps receptor-specific, hormonal therapies can and should be used to optimize the health of women as they transition through menopause, while reducing the undesired complications that have limited the efficacy and use of traditional hormone replacement interventions. Copyright © 2017 Endocrine Society.

  1. Molecular basis of parathyroid hormone receptor signaling and trafficking: a family B GPCR paradigm.

    Science.gov (United States)

    Vilardaga, Jean-Pierre; Romero, Guillermo; Friedman, Peter A; Gardella, Thomas J

    2011-01-01

    The parathyroid hormone (PTH) receptor type 1 (PTHR), a G protein-coupled receptor (GPCR), transmits signals to two hormone systems-PTH, endocrine and homeostatic, and PTH-related peptide (PTHrP), paracrine-to regulate different biological processes. PTHR responds to these hormonal stimuli by activating heterotrimeric G proteins, such as G(S) that stimulates cAMP production. It was thought that the PTHR, as for all other GPCRs, is only active and signals through G proteins on the cell membrane, and internalizes into a cell to be desensitized and eventually degraded or recycled. Recent studies with cultured cell and animal models reveal a new pathway that involves sustained cAMP signaling from intracellular domains. Not only do these studies challenge the paradigm that cAMP production triggered by activated GPCRs originates exclusively at the cell membrane but they also advance a comprehensive model to account for the functional differences between PTH and PTHrP acting through the same receptor.

  2. Height, age at menarche and risk of hormone receptor-positive and -negative breast cancer: A cohort study

    NARCIS (Netherlands)

    Ritte, R.; Lukanova, A.; Tjonneland, A.; Olsen, A.; Overvad, K.; Mesrine, S.; Fagherazzi, G.; Dossus, L.; Teucher, B.; Duijnhoven, van F.J.B.

    2013-01-01

    Associations of breast cancer overall with indicators of exposures during puberty are reasonably well characterized; however, uncertainty remains regarding the associations of height, leg length, sitting height and menarcheal age with hormone receptor-defined malignancies. Within the European Prospe

  3. Height, age at menarche and risk of hormone receptor-positive and -negative breast cancer : A cohort study

    NARCIS (Netherlands)

    Ritte, Rebecca; Lukanova, Annekatrin; Tjonneland, Anne; Olsen, Anja; Overvad, Kim; Mesrine, Sylvie; Fagherazzi, Guy; Dossus, Laure; Teucher, Birgit; Steindorf, Karen; Boeing, Heiner; Aleksandrova, Krasimira; Trichopoulou, Antonia; Lagiou, Pagona; Trichopoulos, Dimitrios; Palli, Domenico; Grioni, Sara; Mattiello, Amalia; Tumino, Rosario; Sacerdote, Carlotta; Ramon Quiros, Jose; Buckland, Genevieve; Molina-Montes, Esther; Chirlaque, Maria-Dolores; Ardanaz, Eva; Amiano, Pilar; Bueno-de-Mesquita, Bas; van Duijnhoven, Franzel; van Gils, Carla H.; Peeters, Petra H. M.; Wareham, Nick; Khaw, Kay-Tee; Key, Timothy J.; Travis, Ruth C.; Krum-Hansen, Sanda; Gram, Inger Torhild; Lund, Eiliv; Sund, Malin; Andersson, Anne; Romieu, Isabelle; Rinaldi, Sabina; McCormack, Valerie; Riboli, Elio; Kaaks, Rudolf

    2013-01-01

    Associations of breast cancer overall with indicators of exposures during puberty are reasonably well characterized; however, uncertainty remains regarding the associations of height, leg length, sitting height and menarcheal age with hormone receptor-defined malignancies. Within the European Prospe

  4. Epiphyseal growth plate growth hormone receptor signaling is decreased in chronic kidney disease-related growth retardation.

    Science.gov (United States)

    Troib, Ariel; Landau, Daniel; Kachko, Leonid; Rabkin, Ralph; Segev, Yael

    2013-11-01

    Linear growth retardation in children with chronic kidney disease (CKD) has been ascribed to insensitivity to growth hormone. This resistance state has been attributed to impaired growth hormone signaling through the JAK2/STAT5 pathway in liver and skeletal muscle leading to reduced insulin-like growth factor-I (IGF-I). Here we determine whether systemic and growth plate alterations in growth hormone signaling contribute to CKD-induced linear growth retardation using partially nephrectomized and pair-fed control 20-day-old rats. Serum growth hormone did not change in rats with CKD, yet serum IGF-I levels were decreased and growth retarded. The tibial growth plate hypertrophic zone was wider and vascularization at the primary ossification center was reduced in CKD. This was associated with a decrease in growth plate vascular endothelial growth factor (VEGF) mRNA and immunostainable VEGF and IGF-I levels. Growth plate growth hormone receptor and STAT5 protein levels were unchanged, while JAK2 was reduced. Despite comparable growth hormone and growth hormone receptor levels in CKD and control rats, relative STAT5 phosphorylation was significantly depressed in CKD. Of note, the mRNA of SOCS2, an inhibitor of growth hormone signaling, was increased. Thus, linear growth impairment in CKD can in part be explained by impaired long bone growth plate growth hormone receptor signaling through the JAK2/STAT5 pathway, an abnormality that may be caused by an increase in SOCS2 expression.

  5. The expression of several reproductive hormone receptors can be modified by perfluorooctane sulfonate (PFOS) in adult male rats.

    Science.gov (United States)

    López-Doval, S; Salgado, R; Lafuente, A

    2016-07-01

    This study was undertaken to evaluate the possible role of several reproductive hormone receptors on the disruption of the hypothalamic-pituitary-testis (HPT) axis activity induced by perfluorooctane sulfonate (PFOS). The studied receptors are the gonadotropin-releasing hormone receptor (GnRHr), luteinizing hormone receptor (LHr), follicle-stimulating hormone receptor (FSHr), and the androgen receptor (Ar). Adult male rats were orally treated with 1.0; 3.0 and 6.0 mg of PFOS kg(-1) d(-1) for 28 days. In general terms, PFOS can modify the relative gene and protein expressions of these receptors in several tissues of the reproductive axis. At the testicular level, apart from the expected inhibition of both gene and protein expressions of FSHr and Ar, PFOS also stimulates the GnRHr protein and the LHr gene expression. The receptors of the main hormones involved in the HPT axis may have an important role in the disruption exerted by PFOS on this axis.

  6. Expression of growth hormone receptor and its mRNA in hepatic cirrhosis

    Institute of Scientific and Technical Information of China (English)

    Hong-Tao Wang; Shuang Chen; Jie Wang; Qing-Jia Ou; Chao Liu; Shu-Sen Zheng; Mei-Hai Deng; Xiao-Ping Liu

    2003-01-01

    AIM: To investigate the expression of growth hormone receptor (GHR) and mRNA of GHR in cirrhotic livers of rats with the intension to find the basis for application of recombinant human growth hormone (rhGH) to patients with liver cirrhosis.METHODS: Hepatic cirrhosis was induced in SpragueDawley rats by administration of thioacetamide intraperitoneally for 9-12 weeks. Collagenase Ⅳ was perfused in situ for isolation of hepatocytes. The expression of GHR and its mRNA in cirrhotic livers was studied with radio-ligand binding assay, RT-PCR and digital image analysis.RESULTS: One class of specific growth hormone-binding site, GHR, was detected in hepatocytes and hepatic tissue of cirrhotic livers. The binding capacity of GHR (RT, fmol/mg protein) in rat cirrhotic liver tissue (30.8±1.9) was significantly lower than that in normal control (74.9±3.9) at the time point of the ninth week after initiation of induction of cirrhosis (n=10, P<0.05), and it decreased gradually along with the accumulation of collagen in the process of formation and development of liver cirrhosis (P<0.05). The number of binding sites (×10 4/cell) of GHR on rat cirrhotic hepatocytes (0.86±0.16) was significantly lower than that (1.28±0.24)in control (n= 10, P<0.05). The binding affinity of GHR among liver tissue, hepatocytes of various groups had no significant difference (P>0.05). The expression of GHR mRNA (riOD,pixel) in rat cirrhotic hepatic tissues (23.3±3.1) was also significantly lower than that (29.3±3.4) in normal control (n=10, P<0.05).CONCLUSION: The growth hormone receptor was expressed in a reduced level in liver tissue of cirrhotic rats,and lesser expression of growth hormone receptors was found in a later stage of cirrhosis. The reduced expression of growth hormone receptor was partly due to its decreased expression on cirrhotic hepatocytes and the reduced expression of its mRNA in cirrhotic liver tissue.

  7. Study of V2 vasopressin receptor hormone binding site using in silico methods.

    Science.gov (United States)

    Sebti, Yeganeh; Sardari, Soroush; Sadeghi, Hamid Mir Mohammad; Ghahremani, Mohammad Hossein; Innamorati, Giulio

    2015-01-01

    The antidiuretic effect of arginine vasopressin (AVP) is mediated by the vasopressin V2 receptor. The docking study of AVP as a ligand to V2 receptor helps in identifying important amino acid residues that might be involved in AVP binding for predicting the lowest free energy state of the protein complex. Whereas previous researchers were not able to detect the exact site of the ligand-receptor binding, we designed the current study to identify the vasopressin V2 receptor hormone binding site using bioinformatic methods. The 3D structure of nonapeptide hormone vasopressin was extracted from Protein Data Bank. Since no suitable template resembling V2 receptor was found, an ab initio approach was chosen to model the protein receptor. Using protein docking methods such as Hex protein-protein docking, the model of V2 receptor was docked to the peptide ligand AVP to identify possible binding sites. The residues that involved in binding site are W293, W296, D297, A300, and P301. The lowest free energy state of the protein complex was predicted after mutation in the above residues. The amount of gained energies permits us to compare the mutant forms with native forms and help to asses critical changes such as positive and negative mutations followed by ranking the best mutations. Based on the mutation/docking predictions, we found some mutants such as W293D and A300E possess positively inducing effect in ligand binding and some of them such as A300R present negatively inducing effect in ligand binding.

  8. Agonist-regulated Cleavage of the Extracellular Domain of Parathyroid Hormone Receptor Type 1*

    Science.gov (United States)

    Klenk, Christoph; Schulz, Stefan; Calebiro, Davide; Lohse, Martin J.

    2010-01-01

    The receptor for parathyroid hormone (PTHR) is a main regulator of calcium homeostasis and bone maintenance. As a member of class B of G protein-coupled receptors, it harbors a large extracellular domain, which is required for ligand binding. Here, we demonstrate that the PTHR extracellular domain is cleaved by a protease belonging to the family of extracellular metalloproteinases. We show that the cleavage takes place in a region of the extracellular domain that belongs to an unstructured loop connecting the ligand-binding parts and that the N-terminal 10-kDa fragment is connected to the receptor core by a disulfide bond. Cleaved receptor revealed reduced protein stability compared with noncleaved receptor, suggesting degradation of the whole receptor. In the presence of the agonistic peptides PTH(1–34), PTH(1–14), or PTH(1–31), the processing of the PTHR extracellular domain was inhibited, and receptor protein levels were stabilized. A processed form of the PTHR was also detected in human kidney. These findings suggest a new model of PTHR processing and regulation of its stability. PMID:20080964

  9. Agonist-regulated cleavage of the extracellular domain of parathyroid hormone receptor type 1.

    Science.gov (United States)

    Klenk, Christoph; Schulz, Stefan; Calebiro, Davide; Lohse, Martin J

    2010-03-19

    The receptor for parathyroid hormone (PTHR) is a main regulator of calcium homeostasis and bone maintenance. As a member of class B of G protein-coupled receptors, it harbors a large extracellular domain, which is required for ligand binding. Here, we demonstrate that the PTHR extracellular domain is cleaved by a protease belonging to the family of extracellular metalloproteinases. We show that the cleavage takes place in a region of the extracellular domain that belongs to an unstructured loop connecting the ligand-binding parts and that the N-terminal 10-kDa fragment is connected to the receptor core by a disulfide bond. Cleaved receptor revealed reduced protein stability compared with noncleaved receptor, suggesting degradation of the whole receptor. In the presence of the agonistic peptides PTH(1-34), PTH(1-14), or PTH(1-31), the processing of the PTHR extracellular domain was inhibited, and receptor protein levels were stabilized. A processed form of the PTHR was also detected in human kidney. These findings suggest a new model of PTHR processing and regulation of its stability.

  10. Altered metabolism of growth hormone receptor mutant mice: a combined NMR metabonomics and microarray study.

    Directory of Open Access Journals (Sweden)

    Horst Joachim Schirra

    Full Text Available BACKGROUND: Growth hormone is an important regulator of post-natal growth and metabolism. We have investigated the metabolic consequences of altered growth hormone signalling in mutant mice that have truncations at position 569 and 391 of the intracellular domain of the growth hormone receptor, and thus exhibit either low (around 30% maximum or no growth hormone-dependent STAT5 signalling respectively. These mutations result in altered liver metabolism, obesity and insulin resistance. METHODOLOGY/PRINCIPAL FINDINGS: The analysis of metabolic changes was performed using microarray analysis of liver tissue and NMR metabonomics of urine and liver tissue. Data were analyzed using multivariate statistics and Gene Ontology tools. The metabolic profiles characteristic for each of the two mutant groups and wild-type mice were identified with NMR metabonomics. We found decreased urinary levels of taurine, citrate and 2-oxoglutarate, and increased levels of trimethylamine, creatine and creatinine when compared to wild-type mice. These results indicate significant changes in lipid and choline metabolism, and were coupled with increased fat deposition, leading to obesity. The microarray analysis identified changes in expression of metabolic enzymes correlating with alterations in metabolite concentration both in urine and liver. Similarity of mutant 569 to the wild-type was seen in young mice, but the pattern of metabolites shifted to that of the 391 mutant as the 569 mice became obese after six months age. CONCLUSIONS/SIGNIFICANCE: The metabonomic observations were consistent with the parallel analysis of gene expression and pathway mapping using microarray data, identifying metabolites and gene transcripts involved in hepatic metabolism, especially for taurine, choline and creatinine metabolism. The systems biology approach applied in this study provides a coherent picture of metabolic changes resulting from impaired STAT5 signalling by the growth hormone

  11. Family history and breast cancer hormone receptor status in a Spanish cohort.

    Directory of Open Access Journals (Sweden)

    Xuejuan Jiang

    Full Text Available BACKGROUND: Breast cancer is a heterogenous disease that impacts racial/ethnic groups differently. Differences in genetic composition, lifestyles, reproductive factors, or environmental exposures may contribute to the differential presentation of breast cancer among Hispanic women. MATERIALS AND METHODS: A population-based study was conducted in the city of Santiago de Compostela, Spain. A total of 645 women diagnosed with operable invasive breast cancer between 1992 and 2005 participated in the study. Data on demographics, breast cancer risk factors, and clinico-pathological characteristics of the tumors were collected. Hormone receptor negative tumors were compared with hormone receptor postive tumors on their clinico-pathological characteristics as well as risk factor profiles. RESULTS: Among the 645 breast cancer patients, 78% were estrogen receptor-positive (ER+ or progesterone receptor-positive (PR+, and 22% were ER-&PR-. Women with a family history of breast cancer were more likely to have ER-&PR- tumors than women without a family history (Odds ratio, 1.43; 95% confidence interval, 0.91-2.26. This association was limited to cancers diagnosed before age 50 (Odds ratio, 2.79; 95% confidence interval, 1.34-5.81. CONCLUSIONS: An increased proportion of ER-&PR- breast cancer was observed among younger Spanish women with a family history of the disease.

  12. The Nuclear Hormone Receptor PPARγ as a Therapeutic Target in Major Diseases

    Directory of Open Access Journals (Sweden)

    Martina Victoria Schmidt

    2010-01-01

    Full Text Available The peroxisome proliferator-activated receptor γ (PPARγ belongs to the nuclear hormone receptor superfamily and regulates gene expression upon heterodimerization with the retinoid X receptor by ligating to peroxisome proliferator response elements (PPREs in the promoter region of target genes. Originally, PPARγ was identified as being essential for glucose metabolism. Thus, synthetic PPARγ agonists, the thiazolidinediones (TZDs, are used in type 2 diabetes therapy as insulin sensitizers. More recent evidence implied an important role for the nuclear hormone receptor PPARγ in controlling various diseases based on its anti-inflammatory, cell cycle arresting, and proapoptotic properties. In this regard, expression of PPARγ is not restricted to adipocytes, but is also found in immune cells, such as B and T lymphocytes, monocytes, macrophages, dendritic cells, and granulocytes. The expression of PPARγ in lymphoid organs and its modulation of macrophage inflammatory responses, lymphocyte proliferation, cytokine production, and apoptosis underscore its immune regulating functions. Moreover, PPARγ expression is found in tumor cells, where its activation facilitates antitumorigenic actions. This review provides an overview about the role of PPARγ as a possible therapeutic target approaching major, severe diseases, such as sepsis, cancer, and atherosclerosis.

  13. Parathyroid hormone receptor recycling: role of receptor dephosphorylation and beta-arrestin.

    Science.gov (United States)

    Chauvin, Stephanie; Bencsik, Margaret; Bambino, Tom; Nissenson, Robert A

    2002-12-01

    The recovery of PTH receptor (PTHR) function after acute homologous receptor desensitization and down-regulation in bone and kidney cells has been attributed to receptor recycling. To determine the role of receptor dephosphorylation in PTHR recycling, we performed morphological and functional assays on human embryonic kidney 293 cells stably expressing wild-type (wt) or mutant PTHRs. Confocal microscopy and ligand binding assays revealed that the wt PTHR is rapidly recycled back to the plasma membrane after removal of the agonist. Receptors that were engineered to either lack the sites of phosphorylation or to resemble constitutively phosphorylated receptors were able to recycle back to the plasma membrane with the same kinetics as the wt PTHR. The PTHR was found to be dephosphorylated by an enzyme apparently distinct from protein phosphatases 1 or 2A. The PTHR and beta-arrestin-2-green fluorescent protein (GFP) were found to stably colocalize during PTHR internalization, whereas after agonist removal and during receptor recycling, the colocalization slowly disappeared. Experiments using phosphorylation-deficient PTHRs and a dominant-negative form of beta-arrestin showed that beta-arrestin does not regulate the efficiency of PTHR recycling. These studies indicate that, unlike many G protein-coupled receptors, PTHR recycling does not require receptor dephosphorylation or its dissociation from beta-arrestin.

  14. Origin of an ancient hormone/receptor couple revealed by resurrection of an ancestral estrogen.

    Science.gov (United States)

    Markov, Gabriel V; Gutierrez-Mazariegos, Juliana; Pitrat, Delphine; Billas, Isabelle M L; Bonneton, François; Moras, Dino; Hasserodt, Jens; Lecointre, Guillaume; Laudet, Vincent

    2017-03-01

    The origin of ancient ligand/receptor couples is often analyzed via reconstruction of ancient receptors and, when ligands are products of metabolic pathways, they are not supposed to evolve. However, because metabolic pathways are inherited by descent with modification, their structure can be compared using cladistic analysis. Using this approach, we studied the evolution of steroid hormones. We show that side-chain cleavage is common to most vertebrate steroids, whereas aromatization was co-opted for estrogen synthesis from a more ancient pathway. The ancestral products of aromatic activity were aromatized steroids with a side chain, which we named "paraestrols." We synthesized paraestrol A and show that it effectively binds and activates the ancestral steroid receptor. Our study opens the way to comparative studies of biologically active small molecules.

  15. Obesity at diagnosis is associated with inferior outcomes in hormone receptor-positive operable breast cancer.

    Science.gov (United States)

    Sparano, Joseph A; Wang, Molin; Zhao, Fengmin; Stearns, Vered; Martino, Silvana; Ligibel, Jennifer A; Perez, Edith A; Saphner, Tom; Wolff, Antonio C; Sledge, George W; Wood, William C; Fetting, John; Davidson, Nancy E

    2012-12-01

    Obesity has been associated with inferior outcomes in operable breast cancer, but the relation between body mass index (BMI) and outcomes by breast cancer subtype has not been previously evaluated. The authors evaluated the relation between BMI and outcomes in 3 adjuvant trials coordinated by the Eastern Cooperative Oncology Group that included chemotherapy regimens with doxorubicin and cyclophosphamide, including E1199, E5188, and E3189. Results are expressed as hazard ratios (HRs) from Cox proportional hazards models (HR >1 indicates a worse outcome). All P values are 2-sided. When evaluated as a continuous variable in trial E1199, increasing BMI within the obese (BMI, ≥ 30 kg/m(2)) and overweight (BMI, 25-29.9 kg/m(2)) ranges was associated with inferior outcomes in hormone receptor-positive, human epidermal growth receptor 2 (HER-2)/neu-negative disease for disease-free survival (DFS; P = .0006) and overall survival (OS; P = .0007), but not in HER-2/neu-overexpressing or triple-negative disease. When evaluated as a categorical variable, obesity was associated with inferior DFS (HR, 1.24; 95% confidence interval [CI], 1.06-1.46; P = .0008) and OS (HR, 1.37; 95% CI, 1.13-1.67; P = .002) in hormone receptor-positive disease, but not other subtypes. In a model including obesity, disease subtype, and their interaction, the interaction term was significant for OS (P = .02) and showed a strong trend for DFS (P = .07). Similar results were found in 2 other trials (E5188, E3189). In a clinical trial population that excluded patients with significant comorbidities, obesity was associated with inferior outcomes specifically in patients with hormone receptor-positive operable breast cancer treated with standard chemohormonal therapy. Copyright © 2012 American Cancer Society.

  16. Characterization of pituitary growth hormone and its receptor in the green iguana (Iguana iguana).

    Science.gov (United States)

    Ávila-Mendoza, José; Carranza, Martha; Pérez-Rueda, Ernesto; Luna, Maricela; Arámburo, Carlos

    2014-07-01

    Pituitary growth hormone (GH) has been studied in most vertebrate groups; however, only a few studies have been carried out in reptiles. Little is known about pituitary hormones in the order Squamata, to which the green iguana (gi) belongs. In this work, we characterized the hypophysis of Iguana iguana morphologically. The somatotrophs (round cells of 7.6-10 μm containing 250- to 300-nm secretory granules where the giGH is stored) were found, by immunohistochemistry and in situ hybridization, exclusively in the caudal lobe of the pars distalis, whereas the lactotrophs were distributed only in the rostral lobe. A pituitary giGH-like protein was obtained by immuno-affinity chromatography employing a heterologous antibody against chicken GH. giGH showed molecular heterogeneity (22, 44, and 88 kDa by SDS-PAGE/Western blot under non-reducing conditions and at least four charge variants (pIs 6.2, 6.5, 6.9, 7.4) by isoelectric focusing. The pituitary giGH cDNA (1016 bp), amplified by PCR and RACE, encodes a pre-hormone of 218 aa, of which 190 aa correspond to the mature protein and 28 aa to the signal peptide. The giGH receptor cDNA was also partially sequenced. Phylogenetic analyses of the amino acid sequences of giGH and giGHR homologs in vertebrates suggest a parallel evolution and functional relationship between the GH and its receptor.

  17. Formation of a Ternary Complex among NHERF1, β-Arrestin, and Parathyroid Hormone Receptor*

    Science.gov (United States)

    Klenk, Christoph; Vetter, Thorsten; Zürn, Alexander; Vilardaga, Jean-Pierre; Friedman, Peter A.; Wang, Bin; Lohse, Martin J.

    2010-01-01

    β-Arrestins are crucial regulators of G-protein coupled receptor (GPCR) signaling, desensitization, and internalization. Despite the long-standing paradigm that agonist-promoted receptor phosphorylation is required for β-arrestin2 recruitment, emerging evidence suggests that phosphorylation-independent mechanisms play a role in β-arrestin2 recruitment by GPCRs. Several PDZ proteins are known to interact with GPCRs and serve as cytosolic adaptors to modulate receptor signaling and trafficking. Na+/H+ exchange regulatory factors (NHERFs) exert a major role in GPCR signaling. By combining imaging and biochemical and biophysical methods we investigated the interplay among NHERF1, β-arrestin2, and the parathyroid hormone receptor type 1 (PTHR). We show that NHERF1 and β-arrestin2 can independently bind to the PTHR and form a ternary complex in cultured human embryonic kidney cells and Chinese hamster ovary cells. Although NHERF1 interacts constitutively with the PTHR, β-arrestin2 binding is promoted by receptor activation. NHERF1 interacts directly with β-arrestin2 without using the PTHR as an interface. Fluorescence resonance energy transfer studies revealed that the kinetics of PTHR and β-arrestin2 interactions were modulated by NHERF1. These findings suggest a model in which NHERF1 may serve as an adaptor, bringing β-arrestin2 into close proximity to the PTHR, thereby facilitating β-arrestin2 recruitment after receptor activation. PMID:20656684

  18. Formation of a ternary complex among NHERF1, beta-arrestin, and parathyroid hormone receptor.

    Science.gov (United States)

    Klenk, Christoph; Vetter, Thorsten; Zürn, Alexander; Vilardaga, Jean-Pierre; Friedman, Peter A; Wang, Bin; Lohse, Martin J

    2010-09-24

    β-Arrestins are crucial regulators of G-protein coupled receptor (GPCR) signaling, desensitization, and internalization. Despite the long-standing paradigm that agonist-promoted receptor phosphorylation is required for β-arrestin2 recruitment, emerging evidence suggests that phosphorylation-independent mechanisms play a role in β-arrestin2 recruitment by GPCRs. Several PDZ proteins are known to interact with GPCRs and serve as cytosolic adaptors to modulate receptor signaling and trafficking. Na(+)/H(+) exchange regulatory factors (NHERFs) exert a major role in GPCR signaling. By combining imaging and biochemical and biophysical methods we investigated the interplay among NHERF1, β-arrestin2, and the parathyroid hormone receptor type 1 (PTHR). We show that NHERF1 and β-arrestin2 can independently bind to the PTHR and form a ternary complex in cultured human embryonic kidney cells and Chinese hamster ovary cells. Although NHERF1 interacts constitutively with the PTHR, β-arrestin2 binding is promoted by receptor activation. NHERF1 interacts directly with β-arrestin2 without using the PTHR as an interface. Fluorescence resonance energy transfer studies revealed that the kinetics of PTHR and β-arrestin2 interactions were modulated by NHERF1. These findings suggest a model in which NHERF1 may serve as an adaptor, bringing β-arrestin2 into close proximity to the PTHR, thereby facilitating β-arrestin2 recruitment after receptor activation.

  19. Nuclear hormone receptor NHR-49 controls fat consumption and fatty acid composition in C. elegans.

    Directory of Open Access Journals (Sweden)

    Marc R Van Gilst

    2005-02-01

    Full Text Available Mammalian nuclear hormone receptors (NHRs, such as liver X receptor, farnesoid X receptor, and peroxisome proliferator-activated receptors (PPARs, precisely control energy metabolism. Consequently, these receptors are important targets for the treatment of metabolic diseases, including diabetes and obesity. A thorough understanding of NHR fat regulatory networks has been limited, however, by a lack of genetically tractable experimental systems. Here we show that deletion of the Caenorhabditis elegans NHR gene nhr-49 yielded worms with elevated fat content and shortened life span. Employing a quantitative RT-PCR screen, we found that nhr-49 influenced the expression of 13 genes involved in energy metabolism. Indeed, nhr-49 served as a key regulator of fat usage, modulating pathways that control the consumption of fat and maintain a normal balance of fatty acid saturation. We found that the two phenotypes of the nhr-49 knockout were linked to distinct pathways and were separable: The high-fat phenotype was due to reduced expression of enzymes in fatty acid beta-oxidation, and the shortened adult life span resulted from impaired expression of a stearoyl-CoA desaturase. Despite its sequence relationship with the mammalian hepatocyte nuclear factor 4 receptor, the biological activities of nhr-49 were most similar to those of the mammalian PPARs, implying an evolutionarily conserved role for NHRs in modulating fat consumption and composition. Our findings in C. elegans provide novel insights into how NHR regulatory networks are coordinated to govern fat metabolism.

  20. Hormonal regulation of c-KIT receptor and its ligand: implications for human infertility?

    Science.gov (United States)

    Figueira, Marília I; Cardoso, Henrique J; Correia, Sara; Maia, Cláudio J; Socorro, Sílvia

    2014-09-01

    The c-KIT, a tyrosine kinase receptor, and its ligand the stem cell factor (SCF) play an important role in the production of male and female gametes. The interaction of SCF with c-KIT is required for germ cell survival and growth, and abnormalities in the activity of the SCF/c-KIT system have been associated with human infertility. Recently, it was demonstrated that gonadotropic and sex steroid hormones, among others, regulate the expression of SCF and c-KIT in testicular and ovarian cells. Therefore, the hormonal (de)regulation of SCF/c-KIT system in the testis and ovary may be a cause underpinning infertility. In the present review, we will discuss the effects of hormones modulating the expression levels of SCF and c-KIT in the human gonads. In addition, the implications of hormonal regulation of SCF/c-KIT system for germ cell development and fertility will be highlighted. Copyright © 2014. Published by Elsevier GmbH.

  1. Identification of a novel modulator of thyroid hormone receptor-mediated action.

    Directory of Open Access Journals (Sweden)

    Bernhard G Baumgartner

    Full Text Available BACKGROUND: Diabetes is characterized by reduced thyroid function and altered myogenesis after muscle injury. Here we identify a novel component of thyroid hormone action that is repressed in diabetic rat muscle. METHODOLOGY/PRINCIPAL FINDINGS: We have identified a gene, named DOR, abundantly expressed in insulin-sensitive tissues such as skeletal muscle and heart, whose expression is highly repressed in muscle from obese diabetic rats. DOR expression is up-regulated during muscle differentiation and its loss-of-function has a negative impact on gene expression programmes linked to myogenesis or driven by thyroid hormones. In agreement with this, DOR enhances the transcriptional activity of the thyroid hormone receptor TR(alpha1. This function is driven by the N-terminal part of the protein. Moreover, DOR physically interacts with TR( alpha1 and to T(3-responsive promoters, as shown by ChIP assays. T(3 stimulation also promotes the mobilization of DOR from its localization in nuclear PML bodies, thereby indicating that its nuclear localization and cellular function may be related. CONCLUSIONS/SIGNIFICANCE: Our data indicate that DOR modulates thyroid hormone function and controls myogenesis. DOR expression is down-regulated in skeletal muscle in diabetes. This finding may be of relevance for the alterations in muscle function associated with this disease.

  2. Divergent roles for thyroid hormone receptor β isoforms in the endocrine axis and auditory system

    Science.gov (United States)

    Abel, E. Dale; Boers, Mary-Ellen; Pazos-Moura, Carmen; Moura, Egberto; Kaulbach, Helen; Zakaria, Marjorie; Lowell, Bradford; Radovick, Sally; Liberman, M. Charles; Wondisford, Fredric

    1999-01-01

    Thyroid hormone receptors (TRs) modulate various physiological functions in many organ systems. The TRα and TRβ isoforms are products of 2 distinct genes, and the β1 and β2 isoforms are splice variants of the same gene. Whereas TRα1 and TRβ1 are widely expressed, expression of the TRβ2 isoform is mainly limited to the pituitary, triiodothyronine-responsive TRH neurons, the developing inner ear, and the retina. Mice with targeted disruption of the entire TRβ locus (TRβ-null) exhibit elevated thyroid hormone levels as a result of abnormal central regulation of thyrotropin, and also develop profound hearing loss. To clarify the contribution of the TRβ2 isoform to the function of the endocrine and auditory systems in vivo, we have generated mice with targeted disruption of the TRβ2 isoform. TRβ2-null mice have preserved expression of the TRα and TRβ1 isoforms. They develop a similar degree of central resistance to thyroid hormone as TRβ-null mice, indicating the important role of TRβ2 in the regulation of the hypothalamic-pituitary-thyroid axis. Growth hormone gene expression is marginally reduced. In contrast, TRβ2-null mice exhibit no evidence of hearing impairment, indicating that TRβ1 and TRβ2 subserve divergent roles in the regulation of auditory function. PMID:10430610

  3. Alternative splicing of follicle-stimulating hormone receptor pre-mRNA: cloning and characterization of two alternatively spliced mRNA transcripts

    NARCIS (Netherlands)

    R. Kraaij (Robert); M. Verhoef-Post (Miriam); J.A. Grootegoed (Anton); A.P.N. Themmen (Axel)

    1998-01-01

    textabstractGlycoprotein hormone receptors contain a large extracellular domain that is encoded by multiple exons, facilitating the possibility of expressing alternatively spliced transcripts. We have cloned two new splice variants of the rat follicle-stimulating hormon

  4. Expression level of nuclear steroid hormone receptors in endometrium influence on female reproductive function

    Directory of Open Access Journals (Sweden)

    N. V. Avramenko

    2015-10-01

    Full Text Available Background. In recent years, rate of hyperplastic processes of reproductive system that relate to the common genital pathology in women of all age groups increased and ranges from 17 to 59% of all gynecological pathology. Recent studies have shown that the functional state of the endometrium is determined by the number of endometrial tissue receptors to corresponding steroid hormones. Objective. To explore the state of steroid hormones receptors in endometrial hyperplasia in compare with ultrasound, hysteroscopy and histological and hormonal background data research to improve diagnosis and recovery endometrium state. Methods: medical history analysis, clinical laboratory analysis, ultrasound diagnostics, hysteroscopy, histological methods. Hormones levels (FSH, LH, prolactin, estradiol, free testosterone, and expression of estrogen and progesterone receptors in the stroma and glands was evaluated by Histochemical score. Results. 50 women of 23–52 years with hyperplasia of endometrim, were divided into 3 randomized groups: I – 20 women with primary infertility, II – 13 women with secondary infertility, III – 17 women without infertility. Early sexual activity was almost twice as often observed in the first two groups of women (respectively 61.54%, 60.00% against 29.41% in the third group. Gynecological history was weighed almost all three groups of women with chronic bilateral salpingoophoritis, obesity (I gr. – 85%, II in December. – 76.92%, III gr. – 76.47%. Uterine leiomyoma found in every second woman III gr. – 9 (52.94%, p <0.05, 3 women (15%. At primary infertility there was US endometrial hyperplasia in every from four women, endometrial thickness less than the corresponding day of the cycle, which may indicate a lack of estrogen effect on the endometrium. In secondary infertility hyperplasia was detected in 14.29% of cases, in the third group – 7.14%. Estrogen (more and progesterone (less receptors level inhibition on

  5. Infertility in Female Mice with a Gain-of-Function Mutation in the Luteinizing Hormone Receptor Is Due to Irregular Estrous Cyclicity, Anovulation, Hormonal Alterations, and Polycystic Ovaries1

    National Research Council Canada - National Science Library

    Lan Hai; Stacey R. McGee; Amanda C. Rabideau; Marilène Paquet; Prema Narayan

    2015-01-01

    ABSTRACT The luteinizing hormone receptor, LHCGR, is essential for fertility in males and females, and genetic mutations in the receptor have been identified that result in developmental and reproductive defects...

  6. Targeting the thyroid-stimulating hormone receptor with small molecule ligands and antibodies

    Science.gov (United States)

    Davies, Terry F; Latif, Rauf

    2015-01-01

    Introduction The thyroid-stimulating hormone receptor (TSHR) is the essential molecule for thyroid growth and thyroid hormone production. Since it is also a key autoantigen in Graves’ disease and is involved in thyroid cancer pathophysiology, the targeting of the TSHR offers a logical model for disease control. Areas covered We review the structure and function of the TSHR and the progress in both small molecule ligands and TSHR antibodies for their therapeutic potential. Expert opinion Stabilization of a preferential conformation for the TSHR by allosteric ligands and TSHR antibodies with selective modulation of the signaling pathways is now possible. These tools may be the next generation of therapeutics for controlling the pathophysiological consequences mediated by the effects of the TSHR in the thyroid and other extrathyroidal tissues. PMID:25768836

  7. Growth Hormone Receptor Antagonist Treatment Reduces Exercise Performance in Young Males

    DEFF Research Database (Denmark)

    Goto, K.; Doessing, S.; Nielsen, R.H.

    2009-01-01

    period, they exercised to determine exercise performance and hormonal and metabolic responses. Participants: Twenty healthy males participated in the study. Intervention: Subjects were treated with the GHR antagonist (n = 10; 10 mg/d) or placebo (n = 10). After the treatment period, they performed...... a maximal oxygen uptake ((V) over dotO(2max)) test and a prolonged exercise test, consisting of 60 min of submaximal cycling followed by exercise to fatigue at 90% of (V) over dotO(2max). Main Outcome Measures: (V) over dotO(2max) was measured before and after the treatment period. Hormonal and metabolic......Context: The effects of GH on exercise performance remain unclear. Objective: The aim of the study was to examine the effects of GH receptor (GHR) antagonist treatment on exercise performance. Design: Subjects were treated with the GHR antagonist pegvisomant or placebo for 16 d. After the treatment...

  8. The Arabidopsis NPR1 Protein Is a Receptor for the Plant Defense Hormone Salicylic Acid

    Directory of Open Access Journals (Sweden)

    Yue Wu

    2012-06-01

    Full Text Available Salicylic acid (SA is an essential hormone in plant immunity, but its receptor has remained elusive for decades. The transcriptional coregulator NPR1 is central to the activation of SA-dependent defense genes, and we previously found that Cys521 and Cys529 of Arabidopsis NPR1's transactivation domain are critical for coactivator function. Here, we demonstrate that NPR1 directly binds SA, but not inactive structural analogs, with an affinity similar to that of other hormone-receptor interactions and consistent with in vivo Arabidopsis SA concentrations. Binding of SA occurs through Cys521/529 via the transition metal copper. Mechanistically, our results suggest that binding of SA causes a conformational change in NPR1 that is accompanied by the release of the C-terminal transactivation domain from the N-terminal autoinhibitory BTB/POZ domain. While NPR1 is already known as a link between the SA signaling molecule and defense-gene activation, we now show that NPR1 is the receptor for SA.

  9. Thyroid hormone exerts negative feedback on hypothalamic type 4 melanocortin receptor expression.

    Science.gov (United States)

    Decherf, Stéphanie; Seugnet, Isabelle; Kouidhi, Soumaya; Lopez-Juarez, Alejandra; Clerget-Froidevaux, Marie-Stéphanie; Demeneix, Barbara A

    2010-03-01

    The type 4 melanocortin receptor MC4R, a key relay in leptin signaling, links central energy control to peripheral reserve status. MC4R activation in different brain areas reduces food intake and increases energy expenditure. Mice lacking Mc4r are obese. Mc4r is expressed by hypothalamic paraventricular Thyrotropin-releasing hormone (TRH) neurons and increases energy usage through activation of Trh and production of the thyroid hormone tri-iodothyronine (T(3)). These facts led us to test the hypothesis that energy homeostasis should require negative feedback by T(3) on Mc4r expression. Quantitative PCR and in situ hybridization showed hyperthyroidism reduces Mc4r mRNA levels in the paraventricular nucleus. Comparative in silico analysis of Mc4r regulatory regions revealed two evolutionarily conserved potential negative thyroid hormone-response elements (nTREs). In vivo ChIP assays on mouse hypothalamus demonstrated association of thyroid hormone receptors (TRs) with a region spanning one nTRE. Further, in vivo gene reporter assays revealed dose-dependent T(3) repression of transcription from the Mc4r promoter in mouse hypothalamus, in parallel with T(3)-dependent Trh repression. Mutagenesis of the nTREs in the Mc4r promoter demonstrated direct regulation by T(3), consolidating the ChIP results. In vivo shRNA knockdown, TR over-expression approaches and use of mutant mice lacking specific TRs showed that both TRalpha and TRbeta contribute to Mc4r regulation. T(3) repression of Mc4r transcription ensures that the energy-saving effects of T(3) feedback on Trh are not overridden by MC4R activation of Trh. Thus parallel repression by T(3) on hypothalamic Mc4r and Trh contributes to energy homeostasis.

  10. Molecular cloning and functional analysis of Chinese sturgeon (Acipenser sinensis) growth hormone receptor

    Institute of Scientific and Technical Information of China (English)

    LIAO ZhiYong; CHEN XiaoLi; WU MingJiang

    2009-01-01

    A full length cDNA encoding the growth hormone receptor (GHR) of Chinese sturgeon was cloned in order to investigate the mechanism of growth hormone in regulating the growth of Chinese sturgeon.The open reading frame of the cloned Chinese sturgeon growth hormone receptor (csGHR) cDNA encodes a trans-membrane protein of 611 amino acids containing all the characteristic motifs of GHR. By sequence alignment, substitutions of amino acid residues highly conserved in other species were identified. Using the CHO cell culture system, the function of csGHR and the biological significance of the amino acid substitution in csGHR were examined. The promoter of serine protease inhibitor 2.1(Spi2.1) was trana-activated upon stimulation of seabream GH (sbGH) in the csGHR-expressing CHO cells. Furthermore, CHO cells stably expressing csGHR were stimulated to proliferate by sbGH. In agreement with our previous report, Chinese sturgeon growth hormone-binding protein (csGHBP) was detected in the culture medium of CHO cells stably expressing csGHR. Mutation of Asp residue in the ligand binding motif in csGHR to Glu significantly enhanced csGHR's biological function, whereas mutation of Asp residue to Ala decreased its biological function. The results demonstrated that the cloned csGHR was of full biological function and the csGHBP could be generated through proteolysis of csGHR. These findings might provide new insights into thoroughly understanding the regulatory mechanism of Chinese sturgeon growth.

  11. Molecular cloning and functional analysis of Chinese sturgeon (Acipenser sinensis) growth hormone receptor

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    A full length cDNA encoding the growth hormone receptor (GHR) of Chinese sturgeon was cloned in order to investigate the mechanism of growth hormone in regulating the growth of Chinese sturgeon. The open reading frame of the cloned Chinese sturgeon growth hormone receptor (csGHR) cDNA encodes a trans-membrane protein of 611 amino acids containing all the characteristic motifs of GHR. By sequence alignment, substitutions of amino acid residues highly conserved in other species were identified. Using the CHO cell culture system, the function of csGHR and the biological significance of the amino acid substitution in csGHR were examined. The promoter of serine protease inhibitor 2.1 (Spi2.1) was trans-activated upon stimulation of seabream GH (sbGH) in the csGHR-expressing CHO cells. Furthermore, CHO cells stably expressing csGHR were stimulated to proliferate by sbGH. In agreement with our previous report, Chinese sturgeon growth hormone-binding protein (csGHBP) was detected in the culture medium of CHO cells stably expressing csGHR. Mutation of Asp residue in the ligand binding motif in csGHR to Glu significantly enhanced csGHR’s biological function, whereas mutation of Asp residue to Ala decreased its biological function. The results demonstrated that the cloned csGHR was of full biological function and the csGHBP could be generated through proteolysis of csGHR. These findings might provide new insights into thoroughly understanding the regulatory mechanism of Chinese sturgeon growth.

  12. Morphological and Hormonal Identiifcation of Porcine Atretic Follicles and Relationship Analysis of Hormone Receptor Levels During Granulosa Cell Apoptosis In vivo

    Institute of Scientific and Technical Information of China (English)

    YU De-bing; YU Min-li; LIN Fei; JIANG Bao-chun; YANG Li-na; WANG Si-yu; ZHAO Ying; WNAG Zheng-chao

    2014-01-01

    Recent reports have demonstrated that follicular atresia is initiated or caused by granulosa cell apoptosis followed by theca cell degeneration in mammalian ovaries, but the mechanism of follicular atresia is still to be elucidated. Therefore, our present study was designed to examine our hypothesis that the changes of follicular microenvironment induce the granulosa cell apoptosis during pocrine follicular atresia in vivo. We ifrstly isolated intact porcine antral follicles and identiifed them into three groups, healthy follicles (HF), early atretic follicles (EAF) and progressed atretic follicles (PAF) through morphology and histology. To further conifrm their status, we detected hormone levels in follicular lfuids and the expression level of apoptosis gene Bax in granulosa cells. The rate of progesterone (P) and estradiol (E2) was increased with the expression of Bax, indicating hormone can be used as a marker of granulosa cell apoptosis or follicular atresia. Finally, we analyzed the expression level of hormone receptor genes in granulosa cells and their relationship with follicular atresia. In PAF, the expression of Progesterone receptor (PGR) was increased signiifcantly while estradiol receptor (ER) had no notable changes, which suggesting the increased-PGR accelerated the effect of P-stimulated granulosa cell apoptosis. The dramatic increasing of androgen receptor (AR) expression in PAF and the obvious increase of tumor necrosis factor-αreceptor (TNFR) in EAF indicated that there are different pathways regulating granulosa cell apoptosis during follicular atresia. Together, our results suggested that different pathways of granulosa cell apoptosis was induced by changing the follicular microenvironment during follicular atresia.

  13. HER-2,P53 and Hormonal Receptors Protein Expression as Predictive Factors in Breast Cancer Prognosis

    Institute of Scientific and Technical Information of China (English)

    seyed Mohanmmad Rabiee Hashemi; Somayeh Rabiee Hashemi

    2008-01-01

    Breast cancer is a heterogeneous disease with vari-able biological and clinical characteristics. We conducted a study to evaluate P53,HER-2/neu and hormonal receptor expression as predictors of prognosis in breast cancer. METHODS In a prospective study, we recruited 81 consecutive patients with primary operable breast cancer who were treated with mastectomy followed by locoregional radiotherapy or che-motherapy and studied the presence of P53,HER-2/neu and hormonal receptors(ER/PR) expression in tumor tissues by im-munohistochemical staining. Associations between these markers expression and clinical outcomes, including local and regional recurrence and metastasis were evaluated. Statistical analysis was performed with the SPSS software. RESUITS The mean time of follow-up was (47.3±4.6)months. Expression of P53, HER-2/neu, Estrogen receptors and progester-one receptors were observed in 31.1%, 38.5%, 31.8%and 51.7%ofthe patients, respectively. P53,HER-2/neu and Negative ER status were potent predictors of local-regional recurrence(P=0.034,0.038,0.044,respectively).Also HER-2/neu,Negative ER and Negative PR status were strong predictors of metastasis(P=0.001,0.042,0.054,respectively).CONCLUSION OP53 and HER-2/neu expression and also steroid receptors status(ER/PR status)have an important role in predict-ing the outcome of breast cancer and thus may be of value in se-lecting suitable therapeutic strategy and determining prognosis in these patients.

  14. Receptors and effects of gut hormones in three osteoblastic cell lines

    Directory of Open Access Journals (Sweden)

    Wilson Peter JM

    2011-07-01

    Full Text Available Abstract Background In recent years the interest on the relationship of gut hormones to bone processes has increased and represents one of the most interesting aspects in skeletal research. The proportion of bone mass to soft tissue is a relationship that seems to be controlled by delicate and subtle regulations that imply "cross-talks" between the nutrient intake and tissues like fat. Thus, recognition of the mechanisms that integrate a gastrointestinal-fat-bone axis and its application to several aspects of human health is vital for improving treatments related to bone diseases. This work analysed the effects of gut hormones in cell cultures of three osteoblastic cell lines which represent different stages in osteoblastic development. Also, this is the first time that there is a report on the direct effects of glucagon-like peptide 2, and obestatin on osteoblast-like cells. Methods mRNA expression levels of five gut hormone receptors (glucose-dependent insulinotropic peptide [GIP], glucagon-like peptide 1 [GLP-1], glucagon-like peptide 2 [GLP-2], ghrelin [GHR] and obestatin [OB] were analysed in three osteoblastic cell lines (Saos-2, TE-85 and MG-63 showing different stages of osteoblast development using reverse transcription and real time polymerase chain reaction. The responses to the gut peptides were studied using assays for cell viability, and biochemical bone markers: alkaline phosphatase (ALP, procollagen type 1 amino-terminal propeptides (P1NP, and osteocalcin production. Results The gut hormone receptor mRNA displayed the highest levels for GIP in Saos-2 and the lowest levels in MG-63, whereas GHR and GPR39 (the putative obestatin receptor expression was higher in TE-85 and MG-63 and lower in Saos-2. GLP-1 and GLP-2 were expressed only in MG-63 and TE-85. Treatment of gut hormones to cell lines showed differential responses: higher levels in cell viability in Saos-2 after GIP, in TE-85 and MG-63 after GLP-1, GLP-2, ghrelin and

  15. Estrogen receptor activation by tobacco smoke condensate in hormonal therapy-resistant breast cancer cells.

    Science.gov (United States)

    Niwa, Toshifumi; Shinagawa, Yuri; Asari, Yosuke; Suzuki, Kanae; Takanobu, Junko; Gohno, Tatsuyuki; Yamaguchi, Yuri; Hayashi, Shin-Ichi

    2017-01-01

    The relationship between tobacco smoke and breast cancer incidence has been studied for many years, but the effect of smoking on hormonal therapy has not been previously reported. We investigated the effect of smoking on hormonal therapy by performing in vitro experiments. We first prepared tobacco smoke condensate (TSC) and examined its effect on estrogen receptor (ER) activity. The ER activity was analyzed using MCF-7-E10 cells into which the estrogen-responsive element (ERE)-green fluorescent protein (GFP) reporter gene had been stably introduced (GFP assay) and performing an ERE-luciferase assay. TSC significantly activated ERs, and upregulated its endogenous target genes. This activation was inhibited by fulvestrant but more weakly by tamoxifen. These results suggest that the activation mechanism may be different from that for estrogen. Furthermore, using E10 estrogen depletion-resistant cells (EDR cells) established as a hormonal therapy-resistant model showing estrogen-independent ER activity, ER activation and induction of ER target genes were significantly higher following TSC treatment than by estradiol (E2). These responses were much higher than those of the parental E10 cells. In addition, the phosphorylation status of signaling factors (ERK1/2, Akt) and ER in the E10-EDR cells treated with TSC increased. The gene expression profile induced by estrogenic effects of TSC was characterized by microarray analysis. The findings suggested that TSC activates ER by both ligand-dependent and -independent mechanisms. Although TSC constituents will be metabolized in vivo, breast cancer tissues might be exposed for a long period along with hormonal therapy. Tobacco smoke may have a possibility to interfere with hormonal therapy for breast cancer, which may have important implications for the management of therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Thyroid hormone regulation of gene expression in primary cerebrocortical cells: role of thyroid hormone receptor subtypes and interactions with retinoic acid and glucocorticoids.

    Directory of Open Access Journals (Sweden)

    Pilar Gil-Ibáñez

    Full Text Available The effects of thyroid hormone on brain development and function are largely mediated by the binding of 3,5,3'-triiodo-L-thyronine (T3 to its nuclear receptors (TR to regulate positively or negatively gene expression. We have analyzed by quantitative polymerase chain reaction the effect of T3 on primary cultured cells from the embryonic mouse cerebral cortex, on the expression of Hr, Klf9, Shh, Dio3, Aldh1a1, and Aldh1a3. In particular we focused on T3 receptor specificity, and on the crosstalk between T3, retinoic acid and dexamethasone. To check for receptor subtype specificity we used cerebrocortical cells derived from wild type mice and from mice deficient in thyroid hormone receptor subtypes. Receptor subtype specificity was found for Dio3 and Aldh1a1, which were induced by T3 only in cells expressing the T3 receptor alpha 1 subtype. Interactions of T3 with retinoic acid signaling through the control of retinoic acid metabolism are likely to be important during development. T3 had opposing influences on retinoic acid synthesizing enzymes, increasing the expression of Aldh1a1, and decreasing Aldh1a3, while increasing the retinoic acid degrading enzyme Cyp26b1. Dexamethasone increased Klf9 and Aldh1a1 expression. The effects of T3 and dexamethasone on Aldh1a1 were highly synergistic, with mRNA increments of up to 20 fold. The results provide new data on thyroid hormone regulation of gene expression and underscore the importance of thyroid hormone interactions with retinoic acid and glucocorticoids during neural development.

  17. Novel growth hormone receptor mutation in a Chinese patient with Laron syndrome.

    Science.gov (United States)

    Hui, Hamilton N T; Metherell, Louise A; Ng, K L; Savage, Martin O; Camacho-Hübner, Cecilia; Clark, Adrian J L

    2005-02-01

    Laron syndrome, growth hormone (GH) insensitivity syndrome, caused by a mutation of the GH receptor (GHR) gene, is extremely rare in the Chinese population. We report a Chinese girl diagnosed with Laron syndrome at age 1.9 years with height -4.9 SDS, basal GH 344 mIU/ml, IGF-I <12 ng/ml, IGFBP-3 <0.2 mg/ml, and undetectable GHBP. A novel mutation of the GHR, not previously described, was identified at the donor splice site of intron 6.

  18. Perfluorooctane sulfonate (PFOS) affects hormone receptor activity, steroidogenesis, and expression of endocrine-related genes in vitro and in vivo.

    Science.gov (United States)

    Du, Guizhen; Hu, Jialei; Huang, Hongyu; Qin, Yufeng; Han, Xiumei; Wu, Di; Song, Ling; Xia, Yankai; Wang, Xinru

    2013-02-01

    Perfluorooctane sulfonate (PFOS) is a widespread and persistent chemical in the environment. We investigated the endocrine-disrupting effects of PFOS using a combination of in vitro and in vivo assays. Reporter gene assays were used to detect receptor-mediated (anti-)estrogenic, (anti-)androgenic, and (anti-)thyroid hormone activities. The effect of PFOS on steroidogenesis was assessed both at hormone levels in the supernatant and at expression levels of hormone-induced genes in the H295R cell. A zebrafish-based short-term screening method was developed to detect the effect of PFOS on endocrine function in vivo. The results indicate that PFOS can act as an estrogen receptor agonist and thyroid hormone receptor antagonist. Exposure to PFOS decreased supernatant testosterone (T), increased estradiol (E2) concentrations in H295R cell medium and altered the expression of several genes involved in steroidogenesis. In addition, PFOS increased early thyroid development gene (hhex and pax8) expression in a concentration-dependent manner, decreased steroidogenic enzyme gene (CYP17, CYP19a, CYP19b) expression, and changed the expression pattern of estrogen receptor production genes (esr1, esr2b) after 500 µg/L PFOS treatment in zebrafish embryos. These results indicate that PFOS has the ability to act as an endocrine disruptor both in vitro and in vivo by disrupting the function of nuclear hormone receptors, interfering with steroidogenesis, and altering the expression of endocrine-related genes in zebrafish embryo.

  19. Evolution of parathyroid hormone receptor family and their ligands in vertebrate

    Directory of Open Access Journals (Sweden)

    Jason S.W. eOn

    2015-03-01

    Full Text Available The presence of the parathyroid hormones in vertebrates, including PTH, PTH-related peptide (PTHrP and tuberoinfundibular peptide of 39 residues (TIP39, has been proposed to be the result of two rounds of whole genome duplication in the beginning of vertebrate diversification. Bioinformatics analyses, in particular chromosomal synteny study and the characterization of the PTH ligands and their receptors from various vertebrate species, provide evidence that strongly supports this hypothesis. In this mini-review, we summarize recent advances in studies regarding the molecular evolution and physiology of the PTH ligands and their receptors, with particular focus on non-mammalian vertebrates. In summary, the PTH family of peptides probably predates early vertebrate evolution, indicating a more ancient existence as well as a function of these peptides in invertebrates.

  20. Effect of thyrotrophin releasing hormone on opiate receptors of the rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Balashov, A.M.; Shchurin, M.R.

    1987-01-01

    It has recently been shown that the hypothalamic thyrotropin releasing hormone (TRH) has the properties of a morphine antagonist, blocking its inhibitory action on respiration and, to a lesser degree, its analgesic action. This suggests that the antagonistic effects of TRH are mediated through its interaction with opiate receptors. The aim of this paper is to study this hypothesis experimentally. Tritium-labelled enkephalins in conjunction with scintillation spectroscopy were used to assess the receptor binding behavior. The results indicate the existence of interconnections between the opiate systems and TRH. Although it is too early to reach definite conclusions on the mechanisms of this mutual influence and its physiological significance it can be tentatively suggested that TRH abolishes the pharmacological effects of morphine by modulating the functional state of opiate reception.

  1. Thyroid hormone and reproduction: regulation of estrogen receptors in goldfish gonads.

    Science.gov (United States)

    Nelson, Erik R; Allan, Euan R O; Pang, Flora Y; Habibi, Hamid R

    2010-09-01

    There is increasing evidence that thyroid hormones influence reproduction in vertebrates. However, little information is available on the mechanisms by which this happens. As a first step in determining these mechanisms, we test the hypothesis that the estrogen receptor subtypes (ERalpha, ERbeta-1, and ERbeta-2) are regulated by the thyroid hormone, (T(3)), in the gonads of goldfish. All three subtypes were down-regulated by T(3) in the testis or ovary. We also found evidence that T(3) decreased pituitary gonadotropin expression and decreased transcript for gonadal aromatase. Collectively, it appears that T(3) acts to diminish estrogen signaling by (1) decreasing pituitary LH expression and thus steroidogenesis, (2) down-regulating gonadal aromatase expression and thus decreasing estrogen synthesis from androgens, and (3) decreasing sensitivity to estrogen by down-regulating the ER subtypes. Goldfish are seasonal breeders, spawning once a year, and thus have two distinct periods of growth: somatic and reproductive. Circulating thyroid hormone levels have been found to increase just after spawning. Therefore, we propose that this may be an endocrine mechanism that goldfish use to switch their energy expenditure from reproductive to growth efforts in the goldfish. (c) 2010 Wiley-Liss, Inc.

  2. Ghrelin counteracts insulin-induced activation of vagal afferent neurons via growth hormone secretagogue receptor.

    Science.gov (United States)

    Iwasaki, Yusaku; Dezaki, Katsuya; Kumari, Parmila; Kakei, Masafumi; Yada, Toshihiko

    2015-08-01

    Vagal afferent nerves sense meal-related gastrointestinal and pancreatic hormones and convey their information to the brain, thereby regulating brain functions including feeding. We have recently demonstrated that postprandial insulin directly acts on the vagal afferent neurons. Plasma concentrations of orexigenic ghrelin and anorexigenic insulin show reciprocal dynamics before and after meals. The present study examined interactive effects of ghrelin and insulin on vagal afferent nerves. Cytosolic Ca(2+) concentration ([Ca(2+)]i) in isolated nodose ganglion (NG) neurons was measured to monitor their activity. Insulin at 10(-7)M increased [Ca(2+)]i in NG neurons, and the insulin-induced [Ca(2+)]i increase was inhibited by treatment with ghrelin at 10(-8)M. This inhibitory effect of ghrelin was attenuated by [D-Lys(3)]-GHRP-6, an antagonist of growth hormone-secretagogue receptor (GHSR). Des-acyl ghrelin had little effect on insulin-induced [Ca(2+)]i increases in NG neurons. Ghrelin did not affect [Ca(2+)]i increases in response to cholecystokinin (CCK), a hormone that inhibits feeding via vagal afferent neurons, indicating that ghrelin selectively counteracts the insulin action. These results demonstrate that ghrelin via GHSR suppresses insulin-induced activation of NG neurons. The action of ghrelin to counteract insulin effects on NG might serve to efficiently inform the brain of the systemic change between fasting-associated ghrelin-dominant and fed-associated insulin-dominant states for the homeostatic central regulation of feeding and metabolism.

  3. Characterization of parathyroid hormone/parathyroid hormone-related protein receptor and signaling in hypercalcemic Walker 256 tumor cells.

    Science.gov (United States)

    Esbrit, P; Benítez-Verguizas, J; de Miguel, F; Valín, A; García-Ocaña, A

    2000-07-01

    Parathyroid hormone (PTH)-related protein (PTHrP) is the main factor responsible for humoral hypercalcemia of malignancy. Both PTH and PTHrP bind to the common type I PTH/PTHrP receptor (PTHR), thereby activating phospholipase C and adenylate cyclase through various G proteins, in bone and renal cells. However, various normal and transformed cell types, including hypercalcemic Walker 256 (W256) tumor cells, do not produce cAMP after PTHrP stimulation. We characterized the PTHrP receptor and the signaling mechanism upon its activation in the latter cells. Scatchard analysis of PTHrP-binding data in W256 tumor cells revealed the presence of high affinity binding sites with an apparent K(d) of 17 nM, and a density of 90 000 sites/cell. In addition, W256 tumor cells immunostained with an anti-PTHR antibody, recognizing its extracellular domain. Furthermore, reverse transcription followed by PCR, using primers amplifying two different regions in the PTHR cDNA corresponding to the N- and C-terminal domains, yielded products from W256 tumor cell RNA which were identical to the corresponding products obtained from rat kidney RNA. Consistent with our previous findings on cAMP production, 1 microM PTHrP(1-34), in contrast to 10 microg/ml cholera toxin or 1 microM isoproterenol, failed to affect protein kinase A activity in W256 tumor cells. However, in these cells we found a functional PTHR coupling to G(alpha)(q/11), whose presence was demonstrated in these tumor cell membranes by Western blot analysis. Our findings indicate that W256 tumor cells express the PTHR, which seems to be coupled to G(alpha)(q/11). Taken together with previous data, these results support the hypothesis that a switch from the cAMP pathway to the phospholipase C-intracellular calcium pathway, associated with PTHR activation, occurs in malignant cells.

  4. Vitamin D3 differentially regulates parathyroid hormone/parathyroid hormone-related peptide receptor expression in bone and cartilage.

    Science.gov (United States)

    Amizuka, N; Kwan, M Y; Goltzman, D; Ozawa, H; White, J H

    1999-02-01

    Transcription of the mouse parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor (PTHR) gene is controlled by promoters P1 and P2. We performed transcript-specific in situ hybridization and found that P2 is the predominant promoter controlling PTHR gene expression in bone and cartilage. Treatment with 1alpha, 25-dihydroxyvitamin D3 (D3) in vivo specifically downregulated P2-specific transcripts in osteoblasts, but not in chondrocytes, under conditions where it enhanced bone resorption. Treatment of the osteoblastic cell line MC3T3-E1 with D3 in vitro reduced expression of both P2-specific transcripts and PTHR protein. This effect was not blocked by cycloheximide, indicating that D3 inhibits PTHR expression by downregulating transcription of the P2 promoter. A similar inhibitory effect of D3 was not observed in the chondrocytic cell line CFK2. Gene-transfer experiments showed that P2, but not P1, is active in both MC3T3-E1 and CFK2 cells, and that D3 specifically inhibited P2 promoter activity in MC3T3-E1, but not in CFK2 cells. Inhibition of P2 activity by D3 required promoter sequences lying more that 1.6 kb upstream of the P2 transcription start site. Thus, the P2 promoter controls PTHR gene expression in both osteoblasts and chondrocytes. D3 downregulates PTHR gene transcription in a cell-specific manner by inhibiting P2 promoter activity in osteoblasts, but not in chondrocytes.

  5. Riboswitches as hormone receptors: hypothetical cytokinin-binding riboswitches in Arabidopsis thaliana

    Directory of Open Access Journals (Sweden)

    Downes Brian

    2010-10-01

    Full Text Available Abstract Background Riboswitches are mRNA elements that change conformation when bound to small molecules. They are known to be key regulators of biosynthetic pathways in both prokaryotes and eukaryotes. Presentation of the Hypothesis The hypothesis presented here is that riboswitches function as receptors in hormone perception. We propose that riboswitches initiate or integrate signaling cascades upon binding to classic signaling molecules. The molecular interactions for ligand binding and gene expression control would be the same as for biosynthetic pathways, but the context and the cadre of ligands to consider is dramatically different. The hypothesis arose from the observation that a compound used to identify adenine binding RNA sequences is chemically similar to the classic plant hormone, or growth regulator, cytokinin. A general tenet of the hypothesis is that riboswitch-binding metabolites can be used to make predictions about chemically related signaling molecules. In fact, all cell permeable signaling compounds can be considered as potential riboswitch ligands. The hypothesis is plausible, as demonstrated by a cursory review of the transcriptome and genome of the model plant Arabidopsis thaliana for transcripts that i contain an adenine aptamer motif, and ii are also predicted to be cytokinin-regulated. Here, one gene, CRK10 (for Cysteine-rich Receptor-like Kinase 10, At4g23180, contains an adenine aptamer-related sequence and is down-regulated by cytokinin approximately three-fold in public gene expression data. To illustrate the hypothesis, implications of cytokinin-binding to the CRK10 mRNA are discussed. Testing the hypothesis At the broadest level, screening various cell permeable signaling molecules against random RNA libraries and comparing hits to sequence and gene expression data bases could determine how broadly the hypothesis applies. Specific cases, such as CRK10 presented here, will require experimental validation of direct

  6. Developing in vitro reporter gene assays to assess the hormone receptor activities of chemicals frequently detected in drinking water.

    Science.gov (United States)

    Sun, Hong; Si, Chaozong; Bian, Qian; Chen, Xiaodong; Chen, Liansheng; Wang, Xinru

    2012-08-01

    The present study intended to develop receptor-mediated luciferase reporter gene assays to evaluate and compare the estrogen receptor (ER), androgen receptor (AR) and thyroid hormone receptor (TR) activities of target chemicals. Di-2-ethylhexyl-phthalate (DEHP), chlorpyrifos (CPF), 2,4-dichlorophenoxyacetic acid (2,4-D) and bisphenol A (BPA) are some of the most common contaminants in drinking water and are frequently detected in China and worldwide. The chemicals were tested at concentrations of 0.1, 1, 10 and 100 times their maximum contaminant level in drinking water. The results showed that BPA possessed various activities on ER, AR and TR. DEHP and CPF could suppress 17β-estradiol or testosterone activity with different potencies, and DEHP possessed weaker anti-thyroid hormone activity. 2,4-D showed no agonist or antagonist activity against these hormone receptors, but it significantly enhanced the activity of testosterone through AR. Furthermore, the mixture of DEHP and CPF exhibited stronger ER and AR antagonist activities than each single component alone, but their combined effects were less than the expected effects based on the additive model. These results implied that the transcription activation mediated by hormone receptors was the potential endocrine-disrupting mechanism of the test chemicals. Our study also provided useful tools for evaluation of their endocrine disrupting activity.

  7. The normal genital tract of the female California sea lion (Zalophus californianus): cyclic changes in histomorphology and hormone receptor distribution.

    Science.gov (United States)

    Colegrove, Kathleen M; Gulland, Frances M D; Naydan, Diane K; Lowenstine, Linda J

    2009-11-01

    Changes in reproductive tract histomorphology, and estrogen (ERalpha) and progesterone receptor (PR) expression throughout the breeding cycle were evaluated in free-ranging stranded female California sea lions (Zalophus californianus). Hormone receptor expression in the ovaries, uterus, cervix, and vagina was evaluated using an immunohistochemical technique with monoclonal antibodies. During a large portion of the cycle, ovaries contained both a corpora lutea (CL) and follicles in varying stages of development. In the periods of pupping and estrus during June and July, and in the spring morphologic features of the endometrium suggested estrogen influence. There were areas of squamous differentiation in the pseudostratified columnar epithelium of the cervix and vagina in some animals during estrus and in the spring. Estrogen receptor immunohistochemical scores were highest during pupping and estrus and in the spring and lowest during embryonic diapause. Cyclic changes in uterine PR expression throughout the cycle were minimal. Both ERalpha and PR were expressed in epithelial and stromal cells throughout the cervix and vagina, however, receptor expression was typically higher in the stroma. Stromal cell hormone receptors may play an important role in epithelial responses to circulating sex hormones. The results of this investigation add to the general knowledge of California sea lion reproduction and establish baseline information on reproductive tract hormone receptors that will aid in determining the factors involved in urogenital cancer development in sea lions.

  8. Thyroid Hormone Receptor α1 Follows a Cooperative CRM1/Calreticulin-mediated Nuclear Export Pathway*

    Science.gov (United States)

    Grespin, Matthew E.; Bonamy, Ghislain M. C.; Roggero, Vincent R.; Cameron, Nicole G.; Adam, Lindsay E.; Atchison, Andrew P.; Fratto, Victoria M.; Allison, Lizabeth A.

    2008-01-01

    The thyroid hormone receptor α1 (TRα) exhibits a dual role as an activator or repressor of its target genes in response to thyroid hormone (T3). Previously, we have shown that TRα, formerly thought to reside solely in the nucleus bound to DNA, actually shuttles rapidly between the nucleus and cytoplasm. An important aspect of the shuttling activity of TRα is its ability to exit the nucleus through the nuclear pore complex. TRα export is not sensitive to treatment with the CRM1-specific inhibitor leptomycin B (LMB) in heterokaryon assays, suggesting a role for an export receptor other than CRM1. Here, we have used a combined approach of in vivo fluorescence recovery after photobleaching experiments, in vitro permeabilized cell nuclear export assays, and glutathione S-transferase pull-down assays to investigate the export pathway used by TRα. We show that, in addition to shuttling in heterokaryons, TRα shuttles rapidly in an unfused monokaryon system as well. Furthermore, our data show that TRα directly interacts with calreticulin, and point to the intriguing possibility that TRα follows a cooperative export pathway in which both calreticulin and CRM1 play a role in facilitating efficient translocation of TRα from the nucleus to cytoplasm. PMID:18641393

  9. Thyroid hormone receptor alpha1 follows a cooperative CRM1/calreticulin-mediated nuclear export pathway.

    Science.gov (United States)

    Grespin, Matthew E; Bonamy, Ghislain M C; Roggero, Vincent R; Cameron, Nicole G; Adam, Lindsay E; Atchison, Andrew P; Fratto, Victoria M; Allison, Lizabeth A

    2008-09-12

    The thyroid hormone receptor alpha1 (TRalpha) exhibits a dual role as an activator or repressor of its target genes in response to thyroid hormone (T(3)). Previously, we have shown that TRalpha, formerly thought to reside solely in the nucleus bound to DNA, actually shuttles rapidly between the nucleus and cytoplasm. An important aspect of the shuttling activity of TRalpha is its ability to exit the nucleus through the nuclear pore complex. TRalpha export is not sensitive to treatment with the CRM1-specific inhibitor leptomycin B (LMB) in heterokaryon assays, suggesting a role for an export receptor other than CRM1. Here, we have used a combined approach of in vivo fluorescence recovery after photobleaching experiments, in vitro permeabilized cell nuclear export assays, and glutathione S-transferase pull-down assays to investigate the export pathway used by TRalpha. We show that, in addition to shuttling in heterokaryons, TRalpha shuttles rapidly in an unfused monokaryon system as well. Furthermore, our data show that TRalpha directly interacts with calreticulin, and point to the intriguing possibility that TRalpha follows a cooperative export pathway in which both calreticulin and CRM1 play a role in facilitating efficient translocation of TRalpha from the nucleus to cytoplasm.

  10. RETRACTION: Challenges of combined everolimus/endocrine therapy in hormone receptor-positive metastatic breast cancer

    Directory of Open Access Journals (Sweden)

    Camillo Porta

    2014-06-01

    Full Text Available To our readers:With deep regrets, we inform our Readers that the article Challenges of combined everolimus/endocrine therapy in hormone receptor-positive metastatic breast cancer (DOI: http://dx.doi.org/10.4081/oncol.2014.236, which has been published Ahead of Print in the first issue of Oncology Reviews (2014, contains verbatim text plagiarized from another paper.1The manuscript must be considered as retracted. On behalf of the Editorial Board of Oncology Reviews, I apologize to the Author of the manuscript whose text was plagiarized by Y. Abubakr and Y. Albushra that this was not picked up in the peer review process. I also apologize to the affected journal for the violation of copyright due to plagiarism. Oncology Reviews is uncompromising in its commitment to scientific integrity. When credible evidence of misconduct is brought to our attention, our commitment to the scientific record and to our readership requires immediate notification. Oncology Reviews is increasingly employing sophisticated software to detect plagiarism. Other journals use similar tools. Authors should be aware that most journals routinely employ plagiarism detection software, and that any plagiarism is likely to be detected.Camillo Porta, Editor-in-Chief Oncology Reviews Reference 1. André F. Enhancing effectiveness of endocrine therapy in hormone receptor-positive advanced breast cancer. Medscape Education Oncology. CME Released: 05/24/2013; Valid for credit through 05/24/2014. http://www.medscape.org/viewarticle/804496

  11. Identification and characterization of growth hormone receptors in snakehead fish (Ophiocephalus argus cantor) liver.

    Science.gov (United States)

    Sun, X; Zhu, S; Chan, S S; Toresson, G; Cheng, C H

    1997-12-01

    The specific binding of 125I-labeled fish growth hormone (GH) to hepatic membranes prepared from several freshwater fish was assessed. A high level of growth hormone receptor (GHR) was detected on the hepatic membranes of the snakehead fish (Ophiocephalus argus Cantor). Scatchard analysis of the binding data showed a single class of high affinity binding site with a binding affinity (Ka) of 1.45 +/- 0.23 x 10(9) M-1 and a binding capacity (Bmax) of 198 +/- 57 fmol/mg protein. The binding was specific for fish GH and was saturable. In addition, the specific binding was temperature- and time-dependent, reaching a steady state after 16 hr of incubation at 25 degrees . The molecular weight of GHR as measured by Sephadex G-200 column chromatography and Western blot analysis using a monoclonal antibody (Mab263) against GHR was found to be 200-400 and 90-93 kDa, respectively. Two bands at 65 and 89 kDa were identified in ligand crosslinking studies of membrane receptors. A sensitive teleost GH radioreceptor assay (RRA) was developed, using recombinant fish GH and a membrane preparation from snakehead fish liver, capable of measuring bioactive GH in fish sera or other samples.

  12. Effect of two human growth hormone receptor antagonists on glomerulosclerosis in streptozotocin-induced diabetic rats

    Institute of Scientific and Technical Information of China (English)

    Wei LI; Shui-xian SHEN; Li-hua ZHU; En-bi WANG; Zeng-can YE; Jun LIN; Li-he GUO; Fei-hong LUO; Xi-hong LIU; Xin FANG

    2004-01-01

    AIM: To explore the feasibility of human growth hormone (hGH) receptor antagonist in the treatment of end-stage diabetic renal complications. METHODS: Two hGH mutants, hGHA1 (Cys-hGH-dell-4, G120R, K168A, E174A,C182S, de1186-191) and hGHA2 (hGH-H21A, G120R, E174A) were expressed in E coli. The IC50 (Mean±SD)values for the mutants for inhibiting 125I-hGH binding to rabbit growth hormone receptor were (65±10) ng for hGHA1, (27±5.6) ng for hGHA2, and (10±0.6) ng for wild type hGH, respectively. RESULTS: After treatment for 12 weeks, the renal histology analysis showed that treatment with hGHA2 at 4 mg/kg body weight daily markedly suppressed glomerulosclerosis in streptozotocin-induced diabetic Sprague-Dawley (SD) rats; hGHA1 at the same dosage slightly increased the renal damage compared with saline; while wild type hGH at 1 U/kg body weight daily severely worsened the glomerulo-sclerosis in diabetic SD rats. CONCLUSION: The data indicated that hGHA2 inhibited the end-stage glomerulosclerosis in diabetic rats, but hGHA1 mildly increased the glomerulosclerosis.

  13. Pegvisomant: a growth hormone receptor antagonist used in the treatment of acromegaly.

    Science.gov (United States)

    Tritos, Nicholas A; Biller, Beverly M K

    2017-02-01

    To review published data on pegvisomant and its therapeutic role in acromegaly. Electronic searches of the published literature were conducted using the keywords: acromegaly, growth hormone (GH) receptor (antagonist), pegvisomant, therapy. Relevant articles (n = 141) were retrieved and considered for inclusion in this manuscript. Pegvisomant is a genetically engineered, recombinant growth hormone receptor antagonist, which is effective in normalizing serum insulin-like growth factor 1 (IGF-1) levels in the majority of patients with acromegaly and ameliorating symptoms and signs associated with GH excess. Pegvisomant does not have direct antiproliferative effects on the underlying somatotroph pituitary adenoma, which is the etiology of GH excess in the vast majority of patients with acromegaly. Therefore, patients receiving pegvisomant monotherapy require regular pituitary imaging in order to monitor for possible increase in tumor size. Adverse events in patients on pegvisomant therapy include skin rashes, lipohypertrophy at injection sites, and idiosyncratic liver toxicity (generally asymptomatic transaminitis that is reversible upon drug discontinuation), thus necessitating regular patient monitoring. Pegvisomant is an effective therapeutic agent in patients with acromegaly who are not in remission after undergoing pituitary surgery. It mitigates excess GH action, as demonstrated by IGF-1 normalization, but has no direct effects on pituitary tumors causing acromegaly. Regular surveillance for possible tumor growth and adverse effects (hepatotoxicity, skin manifestations) is warranted.

  14. Association of the thyroid stimulating hormone receptor gene (TSHR) with Graves' disease.

    Science.gov (United States)

    Brand, Oliver J; Barrett, Jeffrey C; Simmonds, Matthew J; Newby, Paul R; McCabe, Christopher J; Bruce, Christopher K; Kysela, Boris; Carr-Smith, Jackie D; Brix, Thomas; Hunt, Penny J; Wiersinga, Wilmar M; Hegedüs, Laszlo; Connell, John; Wass, John A H; Franklyn, Jayne A; Weetman, Anthony P; Heward, Joanne M; Gough, Stephen C L

    2009-05-01

    Graves' disease (GD) is a common autoimmune disease (AID) that shares many of its susceptibility loci with other AIDs. The thyroid stimulating hormone receptor (TSHR) represents the primary autoantigen in GD, in which autoantibodies bind to the receptor and mimic its ligand, thyroid stimulating hormone, causing the characteristic clinical phenotype. Although early studies investigating the TSHR and GD proved inconclusive, more recently we provided convincing evidence for association of the TSHR region with disease. In the current study, we investigated a combined panel of 98 SNPs, including 70 tag SNPs, across an extended 800 kb region of the TSHR to refine association in a cohort of 768 GD subjects and 768 matched controls. In total, 28 SNPs revealed association with GD (P associations at rs179247 (chi(2) = 32.45, P = 8.90 x 10(-8), OR = 1.53, 95% CI = 1.32-1.78) and rs12101255 (chi(2) = 30.91, P = 1.95 x 10(-7), OR = 1.55, 95% CI = 1.33-1.81), both located in intron 1 of the TSHR. Association of the most associated SNP, rs179247, was replicated in 303 GD families (P = 7.8 x 10(-4)). In addition, we provide preliminary evidence that the disease-associated genotypes of rs179247 (AA) and rs12101255 (TT) show reduced mRNA expression ratios of flTSHR relative to two alternate TSHR mRNA splice variants.

  15. Ghrelin and the growth hormone secretagogue receptor in growth and development.

    Science.gov (United States)

    Chanoine, J-P; De Waele, K; Walia, P

    2009-04-01

    The pancreas is a major source of ghrelin in the perinatal period, whereas gastric production progressively increases after birth. Loss of function of the genes for ghrelin or for the constitutively activated growth hormone secretagogue receptor (GHSR) does not affect birth weight and early postnatal growth. However, ghrl(-/-) or ghsr(-/-) mice fed a high fat diet starting soon after weaning are resistant to diet-induced obesity, suggesting that ghrelin affects the maturation of the metabolic axes involved in energy balance. In addition, animal and human studies suggest that GHSR plays a physiological role in linear growth. In mice, absence of the GHSR gene is associated with lower insulin-like growth factor 1 concentrations and lower body mass in adult animals, independently of food intake. In humans, a mutation of the GHSR gene that impairs the constitutive activity of the receptor was found in two families with short stature. Administration of acylated ghrelin to rat pups directly does not affect weight gain. In contrast, administration of ghrelin to pregnant or lactating rats results in greater fetal weight and postnatal weight gain, respectively, suggesting that maternal ghrelin may stimulate perinatal growth. These data point toward a physiological role for ghrelin and GHSR in growth and/or in the maturation of hormonal systems involved in the regulation of energy balance.

  16. Genome inventory and analysis of nuclear hormone receptors in Tetraodon nigroviridis

    Indian Academy of Sciences (India)

    Raghu Prasad Rao Metpally; Ramakrishnan Vigneshwar; Ramanathan Sowdhamini

    2007-01-01

    Nuclear hormone receptors (NRs) form a large superfamily of ligand-activated transcription factors, which regulate genes underlying a wide range of (patho) physiological phenomena. Availability of the full genome sequence of Tetraodon nigroviridis facilitated a genome wide analysis of the NRs in fish genome. Seventy one NRs were found in Tetraodon and were compared with mammalian and fish NR family members. In general, there is a higher representation of NRs in fish genomes compared to mammalian ones. They showed high diversity across classes as observed by phylogenetic analysis. Nucleotide substitution rates show strong negative selection among fish NRs except for pregnane X receptor (PXR), estrogen receptor (ER) and liver X receptor (LXR). This may be attributed to crucial role played by them in metabolism and detoxification of xenobiotic and endobiotic compounds and might have resulted in slight positive selection. Chromosomal mapping and pairwise comparisons of NR distribution in Tetraodon and humans led to the identification of nine syntenic NR regions, of which three are common among fully sequenced vertebrate genomes. Gene structure analysis shows strong conservation of exon structures among orthologoues. Whereas paralogous members show different splicing patterns with intron gain or loss and addition or substitution of exons played a major role in evolution of NR superfamily.

  17. Interactions between N-Ethylmaleimide-sensitive factor and GluA2 contribute to effects of glucocorticoid hormones on AMPA receptor function in the rodent hippocampus.

    NARCIS (Netherlands)

    Xiong, H.; Cassé, F.; Zhou, M.; Xiong, Z.Q.; Joels, M.; Martin, S.; Krugers, H.J.

    2016-01-01

    Glucocorticoid hormones, via activation of their receptors, promote memory consolidation, but the exact underlying mechanisms remain elusive. We examined how corticosterone regulates AMPA receptor (AMPAR) availability in the synapse, which is important for synaptic plasticity and memory formation.

  18. Interactions between N-Ethylmaleimide-Sensitive Factor and GluA2 contribute to effects of glucocorticoid hormones on AMPA receptor function in the rodent hippocampus

    NARCIS (Netherlands)

    Xiong, Hui; Cassé, Frédéric; Zhou, Ming; Xiong, Zhi-Qi; Joels, Marian; Martin, Stéphane; Krugers, Harm J

    Glucocorticoid hormones, via activation of their receptors, promote memory consolidation, but the exact underlying mechanisms remain elusive. We examined how corticosterone regulates AMPA receptor (AMPAR) availability in the synapse, which is important for synaptic plasticity and memory formation.

  19. Low concentrations of bisphenol a suppress thyroid hormone receptor transcription through a nongenomic mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Sheng, Zhi-Guo [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese Academy of Sciences, 18 Shuangqing Road, Beijing 100085 (China); Tang, Yuan [Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, 30 Yanzheng Street, Chongqing 400038 (China); Liu, Yu-Xiang [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese Academy of Sciences, 18 Shuangqing Road, Beijing 100085 (China); Yuan, Ye; Zhao, Bao-Quan [Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850 (China); Chao, Xi-Juan [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese Academy of Sciences, 18 Shuangqing Road, Beijing 100085 (China); Zhu, Ben-Zhan, E-mail: bzhu@rcees.ac.cn [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese Academy of Sciences, 18 Shuangqing Road, Beijing 100085 (China)

    2012-02-15

    Bisphenol (BPA) is one of the highest-volume chemicals produced worldwide, and human exposure to BPA is thought to be ubiquitous. Various rodent and in vitro studies have shown that thyroid hormone (TH) function can be impaired by BPA. However, it is still unknown if low concentrations of BPA can suppress the thyroid hormone receptor (TR) transcription. The present study aims to investigate the possible suppressing effects of low concentrations of BPA on TR transcription and the involved mechanism(s) in CV-1 cells derived from cercopithecus aethiops monkey kidneys. Using gene reporter assays, BPA at concentrations as low as 10{sup −9} M suppresses TR or steroid receptor coactivator-1(SRC-1)-enhanced TR transcription, but not reducing TR/SRC-1 interaction in mammalian two-hybrid and glutathione S-transferase pull-down studies. It has been further shown that both nuclear receptor co-repressor (N-CoR) and silencing mediator for retinoid and thyroid hormone receptors (SMRT) are recruited to the TR-β1 by BPA in the presence of physiologic concentrations of T3 or T4. However, the overexpression of β3 integrin or c-Src significantly reduces BPA-induced recruitment of N-CoR/SMRT to TR or suppression of TR transcription. Furthermore, BPA inhibits the T3/T4-mediated interassociation of the β3 integrin/c-Src/MAPK/TR-β1 pathways by the co-immunoprecipitation. These results indicate that low concentrations of BPA suppress the TR transcription by disrupting physiologic concentrations of T3/T4-mediated β3 integrin/c-Src/MAPK/TR-β1 pathways, followed by recruiting N-CoR/SMRT to TR-β1, providing a novel insight regarding the TH disruption effects of low concentration BPA. -- Highlights: ► Environmentally relevant concentrations of BPA suppress TR transcription. ► BPA recruits the N-CoR/SMRT to TR under the physiologic concentrations of T3/T4. ► BPA disrupts T3/T4-mediated β3 integrin/c-Src/MAPK/TR-β1 pathways.

  20. Patterns of resource utilization and cost for postmenopausal women with hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer in Europe.

    Science.gov (United States)

    Jerusalem, Guy; Neven, Patrick; Marinsek, Nina; Zhang, Jie; Degun, Ravi; Benelli, Giancarlo; Saletan, Stephen; Ricci, Jean-François; Andre, Fabrice

    2015-10-24

    Healthcare resource utilization in breast cancer varies by disease characteristics and treatment choices. However, lack of clarity in guidelines can result in varied interpretation and heterogeneous treatment management and costs. In Europe, the extent of this variability is unclear. Therefore, evaluation of chemotherapy use and costs versus hormone therapy across Europe is needed. This retrospective chart review (N = 355) examined primarily direct costs for chemotherapy versus hormone therapy in postmenopausal women with hormone-receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer across 5 European countries (France, Germany, The Netherlands, Belgium, and Sweden). Total direct costs across the first 3 treatment lines were approximately €10,000 to €14,000 lower for an additional line of hormone therapy-based treatment versus switching to chemotherapy-based treatment. Direct cost difference between chemotherapy-based and hormone therapy-based regimens was approximately €1900 to €2500 per month. Chemotherapy-based regimens were associated with increased resource utilization (managing side effects; concomitant targeted therapy use; and increased frequencies of hospitalizations, provider visits, and monitoring tests). The proportion of patients taking sick leave doubled after switching from hormone therapy to chemotherapy. These results suggest chemotherapy is associated with increased direct costs and potentially with increased indirect costs (lower productivity of working patients) versus hormone therapy in HR+, HER2- advanced breast cancer.

  1. Autocrine role of estrogens in the augmentation of luteinizing hormone receptor formation in cultured rat granulosa cells.

    Science.gov (United States)

    Kessel, B; Liu, Y X; Jia, X C; Hsueh, A J

    1985-06-01

    The effects of estrogens on gonadotropin-stimulated luteinizing hormone (LH) receptor formation were examined in primary cultures of rat granulosa cells. Granulosa cells were cultured for 3 days with increasing concentrations of follicle-stimulating hormone (FSH) in the presence or absence of native and synthetic estrogens. Follicle-stimulating hormone stimulated LH receptor formation in a dose-dependent fashion, and estrogens enhanced the FSH-stimulated LH receptor content by decreasing the apparent ED50 of FSH. At 6.25 ng/ml FSH, the enhancement in LH receptor was estrogen dose dependent, with an ED50 value of about 3 X 10(-9) M for 17 beta-estradiol. The increased LH receptor content seen in cells treated with FSH and estrogen was correlated with increased cAMP production by these cells in response to LH stimulation. Time course studies revealed enhancement of FSH-stimulated LH receptor induction at 48 and 72 h of culture. Granulosa cells were also cultured with FSH for 2 days to induce functional LH receptors, then further cultured for 3 days with LH in the presence or absence of estrogens. At 30 ng/ml LH, increasing concentrations of estrogens maintained LH receptor content in a dose-dependent fashion, with their relative estrogenic potencies in keeping with reported binding affinities to estrogen receptors. An autocrine role of estrogens on LH receptor formation was further tested in granulosa cells treated with FSH and an aromatase substrate (androstenedione) to increase estrogen biosynthesis. Cotreatment with semipurified estrogen antibodies partially blocked the FSH stimulation of LH receptors, whereas nonimmune serum was ineffective. Also, inclusion of diethylstilbestrol prevented the inhibitory effect of the estrogen antibodies. Thus, local estrogens in ovarian follicles may play an autocrine role in granulosa cells to enhance LH receptor formation and to increase granulosa cell responsiveness to the LH surge, with subsequent ovulation and adequate

  2. Identification of a novel mutation in the human growth hormone receptor gene (GHR) in a patient with Laron syndrome.

    Science.gov (United States)

    Gennero, Isabelle; Edouard, Thomas; Rashad, Mona; Bieth, Eric; Conte-Aurio, Françoise; Marin, Françoise; Tauber, Maithé; Salles, Jean Pierre; El Kholy, Mohamed

    2007-07-01

    Deletions and mutations in the growth hormone receptor (GHR) gene are the underlying etiology of Laron syndrome (LS) or growth hormone (GH) insensitivity syndrome (GHIS), an autosomal recessive disease. Most patients are distributed in or originate from Mediterranean and Middle-Eastern countries. Sixty mutations have been described so far. We report a novel mutation in the GHR gene in a patient with LS. Genomic DNA sequencing of exon 5 revealed a TT insertion at nucleotide 422 after codon 122. The insertion resulted in a frameshift introducing a premature termination codon that led to a truncated receptor. We present clinical, biochemical and molecular evidence of LS as the result of this homozygous insertion.

  3. CORRELATION OF PARATHYROID HORMONE-1 RECEPTOR EXPRESSION TO BONE METASTASIS OF BREAST CARCINOMA PATIENTS

    Directory of Open Access Journals (Sweden)

    P. A. Tusta-Adiputra

    2014-01-01

    Full Text Available Background: Bone metastasis is a common complication of metastasis of breast cancer and it is a unique pathobiology process. The Parathyroid Hormone-related Peptide (PTHrP is a protein which has an important role in breast cancer cells to invade and infiltrate bones or bone marrow and accelerate angiogenetic process. The objective of this study is to reveal the relationship of PTHrP receptor named Parathyroid Hormone-1 Receptor (PTH1R expression to bone metastasis in breast cancer patients. Methods: This was an analytical cross-sectional study, applying a non probability consecutive sampling. Samples were divided into two groups, i.e. one group of breast cancer metastasis to bone (+others and another group with non-bone metastasis. Patients were collected from an existed data base (from medical record, cancer register, histopathology, since 2007. The specimen paraffin blocks were re-examined using IHC technique for PTHrP receptor. The data were analyzed and tested with Chi-Square (X2, otherwise it would be tested using Fisher Exact Test. Each group would be allocated minimal of 17 patients/samples. Results: The Chi-Square test failed to show the association between PTH1R expression in breast cancer patients with bone metastasis (p=0.295. The relative prevalence result for positive PTH1R expression was 1.48. There was no proof that positive PTH1R expression was an associated factor for bone metastasis (95% confidence interval. Conclusion: PTH1R expression is not a factor associated with bone metastasis in breast cancer patients. 

  4. Functional Authentication of a Novel Gastropod Gonadotropin-Releasing Hormone Receptor Reveals Unusual Features and Evolutionary Insight

    OpenAIRE

    Kavanaugh, Scott I.; Tsai, Pei-San

    2016-01-01

    A gonadotropin-releasing hormone (GnRH)-like molecule was previously identified in a gastropod, Aplysia californica, and named ap-GnRH. In this study, we cloned the full-length cDNA of a putative ap-GnRH receptor (ap-GnRHR) and functionally authenticated this receptor as a bona fide ap-GnRHR. This receptor contains two potential translation start sites, each accompanied by a Kozak sequence, suggesting the translation of a long and a short form of the receptor is possible. The putative ap-GnRH...

  5. Requirement of tyrosine residues 333 and 338 of the growth hormone (GH) receptor for selected GH-stimulated function

    DEFF Research Database (Denmark)

    Lobie, P E; Allevato, G; Norstedt, G

    1995-01-01

    We have examined the involvement of tyrosine residues 333 and 338 of the growth hormone (GH) receptor in the cellular response to GH. Stable Chinese hamster ovary (CHO) cell clones expressing a receptor with tyrosine residues at position 333 and 338 of the receptor substituted for phenylalanine (...... acetyltransferase cDNA expression driven by the GH-responsive region of the SPI 2.1 gene) was not affected by Y333F,Y338F substitution. Thus we provide the first experimental evidence that specific tyrosine residues of the GH receptor are required for selected cellular responses to GH....

  6. Mitochondria and the insect steroid hormone receptor (EcR): A complex relationship.

    Science.gov (United States)

    Vafopoulou, Xanthe; Steel, Colin G H

    2016-10-01

    The actions of the insect steroid molting hormones, ecdysteroids, on the genome of target cells has been well studied, but little is known of their extranuclear actions. We previously showed in Rhodnius prolixus that much of the ecdysteroid receptor (EcR) resides in the cytoplasm of various cell types and undergoes shuttling between nucleus and cytoplasm with circadian periodicity, possibly using microtubules as tracks for translocation to the nucleus. Here we report that cytoplasmic EcR appears to be also involved in extranuclear actions of ecdysteroids by association with the mitochondria. Western blots of subcellular fractions of brain lysates revealed that EcR is localized in the mitochondrial fraction, indicating an intimate association of EcR with mitochondria. Confocal laser microscopy and immunohistochemistry using anti-EcR revealed abundant co-localization of EcR with mitochondria in brain neurons and their axons, especially intense in the subplasmalemmal region, raising the possibility of EcR involvement in mitochondrial functions in subplasmalemmal microdomains. When mitochondria are dispersed by disruption of microtubules with colchicine, EcR remains associated with mitochondria showing strong receptor association with mitochondria. Treatment in vitro with ecdysteroids of brains of developmentally arrested R. prolixus (containing neither ecdysteroids nor EcR) induces EcR and abundant co-localization with mitochondria in neurons, concurrently with a sharp increase of the mitochondrial protein COX 1, suggesting involvement of EcR in mitochondrial function. These findings align EcR with various vertebrate steroid receptors, where actions of steroid receptors on mitochondria are widely known and suggest that steroid receptors across distant phyla share similar functional attributes. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. EP3 receptors inhibit antidiuretic-hormone-dependent sodium transport across frog skin epithelium.

    Science.gov (United States)

    Rytved, K A; Nielsen, R

    1999-01-01

    We examined the effect of prostaglandin E2 (PGE2) on antidiuretic hormone (ADH)-dependent Na+ transport and cAMP production in isolated frog skin epithelium. ADH caused an increase in transepithelial Na+ transport and a decrease in cellular potential, indicating an increase in apical Na+ permeability. Subsequent addition of PGE2 decreased Na+ transport and repolarised the cells. The PGE2 receptor EP1/3-selective analogue sulprostone and the PGE2 receptor EP2/3-selective analogue misoprostol were able to mimic the effect of PGE2. ADH increased cellular cAMP levels, whereas PGE2, sulprostone and misoprostol were able to reduce the ADH-dependent cAMP production. Measurements of intracellular Ca2+ concentration ([Ca2+]i) revealed that it was unaffected by both PGE2 and sulprostone. The inhibitory effect of PGE2 on ADH-dependent Na+ transport was also observed in Ca2+-depleted epithelia. We conclude that ADH stimulates transepithelial Na+ transport by increasing cellular cAMP levels, whereas PGE2 inhibits ADH-dependent Na+ transport by activating EP3-type receptors, which decrease cellular cAMP levels. We have found no evidence that [Ca2+]i is involved in the regulation of ADH-dependent Na+ transport by PGE2.

  8. Usefulness of liquid-based cytology in hormone receptor analysis of breast cancer specimens.

    Science.gov (United States)

    Nishimura, Rieko; Aogi, Kenjiro; Yamamoto, Tamami; Takabatake, Daisuke; Takashima, Seiki; Teramoto, Norihiro; Kagawa, Akihiro; Morita, Sachiko

    2011-02-01

    Immunohistochemical (IHC) analysis of the hormone receptor (HR) in breast cancer cytology is an important issue nowadays. Several studies have shown discrepancy in the HR status between the primary tumor and metastases. Cytology can be used for patients with metastatic disease. Although cytological assessment of HR is an excellent method, it has not been routinely used because of the difficulty in consistently preparing multiple good quality slides. Liquid-based cytology (LBC) preparation is considered as the key to resolving the aforementioned problem; however, few studies have reported the HR assessment in breast cancer using LBC. Therefore, the HR status of LBC slides from 82 breast cancers was compared with that of the corresponding surgical specimens. The HR assay in both the LBC slides and surgical specimens was conducted by IHC using an autostainer. For the IHC staining, the protocol recommended by the manufacturer for paraffin-embedded sections was used for both the cytology and histology specimens. The HR results of the cytology agreed with those of the histology in 80 of the 82 cases (accuracy rate, 98%) for estrogen receptor, and in 78 of the 82 cases (accuracy rate, 95%) for progesterone receptor. The overall accuracy of the HR status on the cytology and the histology was 99% in 81 of the 82 cases. In conclusion, in HR analysis of breast cancers, LBC followed by IHC using an autostainer was useful for the standard processing of cytological specimens and showed a good correlation with the results of analysis on the histology specimens.

  9. Chemotherapy-induced prospective memory impairment in breast cancer patients with different hormone receptor expression

    Science.gov (United States)

    Li, Wen; Gan, Chen; Lv, Yue; Wang, Shanghu; Cheng, Huaidong

    2017-01-01

    Abstract This study aimed to investigate prospective memory impairment in patients with breast cancer with different expression of hormone receptors, including the estrogen receptor (ER) and the progesterone receptor (PR). A total of 120 patients with breast cancer who underwent chemotherapy following surgery were divided into 2 groups. The A group included 60 patients with ER−/PR− status, and the B group included 60 patients with ER+/PR+ status. After 6 cycles of postoperative adjuvant chemotherapy, all patients were administered neuropsychological and prospective memory tests, such as the Mini-Mental State Examination (MMSE), verbal fluency test (VFT), and digit span test (DST), as well as examination of event-based prospective memory (EBPM) and time-based prospective memory (TBPM). As the neuropsychological background test results showed, there were no significant differences in MMSE, DST, and TBPM scores (∗:P > 0.05) between patients with breast cancer in the ER−/PR− and ER+/PR+ groups, while the VFT and EBPM scores were significantly greater in patients with breast cancer with ER+/PR+ status than in those with ER−/PR− status (∗∗: P memory impairment. PMID:28353608

  10. High-throughput screening of novel antagonists on melanin-concentrat-ing hormone receptor-1

    Institute of Scientific and Technical Information of China (English)

    Jian-hua YAN; Qun-yi LI; Jean A BOUTIN; M Pierre RENARD; Yi-xiang DING; Xiao-jiang HAO; Wei-min ZHAO; Ming-wei WANG

    2008-01-01

    Aim: To find new antagonists on human melanin-concentrating hormone recep-tor- 1 (MCHR-1) through high-throughput screening (HTS) of a diverse com-pound library. Methods: MCHR-1, [3H]SNAP7941, and FlashBlue G-protein-coupled receptor beads were used to measure the receptor-binding activities of various compounds based on scintillation proximity assay (SPA) technology. The guanosine 5' (γ-[35S]thio) triphosphate ([35S]GTPγS) binding assay was sub-sequently applied to functionally characterize the "hits" identified by the HTS campaign. Results: Of the 48 240 compounds screened with the SPA method, 12 hits were confirmed to possess MCHR-1 binding activities, 8 were function-ally studied subsequently with the [35S]GTPγS binding assay, and only 1 com-pound (NC 127816) displayed moderate human MCHR- 1 binding affinity (Ki=115.7 nmol/L) and relatively potent antagonism (KB=23.8 nmol/L). This compound shares a novel scaffold (1-ethoxy-2H-2-aza-1-phospha-naphthalene 1-oxide) with 3 other analogs in the group. Conclusion: Considering the marked difference in molecular shape and electrostatic status between NC127816 and the structures reported elsewhere, we anticipate that its derivatives may repre-sent a new class of potent MCHR-1 modulators.

  11. Steroid hormone receptors and prostate cancer: role of structural dynamics in therapeutic targeting

    Science.gov (United States)

    Kumar, Raj

    2016-01-01

    Steroid hormone receptors (SHRs) act in cell type- and gene-specific manner through interactions with coregulatory proteins to regulate numerous physiological and pathological processes at the level of gene regulation. Binding of steroid receptor modulator (SRM) ligand leads to allosteric changes in SHR to exert positive or negative effects on the expression of target genes. Due, in part, to the fact that current SRMs generally target ligand binding domain (LBD)/AF2 and neglect intrinsically disordered (ID) N-terminal domain (NTD)/AF1, clinically relevant SRMs lack selectivity and are also prone to the development of resistance over time. Therefore, to maximize the efficacy of SHR-based therapeutics, the possibility of developing unique modulators that act to control AF1 activity must be considered. Recent studies targeting androgen receptor's (AR's) ID AF1 domain for the castration-resistant prostate cancer has provided the possibility of therapeutically targeting ID NTD/AF1 surfaces by allosteric modulations to achieve desired effects. In this review article, we discuss how inter- and intra- molecular allosteric regulations controlled by AR's structural flexibility and dynamics particularly the ID NTD/AF1 is an emerging area of investigation, which could be exploited for drug development and therapeutic targeting of prostate cancer. PMID:27364545

  12. Human insulin analogues modified at the B26 site reveal a hormone conformation that is undetected in the receptor complex

    Energy Technology Data Exchange (ETDEWEB)

    Žáková, Lenka; Kletvíková, Emília; Lepšík, Martin; Collinsová, Michaela [Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 10 Prague 6 (Czech Republic); Watson, Christopher J.; Turkenburg, Johan P. [The University of York, Heslington, York YO10 5DD (United Kingdom); Jiráček, Jiří [Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 10 Prague 6 (Czech Republic); Brzozowski, Andrzej M., E-mail: marek.brzozowski@york.ac.uk [The University of York, Heslington, York YO10 5DD (United Kingdom); Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 10 Prague 6 (Czech Republic)

    2014-10-01

    [AsnB26]- and [GlyB26]-insulin mutants attain a B26-turn like fold without assistance of chemical modifications. Their structures match the insulin receptor interface and expand the spectrum of insulin conformations. The structural characterization of the insulin–insulin receptor (IR) interaction still lacks the conformation of the crucial B21–B30 insulin region, which must be different from that in its storage forms to ensure effective receptor binding. Here, it is shown that insulin analogues modified by natural amino acids at the TyrB26 site can represent an active form of this hormone. In particular, [AsnB26]-insulin and [GlyB26]-insulin attain a B26-turn-like conformation that differs from that in all known structures of the native hormone. It also matches the receptor interface, avoiding substantial steric clashes. This indicates that insulin may attain a B26-turn-like conformation upon IR binding. Moreover, there is an unexpected, but significant, binding specificity of the AsnB26 mutant for predominantly the metabolic B isoform of the receptor. As it is correlated with the B26 bend of the B-chain of the hormone, the structures of AsnB26 analogues may provide the first structural insight into the structural origins of differential insulin signalling through insulin receptor A and B isoforms.

  13. Regulation of gene expression in ovarian cancer cells by luteinizing hormone receptor expression and activation

    Directory of Open Access Journals (Sweden)

    Dam Phuongan

    2011-06-01

    Full Text Available Abstract Background Since a substantial percentage of ovarian cancers express gonadotropin receptors and are responsive to the relatively high concentrations of pituitary gonadotropins during the postmenopausal years, it has been suggested that receptor activation may contribute to the etiology and/or progression of the neoplasm. The goal of the present study was to develop a cell model to determine the impact of luteinizing hormone (LH receptor (LHR expression and LH-mediated LHR activation on gene expression and thus obtain insights into the mechanism of gonadotropin action on ovarian surface epithelial (OSE carcinoma cells. Methods The human ovarian cancer cell line, SKOV-3, was stably transfected to express functional LHR and incubated with LH for various periods of time (0-20 hours. Transcriptomic profiling was performed on these cells to identify LHR expression/activation-dependent changes in gene expression levels and pathways by microarray and qRT-PCR analyses. Results Through comparative analysis on the LHR-transfected SKOV-3 cells exposed to LH, we observed the differential expression of 1,783 genes in response to LH treatment, among which five significant families were enriched, including those of growth factors, translation regulators, transporters, G-protein coupled receptors, and ligand-dependent nuclear receptors. The most highly induced early and intermediate responses were found to occupy a network impacting transcriptional regulation, cell growth, apoptosis, and multiple signaling transductions, giving indications of LH-induced apoptosis and cell growth inhibition through the significant changes in, for example, tumor necrosis factor, Jun and many others, supportive of the observed cell growth reduction in in vitro assays. However, other observations, e.g. the substantial up-regulation of the genes encoding the endothelin-1 subtype A receptor, stromal cell-derived factor 1, and insulin-like growth factor II, all of which are

  14. Thyroid hormone receptor inhibits hepatoma cell migration through transcriptional activation of Dickkopf 4

    Energy Technology Data Exchange (ETDEWEB)

    Chi, Hsiang-Cheng; Liao, Chen-Hsin [Department of Biochemistry, School of Medicine, Chang-Gung University, Taoyuan 333, Taiwan, ROC (China); Huang, Ya-Hui [Medical Research Central, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan, ROC (China); Wu, Sheng-Ming; Tsai, Chung-Ying; Liao, Chia-Jung; Tseng, Yi-Hsin; Lin, Yang-Hsiang; Chen, Cheng-Yi; Chung, I-Hsiao; Wu, Tzu-I [Department of Biochemistry, School of Medicine, Chang-Gung University, Taoyuan 333, Taiwan, ROC (China); Chen, Wei-Jan [First Cardiovascular Division, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan, ROC (China); Lin, Kwang-Huei, E-mail: khlin@mail.cgu.edu.tw [Department of Biochemistry, School of Medicine, Chang-Gung University, Taoyuan 333, Taiwan, ROC (China)

    2013-09-13

    Highlights: •T{sub 3} affects DKK4 mRNA and protein expression in HepG2-TR cells. •Regulation of DKK4 by T{sub 3} is at transcriptional level. •DKK4 overexpression suppresses hepatoma cell metastasis. -- Abstract: Triiodothyronine (T{sub 3}) is a potent form of thyroid hormone mediates several physiological processes including cellular growth, development, and differentiation via binding to the nuclear thyroid hormone receptor (TR). Recent studies have demonstrated critical roles of T{sub 3}/TR in tumor progression. Moreover, long-term hypothyroidism appears to be associated with the incidence of human hepatocellular carcinoma (HCC), independent of other major HCC risk factors. Dickkopf (DKK) 4, a secreted protein that antagonizes the canonical Wnt signaling pathway, is induced by T{sub 3} at both mRNA and protein levels in HCC cell lines. However, the mechanism underlying T{sub 3}-mediated regulation of DKK4 remains unknown. In the present study, the 5′ promoter region of DKK4 was serially deleted, and the reporter assay performed to localize the T{sub 3} response element (TRE). Consequently, we identified an atypical direct repeat TRE between nucleotides −1645 and −1629 conferring T{sub 3} responsiveness to the DKK4 gene. This region was further validated using chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA). Stable DKK4 overexpression in SK-Hep-1 cells suppressed cell invasion and metastatic potential, both in vivo andin vitro, via reduction of matrix metalloproteinase-2 (MMP-2) expression. Our findings collectively suggest that DKK4 upregulated by T{sub 3}/TR antagonizes the Wnt signal pathway to suppress tumor cell progression, thus providing new insights into the molecular mechanism underlying thyroid hormone activity in HCC.

  15. Phosphorylation of the androgen receptor by PIM1 in hormone refractory prostate cancer.

    Science.gov (United States)

    Ha, S; Iqbal, N J; Mita, P; Ruoff, R; Gerald, W L; Lepor, H; Taneja, S S; Lee, P; Melamed, J; Garabedian, M J; Logan, S K

    2013-08-22

    Integration of cellular signaling pathways with androgen receptor (AR) signaling can be achieved through phosphorylation of AR by cellular kinases. However, the kinases responsible for phosphorylating the AR at numerous sites and the functional consequences of AR phosphorylation are only partially understood. Bioinformatic analysis revealed AR serine 213 (S213) as a putative substrate for PIM1, a kinase overexpressed in prostate cancer. Therefore, phosphorylation of AR serine 213 by PIM1 was examined using a phosphorylation site-specific antibody. Wild-type PIM1, but not catalytically inactive PIM1, specifically phosphorylated AR but not an AR serine-to-alanine mutant (S213A). In vitro kinase assays confirmed that PIM1 can phosphorylate AR S213 in a ligand-independent manner and cell type-specific phosphorylation was observed in prostate cancer cell lines. Upon PIM1 overexpression, AR phosphorylation was observed in the absence of hormone and was further increased in the presence of hormone in LNCaP, LNCaP-abl and VCaP cells. Moreover, phosphorylation of AR was reduced in the presence of PIM kinase inhibitors. An examination of AR-mediated transcription showed that reporter gene activity was reduced in the presence of PIM1 and wild-type AR, but not S213A mutant AR. Androgen-mediated transcription of endogenous PSA, Nkx3.1 and IGFBP5 was also decreased in the presence of PIM1, whereas IL6, cyclin A1 and caveolin 2 were increased. Immunohistochemical analysis of prostate cancer tissue microarrays showed significant P-AR S213 expression that was associated with hormone refractory prostate cancers, likely identifying cells with catalytically active PIM1. In addition, prostate cancers expressing a high level of P-AR S213 were twice as likely to be from biochemically recurrent cancers. Thus, AR phosphorylation by PIM1 at S213 impacts gene transcription and is highly prevalent in aggressive prostate cancer.

  16. Taltirelin is a superagonist at the human thyrotropin-releasing hormone receptor

    Directory of Open Access Journals (Sweden)

    Nanthakumar eThirunarayanan

    2012-10-01

    Full Text Available Taltirelin (TAL is a thyrotropin-releasing hormone (TRH analog that is approved for use in humans in Japan. In this study, we characterized TAL binding to and signaling by the human TRH receptor (TRH-R in a model cell system. We found that TAL exhibited lower binding affinities than TRH and lower signaling potency via the inositol-1,4,5-trisphosphate/calcium pathway than TRH. However, TAL exhibited higher intrinsic efficacy than TRH in stimulating inositol-1,4,5-trisphosphate second messenger generation. This is the first study that elucidates the pharmacology of TAL at TRH-R and shows that TAL is a superagonist at TRH-R. We suggest the superagonism exhibited by TAL may in part explain its higher activity in mediating CNS effects in humans compared to TRH.

  17. Parathyroid hormone receptor signalling in osterix-expressing mesenchymal progenitors is essential for tooth root formation.

    Science.gov (United States)

    Ono, Wanida; Sakagami, Naoko; Nishimori, Shigeki; Ono, Noriaki; Kronenberg, Henry M

    2016-04-12

    Dental root formation is a dynamic process in which mesenchymal cells migrate toward the site of the future root, differentiate and secrete dentin and cementum. However, the identities of dental mesenchymal progenitors are largely unknown. Here we show that cells expressing osterix are mesenchymal progenitors contributing to all relevant cell types during morphogenesis. The majority of cells expressing parathyroid hormone-related peptide (PTHrP) are in the dental follicle and on the root surface, and deletion of its receptor (PPR) in these progenitors leads to failure of eruption and significantly truncated roots lacking periodontal ligaments. The PPR-deficient progenitors exhibit accelerated cementoblast differentiation with upregulation of nuclear factor I/C (Nfic). Deletion of histone deacetylase-4 (HDAC4) partially recapitulates the PPR deletion root phenotype. These findings indicate that PPR signalling in dental mesenchymal progenitors is essential for tooth root formation, underscoring importance of the PTHrP-PPR system during root morphogenesis and tooth eruption.

  18. Evaluation of growth hormone (GH) action in mice: discovery of GH receptor antagonists and clinical indications.

    Science.gov (United States)

    Kopchick, John J; List, Edward O; Kelder, Bruce; Gosney, Elahu S; Berryman, Darlene E

    2014-04-05

    The discovery of a growth hormone receptor antagonist (GHA) was initially established via expression of mutated GH genes in transgenic mice. Following this discovery, development of the compound resulted in a drug termed pegvisomant, which has been approved for use in patients with acromegaly. Pegvisomant treatment in a dose dependent manner results in normalization of IGF-1 levels in most patients. Thus, it is a very efficacious and safe drug. Since the GH/IGF-1 axis has been implicated in the progression of several types of cancers, many have suggested the use of pegvisomant as an anti-cancer therapeutic. In this manuscript, we will review the use of mouse strains that possess elevated or depressed levels of GH action for unraveling many of GH actions. Additionally, we will describe experiments in which the GHA was discovered, review results of pegvisomant's preclinical and clinical trials, and provide data suggesting pegvisomant's therapeutic value in selected types of cancer.

  19. Superovulation and expression of follicle-stimulating hormone receptor in young rabbit females

    Directory of Open Access Journals (Sweden)

    Hao Zhang

    2017-06-01

    Full Text Available To optimise the use of juvenile in vitro embryo transfer technologies in young rabbit females, superovulation was performed in New Zealand White young rabbit females at different ages and the expression mode of follicle-stimulating hormone receptor (FSHR was explored using real-time quantitative polymerase chain reaction, and in vitro maturation (IVM together with fertilisation (IVF was conducted immediately after superovulation. The results showed that (1 the age factor significantly affected superovulation in young rabbit females, with 60 d as an optimal age; (2 the mRNA level of FSHR exhibited a rising trend, though it was lower at 30 to 40 d of age; (3 the maturation rate of the oocytes from 60 d old rabbits was significantly higher than in those from 50 d old rabbits; (4 the fertilisation rate of oocytes was not significantly different among rabbits 50, 60 and 70 d old.

  20. Epigenetics of Estrogen Receptor Signaling: Role in Hormonal Cancer Progression and Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Mann, Monica; Cortez, Valerie [Department of Cellular and Structural Biology, UTHSCSA, 7703 Floyd Curl Drive, San Antonio, TX 78229 (United States); Vadlamudi, Ratna K., E-mail: vadlamudi@uthscsa.edu [Department of Obstetrics and Gynecology, UTHSCSA, 7703 Floyd Curl Drive, San Antonio, TX 78229 (United States)

    2011-03-29

    Estrogen receptor (ERα) signaling plays a key role in hormonal cancer progression. ERα is a ligand-dependent transcription factor that modulates gene transcription via recruitment to the target gene chromatin. Emerging evidence suggests that ERα signaling has the potential to contribute to epigenetic changes. Estrogen stimulation is shown to induce several histone modifications at the ERα target gene promoters including acetylation, phosphorylation and methylation via dynamic interactions with histone modifying enzymes. Deregulation of enzymes involved in the ERα -mediated epigenetic pathway could play a vital role in ERα driven neoplastic processes. Unlike genetic alterations, epigenetic changes are reversible, and hence offer novel therapeutic opportunities to reverse ERα driven epigenetic changes. In this review, we summarize current knowledge on mechanisms by which ERα signaling potentiates epigenetic changes in cancer cells via histone modifications.

  1. Hormone-receptor positive breast cancer: highlights from the 39(TH) San Antonio Breast Cancer Symposium.

    Science.gov (United States)

    Zucchini, Giorgia; Montemurro, Filippo

    2017-06-01

    The San Antonio Breast Cancer Symposium is considered one of the most influential international meetings focusing on breast cancer management, covering several areas of study from basic research to clinical practice topics. a number of oral presentations addressing hormone receptor-positive breast cancer brought new data about critical subjects like the optimal duration of adjuvant endocrine therapy, new prognostic markers and their potential role in guiding adjuvant treatment choices, new insights into genomic alterations acquired during the metastatic process, and pharmacologic strategies to overcome resistance to endocrine therapy. This article aims at summarizing some of the presentations that, in our opinion, are expected to have an impact on clinical practice and research programs in this patient population.

  2. Reproductive factors and hormone receptor status among very young (<35 years) breast cancer patients.

    Science.gov (United States)

    Jia, Xiaoqing; Liu, Guangyu; Mo, Miao; Cheng, Jingyi; Shen, Zhenzhou; Shao, Zhimin

    2015-09-15

    The prognosis for breast cancer occurs in young women is usually poor. The impact of different reproductive factors on disease characteristics is still largely unknown. We analyzed 261 patients aged ≤35 years old who were treated at the Cancer Hospital of Fudan University, Shanghai, China. The relationships between certain reproductive factors (age at menarche, parity, number of children, breastfeeding, history of abortion, age at first full-term pregnancy and oral contraceptive (OC) use) and disease characteristics were evaluated. Compared with patients who experienced fewer full-term pregnancies (menarche was ≥15 years exhibited a greater chance of PR-positive tumors (64.8%) (P = 0.036) compared with those whose age of menarche was menarche are more possible to exhibit hormone receptor-positive tumors. Additionally, patients who have taken OCs are more likely to present with advanced disease.

  3. Pharmacological Activation of Thyroid Hormone Receptors Elicits a Functional Conversion of White to Brown Fat

    Directory of Open Access Journals (Sweden)

    Jean Z. Lin

    2015-11-01

    Full Text Available The functional conversion of white adipose tissue (WAT into a tissue with brown adipose tissue (BAT-like activity, often referred to as “browning,” represents an intriguing strategy for combating obesity and metabolic disease. We demonstrate that thyroid hormone receptor (TR activation by a synthetic agonist markedly induces a program of adaptive thermogenesis in subcutaneous WAT that coincides with a restoration of cold tolerance to cold-intolerant mice. Distinct from most other browning agents, pharmacological TR activation dissociates the browning of WAT from activation of classical BAT. TR agonism also induces the browning of white adipocytes in vitro, indicating that TR-mediated browning is cell autonomous. These data establish TR agonists as a class of browning agents, implicate the TRs in the browning of WAT, and suggest a profound pharmacological potential of this action.

  4. The growth hormone receptor gene-disrupted mouse fails to respond to an intermittent fasting diet.

    Science.gov (United States)

    Arum, Oge; Bonkowski, Michael S; Rocha, Juliana S; Bartke, Andrzej

    2009-12-01

    The interaction of longevity-conferring genes with longevity-conferring diets is poorly understood. The growth hormone receptor gene-disrupted (GHR-KO) mouse is long lived; and this longevity is not responsive to 30% caloric restriction, in contrast to wild-type animals from the same strain. To determine whether this may have been limited to a particular level of dietary restriction, we subjected GHR-KO mice to a different dietary restriction regimen, an intermittent fasting diet. The intermittent fasting diet increased the survivorship and improved insulin sensitivity of normal males, but failed to affect either parameter in GHR-KO mice. From the results of two paradigms of dietary restriction, we postulate that GHR-KO mice would be resistant to any manner of dietary restriction; potentially due to their inability to further enhance insulin sensitivity. Insulin sensitivity may be a mechanism and/or a marker of the lifespan extending potential of an intervention.

  5. Distinct expression profiles of transcriptional coactivators for thyroid hormone receptors during Xenopus laevis metamorphosis

    Institute of Scientific and Technical Information of China (English)

    BINDU D PAUL; YUN-BO SHI

    2003-01-01

    The biological effects of thyroid hormone(T3)are mediated by the thyroid hormone receptor(TR).Amphibian metamorphosis is one of the most dramatic processes that are dependent on T3.T3 regulates a series of orchestrated developmental changes,which ultimately result in the conversion of an aquatic herbivorous tadpole to a terrestrial carnivorous frog.T3 is presumed to bind to TRs,which in turn recruit coactivators,leading to gene activation.The best-studied coactivators belong to the p 160 or SRC family.Members of this family include SRC 1/NCoA- 1,SRC2/TIF2/GRIP 1,and SRC3/pCIP/ACTR/AIB- 1/RAC-3/TRAM- 1.These SRCs interact directly with liganded TR and function as adapter molecules to recruit other coactivators such as p300/CBP.Here,we studied the expression patterns of these coactivators during various stages of development.Amongst the coactivators cloned in Xenopus laevis,SRC3 was found to be dramatically upregulated during natural and T3-induced metamorphosis,and SRC2 and p300 are expressed throughout postembryonic development with little change in their expression levels.These results support the view that these coactivators participate in gene regulation by TR during metamorphosis.

  6. The axolotl (Ambystoma mexicanum), a neotenic amphibian, expresses functional thyroid hormone receptors.

    Science.gov (United States)

    Safi, Rachid; Bertrand, Stéphanie; Marchand, Oriane; Duffraisse, Marilyne; de Luze, Amaury; Vanacker, Jean-Marc; Maraninchi, Marie; Margotat, Alain; Demeneix, Barbara; Laudet, Vincent

    2004-02-01

    Neotenic amphibians such as the axolotl (Ambystoma mexicanum) are often unable to undergo metamorphosis under natural conditions. It is thought that neoteny represents a deviation from the standard course of amphibian ontogeny, affecting the thyroid axis at different levels from the central nervous system to peripheral organs. Thyroid hormone receptors (TRs) that bind the thyroid hormone (TH) T(3) have been described in axolotl. However, the full sequences of TR were needed to better characterize the TH response and to be able to assess their functional capacity at the molecular level. We report that each of the alpha and beta axolotl TRs bind both DNA and TH, and they activate transcription in response to TH in a mammalian cell-based transient transfection assay. Moreover, both TRs are expressed in axolotl tissues. Interestingly, each TR gene generates alternatively spliced isoforms, harboring partial or total deletions of the ligand-binding domain, which are expressed in vivo. Further, we found that in the axolotl, TH regulates the expression of stromelysin 3 and collagenase 3, which are TH target genes in Xenopus. Taken together, these results suggest that axolotl TRs are functional and that the molecular basis of neoteny in the axolotl is not linked to a major defect in TH response in peripheral tissues.

  7. Structure-activity relations in binding of perfluoroalkyl compounds to human thyroid hormone T3 receptor.

    Science.gov (United States)

    Ren, Xiao-Min; Zhang, Yin-Feng; Guo, Liang-Hong; Qin, Zhan-Fen; Lv, Qi-Yan; Zhang, Lian-Ying

    2015-02-01

    Perfluoroalkyl compounds (PFCs) have been shown to disrupt thyroid functions through thyroid hormone receptor (TR)-mediated pathways, but direct binding of PFCs with TR has not been demonstrated. We investigated the binding interactions of 16 structurally diverse PFCs with human TR, their activities on TR in cells, and the activity of perfluorooctane sulfonate (PFOS) in vivo. In fluorescence competitive binding assays, most of the 16 PFCs were found to bind to TR with relative binding potency in the range of 0.0003-0.05 compared with triiodothyronine (T3). A structure-binding relationship for PFCs was observed, where fluorinated alkyl chain length longer than ten, and an acid end group were optimal for TR binding. In thyroid hormone (TH)-responsive cell proliferation assays, PFOS, perfluorohexadecanoic acid, and perfluorooctadecanoic acid exhibited agonistic activity by promoting cell growth. Furthermore, similar to T3, PFOS exposure promoted expression of three TH upregulated genes and inhibited three TH downregulated genes in amphibians. Molecular docking analysis revealed that most of the tested PFCs efficiently fit into the T3-binding pocket in TR and formed a hydrogen bond with arginine 228 in a manner similar to T3. The combined in vitro, in vivo, and computational data strongly suggest that some PFCs disrupt the normal activity of TR pathways by directly binding to TR.

  8. Egg size-dependent expression of growth hormone receptor accompanies compensatory growth in fish.

    Science.gov (United States)

    Segers, F H I D; Berishvili, G; Taborsky, B

    2012-02-07

    Large egg size usually boosts offspring survival, but mothers have to trade off egg size against egg number. Therefore, females often produce smaller eggs when environmental conditions for offspring are favourable, which is subsequently compensated for by accelerated juvenile growth. How this rapid growth is modulated on a molecular level is still unclear. As the somatotropic axis is a key regulator of early growth in vertebrates, we investigated the effect of egg size on three key genes belonging to this axis, at different ontogenetic stages in a mouthbrooding cichlid (Simochromis pleurospilus). The expression levels of one of them, the growth hormone receptor (GHR), were significantly higher in large than in small eggs, but remarkably, this pattern was reversed after hatching: young originating from small eggs had significantly higher GHR expression levels as yolk sac larvae and as juveniles. GHR expression in yolk sac larvae was positively correlated with juvenile growth rate and correspondingly fish originating from small eggs grew faster. This enabled them to catch up fully in size within eight weeks with conspecifics from larger eggs. This is the first evidence for a potential link between egg size, an important maternal effect, and offspring gene expression, which mediates an adaptive adjustment in a relevant hormonal axis.

  9. Non-mammalian models reveal the role of alternative ligands for thyroid hormone receptors.

    Science.gov (United States)

    Orozco, Aurea; Lazcano, Iván; Hernández-Puga, Gabriela; Olvera, Aurora

    2017-03-04

    Thyroid hormones, or THs, are well-known regulators of a wide range of biological processes that occur throughout the lifespan of all vertebrates. THs act through genomic mechanisms mediated by thyroid hormone receptors (TRs). The main product of the thyroid gland is thyroxine or T4, which can be further transformed by different biochemical pathways to produce at least 15 active or inactive molecules. T3, a product of T4 outer-ring deiodination, has been recognized as the main bioactive TH. However, growing evidence has shown that other TH derivatives are able to bind to, and/or activate TRs, to induce thyromimetic effects. The compiled data in this review points to at least two of these TR alternative ligands: TRIAC and T2. Taking this into account, non-mammalian models have proven to be advantageous to explore new TH derivatives with potential novel actions, prompting a re-evaluation of the role and mechanism of action of TR alternative ligands that were previously believed to be inactive. The functional implications of these ligands across different vertebrates may require us to reconsider current established notions of thyroid physiology. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Egg size-dependent expression of growth hormone receptor accompanies compensatory growth in fish

    Science.gov (United States)

    Segers, F. H. I. D.; Berishvili, G.; Taborsky, B.

    2012-01-01

    Large egg size usually boosts offspring survival, but mothers have to trade off egg size against egg number. Therefore, females often produce smaller eggs when environmental conditions for offspring are favourable, which is subsequently compensated for by accelerated juvenile growth. How this rapid growth is modulated on a molecular level is still unclear. As the somatotropic axis is a key regulator of early growth in vertebrates, we investigated the effect of egg size on three key genes belonging to this axis, at different ontogenetic stages in a mouthbrooding cichlid (Simochromis pleurospilus). The expression levels of one of them, the growth hormone receptor (GHR), were significantly higher in large than in small eggs, but remarkably, this pattern was reversed after hatching: young originating from small eggs had significantly higher GHR expression levels as yolk sac larvae and as juveniles. GHR expression in yolk sac larvae was positively correlated with juvenile growth rate and correspondingly fish originating from small eggs grew faster. This enabled them to catch up fully in size within eight weeks with conspecifics from larger eggs. This is the first evidence for a potential link between egg size, an important maternal effect, and offspring gene expression, which mediates an adaptive adjustment in a relevant hormonal axis. PMID:21752823

  11. Actin-Sorting Nexin 27 (SNX27)-Retromer Complex Mediates Rapid Parathyroid Hormone Receptor Recycling.

    Science.gov (United States)

    McGarvey, Jennifer C; Xiao, Kunhong; Bowman, Shanna L; Mamonova, Tatyana; Zhang, Qiangmin; Bisello, Alessandro; Sneddon, W Bruce; Ardura, Juan A; Jean-Alphonse, Frederic; Vilardaga, Jean-Pierre; Puthenveedu, Manojkumar A; Friedman, Peter A

    2016-05-20

    The G protein-coupled parathyroid hormone receptor (PTHR) regulates mineral-ion homeostasis and bone remodeling. Upon parathyroid hormone (PTH) stimulation, the PTHR internalizes into early endosomes and subsequently traffics to the retromer complex, a sorting platform on early endosomes that promotes recycling of surface receptors. The C terminus of the PTHR contains a type I PDZ ligand that binds PDZ domain-containing proteins. Mass spectrometry identified sorting nexin 27 (SNX27) in isolated endosomes as a PTHR binding partner. PTH treatment enriched endosomal PTHR. SNX27 contains a PDZ domain and serves as a cargo selector for the retromer complex. VPS26, VPS29, and VPS35 retromer subunits were isolated with PTHR in endosomes from cells stimulated with PTH. Molecular dynamics and protein binding studies establish that PTHR and SNX27 interactions depend on the PDZ recognition motif in PTHR and the PDZ domain of SNX27. Depletion of either SNX27 or VPS35 or actin depolymerization decreased the rate of PTHR recycling following agonist stimulation. Mutating the PDZ ligand of PTHR abolished the interaction with SNX27 but did not affect the overall rate of recycling, suggesting that PTHR may directly engage the retromer complex. Coimmunoprecipitation and overlay experiments show that both intact and mutated PTHR bind retromer through the VPS26 protomer and sequentially assemble a ternary complex with PTHR and SNX27. SNX27-independent recycling may involve N-ethylmaleimide-sensitive factor, which binds both PDZ intact and mutant PTHRs. We conclude that PTHR recycles rapidly through at least two pathways, one involving the ASRT complex of actin, SNX27, and retromer and another possibly involving N-ethylmaleimide-sensitive factor.

  12. Actin-Sorting Nexin 27 (SNX27)-Retromer Complex Mediates Rapid Parathyroid Hormone Receptor Recycling*

    Science.gov (United States)

    McGarvey, Jennifer C.; Xiao, Kunhong; Bowman, Shanna L.; Mamonova, Tatyana; Zhang, Qiangmin; Bisello, Alessandro; Sneddon, W. Bruce; Ardura, Juan A.; Jean-Alphonse, Frederic; Vilardaga, Jean-Pierre; Puthenveedu, Manojkumar A.; Friedman, Peter A.

    2016-01-01

    The G protein-coupled parathyroid hormone receptor (PTHR) regulates mineral-ion homeostasis and bone remodeling. Upon parathyroid hormone (PTH) stimulation, the PTHR internalizes into early endosomes and subsequently traffics to the retromer complex, a sorting platform on early endosomes that promotes recycling of surface receptors. The C terminus of the PTHR contains a type I PDZ ligand that binds PDZ domain-containing proteins. Mass spectrometry identified sorting nexin 27 (SNX27) in isolated endosomes as a PTHR binding partner. PTH treatment enriched endosomal PTHR. SNX27 contains a PDZ domain and serves as a cargo selector for the retromer complex. VPS26, VPS29, and VPS35 retromer subunits were isolated with PTHR in endosomes from cells stimulated with PTH. Molecular dynamics and protein binding studies establish that PTHR and SNX27 interactions depend on the PDZ recognition motif in PTHR and the PDZ domain of SNX27. Depletion of either SNX27 or VPS35 or actin depolymerization decreased the rate of PTHR recycling following agonist stimulation. Mutating the PDZ ligand of PTHR abolished the interaction with SNX27 but did not affect the overall rate of recycling, suggesting that PTHR may directly engage the retromer complex. Coimmunoprecipitation and overlay experiments show that both intact and mutated PTHR bind retromer through the VPS26 protomer and sequentially assemble a ternary complex with PTHR and SNX27. SNX27-independent recycling may involve N-ethylmaleimide-sensitive factor, which binds both PDZ intact and mutant PTHRs. We conclude that PTHR recycles rapidly through at least two pathways, one involving the ASRT complex of actin, SNX27, and retromer and another possibly involving N-ethylmaleimide-sensitive factor. PMID:27008860

  13. The SOCS2 ubiquitin ligase complex regulates growth hormone receptor levels.

    Directory of Open Access Journals (Sweden)

    Mattias Vesterlund

    Full Text Available Growth Hormone is essential for the regulation of growth and the homeostatic control of intermediary metabolism. GH actions are mediated by the Growth Hormone Receptor; a member of the cytokine receptor super family that signals chiefly through the JAK2/STAT5 pathway. Target tissue responsiveness to GH is under regulatory control to avoid excessive and off-target effects upon GHR activation. The suppressor of cytokine signalling 2 (SOCS is a key regulator of GHR sensitivity. This is clearly shown in mice where the SOCS2 gene has been inactivated, which show 30-40% increase in body length, a phenotype that is dependent on endogenous GH secretion. SOCS2 is a GH-stimulated, STAT5b-regulated gene that acts in a negative feedback loop to downregulate GHR signalling. Since the biochemical basis for these actions is poorly understood, we studied the molecular function of SOCS2. We demonstrated that SOCS2 is part of a multimeric complex with intrinsic ubiquitin ligase activity. Mutational analysis shows that the interaction with Elongin B/C controls SOCS2 protein turnover and affects its molecular activity. Increased GHR levels were observed in livers from SOCS2⁻/⁻ mice and in the absence of SOCS2 in in vitro experiments. We showed that SOCS2 regulates cellular GHR levels through direct ubiquitination and in a proteasomally dependent manner. We also confirmed the importance of the SOCS-box for the proper function of SOCS2. Finally, we identified two phosphotyrosine residues in the GHR to be responsible for the interaction with SOCS2, but only Y487 to account for the effects of SOCS2. The demonstration that SOCS2 is an ubiquitin ligase for the GHR unveils the molecular basis for its physiological actions.

  14. Brain receptors for thyrotropin releasing hormone in morphine tolerant-dependent rats

    Energy Technology Data Exchange (ETDEWEB)

    Bhargava, H.N.; Das, S.

    1986-03-01

    The effect of chronic treatment of rats with morphine and its subsequent withdrawal on the brain receptors for thyrotropin releasing hormone (TRH) labeled with /sup 3/H-(3MeHis/sup 2/)TRH (MeTRH). Male Sprague Dawley rats were implanted with 4 morphine pellets (each containing 75 mg morphine base) during a 3-day period. Placebo pellet implanted rats served as controls. Both tolerance to and dependence on morphine developed as a result of this procedure. For characterization of brain TRH receptors, the animals were sacrificed 72 h after the implantation of first pellet. In another set of animals the pellets were removed and were sacrificed 24 h later. The binding of /sup 3/H-MeTRH to membranes prepared from brain without the cerebellum was determined. /sup 3/H-MeTRH bound to brain membranes prepared from placebo pellet implanted rats at a single high affinity site with a B/sub max/ value of 33.50 +/- 0.97 fmol/mg protein and a K/sub d/ of 5.18 +/- 0.21 nM. Implantation of morphine pellets did not alter the B/sub max/ value of /sup 3/H-MeTRH but decreased the K/sub d/ value significantly. Abrupt or naloxone precipitated withdrawal of morphine did not alter B/sub max/ or the K/sub d/ values. The binding of /sup 3/H-MeTRH to brain areas was also determined. The results suggest that the development of tolerance to morphine is associated with enhanced sensitivity of brain TRH receptors, however abrupt withdrawal of morphine does not change the characteristics of brain TRH receptors.

  15. ICON 2013: Practical consensus recommendations for hormone receptor-positive Her2-negative advanced or metastatic breastcancer

    Directory of Open Access Journals (Sweden)

    P M Parikh

    2014-01-01

    Full Text Available The management of hormone receptor-positive Her2-negative breast cancer patients with advanced or metastatic disease is a common problem in India and other countries in this region. This expert group used data from published literature, practical experience, and opinion of a large group of academic oncologists, to arrive at practical consensus recommendations for use by the community oncologists.

  16. Lack of thyroid hormone receptor alpha1 is associated with selective alterations in behavior and hippocampal circuits.

    Science.gov (United States)

    Guadaño-Ferraz, A; Benavides-Piccione, R; Venero, C; Lancha, C; Vennström, B; Sandi, C; DeFelipe, J; Bernal, J

    2003-01-01

    Brain development and function are dependent on thyroid hormone (T3), which acts through nuclear hormone receptors. T3 receptors (TRs) are transcription factors that activate or suppress target gene expression in a hormone-dependent or -independent fashion. Two distinct genes, TRalpha and TRbeta, encode several receptor isoforms with specific functions defined in many tissues but not in the brain. Mutations in the TRbeta gene cause the syndrome of peripheral resistance to thyroid hormone; however, no alterations of the TRalpha gene have been described in humans. Here we demonstrate that mice lacking the TRalpha1 isoform display behavioral abnormalities of hippocampal origin, as shown by the open field and fear conditioning tests. In the open field test mutant mice revealed less exploratory behavior than wild-type mice. In the contextual fear conditioning test mutant mice showed a significantly higher freezing response than wild-type controls when tested 1 week after training. These findings correlated with fewer GABAergic terminals on the CA1 pyramidal neurons in the mutant mice. Our results indicate that TRalpha1 is involved in the regulation of hippocampal structure and function, and raise the possibility that deletions or mutations of this receptor isoform may lead to behavioral changes or even psychiatric syndromes in humans.

  17. Growth hormone preferentially induces the rapid, transient expression of SOCS-3, a novel inhibitor of cytokine receptor signaling

    DEFF Research Database (Denmark)

    Adams, T E; Hansen, J A; Starr, R;

    1998-01-01

    Four members (SOCS-1, SOCS-2, SOCS-3, and CIS) of a family of cytokine-inducible, negative regulators of cytokine receptor signaling have recently been identified. To address whether any of these genes are induced in response to growth hormone (GH), serum-starved 3T3-F442A fibroblasts were...

  18. Thyroid Hormone Regulates the mRNA Expression of Small Heterodimer Partner through Liver Receptor Homolog-1

    Directory of Open Access Journals (Sweden)

    Hwa Young Ahn

    2015-12-01

    Full Text Available BackgroundExpression of hepatic cholesterol 7α-hydroxylase (CYP7A1 is negatively regulated by orphan nuclear receptor small heterodimer partner (SHP. In this study, we aimed to find whether thyroid hormone regulates SHP expression by modulating the transcriptional activities of liver receptor homolog-1 (LRH-1.MethodsWe injected thyroid hormone (triiodothyronine, T3 to C57BL/6J wild type. RNA was isolated from mouse liver and used for microarray analysis and quantitative real-time polymerase chain reaction (PCR. Human hepatoma cell and primary hepatocytes from mouse liver were used to confirm the effect of T3 in vitro. Promoter assay and electrophoretic mobility-shift assay (EMSA were also performed using human hepatoma cell lineResultsInitial microarray results indicated that SHP expression is markedly decreased in livers of T3 treated mice. We confirmed that T3 repressed SHP expression in the liver of mice as well as in mouse primary hepatocytes and human hepatoma cells by real-time PCR analysis. LRH-1 increased the promoter activity of SHP; however, this increased activity was markedly decreased after thyroid hormone receptor β/retinoid X receptor α/T3 administration. EMSA revealed that T3 inhibits specific LRH-1 DNA binding.ConclusionWe found that thyroid hormone regulates the expression of SHP mRNA through interference with the transcription factor, LRH-1.

  19. ICON 2013: practical consensus recommendations for hormone receptor-positive Her2-negative advanced or metastatic breastcancer.

    Science.gov (United States)

    Parikh, P M; Gupta, S; Dawood, S; Rugo, H; Bhattacharyya, G S; Agarwal, A; Chacko, R; Sahoo, T P; Babu, G; Agarwal, S; Munshi, A; Goswami, C; Smruti, B K; Bondarde, S; Desai, C; Rajappa, S; Somani, N; Singh, M; Nimmagadda, R; Pavitran, K; Mehta, A; Parmar, V; Desai, S; Nair, R; Doval, D

    2014-01-01

    The management of hormone receptor-positive Her2-negative breast cancer patients with advanced or metastatic disease is a common problem in India and other countries in this region. This expert group used data from published literature, practical experience, and opinion of a large group of academic oncologists, to arrive at practical consensus recommendations for use by the community oncologists.

  20. TBLR1 regulates the expression of nuclear hormone receptor co-repressors

    Directory of Open Access Journals (Sweden)

    Brown Stuart

    2006-08-01

    Full Text Available Abstract Background Transcription is regulated by a complex interaction of activators and repressors. The effectors of repression are large multimeric complexes which contain both the repressor proteins that bind to transcription factors and a number of co-repressors that actually mediate transcriptional silencing either by inhibiting the basal transcription machinery or by recruiting chromatin-modifying enzymes. Results TBLR1 [GenBank: NM024665] is a co-repressor of nuclear hormone transcription factors. A single highly conserved gene encodes a small family of protein molecules. Different isoforms are produced by differential exon utilization. Although the ORF of the predominant form contains only 1545 bp, the human gene occupies ~200 kb of genomic DNA on chromosome 3q and contains 16 exons. The genomic sequence overlaps with the putative DC42 [GenBank: NM030921] locus. The murine homologue is structurally similar and is also located on Chromosome 3. TBLR1 is closely related (79% homology at the mRNA level to TBL1X and TBL1Y, which are located on Chromosomes X and Y. The expression of TBLR1 overlaps but is distinct from that of TBL1. An alternatively spliced form of TBLR1 has been demonstrated in human material and it too has an unique pattern of expression. TBLR1 and the homologous genes interact with proteins that regulate the nuclear hormone receptor family of transcription factors. In resting cells TBLR1 is primarily cytoplasmic but after perturbation the protein translocates to the nucleus. TBLR1 co-precipitates with SMRT, a co-repressor of nuclear hormone receptors, and co-precipitates in complexes immunoprecipitated by antiserum to HDAC3. Cells engineered to over express either TBLR1 or N- and C-terminal deletion variants, have elevated levels of endogenous N-CoR. Co-transfection of TBLR1 and SMRT results in increased expression of SMRT. This co-repressor undergoes ubiquitin-mediated degradation and we suggest that the stabilization of

  1. Genetic polymorphisms and protein structures in growth hormone, growth hormone receptor, ghrelin, insulin-like growth factor 1 and leptin in Mehraban sheep.

    Science.gov (United States)

    Bahrami, A; Behzadi, Sh; Miraei-Ashtiani, S R; Roh, S-G; Katoh, K

    2013-09-15

    The somatotropic axis, the control system for growth hormone (GH) secretion and its endogenous factors involved in the regulation of metabolism and energy partitioning, has promising potentials for producing economically valuable traits in farm animals. Here we investigated single nucleotide polymorphisms (SNPs) of the genes of factors involved in the somatotropic axis for growth hormone (GH1), growth hormone receptor (GHR), ghrelin (GHRL), insulin-like growth factor 1 (IGF-I) and leptin (LEP), using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and DNA sequencing methods in 452 individual Mehraban sheep. A nonradioactive method to allow SSCP detection was used for genomic DNA and PCR amplification of six fragments: exons 4 and 5 of GH1; exon 10 of GH receptor (GHR); exon 1 of ghrelin (GHRL); exon 1 of insulin-like growth factor-I (IGF-I), and exon 3 of leptin (LEP). Polymorphisms were detected in five of the six PCR products. Two electrophoretic patterns were detected for GH1 exon 4. Five conformational patterns were detected for GH1 exon 5 and LEP exon 3, and three for IGF-I exon 1. Only GHR and GHRL were monomorphic. Changes in protein structures due to variable SNPs were also analyzed. The results suggest that Mehraban sheep, a major breed that is important for the animal industry in Middle East countries, has high genetic variability, opening interesting prospects for future selection programs and preservation strategies.

  2. Thyroid hormone and adrenergic signaling interact to control pineal expression of the dopamine receptor D4 gene (Drd4)

    DEFF Research Database (Denmark)

    Kim, Jong-So; Bailey, Michael J; Weller, Joan L;

    2009-01-01

    . Our studies indicate that Drd4 is the dominant dopamine receptor gene expressed in the pineal gland. The gene is expressed in pinealocytes at levels which are approximately 100-fold greater than in other tissues, except the retina, in which transcript levels are similar. Pineal Drd4 expression...... and whether thyroid hormone controls expression of other genes in the pineal gland.......Dopamine plays diverse and important roles in vertebrate biology, impacting behavior and physiology through actions mediated by specific G-protein-coupled receptors, one of which is the dopamine receptor D4 (Drd4). Here we present studies on the >100-fold daily rhythm in rat pineal Drd4 expression...

  3. Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats

    Science.gov (United States)

    Gowen, Maxine; Stroup, George B.; Dodds, Robert A.; James, Ian E.; Votta, Bart J.; Smith, Brian R.; Bhatnagar, Pradip K.; Lago, Amparo M.; Callahan, James F.; DelMar, Eric G.; Miller, Michael A.; Nemeth, Edward F.; Fox, John

    2000-01-01

    Parathyroid hormone (PTH) is an effective bone anabolic agent, but it must be administered parenterally. An orally active anabolic agent would provide a valuable alternative for treating osteoporosis. NPS 2143 is a novel, selective antagonist (a “calcilytic”) of the parathyroid cell Ca2+ receptor. Daily oral administration of NPS 2143 to osteopenic ovariectomized (OVX) rats caused a sustained increase in plasma PTH levels, provoking a dramatic increase in bone turnover but no net change in bone mineral density. Concurrent oral administration of NPS 2143 and subcutaneous infusion of 17β-estradiol also resulted in increased bone turnover. However, the antiresorptive action of estrogen decreased the extent of bone resorption stimulated by the elevated PTH levels, leading to an increase in bone mass compared with OVX controls or to either treatment alone. Despite the sustained stimulation to the parathyroid gland, parathyroid cells did not undergo hyperplasia. These data demonstrate that an increase in endogenous PTH secretion, induced by antagonism of the parathyroid cell Ca2+ receptor with a small molecule, leads to a dramatic increase in bone turnover, and they suggest a novel approach to the treatment of osteoporosis. PMID:10841518

  4. Spinal cord thyrotropin releasing hormone receptors of morphine tolerant-dependent and abstinent rats

    Energy Technology Data Exchange (ETDEWEB)

    Rahmani, N.H.; Gulati, A.; Bhargava, H.N. (Univ. of Illinois, Chicago (USA))

    1990-07-01

    The effect of chronic administration of morphine and its withdrawal on the binding of 3H-(3-MeHis2)thyrotropin releasing hormone (3H-MeTRH) to membranes of the spinal cord of the rat was determined. Male Sprague-Dawley rats were implanted with either 6 placebo or 6 morphine pellets (each containing 75-mg morphine base) during a 7-day period. Two sets of animals were used. In one, the pellets were left intact at the time of sacrificing (tolerant-dependent) and in the other, the pellets were removed 16 hours prior to sacrificing (abstinent rats). In placebo-pellet-implanted rats, 3H-MeTRH bound to the spinal cord membranes at a single high affinity binding site with a Bmax of 21.3 +/- 1.6 fmol/mg protein, and an apparent dissociation constant Kd of 4.7 +/- 0.8 nM. In morphine tolerant-dependent or abstinent rats, the binding constants of 3H-MeTRH to spinal cord membranes were unaffected. Previous studies from this laboratory indicate that TRH can inhibit morphine tolerance-dependence and abstinence processes without modifying brain TRH receptors. Together with the present results, it appears that the inhibitory effect of TRH on morphine tolerance-dependence and abstinence is probably not mediated via central TRH receptors but may be due to its interaction with other neurotransmitter systems.

  5. Transmembrane signal transduction by peptide hormones via family B G protein-coupled receptors

    Directory of Open Access Journals (Sweden)

    Kelly J Culhane

    2015-11-01

    Full Text Available Although family B G protein-coupled receptors (GPCRs contain only 15 members, they play key roles in transmembrane signal transduction of hormones. Family B GPCRs are drug targets for developing therapeutics for diseases ranging from metabolic to neurological disorders. Despite their importance, the molecular mechanism of activation of family B GPCRs remains largely unexplored due to the challenges in expression and purification of functional receptors to the quantity for biophysical characterization. Currently, there is no crystal structure available of a full-length family B GPCR. However, structures of key domains, including the extracellular ligand binding regions and seven-helical transmembrane regions, have been solved by X-ray crystallography and NMR, providing insights into the mechanisms of ligand recognition and selectivity, and helical arrangements within the cell membrane. Moreover, biophysical and biochemical methods have been used to explore functions, key residues for signaling, and the kinetics and dynamics of signaling processes. This review summarizes the current knowledge of the signal transduction mechanism of family B GPCRs at the molecular level and comments on the challenges and outlook for mechanistic studies of family B GPCRs.

  6. Cloning and tissue distribution of the chicken type 2 corticotropin-releasing hormone receptor.

    Science.gov (United States)

    de Groef, Bert; Grommen, Sylvia V H; Mertens, Inge; Schoofs, Liliane; Kühn, Eduard R; Darras, Veerle M

    2004-08-01

    We report the cloning of the complete coding sequence of the putative chicken type 2 corticotropin-releasing hormone receptor (CRH-R2) by rapid amplification of cDNA ends (RACE). The chicken CRH-R2 is a 412-amino acid 7-transmembrane G protein-coupled receptor, showing 87% identity to the Xenopus laevis and Oncorhynchus keta CRH-R2s, and 78-80% to mammalian CRH-R2s. The distribution of CRH-R2 mRNA was studied by RT-PCR analysis and compared to CRH-R1 distribution. Both CRH-R1 and CRH-R2 mRNA are expressed in the main chicken brain parts. In peripheral organs, CRH-R1 mRNA shows a more restricted distribution, whereas CRH-R2 mRNA is expressed in every tissue investigated, indicating that a number of actions of CRH and/or CRH-like peptides remain to be discovered in the chicken as well as in other vertebrates.

  7. Steroid hormone receptors and prostate cancer: role of structural dynamics in therapeutic targeting

    Directory of Open Access Journals (Sweden)

    Raj Kumar

    2016-01-01

    Full Text Available Steroid hormone receptors (SHRs act in cell type- and gene-specific manner through interactions with coregulatory proteins to regulate numerous physiological and pathological processes at the level of gene regulation. Binding of steroid receptor modulator (SRM ligand leads to allosteric changes in SHR to exert positive or negative effects on the expression of target genes. Due, in part, to the fact that current SRMs generally target ligand binding domain (LBD/AF2 and neglect intrinsically disordered (ID N-terminal domain (NTD/AF1, clinically relevant SRMs lack selectivity and are also prone to the development of resistance over time. Therefore, to maximize the efficacy of SHR-based therapeutics, the possibility of developing unique modulators that act to control AF1 activity must be considered. Recent studies targeting androgen receptor′s (AR′s ID AF1 domain for the castration-resistant prostate cancer has provided the possibility of therapeutically targeting ID NTD/AF1 surfaces by allosteric modulations to achieve desired effects. In this review article, we discuss how inter- and intra- molecular allosteric regulations controlled by AR′s structural flexibility and dynamics particularly the ID NTD/AF1 is an emerging area of investigation, which could be exploited for drug development and therapeutic targeting of prostate cancer.

  8. [Establishment of HEK293 cell lines stably expressing human parathyroid hormone receptors].

    Science.gov (United States)

    Meng, Yue; Xie, Miaomiao; Lin, Zhen; Yuan, Liang; Li, Wei; Hao, Song; Yang, Dehong

    2013-07-01

    To establish HEK293 cell lines with stable expression of human parathyroid hormone (PTH) receptors. The purified gene fragments of PTH-related peptide receptor (PTHR) and its mutant form (DSEL) were cloned separately into pcDNA3.1(+) vector after digestion with EcoR I and Not I, and the resulted pcDNA3.1(+)-PTHR and pcDNA3.1(+)-DSEL plasmids were verified by restriction enzyme digestion and DNA sequencing. HEK293 cells were transfected with these plasmids and the expression of PTHR and DSEL in the cells were examined by RT-PCR and ELSIA. Sequencing and restriction enzyme digestion analysis showed that PTHR and DSEL cDNAs were correctly cloned into pcDNA3.1(+)vector. After a 48-h transfection of HEK293 cells with the recombinant plasmids and G418 selection, the positive cell clones stably expressing the constructs were obtained, which showed expressions of PTHR and DSEL mRNAs detected by RT-PCR. These positive cells showed high levels of PLC and aAMP production in response to PTH stimulation. The HEK293 cell lines with stable expression of PTH1R or DSEL gene established in this study provide useful cell models for studying the physiological functions of PTH peptides.

  9. Obesity is associated with a poorer prognosis in women with hormone receptor positive breast cancer.

    Science.gov (United States)

    Robinson, Penelope J; Bell, Robin J; Davis, Susan R

    2014-11-01

    Whether moderate to severe obesity (body mass index (BMI)≥30 to breast cancer recurrence and mortality remains uncertain. 1199 women, recruited within 12 months of their diagnosis of hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) invasive breast cancer completed an enrolment questionnaire and an annual follow-up questionnaire every 12 months for another 5 years. The impact of obesity on time to either local or distant recurrence or new breast cancer, or death due to breast cancer was determined by Cox regression. Women in the most extreme categories of BMI (obesity (HR=1.71, 95%CI, 1.12-2.62, p=0.014), disease beyond Stage 1 (HR=2.87, 95% CI 1.73-4.75, pobesity (HR 3.23, 95%CI 1.48-7.03, p=0.003) and OAET use (HR 0.41, 95%CI 0.17-0.98, p=0.046) were significantly associated with an event. Moderate to severe obesity is associated with a poorer invasive breast cancer prognosis; this is also true for women with Stage 1 disease, and is independent of age and treatment. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  10. Distinct growth hormone receptor signaling modes regulate skeletal muscle development and insulin sensitivity in mice.

    Science.gov (United States)

    Mavalli, Mahendra D; DiGirolamo, Douglas J; Fan, Yong; Riddle, Ryan C; Campbell, Kenneth S; van Groen, Thomas; Frank, Stuart J; Sperling, Mark A; Esser, Karyn A; Bamman, Marcas M; Clemens, Thomas L

    2010-11-01

    Skeletal muscle development, nutrient uptake, and nutrient utilization is largely coordinated by growth hormone (GH) and its downstream effectors, in particular, IGF-1. However, it is not clear which effects of GH on skeletal muscle are direct and which are secondary to GH-induced IGF-1 expression. Thus, we generated mice lacking either GH receptor (GHR) or IGF-1 receptor (IGF-1R) specifically in skeletal muscle. Both exhibited impaired skeletal muscle development characterized by reductions in myofiber number and area as well as accompanying deficiencies in functional performance. Defective skeletal muscle development, in both GHR and IGF-1R mutants, was attributable to diminished myoblast fusion and associated with compromised nuclear factor of activated T cells import and activity. Strikingly, mice lacking GHR developed metabolic features that were not observed in the IGF-1R mutants, including marked peripheral adiposity, insulin resistance, and glucose intolerance. Insulin resistance in GHR-deficient myotubes derived from reduced IR protein abundance and increased inhibitory phosphorylation of IRS-1 on Ser 1101. These results identify distinct signaling pathways through which GHR regulates skeletal muscle development and modulates nutrient metabolism.

  11. Gold-nanoparticle-based assay for instantaneous detection of nuclear hormone receptor-response elements interactions.

    Science.gov (United States)

    Tan, Yen Nee; Su, Xiaodi; Liu, Edison T; Thomsen, Jane S

    2010-04-01

    Gold nanoparticles (AuNPs) are widely used as colorimetric probes for biosensing, relying on their unique particle size-dependent and/or interparticle distance-dependent extinction spectrum and solution color. Herein, we describe an AuNP-based colorimetric assay to detect binding interactions between nuclear hormone receptors and their corresponding DNA-binding elements, particularly the human estrogen receptors (ERalpha and ERbeta) and their cognate estrogen response elements (EREs). We found that the protein-DNA (ER-ERE) complexes can stabilize citrate anion-capped AuNPs against salt-induced aggregation to a larger extent than the protein (ER) or the DNA (ERE) alone, due to their unique molecular size and charge properties that provide a strong electrosteric protection. Moreover, our results show that the extent of stabilization is sequence-dependent and can distinguish a single base variation in the ERE associated with minor changes in protein-DNA binding affinity. With this assay, many important parameters of protein-DNA binding events (e.g., sequence selectivity, distinct DNA binding properties of protein subtypes, binding stoichiometry, and sequence-independent transient binding) can be determined instantly without using labels, tedious sample preparations, and sophisticated instrumentation. These benefits, in particular the high-throughput potential, could enable this assay to become the assay of choice to complement conventional techniques for large scale characterization of protein-DNA interactions, a key aspect in biological research.

  12. Involvement of chromatin and histone acetylation in theregulation of HIV-LTR by thyroid hormone receptor

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The HIV-1 LTR controls the expression of HIV-1 viral genes and thus is critical for viral propagation and pathology.Numerous host factors have been shown to participate in the regulation of the LTR promoter.Among them is the thyroid hormone (T3) receptor (TR).TR has been shown to bind to the critical region of the promoter that contain the NFκB and Sp1 binding sites.Interestingly,earlier transient transfection studies in tissue culture cells have yielded contradicting conclusions on the role of TR in LTR regulation,likely due to the use of different cell types and/or lack of proper chromatin organization.Here,using the frog oocyte as a model system that allows replication-coupled chromatin assembly,mimicking that in somatic cells,we demonstrate that unliganded heterodimers of TR and RXR (9-cis retinoic acid receptor) repress LTR while the addition of T3 relieves the repression and further activates the promoter.More importantly,we show that chromatin and unliganded TR/RXR synergize to repress the promoter in a histone deacetylase-dependent manner.

  13. QSAR study of selective ligands for the thyroid hormone receptor beta.

    Science.gov (United States)

    Liu, Huanxiang; Gramatica, Paola

    2007-08-01

    In this paper, an accurate and reliable QSAR model of 87 selective ligands for the thyroid hormone receptor beta 1 (TRbeta1) was developed, based on theoretical molecular descriptors to predict the binding affinity of compounds with receptor. The structural characteristics of compounds were described wholly by a large amount of molecular structural descriptors calculated by DRAGON. Six most relevant structural descriptors to the studied activity were selected as the inputs of QSAR model by a robust optimization algorithm Genetic Algorithm. The built model was fully assessed by various validation methods, including internal and external validation, Y-randomization test, chemical applicability domain, and all the validations indicate that the QSAR model we proposed is robust and satisfactory. Thus, the built QSAR model can be used to fast and accurately predict the binding affinity of compounds (in the defined applicability domain) to TRbeta1. At the same time, the model proposed could also identify and provide some insight into what structural features are related to the biological activity of these compounds and provide some instruction for further designing the new selective ligands for TRbeta1 with high activity.

  14. The Value of Hormone Receptor Assessment in Ultrasound Guided Core Needle Biopsy of the Breast.

    Science.gov (United States)

    Pal, Andrej; Milevcić, Drazen; Bosilj, Doroteja; Purković, Sandra; Cujzek, Ivana; Kopjar, Andrina; Radiković, Sandra

    2015-12-01

    Breast cancer is the most common cancer in women in Western countries after skin tumors. Successful treatment depends on many factors, relies on clinical examination, diagnostic procedures, pathologic evaluation, and good therapy decision. The Pathologic diagnosis should be the determining factor in the decision on therapeutic approach. There are several methods of obtaining tissue samples. The percutaneous ultrasound guided breast Core needle biopsy (CNB) is one of them. The Aim of this Study is to evaluate our experience in the accuracy of hormone receptors assessment in ultrasound guided CNB. In our institution, in last 12 month 60 women (with 67 lesions) underwent Breast CNB. The CNB was performed with 16 Gauge semiautomatic biopsy needle with 15 Gauge coordinated introducer needle. 3-6 specimen (mean 4) were taken during the procedure. We analyzed five factors (histological type, histological grade, estrogen and progesterone receptor status, and HER2 from the biopsied sample. All results were presented at the Multidisciplinary Oncology Team. In addition to demographic data and morphological features of the lesion, we analyzed five pathological factors (histological type, histological grade, estrogen and progesterone receptor status, and HER2 from the biopsied sample. All results were presented at the Multidisciplinary Oncology Team. Ultrasound-guided CNB has proven to be a reliable technique for performing a biopsy for breast. It is a good and reliable, complication free method, for preoperative staging, operative planning as well for prognostic value. It is a cost-effective method, can be performed quickly and in outpatient population, does not deform the breast and multiple lesions can be biopsied. This technique shows a high sensitivity value and offers many advantages over other imaging methods to guide a biopsy. All advantages have made this technique the most widespread used technique to perform a biopsy for a suspicious breast lesion.

  15. A naturally occurring isoform inhibits parathyroid hormone receptor trafficking and signaling.

    Science.gov (United States)

    Alonso, Verónica; Ardura, Juan A; Wang, Bin; Sneddon, W Bruce; Friedman, Peter A

    2011-01-01

    Parathyroid hormone (PTH) regulates calcium homeostasis and bone remodeling through its cognitive receptor (PTHR). We describe here a PTHR isoform harboring an in-frame 42-bp deletion of exon 14 (Δe14-PTHR) that encodes transmembrane domain 7. Δe14-PTHR was detected in human kidney and buccal epithelial cells. We characterized its topology, cellular localization, and signaling, as well as its interactions with PTHR. The C-terminus of the Δe14-PTHR is extracellular, and cell surface expression is strikingly reduced compared with the PTHR. Δe14-PTHR displayed impaired trafficking and accumulated in endoplasmic reticulum. Signaling and activation of cAMP and ERK by Δe14-PTHR was decreased significantly compared with PTHR. Δe14-PTHR acts as a functional dominant-negative by suppressing the action of PTHR. Cells cotransfected with both receptors exhibit markedly reduced PTHR cell membrane expression, colocalization with Δe14-PTHR in endoplasmic reticulum, and diminished cAMP activation and ERK phosphorylation in response to challenge with PTH. Δe14-PTHR forms heterodimers with PTHR, which may account for cytoplasmic retention of PTHR in the presence of Δe14-PTHR. Analysis of the PTHR heteronuclear RNA suggests that base-pair complementarity in introns surrounding exon 14 causes exon skipping and accounts for generation of the Δe14-PTHR isoform. Thus Δe14-PTHR is a poorly functional receptor that acts as a dominant-negative of PTHR trafficking and signaling and may contribute to PTH resistance. © 2011 American Society for Bone and Mineral Research.

  16. A comparison between radioligand and immunohistochemical assay of hormone receptors in primary breast cancer.

    Science.gov (United States)

    Charalambous, D; Kitchen, P R; Stillwell, R G; Smart, P J; Rode, J

    1993-08-01

    The detection of oestrogen and progesterone receptor (ER and PgR) levels in human breast carcinoma has traditionally been performed using a biochemical radioligand binding method. This method has several disadvantages including the requirement for generous tissue samples, the production of radioactive waste products and the inability to exclude non-malignant cellular material from the assay process. An alternative method for detecting hormone receptors is available with the use of a monoclonal antibody specific for the ER or PgR receptor using immunocytochemical assay (ER-ICA or PgR-ICA). Although designed for use on frozen section material, with modifications this method can be used on paraffin sections of routinely fixed and processed tissue, on archival material and on very small specimens. Further, an objective assessment or scoring of staining intensity is possible using computerized video-image analysis. Forty-three cases of primary breast carcinoma, treated from 1989 to 1991 at Goulburn Valley Base Hospital, Shepparton were assessed for ER and PgR content using both the radioligand method and immunohistochemistry with video-image analysis, and the results were compared. Of the 43 cases, ER-ICA and ER had a concordance of 81% (P < 0.001, r = 0.58) and in 39 cases, PgR and PgR-ICA had a concordance of 87% (P < 0.001, r = 0.54). Because the sample for radioligand assay is of uncertain composition and the immunohistochemical stain can be scored specifically for malignant epithelium, a degree of discordance is thought to be mostly attributable to the limitations of the radioligand assay.

  17. Quantitative analysis of agonist-dependent parathyroid hormone receptor trafficking in whole cells using a functional green fluorescent protein conjugate.

    Science.gov (United States)

    Conway, B R; Minor, L K; Xu, J Z; D'Andrea, M R; Ghosh, R N; Demarest, K T

    2001-12-01

    Many G-protein coupled receptors (GPCRs) undergo ligand-dependent internalization upon activation. The parathyroid hormone (PTH) receptor undergoes endocytosis following prolonged exposure to ligand although the ultimate fate of the receptor following internalization is largely unknown. To investigate compartmentalization of the PTH receptor, we have established a stable cell line expressing a PTH receptor-green fluorescent protein (PTHR-GFP) conjugate and an algorithm to quantify PTH receptor internalization. HEK 293 cells expressing the PTHR-GFP were compared with cells expressing the wild-type PTH receptor in whole-cell binding and functional assays. 125I-PTH binding studies revealed similar Bmax and kD values in cells expressing either the PTHR-GFP or the wild-type PTH receptor. PTH-induced cAMP accumulation was similar in both cell lines suggesting that addition of the GFP to the cytoplasmic tail of the PTH receptor does not alter the ligand binding or G-protein coupling properties of the receptor. Using confocal fluorescence microscopy, we demonstrated that PTH treatment of cells expressing the PTHR-GFP conjugate produced a time-dependent redistribution of the receptor to the endosomal compartment which was blocked by pretreatment with PTH antagonist peptides. Treatment with hypertonic sucrose prevented PTH-induced receptor internalization, suggesting that the PTH receptor internalizes via a clathrin-dependent mechanism. Moreover, co-localization with internalized transferrin showed that PTHR-GFP trafficking utilized the endocytic recycling compartment. Experiments using cycloheximide to inhibit protein synthesis demonstrated that recycling of the PTHR-GFP back to the plasma membrane was complete within 1-2 h of ligand removal and was partially blocked by pretreatment with cytochalasin D, but not nocodazole. We also demonstrated that the PTH receptor, upon recycling to the plasma membrane, is capable of undergoing a second round of internalization, a finding

  18. Introduction of exogenous growth hormone receptors augments growth hormone-responsive insulin biosynthesis in rat insulinoma cells

    DEFF Research Database (Denmark)

    Billestrup, N; Møldrup, A; Serup, P

    1990-01-01

    .24 cells compared to 1.9-fold in the nontransfected RIN5-AH cells. The expression of the transfected receptor was stimulated 1.6- and 2.3-fold when cells were cultured in the presence of 25 or 50 microM Zn2+, respectively. The increased expression of the GH receptor by Zn2+ was associated with an increased...

  19. 腹腔注射LHRH-A对黑鲷生长激素及其受体的影响%Effects of Luteinizing Hormone-releasing Hormone Analogue Injection on Growth Hormone and Its Receptor in Black Seabream

    Institute of Scientific and Technical Information of China (English)

    邓利; 林浩然

    2003-01-01

    以海水硬骨鱼类黑鲷为研究对象,腹腔注射溶于生理盐水的促性腺激素,释放激素(gonadotropin-releasing hormone,GnRH)的类似物(analogue of luteinizing hormone- releasing hormone,LHRH-A),对照组注射生理盐水.24 h后注射LHRH-A组黑鲷血清生长激素(growth hormone,GH)水平显著高于对照组(p<0.05),于36 h又恢复到对照组水平.注射LHRH-A组肝脏生长激素受体(growth hormone receptor,GHR)及GHR mRNA均与对照组无显著差异.结果表明,腹腔注射LHRH-A刺激了处于性腺成熟期黑鲷GH的分泌,但对黑鲷肝脏GHR及其基因表达无明显影响.

  20. Muscle-specific growth hormone receptor (GHR) overexpression induces hyperplasia but not hypertrophy in transgenic zebrafish.

    Science.gov (United States)

    Figueiredo, Marcio Azevedo; Mareco, Edson A; Silva, Maeli Dal Pai; Marins, Luis Fernando

    2012-06-01

    Even though growth hormone (GH) transgenesis has demonstrated potential for improved growth of commercially important species, the hormone excess may result in undesired collateral effects. In this context, the aim of this work was to develop a new model of transgenic zebrafish (Danio rerio) characterized by a muscle-specific overexpression of the GH receptor (GHR) gene, evaluating the effect of transgenesis on growth, muscle structure and expression of growth-related genes. In on line of transgenic zebrafish overexpressing GHR in skeletal muscle, no significant difference in total weight in comparison to non-transgenics was observed. This can be explained by a significant reduction in expression of somatotrophic axis-related genes, in special insulin-like growth factor I (IGF-I). In the same sense, a significant increase in expression of the suppressors of cytokine signaling 1 and 3 (SOCS) was encountered in transgenics. Surprisingly, expression of genes coding for the main myogenic regulatory factors (MRFs) was higher in transgenic than non-transgenic zebrafish. Genes coding for muscle proteins did not follow the MRFs profile, showing a significant decrease in their expression. These results were corroborated by the histological analysis, where a hyperplasic muscle growth was observed in transgenics. In conclusion, our results demonstrated that GHR overexpression does not induce hypertrophic muscle growth in transgenic zebrafish probably because of SOCS impairment of the GHR/IGF-I pathway, culminating in IGF-I and muscle proteins decrease. Therefore, it seems that hypertrophy and hyperplasia follow two different routes for entire muscle growth, both of them triggered by GHR activation, but regulated by different mechanisms.

  1. Estrogenic compounds decrease growth hormone receptor abundance and alter osmoregulation in Atlantic salmon

    Science.gov (United States)

    Lerner, Darren T.; Sheridan, Mark A.; McCormick, Stephen D.

    2012-01-01

    Exposure of Atlantic salmon smolts to estrogenic compounds is shown to compromise several aspects of smolt development. We sought to determine the underlying endocrine mechanisms of estrogen impacts on the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis. Smolts in freshwater (FW) were either injected 3 times over 10 days with 2 μg g−1 17β-estradiol (E2) or 150 μg g−1 4-nonylphenol (NP). Seawater (SW)-acclimated fish received intraperitoneal implants of 30 μg g−1 E2 over two weeks. Treatment with these estrogenic compounds increased hepatosomatic index and total plasma calcium. E2 and NP reduced maximum growth hormone binding by 30–60% in hepatic and branchial membranes in FW and SW, but did not alter the dissociation constant. E2 and NP treatment decreased plasma levels of IGF-I levels in both FW and SW. In FW E2 and NP decreased plasma GH whereas in SW plasma GH increased after E2 treatment. Compared to controls, plasma chloride concentrations of E2-treated fish were decreased 5.5 mM in FW and increased 10.5 mM in SW. There was no effect of NP or E2 on gill sodium–potassium adenosine triphosphatase (Na+/K+-ATPase) activity in FW smolts, whereas E2 treatment in SW reduced gill Na+/K+-ATPase activity and altered the number and size of ionocytes. Our data indicate that E2 downregulates the GH/IGF-I-axis and SW tolerance which may be part of its normal function for reproduction and movement into FW. We conclude that the mechanism of endocrine disruption of smolt development by NP is in part through alteration of the GH/IGF-I axis via reduced GH receptor abundance.

  2. Expression of growth hormone and its receptor in chronic atrophic gastritis and its clinical significance

    Institute of Scientific and Technical Information of China (English)

    Jian-Min Si; Qian Cao; Min Gao

    2004-01-01

    AIM: To investigate the growth hormone (GH) and growth hormone receptor (GHR) expression of and its clinical significance in patients with chronic atrophic gastritis (CAG).METHODS:A total of 90 cases were enrolled in the study.Thirty were healthy controls,the other 60 patients were divided into two groups according to the endoscopical and histological diagnosis.Blood samples were drawn in the morning (menarche did not occur during the blood extraction in female patients),gastric mucosa was obtained by endoscopy.Serum GH and gastrice mucosal GHR levels were measured using radioimmunoassay (RIA) and En Vinsion technique.RESULTS:The average GH level was 1.021±0.132μ/L in CAG patients,in controls it was 2.869 0.512μ/L.There was a significant difference between these two groups(P<0.01).The positive rate of GHR in CAG patients was 10%,in controls the rate was 100%.There was a significant difference (P<0.01).There was no significant change of GH level (3.176±0.421μ/L) in patients with gastric carcinoma compared with controls (P>0.05).CONCLUSION:The study shows that levels of GH and GHR expression are low in CAG patients.CAG pathogenesis has a correlation with mucosal nutrient deficiency,decreased levels of GH and GHR have an adverse effect on the repair and regeneration of CAG.There is no significant change of GH in gastric carcinorma patients,GH dose not play a role in the pathogenesis of gastric cancer.

  3. Neurochemical characterization of neurons expressing melanin-concentrating hormone receptor 1 in the mouse hypothalamus1

    Science.gov (United States)

    Chee, Melissa J. S.; Pissios, Pavlos; Maratos-Flier, Eleftheria

    2013-01-01

    Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that acts via MCH receptor 1 (MCHR1) in the mouse. It promotes positive energy balance thus mice lacking MCH or MCHR1 are lean, hyperactive, and resistant to diet-induced obesity. Identifying the cellular targets of MCH is an important step to understanding the mechanisms underlying MCH actions. We generated the Mchr1-cre mouse that expressed cre recombinase driven by the MCHR1 promoter and crossed it with a tdTomato reporter mouse. The resulting Mchr1-cre/tdTomato progeny expressed easily detectable tdTomato fluorescence in MCHR1 neurons, which were found throughout the olfactory system, striatum, and hypothalamus. To chemically identify MCH-targeted cell populations that play a role in energy balance, MCHR1 hypothalamic neurons were characterized by colabeling select hypothalamic neuropeptides with tdTomato fluorescence. TdTomato fluorescence colocalized with dynorphin, oxytocin, vasopressin, enkephalin, thyrothropin-releasing hormone, and corticotropin-releasing factor immunoreactive cells in the paraventricular nucleus. In the lateral hypothalamus, neurotensin but neither orexin nor MCH neurons expressed tdTomato. In the arcuate nucleus, both Neuropeptide Y and proopiomelanocortin cells expressed tdTomato. We further demonstrated that some of these arcuate neurons were also targets of leptin action. Interestingly, MCHR1 was expressed in the vast majority of leptin-sensitive proopiomelanocortin neurons, highlighting their importance for the orexigenic actions of MCH. Taken together, this study supports the use of the Mchr1-cre mouse for outlining the neuroanatomical distribution and neurochemical phenotype of MCHR1 neurons. PMID:23605441

  4. Thyroid hormone receptor orthologues from invertebrate species with emphasis on Schistosoma mansoni

    Directory of Open Access Journals (Sweden)

    Niles Edward G

    2007-08-01

    Full Text Available Abstract Background: Thyroid hormone receptors (TRs function as molecular switches in response to thyroid hormone to regulate gene transcription. TRs were previously believed to be present only in chordates. Results: We isolated two TR genes from the Schistosoma mansoni and identified TR orthologues from other invertebrates: the platyhelminths, S. japonium and Schmidtea mediterranea, the mollusc, Lottia gigantean and the arthropod Daphnia pulex. Phylogenetic analysis of the DNA binding domain and/or ligand binding domain shows that invertebrate and vertebrate TRs cluster together, TRs from the vertebrates and from the jawless vertebrate (lamprey clustered within separate subgroups, Platyhelminth TRs cluster outside of the vertebrate TR subgroups and that the schistosome TRs and S. mediterranea TRs clustered within separate subgroups. Alignment of the C-terminus of the A/B domain revealed a conserved TR-specific motif, termed TR 'N-terminus signature sequence', with a consensus sequence of (G/PYIPSY(M/LXXXGPE(D/EX. Heterodimer formation between S. mansoni TRs and SmRXR1 suggests that the invertebrate TR protein gained the ability to form a heterodimer with RXR. ESMA analysis showed that SmTRα could bind to a conserved DNA core motif as a monomer or homodimer. Conclusion: Vertebrate TR genes originated from a common ancestor of the Bilateria. TR genes underwent duplication independently in the Protostomia and Deuterostomia. The duplication of TRs in deuterostomes occurred after the split of jawless and jawed vertebrates. In protostomes, TR genes underwent duplication in Platyhelminths, occurring independently in trematode and turbellarian lineages. Using S. mansoni TRs as an example, invertebrate TRs exhibited the ability to form a dimer with RXR prior to the emergence of the vertebrate TRs and were able to bind to vertebrate TR core DNA elements as a monomer or homodimer.

  5. Interactions between Two Different G Protein-Coupled Receptors in Reproductive Hormone-Producing Cells: The Role of PACAP and Its Receptor PAC1R

    Science.gov (United States)

    Kanasaki, Haruhiko; Oride, Aki; Hara, Tomomi; Mijiddorj, Tselmeg; Sukhbaatar, Unurjargal; Kyo, Satoru

    2016-01-01

    Gonadotropin-releasing hormone (GnRH) and gonadotropins are indispensable hormones for maintaining female reproductive functions. In a similar manner to other endocrine hormones, GnRH and gonadotropins are controlled by their principle regulators. Although it has been previously established that GnRH regulates the synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH)—both gonadotropins—from pituitary gonadotrophs, it has recently become clear that hypothalamic GnRH is under the control of hypothalamic kisspeptin. Prolactin, which is also known as luteotropic hormone and is released from pituitary lactotrophs, stimulates milk production in mammals. Prolactin is also regulated by hypothalamic factors, and it is thought that prolactin synthesis and release are principally under inhibitory control by dopamine through the dopamine D2 receptor. In addition, although it remains unknown whether it is a physiological regulator, thyrotropin-releasing hormone (TRH) is a strong secretagogue for prolactin. Thus, GnRH, LH and FSH, and prolactin are mainly regulated by hypothalamic kisspeptin, GnRH, and TRH, respectively. However, the synthesis and release of these hormones is also modulated by other neuropeptides in the hypothalamus. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a hypothalamic peptide that was first isolated from sheep hypothalamic extracts based on its ability to stimulate cAMP production in anterior pituitary cells. PACAP acts on GnRH neurons and pituitary gonadotrophs and lactotrophs, resulting in the modulation of their hormone producing/secreting functions. Furthermore, the presence of the PACAP type 1 receptor (PAC1R) has been demonstrated in these cells. We have examined how PACAP and PAC1R affect GnRH- and pituitary hormone-secreting cells and interact with their principle regulators. In this review, we describe our understanding of the role of PACAP and PAC1R in the regulation of GnRH neurons

  6. Interactions between Two Different G Protein-Coupled Receptors in Reproductive Hormone-Producing Cells: The Role of PACAP and Its Receptor PAC1R

    Directory of Open Access Journals (Sweden)

    Haruhiko Kanasaki

    2016-09-01

    Full Text Available Gonadotropin-releasing hormone (GnRH and gonadotropins are indispensable hormones for maintaining female reproductive functions. In a similar manner to other endocrine hormones, GnRH and gonadotropins are controlled by their principle regulators. Although it has been previously established that GnRH regulates the synthesis and secretion of luteinizing hormone (LH and follicle-stimulating hormone (FSH—both gonadotropins—from pituitary gonadotrophs, it has recently become clear that hypothalamic GnRH is under the control of hypothalamic kisspeptin. Prolactin, which is also known as luteotropic hormone and is released from pituitary lactotrophs, stimulates milk production in mammals. Prolactin is also regulated by hypothalamic factors, and it is thought that prolactin synthesis and release are principally under inhibitory control by dopamine through the dopamine D2 receptor. In addition, although it remains unknown whether it is a physiological regulator, thyrotropin-releasing hormone (TRH is a strong secretagogue for prolactin. Thus, GnRH, LH and FSH, and prolactin are mainly regulated by hypothalamic kisspeptin, GnRH, and TRH, respectively. However, the synthesis and release of these hormones is also modulated by other neuropeptides in the hypothalamus. Pituitary adenylate cyclase-activating polypeptide (PACAP is a hypothalamic peptide that was first isolated from sheep hypothalamic extracts based on its ability to stimulate cAMP production in anterior pituitary cells. PACAP acts on GnRH neurons and pituitary gonadotrophs and lactotrophs, resulting in the modulation of their hormone producing/secreting functions. Furthermore, the presence of the PACAP type 1 receptor (PAC1R has been demonstrated in these cells. We have examined how PACAP and PAC1R affect GnRH- and pituitary hormone-secreting cells and interact with their principle regulators. In this review, we describe our understanding of the role of PACAP and PAC1R in the regulation of Gn

  7. Flow cytometry analysis of hormone receptors on human peripheral blood mononuclear cells to identify stress-induced neuroendocrine effects

    Science.gov (United States)

    Meehan, R. T.

    1986-01-01

    Understanding the role of circulating peptide hormones in the pathogenesis of space-flight induced disorders would be greatly facilitated by a method which monitors chronic levels of hormones and their effects upon in vivo cell physiology. Single and simultaneous multiparameter flow cytometry analysis was employed to identify subpopulations of mononuclear cells bearing receptors for ACTH, Endorphin, and Somatomedin-C using monoclonal antibodies and monospecific antisera with indirect immunofluorescence. Blood samples were obtained from normal donors and subjects participating in decompression chamber studies (acute stress), medical student academic examination (chronic stress), and a drug study (Dexamethasone). Preliminary results indicate most ACTH and Endorphin receptor positive cells are monocytes and B-cells, exhibit little diurnal variation but the relative percentages of receptor positive cells are influenced by exposure to various stressors and ACTH inhibition. This study demonstrates the capability of flow cytometry analysis to study cell surface hormone receptor regulation which should allow insight into neuroendocrine modulation of the immune and other cellular systems during exposure to stress or microgravity.

  8. Thyroid hormone receptors bind to the promoter of the mouse histone H10 gene and modulate its transcription.

    Science.gov (United States)

    Bauer-Hofmann, R; Alonso, A

    1995-01-01

    It has been shown that the mouse histone H10 promoter contains a DNA element, composed of a direct repeat of the sequence GGTGACC separated by 7 nt, which is able to bind retinoic acid receptors and to modulate transcription of reporter genes following treatment with retinoic acid. We have now investigated whether this DNA motif is also responsive to thyroid hormone. We co-transfected CV-1 monkey kidney cells with chloramphenicol acetyltransferase (CAT) expression plasmids containing either 740 bp of the H10 wild-type promoter or five copies of the repeat element cloned in front of the thymidine kinase promoter and expression vectors for human thyroid hormone receptors (TRs) alpha or beta and retinoid X receptor alpha (RXR alpha). Treatment of transfected cells with triiodothyronine led to a dose-dependent increase in CAT activity. Transfection experiments with increasing amounts of expression vectors for either TR alpha or RXR alpha resulted in up to 6-fold enhancement of CAT transcription. Furthermore, point mutations within the half-sites of the response element of the H10 promoter, as well as deletions within the interspace region, lowered CAT activity to 60-80% of that of the wild-type control. Electrophoretic mobility shift assays showed that the repeat element was able to form retarded complexes with TR alpha homodimers, as well as with TR alpha-RXR alpha heterodimers. Our results suggest that thyroid hormone receptors are involved in the regulation of mouse histone H10 expression. Images PMID:8559662

  9. Central and direct regulation of testicular activity by gonadotropin-inhibitory hormone and its receptor

    Directory of Open Access Journals (Sweden)

    Takayoshi eUbuka

    2014-01-01

    Full Text Available Gonadotropin-inhibitory hormone (GnIH was first identified in Japanese quail to be an inhibitor of gonadotropin synthesis and release. GnIH peptides have since been identified in all vertebrates, and all share an LPXRFamide (X = L or Q motif at their C-termini. The receptor for GnIH is the G protein-coupled receptor 147 (GPR147, which inhibits cAMP signaling. Cell bodies of GnIH neurons are located in the paraventricular nucleus (PVN in birds and the dorsomedial hypothalamic area (DMH in most mammals. GnIH neurons in the PVN or DMH project to the median eminence to control anterior pituitary function via GPR147 expressed in gonadotropes. Further, GnIH inhibits gonadotropin-releasing hormone (GnRH -induced gonadotropin subunit gene transcription by inhibiting the adenylate cyclase/cAMP/PKA -dependent ERK pathway in an immortalized mouse gonadotrope cell line (LT2 cells. GnIH neurons also project to GnRH neurons that express GPR147 in the preoptic area (POA in birds and mammals. Accordingly, GnIH can inhibit gonadotropin synthesis and release by decreasing the activity of GnRH neurons as well as by directly inhibiting pituitary gonadotrope activity. GnIH and GPR147 can thus centrally suppress testosterone secretion and spermatogenesis by acting in the hypothalamic-pituitary-gonadal axis. GnIH and GPR147 are also expressed in the testis of birds and mammals, possibly acting in an autocrine/paracrine manner to suppress testosterone secretion and spermatogenesis. GnIH expression is also regulated by melatonin, stress and social environment in birds and mammals. Accordingly, the GnIH-GPR147 system may play a role in transducing physical and social environmental information to regulate optimal testicular activity in birds and mammals. This review discusses central and direct inhibitory effects of GnIH and GPR147 on testosterone secretion and spermatogenesis in birds and mammals.

  10. Identification of tyrosine residues in the intracellular domain of the growth hormone receptor required for transcriptional signaling and Stat5 activation

    DEFF Research Database (Denmark)

    Hansen, L. H.; Wang, X.; Kopchick, J J;

    1996-01-01

    The binding of growth hormone (GH) to its receptor results in its dimerization followed by activation of Jak2 kinase and tyrosine phosphorylation of the GH receptor itself, as well as Jak2 and the transcription factors Stat1, -3, and -5. In order to study the role of GH receptor tyrosine phosphor...

  11. Liver expression of steroid hormones and Apolipoprotein D receptors in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    FJ Vizoso; L Rodrigo; M Rodriguez; A Altadill; ML González-Diéguez; A Linares; LO González; S Junquera; F Fresno-Forcelledo; MD Corte

    2007-01-01

    AIM: To evaluate the tissular expression of Androgen (A), Estrogen (E) and Progesterone (Pg) receptors, and Apolipoprotein D (ApoD), in liver tumors from resected hepatocellular carcinoma (HCC) cases in order to assess their possible relationship to prognosis.METHODS We performed an immunohistochemical study using tissue microarrays (containing more than 260 cancer specimens, from 31 HCC patients and controls)to determine the presence of specific antibodies against AR, ER, PgR and ApoD, correlating their findings with several clinico-pathological and biological variables. The staining results were categorized using a semi-quantitive score based on their intensity, and the percentage of immunostained cells was measured.RESULTS: A total of 21 liver tumors (67.7%) were positive for AR; 16 (51.6%) for ER; 26 (83.9%) for PgR and 12 (38.7%) stained for ApoD. We have found a wide variability in the immunostaining score values for each protein, with a median (range) of 11.5 (11.5-229.5) for AR; 11.1 (8.5-65) for ER; 14.2 (4-61) for PgR; and 37.7 (13.8-81.1) for ApoD. A history of heavy ethanol consumption, correlated positively with AR and PgR and negatively with ER status. HCV chronic infection also correlated positively with AR and PgR status. However,the presence of ApoD immunostaining did not correlate with any of these variables. Tumors with a positive immuno-staining for PgR showed a better prognosis.CONCLUSION: Our results indicate a moderate clinical value of the steroid receptor status in HCC, emphasizing the need to perform further studies in order to evaluate the possible role of new hormonal-based therapies.

  12. Optimizing control of acromegaly: integrating a growth hormone receptor antagonist into the treatment algorithm.

    Science.gov (United States)

    Clemmons, David R; Chihara, Kazuo; Freda, Pamela U; Ho, Ken K Y; Klibanski, Anne; Melmed, Shlomo; Shalet, Stephen M; Strasburger, Christian J; Trainer, Peter J; Thorner, Michael O

    2003-10-01

    Acromegaly is associated with significant morbidities and a 2- to 3-fold increase in mortality because of the excessive metabolic action of GH and IGF-I, a marker of GH output. Reductions in morbidity correspond with decreases in IGF-I, and mortality is lowered following normalization of IGF-I or GH levels. Therefore, this has become an important end point. Current guidelines for the treatment of acromegaly have not considered recent advances in medical therapy, in particular, the place of pegvisomant, a GH receptor antagonist. Treatment goals include normalizing biochemical markers, controlling tumor mass, preserving pituitary function, and relieving signs and symptoms. Surgery reduces tumor volume and is considered first-line therapy. Radiation reduces tumor volume and GH and IGF-I levels, but the onset of action is slow and hypopituitarism typically develops. Therefore, pharmacotherapy is often used following surgery or as first-line therapy for nonresectable tumors. Dopamine agonists can be considered in patients exhibiting minimal disease or those with GH-prolactin-cosecreting tumors but will not achieve hormone normalization in most patients. Somatostatin analogs effectively suppress GH and IGF-I in most patients, but intolerance (e.g. diarrhea, cramping, gallstones) can occur. Pegvisomant, the newest therapeutic option, blocks GH action at peripheral receptors, normalizes IGF-I levels, reduces signs and symptoms, and corrects metabolic defects. Pegvisomant does not appear to affect tumor size and has few adverse effects. Pegvisomant is the most effective drug treatment for acromegaly in normalizing IGF-I and producing a clinical response; it is the preferred agent in patients resistant to or intolerant of somatostatin analogs.

  13. Stability of Human Follicle-Stimulating Hormone Receptor mRNA in Stably Transfected Cells

    Institute of Scientific and Technical Information of China (English)

    朱长虹; 田红

    2001-01-01

    In order to assess the impact of mRNA degradation on steady state levels of follicle-stimulating hormone receptor (FSHR) mRNA and on regulation of FSHR gene expression, the stability and half-life of FSHR mRNA were determined in transfected cells expressing recombinant FSHR. Time-dependent changes in FSHR mRNA content were determined by nuclease protection-solution hybridization assay (NPA) or by qualitative reverse transcription-competitive polymerase chain reaction (RT-PCR) in cultured hFSHR-YI cells, cell lines stably transfected with a human FSHR cDNA. FSHR mRNA content remained constant during 8 h control incubations of hFSHR-Y1 cells (NPA, 2.9±0.3 μg/mg RNA; RT-PCR, 2.7±0.3 μg/mg RNA). Actinomycin D (ActD, 5 μg/ml) inhibited mRNA synthesis, as assessed by incorporation of [3 H]uridine into total RNA, by 90 % within 1 h in hFSHR-Y1 cells. No effect of ActD on cellular morphology or viability was observed. ActD caused a time-dependent decrease in FSHR mRNA content in hFSHR-Y1 cell lines with a lag time of 1 h. There were no significant differences in the rate of FSHR mRNA degradation between the two methods of mRNA quantification. The half-life of hFSHR mRNA was 3.6±0.2 h by NPA and 3.1±0.1 h by RT-PCR. The results indicated that degradation of mRNA was an important process in maintenance of steady state expression of the FSHR gene in cells stably expressing recombinant receptor.

  14. Discoidin domain receptor 2 facilitates prostate cancer bone metastasis via regulating parathyroid hormone-related protein.

    Science.gov (United States)

    Yan, Zhang; Jin, Su; Wei, Zhang; Huilian, Hou; Zhanhai, Yin; Yue, Teng; Juan, Li; Jing, Li; Libo, Yao; Xu, Li

    2014-09-01

    Prostate cancer frequently metastasizes to the skeleton but the underlying mechanism remains largely undefined. Discoidin domain receptor 2 (DDR2) is a member of receptor tyrosine kinase (RTK) family and is activated by collagen binding. This study aimed to investigate the function and detailed mechanism of DDR2 in prostate cancer bone dissemination. Herein we found that DDR2 was strongly expressed in bone-metastatic prostate cancer cells and tissues compared to that in normal controls. Enhanced expression of constitutively activated DDR2 led to elevation in motility and invasiveness of prostate cancer cells, whereas knockdown of DDR2 through specific shRNA caused a dramatic repression. Knockdown of DDR2 in prostate cancer cells resulted in significant decrease in the proliferation, differentiation and function of osteoblast. Over-expression of DDR2 in prostate cancer cells resulted in notable acceleration of osteoclast differentiation and bone resorption, whereas knockdown of DDR2 exhibited the opposite effects. An intrabone injection bone metastasis animal model demonstrated that DDR2 promoted osteolytic metastasis in vivo. Molecular evidence demonstrated that DDR2 regulated the expression, secretion, and promoter activity of parathyroid hormone-related protein (PTHrP), via modulating Runx2 phosphorylation and transactivity. DDR2 was responsive to TGF-β and involved in TGF-β-mediated osteoclast activation and bone resorption. In addition, DDR2 facilitated prostate cancer cells adhere to type I collagen. This study reveals for the first time that DDR2 plays an essential role in prostate cancer bone metastasis. The mechanism disclosure may provide therapeutic targets for the treatment of prostate cancer.

  15. Development and validation of in vitro bioassays for thyroid hormone receptor mediated endocrine disruption

    NARCIS (Netherlands)

    Freitas, de J.

    2012-01-01

    Thyroid hormones regulate crucial processes in vertebrates such as reproduction, development and energy metabolism. Endocrine disruption via the thyroid hormone system is gaining more attention both from scientists and regulators, because of the increasing incidence of hormone-related cancers and

  16. Crosstalk between thyroid hormone receptor and liver X receptor in the regulation of selective Alzheimer's disease indicator-1 gene expression.

    Directory of Open Access Journals (Sweden)

    Emi Ishida

    Full Text Available Selective Alzheimer's disease (AD indicator 1 (Seladin-1 has been identified as a gene down-regulated in the degenerated lesions of AD brain. Up-regulation of Seladin-1 reduces the accumulation of β-amyloid and neuronal death. Thyroid hormone (TH exerts an important effect on the development and maintenance of central nervous systems. In the current study, we demonstrated that Seladin-1 gene and protein expression in the forebrain was increased in thyrotoxic mice compared with that of euthyroid mice. However, unexpectedly, no significant decrease in the gene and protein expression was observed in hypothyroid mice. Interestingly, an agonist of liver X receptor (LXR, TO901317 (TO administration in vivo increased Seladin-1 gene and protein expression in the mouse forebrain only in a hypothyroid state and in the presence of mutant TR-β, suggesting that LXR-α would compensate for TR-β function to maintain Seladin-1 gene expression in hypothyroidism and resistance to TH. TH activated the mouse Seladin-1 gene promoter (-1936/+21 bp and site 2 including canonical TH response element (TRE half-site in the region between -159 and -154 bp is responsible for the positive regulation. RXR-α/TR-β heterodimerization was identified on site 2 by gel-shift assay, and chromatin immunoprecipitation assay revealed the recruitment of TR-β to site 2 and the recruitment was increased upon TH administration. On the other hand, LXR-α utilizes a distinct region from site 2 (-120 to -102 bp to activate the mouse Seladin-1 gene promoter. Taking these findings together, we concluded that TH up-regulates Seladin-1 gene expression at the transcriptional level and LXR-α maintains the gene expression.

  17. Synthesis of inositol phosphate ligands of plant hormone-receptor complexes: pathways of inositol hexakisphosphate turnover.

    Science.gov (United States)

    Hanke, David E; Parmar, Paroo N; Caddick, Samuel E K; Green, Porntip; Brearley, Charles A

    2012-06-15

    Reduction of phytate is a major goal of plant breeding programs to improve the nutritional quality of crops. Remarkably, except for the storage organs of crops such as barley, maize and soybean, we know little of the stereoisomeric composition of inositol phosphates in plant tissues. To investigate the metabolic origins of higher inositol phosphates in photosynthetic tissues, we have radiolabelled leaf tissue of Solanum tuberosum with myo-[2-3H]inositol, undertaken a detailed analysis of inositol phosphate stereoisomerism and permeabilized mesophyll protoplasts in media containing inositol phosphates. We describe the inositol phosphate composition of leaf tissue and identify pathways of inositol phosphate metabolism that we reveal to be common to other kingdoms. Our results identify the metabolic origins of a number of higher inositol phosphates including ones that are precursors of cofactors, or cofactors of plant hormone-receptor complexes. The present study affords alternative explanations of the effects of disruption of inositol phosphate metabolism reported in other species, and identifies different inositol phosphates from that described in photosynthetic tissue of the monocot Spirodela polyrhiza. We define the pathways of inositol hexakisphosphate turnover and shed light on the occurrence of a number of inositol phosphates identified in animals, for which metabolic origins have not been defined.

  18. Circulating thyroid stimulating hormone receptor messenger RNA and differentiated thyroid cancer: A diagnostic meta-analysis

    Science.gov (United States)

    Kong, Chao-Yue; Li, Zhan-Ming; Wang, Li-Shun

    2017-01-01

    Thyroid stimulating hormone receptor messenger RNA (TSHR-mRNA) is over-expressed in thyroid cancer patients, which indicates that TSHR-mRNA is a potential biomarker of thyroid cancer. However, system evaluation for TSHR-mRNA as a diagnostic biomarker of thyroid cancer is deficient. The performance of TSHR-mRNA for thyroid cancer diagnosis was evaluated in this study. Three common international databases as well as a Chinese database were applied for literature researching. Quality assessment of the included literatures was conducted by the QUADAS-2 tool. Totally, 1027 patients from nine studies eligible for the meta-analysis were included in this study. Global sensitivity and specificity for the positivity of TSHR-mRNA in the thyroid cancer diagnosis is 72% and 82%. The value of AUC for this test performance was 0.84. Our meta-analysis suggests that TSHR-mRNA might be a potential biomarker to complete present diagnostic methods for early and precision diagnosis of thyroid cancer. Notably, this findings need validation thorough large-scale clinical studies. PMID:28036261

  19. The thyroid hormone receptor β induces DNA damage and premature senescence

    Science.gov (United States)

    Zambrano, Alberto; García-Carpizo, Verónica; Gallardo, María Esther; Villamuera, Raquel; Gómez-Ferrería, Maria Ana; Pascual, Angel; Buisine, Nicolas; Sachs, Laurent M.; Garesse, Rafael

    2014-01-01

    There is increasing evidence that the thyroid hormone (TH) receptors (THRs) can play a role in aging, cancer and degenerative diseases. In this paper, we demonstrate that binding of TH T3 (triiodothyronine) to THRB induces senescence and deoxyribonucleic acid (DNA) damage in cultured cells and in tissues of young hyperthyroid mice. T3 induces a rapid activation of ATM (ataxia telangiectasia mutated)/PRKAA (adenosine monophosphate–activated protein kinase) signal transduction and recruitment of the NRF1 (nuclear respiratory factor 1) and THRB to the promoters of genes with a key role on mitochondrial respiration. Increased respiration leads to production of mitochondrial reactive oxygen species, which in turn causes oxidative stress and DNA double-strand breaks and triggers a DNA damage response that ultimately leads to premature senescence of susceptible cells. Our findings provide a mechanism for integrating metabolic effects of THs with the tumor suppressor activity of THRB, the effect of thyroidal status on longevity, and the occurrence of tissue damage in hyperthyroidism. PMID:24395638

  20. The fax-1 nuclear hormone receptor regulates axon pathfinding and neurotransmitter expression.

    Science.gov (United States)

    Much, J W; Slade, D J; Klampert, K; Garriga, G; Wightman, B

    2000-02-01

    Specification of neuron identity requires the activation of a number of discrete developmental programs. Among these is pathway selection by growth cones: in order for a neuron's growth cone to respond appropriately to guidance cues presented by other cells or the extracellular matrix, the neuron must express genes to mediate the response. The fax-1 gene of C. elegans is required for pathfinding of axons that extend along the ventral nerve cord. We show that fax-1 is also required for pathfinding of axons in the nerve ring, the largest nerve bundle in the nematode, and for normal expression of FMRFamide-like neurotransmitters in the AVK interneurons. The fax-1 gene encodes a member of the superfamily of nuclear hormone receptors and has a DNA-binding domain related to the human PNR and Drosophila Tailless proteins. We observe fax-1 expression in embryonic neurons, including the AVK interneurons, just prior to axon extension, but after neurogenesis. These data suggest that fax-1 coordinately regulates the transcription of genes that function in the selection of axon pathways, neurotransmitter expression and, perhaps, other aspects of the specification of neuron identity.

  1. The growth hormone receptor polymorphism in patients with acromegaly: relationship to BMI and glucose metabolism.

    Science.gov (United States)

    Turgut, Sebahat; Akın, Fulya; Ayada, Ceylan; Topsakal, Senay; Yerlikaya, Emrah; Turgut, Günfer

    2012-09-01

    The aim of this study was to investigate association between the frequencies of Growth Hormone receptor (d3GHR) gene polymorphisms and some clinical parameters of acromegalic patients. Total of 35 acromegalic patients were enrolled to study. The d3GHR polymorphism was identified by using polymerase chain reaction from peripheral blood samples. The levels of systolic and diastolic blood pressure, BMI, fasting plasma glucose (FPG), Fasting insulin, HOMA-IR, IGF-I, GH, IGFBP3, triglyceride, HDL and LDL cholesterol concentrations were evaluated. The frequencies of d3GHR genotypes were found as follows; 5 (14.3%) subjects had d3/d3, 11 (31.4%) had d3/fl and 19 (54.3%) had fl/fl in patients. The prevalence of the d3 and fl alleles was 30 and 70%, respectively. Systolic blood pressure, fasting insulin and HOMA-IR was found significantly increased in homozygote d3GHR genotype group compared to d3/fl subjects (P affect BMI, systolic blood pressure and insulin regulation. At the same time we can say homozygote d3GHR genotype and d3 allele carriers may have more risk than other genotypes for high BMI.

  2. Vaginal estrogen products in hormone receptor-positive breast cancer patients on aromatase inhibitor therapy.

    Science.gov (United States)

    Sulaica, Elisabeth; Han, Tiffany; Wang, Weiqun; Bhat, Raksha; Trivedi, Meghana V; Niravath, Polly

    2016-06-01

    Atrophic vaginitis represents a major barrier to compliance with aromatase inhibitor (AI) therapy in breast cancer (BC) survivors. While local estrogen therapy is effective for postmenopausal vaginal dryness, the efficacy of such therapies has not been evaluated systematically in hormone receptor-positive (HR+) BC patients on AI therapy. Furthermore, the potential risk of breast cancer recurrence with vaginal estrogen therapy represents a long-term safety concern for the patients with HR + BC. Unfortunately, there is no standardized assay to measure very low concentrations of estradiol (E2) in these women being treated with AI therapy. This makes it difficult to evaluate even indirectly the potential risk of BC recurrence with vaginal estrogen therapy in HR + BC patients on AI therapy. In this review, we describe available assays to measure very low concentrations of E2, discuss the Food and Drug Administration-approved vaginal estrogen products on the market, and summarize published and ongoing clinical trials evaluating the safety and efficacy of vaginal estrogen in HR + BC patients on AI therapy. In the absence of any randomized controlled clinical trials, this review serves as a summary of available clinical data and ongoing studies to aid clinicians in selecting the best available option for their patients.

  3. Regulation of the growth hormone (GH) receptor and GH-binding protein mRNA

    Energy Technology Data Exchange (ETDEWEB)

    Kaji, Hidesuke; Ohashi, Shin-Ichirou; Abe, Hiromi; Chihara, Kazuo [Kobe Univ. School of Medicine, Kobe (Japan)

    1994-12-31

    In fasting rats, a transient increase in growth hormone-binding protein (GHBP) mRNA levels was observed after 1 day, in muscle, heart, and liver, but not in fat tissues. The liver GH receptor (GHR) mRNA level was significantly increased after 1 day (but not after 5 days) of bovine GH (bGH) treatment in fed rats. Both the liver GHR mRNA level and the net increment of plasma IGF-I markedly decreased after 5 days of bGH administration in fasting rats. These findings suggest that GHR and GHBP mRNAs in the liver are expressed in a different way and that the expression of GHBP mRNA is regulated differently between tissues, at least in rats. The results also suggest that refractoriness to GH in a sustained fasting state might be beneficial in preventing anabolic effects of GH. In humans, GHR mRNA in lymphocytes, from subjects with either GH-deficiency or acromegaly, could be detected by the reverse transcription-polymerase chain reaction method. In one patient with partial GH insensitivity, a heterozygous missense mutation (P561T) was identified in the cytoplasmic domain of GHR. 15 refs., 4 figs.

  4. Correlation of expression of preprothyrotropin-releasing hormone and receptor with rat testis development

    Institute of Scientific and Technical Information of China (English)

    李臻; 张远强; 刘新平; 许若军

    2002-01-01

    Objective To investigate the expression regulation of thyrotrophin-releasing hormone (TRH) and TRH receptor (TRH-R), and their role in the development of rat testis.Methods Oligonucleotide primers were designed from the sequences of rat hypothalamus prepro TRH (ppTRH) and pituitary TRH-R cDNA for reverse transcription polymerase chain reaction (RT-PCR). Specific fragments of ppTRH and TRH-R cDNA were cloned and sequenced. Expression plasmids containing ppTRH and TRH-R genes were then constructed, and expression was found in E.coli DH5-α. ppTRH and TRH-R mRNA in the testis was quantitated in RNA samples prepared from rats at different developmental stages by real time quantitative RT-PCR.Results The quantitative analyses demonstrated that no ppTRH and TRH mRNA could be detected at the earliest stage (day 8). ppTRH and TRH mRNA signals were detected on day 15 and increased progressively on days 20, 35, 60 and 90. Conclusion Our results suggest that rat testis could specifically express TRH and TRH-R, and the transcriptions of ppTRH and TRH-R genes in the rat testis were development-dependent. The acquirement of expressed products for ppTRH and TRH-R can be used for further research on the physiological significance of TRH and TRH-R expression in rat testis.

  5. Growth hormone receptor exon 3 isoforms and their implication in growth disorders and treatment.

    Science.gov (United States)

    Jorge, Alexander A L; Arnhold, Ivo J P

    2009-04-01

    Human recombinant growth hormone (hGH) has been used to treat short stature in several different conditions, but considerable inter-individual variation in short- and long-term growth response exists. Pharmacogenomics can provide important insights into hGH therapy. The GH receptor (GHR) is the first key molecule mediating GH action. In the past 3 years, a common GHR polymorphism reflecting the presence (GHRfl) or absence (GHRd3) of exon 3 has been under intensive investigation regarding its influence on the response to hGH therapy. Studies that evaluated response to GH treatment determined by these two GHR isoforms in children with GH deficiency, girls with Turner syndrome, children born small for gestational age and patients with acromegaly showed that patients carrying the GHRd3 allele demonstrated a greater GH sensitivity than patients homozygous for the GHRfl allele. Other studies presented contradictory data, however, which may be caused by confounding factors such as small sample sizes and differences in experimental design. This GHR exon 3 genotype is the first identified genetic factor found to modulate the individual response to GH therapy. This article reviews the historical aspects and pharmacogenetic studies published to date in relation to this GHR polymorphism. The analyses of present and future validation studies may define the use of this and other polymorphisms in clinical practice, moving from pharmacogenetics to routine application and allowing individualization of hGH doses to optimize final outcome.

  6. Cross-regulation of signaling pathways: An example of nuclear hormone receptors and the canonical Wnt pathway

    Energy Technology Data Exchange (ETDEWEB)

    Beildeck, Marcy E. [Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, Washington, DC 20057 (United States); Gelmann, Edward P. [Columbia University, Department of Medicine, New York, NY (United States); Byers, Stephen W., E-mail: byerss@georgetown.edu [Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, Washington, DC 20057 (United States)

    2010-07-01

    Predicting the potential physiological outcome(s) of any given molecular pathway is complex because of cross-talk with other pathways. This is particularly evident in the case of the nuclear hormone receptor and canonical Wnt pathways, which regulate cell growth and proliferation, differentiation, apoptosis, and metastatic potential in numerous tissues. These pathways are known to intersect at many levels: in the intracellular space, at the membrane, in the cytoplasm, and within the nucleus. The outcomes of these interactions are important in the control of stem cell differentiation and maintenance, feedback loops, and regulating oncogenic potential. The aim of this review is to demonstrate the importance of considering pathway cross-talk when predicting functional outcomes of signaling, using nuclear hormone receptor/canonical Wnt pathway cross-talk as an example.

  7. Expression of lymphocyte-derived growth hormone (GH) and GH-releasing hormone receptors in aging rats.

    Science.gov (United States)

    Weigent, Douglas A

    2013-04-01

    In the present study, we show that higher levels of lymphocyte GH are expressed in spleen cells from aging animals compared to young animals. Further, leukocytes from primary and secondary immune tissues and splenic T and B cells from aging rats all express higher levels of GHRH receptors compared to younger animals. Bone marrow and splenic T cells express the highest levels of GHRH receptor in aging animals. Spleen cells from aging animals showed no significant change in proliferation or GH induction after treatment with GHRH. Taken together, the data for the first time show alterations in GH synthesis and expression of the GHRH receptor on cells of the immune system that may play a role in the immune response in aging.

  8. The neuroendocrine-derived peptide parathyroid hormone-related protein promotes prostate cancer cell growth by stabilizing the androgen receptor.

    Science.gov (United States)

    DaSilva, John; Gioeli, Daniel; Weber, Michael J; Parsons, Sarah J

    2009-09-15

    During progression to an androgen-independent state following androgen ablation therapy, prostate cancer cells continue to express the androgen receptor (AR) and androgen-regulated genes, indicating that AR is critical for the proliferation of hormone-refractory prostate cancer cells. Multiple mechanisms have been proposed for the development of AR-dependent hormone-refractory disease, including changes in expression of AR coregulatory proteins, AR mutation, growth factor-mediated activation of AR, and AR protein up-regulation. The most prominent of these progressive changes is the up-regulation of AR that occurs in >90% of prostate cancers. A common feature of the most aggressive hormone-refractory prostate cancers is the accumulation of cells with neuroendocrine characteristics that produce paracrine factors and may provide a novel mechanism for the regulation of AR during advanced stages of the disease. In this study, we show that neuroendocrine-derived parathyroid hormone-related protein (PTHrP)-mediated signaling through the epidermal growth factor receptor (EGFR) and Src pathways contributes to the phenotype of advanced prostate cancer by reducing AR protein turnover. PTHrP-induced accumulation of AR depended on the activity of Src and EGFR and consequent phosphorylation of the AR on Tyr(534). PTHrP-induced tyrosine phosphorylation of AR resulted in reduced AR ubiquitination and interaction with the ubiquitin ligase COOH terminus of Hsp70-interacting protein. These events result in increased accumulation of AR and thus enhanced growth of prostate cancer cells at low levels of androgen.

  9. Functional Authentication of a Novel Gastropod Gonadotropin-Releasing Hormone Receptor Reveals Unusual Features and Evolutionary Insight

    Science.gov (United States)

    Kavanaugh, Scott I.

    2016-01-01

    A gonadotropin-releasing hormone (GnRH)-like molecule was previously identified in a gastropod, Aplysia californica, and named ap-GnRH. In this study, we cloned the full-length cDNA of a putative ap-GnRH receptor (ap-GnRHR) and functionally authenticated this receptor as a bona fide ap-GnRHR. This receptor contains two potential translation start sites, each accompanied by a Kozak sequence, suggesting the translation of a long and a short form of the receptor is possible. The putative ap-GnRHR maintains the conserved structural motifs of GnRHR-like receptors and shares 45% sequence identity with the octopus GnRHR. The expression of the putative ap-GnRHR short form is ubiquitous in all tissues examined, whereas the long form is only expressed in parts of the central nervous system, osphradium, small hermaphroditic duct, and ovotestis. The cDNA encoding the long or the short receptor was transfected into the Drosophila S2 cell line and subject to a radioreceptor assay using 125I-labeled ap-GnRH as the radioligand. Further, the transfected cells were treated with various concentrations of ap-GnRH and measured for the accumulation of cAMP and inositol monophosphate (IP1). Radioreceptor assay revealed that only the long receptor bound specifically to the radioligand. Further, only the long receptor responded to ap-GnRH with an increased accumulation of IP1, but not cAMP. Our studies show that despite the more prevalent expression of the short receptor, only the long receptor is the functional ap-GnRHR. Importantly, this is only the second report on the authentication of a protostome GnRHR, and based on the function and the phylogenetic grouping of ap-GnRHR, we suggest that this receptor is more similar to protostome corazonin receptors than chordate GnRHRs. PMID:27467252

  10. Functional Authentication of a Novel Gastropod Gonadotropin-Releasing Hormone Receptor Reveals Unusual Features and Evolutionary Insight.

    Science.gov (United States)

    Kavanaugh, Scott I; Tsai, Pei-San

    2016-01-01

    A gonadotropin-releasing hormone (GnRH)-like molecule was previously identified in a gastropod, Aplysia californica, and named ap-GnRH. In this study, we cloned the full-length cDNA of a putative ap-GnRH receptor (ap-GnRHR) and functionally authenticated this receptor as a bona fide ap-GnRHR. This receptor contains two potential translation start sites, each accompanied by a Kozak sequence, suggesting the translation of a long and a short form of the receptor is possible. The putative ap-GnRHR maintains the conserved structural motifs of GnRHR-like receptors and shares 45% sequence identity with the octopus GnRHR. The expression of the putative ap-GnRHR short form is ubiquitous in all tissues examined, whereas the long form is only expressed in parts of the central nervous system, osphradium, small hermaphroditic duct, and ovotestis. The cDNA encoding the long or the short receptor was transfected into the Drosophila S2 cell line and subject to a radioreceptor assay using 125I-labeled ap-GnRH as the radioligand. Further, the transfected cells were treated with various concentrations of ap-GnRH and measured for the accumulation of cAMP and inositol monophosphate (IP1). Radioreceptor assay revealed that only the long receptor bound specifically to the radioligand. Further, only the long receptor responded to ap-GnRH with an increased accumulation of IP1, but not cAMP. Our studies show that despite the more prevalent expression of the short receptor, only the long receptor is the functional ap-GnRHR. Importantly, this is only the second report on the authentication of a protostome GnRHR, and based on the function and the phylogenetic grouping of ap-GnRHR, we suggest that this receptor is more similar to protostome corazonin receptors than chordate GnRHRs.

  11. Effect of Yoga and Traditional Physical Exercise on Hormones and Percentage Insulin Binding Receptor in Patients with Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Lorenzo Gordon

    2008-01-01

    Full Text Available The objective of the study was to investigate the short-term impact of a brief lifestyle intervention of yoga and traditional Physical Training (PT exercise regimens on: serum insulin, percentage insulin binding receptor, internalization of insulin-receptor complex, T3, T4, TSH and cortisol at baseline, 3 months and 6 months in patients with type 2 diabetes mellitus. A total of 231 patients completed this prospective randomized study with 77 type 2 diabetic patients in the yoga group (62 females and 15 males that were matched with the same number of patients in the traditional Physical Training (PT exercise and control groups. Biochemical parameters such as fasting Blood Glucose (FBG, serum insulin, percentage insulin binding receptor and internalization of insulin-receptor complex were determined at the beginning (baseline and two consecutive three monthly intervals. The effect of the lifestyle interventions on hormones such as cortisol, TSH, T4 and T3 were also investigated. The FBG concentration in the yoga and the traditional PT exercise groups were markedly decreased compared with control (P 0.05. The findings indicates the beneficial effects of yoga and traditional PT exercise regimens in improving glycaemic control by increasing percentage insulin binding receptor in type 2 diabetic patients with no significant change in cortisol and thyroid hormones.

  12. Growth hormone (GH)-independent dimerization of GH receptor by a leucine zipper results in constitutive activation

    DEFF Research Database (Denmark)

    Behncken, S N; Billestrup, Nils; Brown, R;

    2000-01-01

    Growth hormone initiates signaling by inducing homodimerization of two GH receptors. Here, we have sought to determine whether constitutively active receptor can be created in the absence of the extracellular domain by substituting it with high affinity leucine zippers to create dimers of the gro......Growth hormone initiates signaling by inducing homodimerization of two GH receptors. Here, we have sought to determine whether constitutively active receptor can be created in the absence of the extracellular domain by substituting it with high affinity leucine zippers to create dimers...... proliferation after interleukin 3 withdrawal at a rate equal to maximally stimulated wild type GHR-expressing cells. Activation of STAT 5b was also observed in Fos-Jun-GHR-expressing cells at a level equal to that in chronically GH-treated GHR-expressing cells. Thus, forced dimerization of the transmembrane...... and cytoplasmic domains of the GHR in the absence of the extracellular domain can lead to the constitutive activation of known GH signaling end points, supporting the view that proximity of Janus kinase 2 (JAK2) kinases is the essential element in signaling. Such constitutively active GH receptors may have...

  13. Melanin concentrating hormone and estrogen receptor-α are coexstensive but not coexpressed in cells of male rat hypothalamus

    OpenAIRE

    Muschamp, John W.; Hull, Elaine M.

    2007-01-01

    In male rats, estradiol (E2) exerts marked anorectic effects. One mechanism proposed for this effect is an E2-mediated down-regulation of the orexigenic neuropeptide melanin concentrating hormone (MCH). Previous anatomical work has shown that both MCH and estrogen receptor α (ERα) are found in quantity in the lateral hypothalamic area (LHA), a structure long associated with appetite and ingestive behavior. It has been hypothesized that the most direct manner by which E2 could affect MCH expre...

  14. Effect of a corticotropin releasing hormone receptor antagonist on colonic sensory and motor function in patients with irritable bowel syndrome

    OpenAIRE

    2004-01-01

    Background and aims: Corticotropin releasing hormone (CRH) is a major mediator of the stress response in the brain-gut axis. Irritable bowel syndrome (IBS) is presumed to be a disorder of the brain-gut link associated with an exaggerated response to stress. We hypothesised that peripheral administration of α-helical CRH (αhCRH), a non-selective CRH receptor antagonist, would improve gastrointestinal motility, visceral perception, and negative mood in response to gut stimulation in IBS patient...

  15. Dynamic Na+-H+ Exchanger Regulatory Factor-1 Association and Dissociation Regulate Parathyroid Hormone Receptor Trafficking at Membrane Microdomains*

    Science.gov (United States)

    Ardura, Juan A.; Wang, Bin; Watkins, Simon C.; Vilardaga, Jean-Pierre; Friedman, Peter A.

    2011-01-01

    Na/H exchanger regulatory factor-1 (NHERF1) is a cytoplasmic PDZ (postsynaptic density 95/disc large/zona occludens) protein that assembles macromolecular complexes and determines the localization, trafficking, and signaling of select G protein-coupled receptors and other membrane-delimited proteins. The parathyroid hormone receptor (PTHR), which regulates mineral ion homeostasis and bone turnover, is a G protein-coupled receptor harboring a PDZ-binding motif that enables association with NHERF1 and tethering to the actin cytoskeleton. NHERF1 interactions with the PTHR modify its trafficking and signaling. Here, we characterized by live cell imaging the mechanism whereby NHERF1 coordinates the interactions of multiple proteins, as well as the fate of NHERF1 itself upon receptor activation. Upon PTHR stimulation, NHERF1 rapidly dissociates from the receptor and induces receptor aggregation in long lasting clusters that are enriched with the actin-binding protein ezrin and with clathrin. After NHERF1 dissociates from the PTHR, ezrin then directly interacts with the PTHR to stabilize the PTHR at the cell membrane. Recruitment of β-arrestins to the PTHR is delayed until NHERF1 dissociates from the receptor, which is then trafficked to clathrin for internalization. The ability of NHERF to interact dynamically with the PTHR and cognate adapter proteins regulates receptor trafficking and signaling in a spatially and temporally coordinated manner. PMID:21832055

  16. Dynamic Na+-H+ exchanger regulatory factor-1 association and dissociation regulate parathyroid hormone receptor trafficking at membrane microdomains.

    Science.gov (United States)

    Ardura, Juan A; Wang, Bin; Watkins, Simon C; Vilardaga, Jean-Pierre; Friedman, Peter A

    2011-10-07

    Na/H exchanger regulatory factor-1 (NHERF1) is a cytoplasmic PDZ (postsynaptic density 95/disc large/zona occludens) protein that assembles macromolecular complexes and determines the localization, trafficking, and signaling of select G protein-coupled receptors and other membrane-delimited proteins. The parathyroid hormone receptor (PTHR), which regulates mineral ion homeostasis and bone turnover, is a G protein-coupled receptor harboring a PDZ-binding motif that enables association with NHERF1 and tethering to the actin cytoskeleton. NHERF1 interactions with the PTHR modify its trafficking and signaling. Here, we characterized by live cell imaging the mechanism whereby NHERF1 coordinates the interactions of multiple proteins, as well as the fate of NHERF1 itself upon receptor activation. Upon PTHR stimulation, NHERF1 rapidly dissociates from the receptor and induces receptor aggregation in long lasting clusters that are enriched with the actin-binding protein ezrin and with clathrin. After NHERF1 dissociates from the PTHR, ezrin then directly interacts with the PTHR to stabilize the PTHR at the cell membrane. Recruitment of β-arrestins to the PTHR is delayed until NHERF1 dissociates from the receptor, which is then trafficked to clathrin for internalization. The ability of NHERF to interact dynamically with the PTHR and cognate adapter proteins regulates receptor trafficking and signaling in a spatially and temporally coordinated manner.

  17. Detection of multiple hormonal activities in wastewater effluents and surface water, using a panel of steroid receptor CALUX bioassays.

    Science.gov (United States)

    Van der Linden, Sander C; Heringa, Minne B; Man, Hai-Yen; Sonneveld, Edwin; Puijker, Leo M; Brouwer, Abraham; Van der Burg, Bart

    2008-08-01

    It is generally known that there are compounds present in the aquatic environment that can disturb endocrine processes, for example via interaction with the endogenous hormone receptors. Most research so far has focused on compounds that bind to the estrogen and/or androgen receptor, but ligands for other hormone receptors might also be present. In this study, a newly completed panel of human cell derived CALUX reporter gene bioassays was utilized to test water extracts for estrogen (ER), as well as androgen (AR), progesterone (PR), and glucocorticoid (GR) receptor mediated transactivation activity. Effluents from industry, hospital, and municipal sewage treatment plants, as well as tap water and different sources of surface water were tested. The CALUX reporter gene panel showed high sensitivity and specificity to known agonists, enabling discrimination between different receptor based endocrine responses present in the aquatic environment. Our results clearly showed the presence of agonistic activity on the ER, as well as on the AR, PR, and GR in the raw and wastewater and surface water extracts. However, no hormone receptor-mediated transactivation was detected in the drinking water or in the blank water. The levels of estrogenic activity were 0.2-0.5 ng E2-equiv/L for surface water and 0.4-1.0 ng E2-equiv/L for municipal effluents, which was consistent with previous studies. Surprisingly, the other hormonal activities were found to be present in similar or much higher levels. Most notably, glucocorticoid-like activity was detected in all samples, at surprisingly high levels ranging from 0.39-1.3 ng Dex-equiv/L in surface water and 11-243 ng Dex-equiv/L in effluents. When regarding the fact that dexamethasone in the GR CALUX bioassay is a factor 12 more potent than the natural hormone cortisol, results expressed as cortisol equivalents would range up to 2900 ng cortisol equiv/L. Further studies are needed to establish the identity of the active compounds and to

  18. Treatment challenges for community oncologists treating postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer

    Directory of Open Access Journals (Sweden)

    Gradishar WJ

    2016-07-01

    Full Text Available William J Gradishar Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Abstract: Community-based oncologists are faced with challenges and opportunities when delivering quality patient care, including high patient volumes and diminished resources; however, there may be the potential to deliver increased patient education and subsequently improve outcomes. This review discusses the treatment of postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in order to illustrate considerations in the provision of pertinent quality education in the treatment of these patients and the management of therapy-related adverse events. An overview of endocrine-resistant breast cancer and subsequent treatment challenges is also provided. Approved treatment options for endocrine-resistant breast cancer include hormonal therapies and mammalian target of rapamycin inhibitors. Compounds under clinical investigation are also discussed. Keywords: community oncologists, hormone receptor-positive advanced breast cancer, endocrine resistance

  19. Funkce adipokinetických hormonů v metabolismu hmyzích lipidů

    OpenAIRE

    2010-01-01

    This PhD. thesis summarizes the effect of adipokinetic hormones (AKHs) on a spectrum of mobilized lipids in model insect species the locust Locusta migratoria and the firebug Pyrrhocoris apterus. The results revealed that mobilization of diacylglycerols and fatty acids from the fat body into the haemolymph is not uniform and suggested there is partial specificity of individual AKHs. This could contribute to the answer of the question why some insect species have more than one AKH. The results...

  20. Prostate-Derived Ets Transcription Factor Overexpression is Associated with Nodal Metastasis, Hormone Receptor Positivity in Invasive Breast Cancer

    Directory of Open Access Journals (Sweden)

    Simon Turcotte

    2007-10-01

    Full Text Available Prostate-derived Ets transcription factor (PDEF has recently been associated with invasive breast cancer, but no expression profile has been defined in clinical specimens. We undertook a comprehensive PDEF transcriptional expression study of 86 breast cancer clinical specimens, several cell lines, normal tissues. PDEF expression profile was analyzed according to standard clinicopathologic parameters, compared with hormonal receptor, HER-2/neu status, to the expression of the new tumor biomarker Dikkopf-1 (DKK1. Wide ranging PDEF overexpression was observed in 74% of tested tumors, at higher levels than the average expression found in normal breasts. High PDEF expression was associated with hormone receptor positivity (P < .001, moderate to good differentiation (less than grade III, P = .01, dissemination to axillary lymph nodes (P = .002. PDEF was an independent risk factor for nodal involvement (multivariate analysis, odds ratio 1.250, P = .002. It was expressed in a different subgroup compared to DKK1-expressing tumors (P < .001. Our data imply that PDEF mRNA expression could be useful in breast cancer molecular staging. Further insights into PDEF functions at the protein level, possible links with hormone receptors biology, bear great potential for new therapeutic avenues.

  1. Effect of obesity on aromatase inhibitor efficacy in postmenopausal, hormone receptor-positive breast cancer: a systematic review.

    Science.gov (United States)

    Ioannides, S J; Barlow, P L; Elwood, J M; Porter, D

    2014-09-01

    Aromatase inhibitors (AIs) decrease the production of oestrogen, decreasing stimulation of hormone receptor-positive breast cancer. Theoretically, AIs may be less effective in obese women, due to the greater quantity of aromatase in peripheral fatty tissue. We performed a systematic review to assess the effect of obesity on AI efficacy in breast cancer treatment. The review followed PRISMA guidelines. Studies included were interventional or observational studies with comparison groups, of postmenopausal women with hormone receptor-positive breast cancer on treatment with an AI, alone or in combination with other drugs, in which body mass index or another measure of obesity was recorded. Studies in all languages were included; if published as an abstract only, authors were contacted for further information. Outcome measures included overall survival, disease-free survival or time to progressive disease, survival from the start of therapy, mortality measures, local or distant recurrence of primary cancer and time to recurrence. Of 2,344 citations identified from five databases, eight studies met the criteria for inclusion; three randomised controlled trials and five retrospective cohort studies. Due to variability in study factors, it was not possible to perform a quantitative meta-analysis. However, the systematic review showed a trend towards a negative effect of obesity on AI efficacy. There is evidence of a negative effect of obesity on AI efficacy in postmenopausal hormone receptor-positive breast cancer, but the size of the effect cannot be assessed. More information is needed before clinical recommendations are made.

  2. The CB1 receptor mediates the peripheral effects of ghrelin on AMPK activity but not on growth hormone release.

    Science.gov (United States)

    Kola, Blerina; Wittman, Gábor; Bodnár, Ibolya; Amin, Faisal; Lim, Chung Thong; Oláh, Márk; Christ-Crain, Mirjam; Lolli, Francesca; van Thuijl, Hinke; Leontiou, Chrysanthia A; Füzesi, Tamás; Dalino, Paolo; Isidori, Andrea M; Harvey-White, Judith; Kunos, George; Nagy, György M; Grossman, Ashley B; Fekete, Csaba; Korbonits, Márta

    2013-12-01

    This study aimed to investigate whether the growth hormone release and metabolic effects of ghrelin on AMPK activity of peripheral tissues are mediated by cannabinoid receptor type 1 (CB1) and the central nervous system. CB1-knockout (KO) and/or wild-type mice were injected peripherally or intracerebroventricularly with ghrelin and CB1 antagonist rimonabant to study tissue AMPK activity and gene expression (transcription factors SREBP1c, transmembrane protein FAS, enzyme PEPCK, and protein HSL). Growth hormone levels were studied both in vivo and in vitro. Peripherally administered ghrelin in liver, heart, and adipose tissue AMPK activity cannot be observed in CB1-KO or CB1 antagonist-treated mice. Intracerebroventricular ghrelin treatment can influence peripheral AMPK activity. This effect is abolished in CB1-KO mice and by intracerebroventricular rimonabant treatment, suggesting that central CB1 receptors also participate in the signaling pathway that mediates the effects of ghrelin on peripheral tissues. Interestingly, in vivo or in vitro growth hormone release is intact in response to ghrelin in CB1-KO animals. Our data suggest that the metabolic effects of ghrelin on AMPK in peripheral tissues are abolished by the lack of functional CB1 receptor via direct peripheral effect and partially through the central nervous system, thus supporting the existence of a possible ghrelin-cannabinoid-CB1-AMPK pathway.

  3. Expression of receptors for luteinizing hormone, gastric-inhibitory polypeptide, and vasopressin in normal adrenal glands and cortisol-secreting adrenocortical tumors in dogs

    NARCIS (Netherlands)

    Galac, S.; Kars, V.J.; Klarenbeek, S.; Teerds, K.J.; Mol, J.A.; Kooistra, H.S.

    2010-01-01

    Hypercortisolism caused by an adrenocortical tumor (AT) results from adrenocorticotropic hormone (ACTH)-independent hypersecretion of glucocorticoids. Studies in humans demonstrate that steroidogenesis in ATs may be stimulated by ectopic or overexpressed eutopic G protein-coupled receptors. We repor

  4. Novel C617Y mutation in the 7th transmembrane segment of luteinizing hormone/choriogonadotropin receptor in a Japanese boy with peripheral precocious puberty

    National Research Council Canada - National Science Library

    Nagasaki, Keisuke; Katsumata, Noriyuki; Ogawa, Yohei; Kikuchi, Toru; Uchiyama, Makoto

    2010-01-01

    ... mutations of the LHCGR gene encoding the luteinizing hormone/choriogonadotropin receptor (LH/CGR). The patient is an 8-year-old boy who started to develop pubic hair and penile enlargement at 6 years of age...

  5. Regulation of corticotropin releasing hormone receptor type 1 messenger RNA level in Y-79 retinoblastoma cells: potential implications for human stress response and immune/inflammatory reaction

    Directory of Open Access Journals (Sweden)

    N. C. Vamvakopoulos

    1996-01-01

    Full Text Available We report the regulation of type 1 receptor mRNA in Y-79 human retinoblastoma cells, grown in the absence or presence of pharmacological levels of phorbol esters, forskolin, glucocorticoids and their combinations. To control for inducibility and for assessing the sensitivity of the Y-79 system to glucocorticoids, corticotropin releasing hormone mRNA levels were measured in parallel. All treatments stimulated corticotropin releasing hormone receptor type 1 gene expression relative to baseline. A weak suppression of corticotropin releasing hormone mRNA level was observed during dexamethasone treatment. The cell line expressed ten-fold excess of receptor to ligand mRNA under basal conditions. The findings predict the presence of functional phorbol ester, cyclic AMP and glucocorticoid response elements in the promoter region of corticotropin releasing hormone receptor type 1 gene and support a potential role for its product during chronic stress and immune/inflammatory reaction.

  6. Thyroid hormone increases fibroblast growth factor receptor expression and disrupts cell mechanics in the developing organ of corti.

    Science.gov (United States)

    Szarama, Katherine B; Gavara, Núria; Petralia, Ronald S; Chadwick, Richard S; Kelley, Matthew W

    2013-02-09

    Thyroid hormones regulate growth and development. However, the molecular mechanisms by which thyroid hormone regulates cell structural development are not fully understood. The mammalian cochlea is an intriguing system to examine these mechanisms, as cellular structure plays a key role in tissue development, and thyroid hormone is required for the maturation of the cochlea in the first postnatal week. In hypothyroid conditions, we found disruptions in sensory outer hair cell morphology and fewer microtubules in non-sensory supporting pillar cells. To test the functional consequences of these cytoskeletal defects on cell mechanics, we combined atomic force microscopy with live cell imaging. Hypothyroidism stiffened outer hair cells and supporting pillar cells, but pillar cells ultimately showed reduced cell stiffness, in part from a lack of microtubules. Analyses of changes in transcription and protein phosphorylation suggest that hypothyroidism prolonged expression of fibroblast growth factor receptors, and decreased phosphorylated Cofilin. These findings demonstrate that thyroid hormones may be involved in coordinating the processes that regulate cytoskeletal dynamics and suggest that manipulating thyroid hormone sensitivity might provide insight into the relationship between cytoskeletal formation and developing cell mechanical properties.

  7. Regulation of corticotropin releasing hormone receptor type 1 messenger RNA level in Y-79 retinoblastoma cells: potential implications for human stress response and immune/inflammatory reaction

    OpenAIRE

    Vamvakopoulos, N C; Sioutopoulou, T. O.; Mamuris, Z.; Marcoulatos, P.; Avgerinos, P. C.

    1996-01-01

    We report the regulation of type 1 receptor mRNA in Y-79 human retinoblastoma cells, grown in the absence or presence of pharmacological levels of phorbol esters, forskolin, glucocorticoids and their combinations. To control for inducibility and for assessing the sensitivity of the Y-79 system to glucocorticoids, corticotropin releasing hormone mRNA levels were measured in parallel. All treatments stimulated corticotropin releasing hormone receptor type 1 gene expression relative to baseline....

  8. Evolution of the AKH/corazonin/ACP/GnRH receptor superfamily and their ligands in the Protostomia.

    Science.gov (United States)

    Hauser, Frank; Grimmelikhuijzen, Cornelis J P

    2014-12-01

    In this review we trace the evolutionary connections between GnRH receptors from vertebrates and the receptors for adipokinetic hormone (AKH), AKH/corazonin-related peptide (ACP), and corazonin from arthropods. We conclude that these G protein-coupled receptors (GPCRs) are closely related and have a common evolutionary origin, which dates back to the split of Proto- and Deuterostomia, about 700 million years ago. We propose that in the protostomian lineage, the ancestral GnRH-like receptor gene duplicated as did its GnRH-like ligand gene, followed by diversification, leading to (i) a corazonin receptor gene and a corazonin-like ligand gene, and (ii) an AKH receptor gene and an AKH-like ligand gene in the Mollusca and Annelida. Subsequently, the AKH receptor and ligand genes duplicated once more, yielding the situation that we know from arthropods today, where three independent hormonal systems exist, signalling with AKH, ACP, and corazonin. Our model for the evolution of GnRH signaling in the Protostomia is a striking example of receptor-ligand co-evolution. This model has been developed using several bioinformatics tools (TBLASTN searches, phylogenetic tree analyses), which also helped us to annotate six novel AKH preprohormones and their corresponding AKH sequences from the following molluscs: the sea hare Aplysia californica (AKH sequence: pQIHFSPDWGTamide), the sea slug Tritonia diomedea (pQIHFSPGWEPamide), the fresh water snail Bithynia siamensis goniomphalos (pQIHFTPGWGSamide), the owl limpet Lottia gigantea (pQIHFSPTWGSamide), the oyster Crassostrea gigas (pQVSFSTNWGSamide), and the freshwater pearl mussel Hyriopsis cumingii (pQISFSTNWGSamide). We also found AKHs in the tardigrade Hysibius dujardini (pQLSFTGWGHamide), the rotifer Brachionus calycifloros (pQLTFSSDWSGamide), and the penis worm Priapulus caudatus (pQIFFSKGWRGamide). This is the first report, showing that AKH signaling is widespread in molluscs.

  9. Liver X receptor regulation of thyrotropin-releasing hormone transcription in mouse hypothalamus is dependent on thyroid status.

    Directory of Open Access Journals (Sweden)

    Rym Ghaddab-Zroud

    Full Text Available Reversing the escalating rate of obesity requires increased knowledge of the molecular mechanisms controlling energy balance. Liver X receptors (LXRs and thyroid hormone receptors (TRs are key physiological regulators of energetic metabolism. Analysing interactions between these receptors in the periphery has led to a better understanding of the mechanisms involved in metabolic diseases. However, no data is available on such interactions in the brain. We tested the hypothesis that hypothalamic LXR/TR interactions could co-regulate signalling pathways involved in the central regulation of metabolism. Using in vivo gene transfer we show that LXR activation by its synthetic agonist GW3965 represses the transcriptional activity of two key metabolic genes, Thyrotropin-releasing hormone (Trh and Melanocortin receptor type 4 (Mc4r in the hypothalamus of euthyroid mice. Interestingly, this repression did not occur in hypothyroid mice but was restored in the case of Trh by thyroid hormone (TH treatment, highlighting the role of the triiodothyronine (T3 and TRs in this dialogue. Using shLXR to knock-down LXRs in vivo in euthyroid newborn mice, not only abrogated Trh repression but actually increased Trh transcription, revealing a potential inhibitory effect of LXR on the Hypothalamic-Pituitary-Thyroid axis. In vivo chromatin immunoprecipitation (ChIP revealed LXR to be present on the Trh promoter region in the presence of T3 and that Retinoid X Receptor (RXR, a heterodimerization partner for both TR and LXR, was never recruited simultaneously with LXR. Interactions between the TR and LXR pathways were confirmed by qPCR experiments. T3 treatment of newborn mice induced hypothalamic expression of certain key LXR target genes implicated in metabolism and inflammation. Taken together the results indicate that the crosstalk between LXR and TR signalling in the hypothalamus centres on metabolic and inflammatory pathways.

  10. Structural Basis for Parathyroid Hormone-related Protein Binding to the Parathyroid Hormone Receptor and Design of Conformation-selective Peptides

    Energy Technology Data Exchange (ETDEWEB)

    Pioszak, Augen A.; Parker, Naomi R.; Gardella, Thomas J.; Xu, H. Eric; (Van Andel); (Mass. Gen. Hosp.)

    2009-12-01

    Parathyroid hormone (PTH) and PTH-related protein (PTHrP) are two related peptides that control calcium/phosphate homeostasis and bone development, respectively, through activation of the PTH/PTHrP receptor (PTH1R), a class B G protein-coupled receptor. Both peptides hold clinical interest for their capacities to stimulate bone formation. PTH and PTHrP display different selectivity for two distinct PTH1R conformations, but how their binding to the receptor differs is unclear. The high resolution crystal structure of PTHrP bound to the extracellular domain (ECD) of PTH1R reveals that PTHrP binds as an amphipathic {alpha}-helix to the same hydrophobic groove in the ECD as occupied by PTH, but in contrast to a straight, continuous PTH helix, the PTHrP helix is gently curved and C-terminally 'unwound.' The receptor accommodates the altered binding modes by shifting the side chain conformations of two residues within the binding groove: Leu-41 and Ile-115, the former acting as a rotamer toggle switch to accommodate PTH/PTHrP sequence divergence, and the latter adapting to the PTHrP curvature. Binding studies performed with PTH/PTHrP hybrid ligands having reciprocal exchanges of residues involved in different contacts confirmed functional consequences for the altered interactions and enabled the design of altered PTH and PTHrP peptides that adopt the ECD-binding mode of the opposite peptide. Hybrid peptides that bound the ECD poorly were selective for the G protein-coupled PTH1R conformation. These results establish a molecular model for better understanding of how two biologically distinct ligands can act through a single receptor and provide a template for designing better PTH/PTHrP therapeutics.

  11. Structural basis for parathyroid hormone-related protein binding to the parathyroid hormone receptor and design of conformation-selective peptides.

    Science.gov (United States)

    Pioszak, Augen A; Parker, Naomi R; Gardella, Thomas J; Xu, H Eric

    2009-10-09

    Parathyroid hormone (PTH) and PTH-related protein (PTHrP) are two related peptides that control calcium/phosphate homeostasis and bone development, respectively, through activation of the PTH/PTHrP receptor (PTH1R), a class B G protein-coupled receptor. Both peptides hold clinical interest for their capacities to stimulate bone formation. PTH and PTHrP display different selectivity for two distinct PTH1R conformations, but how their binding to the receptor differs is unclear. The high resolution crystal structure of PTHrP bound to the extracellular domain (ECD) of PTH1R reveals that PTHrP binds as an amphipathic alpha-helix to the same hydrophobic groove in the ECD as occupied by PTH, but in contrast to a straight, continuous PTH helix, the PTHrP helix is gently curved and C-terminally "unwound." The receptor accommodates the altered binding modes by shifting the side chain conformations of two residues within the binding groove: Leu-41 and Ile-115, the former acting as a rotamer toggle switch to accommodate PTH/PTHrP sequence divergence, and the latter adapting to the PTHrP curvature. Binding studies performed with PTH/PTHrP hybrid ligands having reciprocal exchanges of residues involved in different contacts confirmed functional consequences for the altered interactions and enabled the design of altered PTH and PTHrP peptides that adopt the ECD-binding mode of the opposite peptide. Hybrid peptides that bound the ECD poorly were selective for the G protein-coupled PTH1R conformation. These results establish a molecular model for better understanding of how two biologically distinct ligands can act through a single receptor and provide a template for designing better PTH/PTHrP therapeutics.

  12. Solid-phase synthesis of a 6-phenylquinolin-2(1H)-one library directed toward nuclear hormone receptors.

    Science.gov (United States)

    Ruda, Marcus; Kann, Nina; Gordon, Sandra; Bergman, Jan; Nelson, William; Agback, Peter; Hagberg, Lars; Koehler, Konrad F

    2005-01-01

    A library of 6-phenylquinolin-2(1H)-ones with diversity at position 1 and the ortho, meta, and para positions of the pendant phenyl ring has been synthesized using solid-phase parallel synthetic techniques. A key step in the synthesis of the library is a tandem alkylation cleavage in which diversity can be introduced at position 1 simultaneously to the cleavage from the resin. The yields of this step were significantly improved over what has previously been reported by addition of cesium carbonate to scavenge the acid that is formed during the reaction. Furthermore, we have shown that the solid support linkage is tolerant to Suzuki coupling and etherification reaction conditions and that selective cleavage of the linkage can take place in the presence of esters. The resulting 6-phenylquinolin-2(1H)-one library was screened against a panel of nuclear hormone receptors (androgen, estrogen alpha and beta isoforms, glucocorticoid, mineralocorticoid, and progesterone). Certain members of this library display moderate affinity for several of these receptors, and consequently, the 6-phenylquinolin-2(1H)-one core of the library may be considered a privileged structure for nuclear hormone receptors. In contrast, other members of the library display high selectivity for a particular receptor. The highest affinity ligand (9{2,1,1}) possesses an affinity of 330 nM for the androgen receptor, whereas the most selective ligand (9{2,4,1}) displays an affinity of 900 nM for the androgen receptor and a selectivity of 140-fold over the next highest affinity receptor.

  13. Hair-cycle-dependent expression of parathyroid hormone-related protein and its type I receptor: evidence for regulation at the anagen to catagen transition.

    Science.gov (United States)

    Cho, Yong Mee; Woodard, Grant L; Dunbar, Maureen; Gocken, Todd; Jimènez, Juan A; Foley, John

    2003-05-01

    The humoral hypercalcemia factor parathyroid hormone-related protein is a paracrine-signaling molecule that regulates the development of several organ systems, including the skin. In pathologic circumstances such as hypercalcemia and in development, parathyroid hormone-related protein signaling appears to be mediated by the type I parathyroid hormone/parathyroid hormone-related protein receptor. In order to clarify the role of the ligand and receptor pair in cutaneous biology, gene expression was monitored in a series of murine skin samples ranging from embryonic day 14 to 2 y with in situ hybridization and RNase protection. In all samples, high levels of parathyroid hormone-related protein transcripts were exclusively expressed in the developing and adult hair follicle but were not observed in the interfollicular epidermis. In the adult, parathyroid hormone-related protein mRNA expression was dynamically regulated as a function of the murine hair cycle in a way similar to other signaling molecules that regulate the anagen to catagen transition. PTH receptor transcripts were abundantly expressed in the developing dermis. In the adult skin, PTH receptor mRNA was markedly reduced, but again demonstrated hair-cycle-dependent expression. The dorsal skin of the keratin 14-parathyroid hormone-related protein mouse was used to evaluate the impact of overexpression of the peptide on the murine hair cycle. All types of hair were 30-40% shorter in adult keratin 14-parathyroid hormone-related protein mice as compared with wild-type littermates. This appeared to result from a premature entry into the catagen phase of the hair cycle. Finally, the relationship between parathyroid hormone-related protein signaling and other growth factors that regulate the hair cycle was examined by cross-breeding experiments employing keratin 14-parathyroid hormone-related protein mice and fibroblast growth factor-5-knockout mice. It appears that parathyroid hormone-related protein and

  14. Search for genetic variants in the retinoid X receptor-gamma-gene by polymerase chain reaction-single-strand conformation polymorphism in patients with resistance to thyroid hormone without mutations in thyroid hormone receptor beta gene.

    Science.gov (United States)

    Romeo, Stefano; Menzaghi, Claudia; Bruno, Rocco; Sentinelli, Federica; Fallarino, Mara; Fioretti, Francesca; Filetti, Sebastiano; Balsamo, Armando; Di Mario, Umberto; Baroni, Marco G

    2004-05-01

    Resistance to thyroid hormone (RTH) is an inherited disease characterized by reduced tissue sensitivity to thyroid hormone. Approximately 90% of subjects with RTH have mutation in the thyroid hormone receptor beta (TRbeta) gene. Approximately 10% of subjects diagnosed as having RTH do not carry mutation in the TRbeta gene. A possible linkage was reported with the retinoid X receptor-gamma (RXR-gamma) gene in two families. The aim of this study is to search for mutation within the RXR-gamma gene in unrelated subjects with diagnosed RTH without mutations in the TRbeta gene. Four subjects with RTH were studied, and sequence variants in the RXR-gamma gene were searched by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP). Analysis of all the 10 exons of the RXR-gamma gene, including intron-exon boundaries, promoter region and 3' untranslated region (UTR) reveled two variant bands in subjects II and III. Sequencing of these variants showed two single nucleotide polymorphisms (SNPs): 447C > T in exon 3 for patients II and IVS9 + 6A > G for patient III. Both SNPs were also present at high frequency in a group of normal subjects and in nonaffected relatives of subject III. In conclusion, in patients with RTH we have found two SNPs in the RXR-gamma gene; these SNPS are common in the general population, thus excluding a role for the RXR-gamma gene in these patients.

  15. The guanine nucleotide exchange factor Vav2 is a negative regulator of parathyroid hormone receptor/Gq signaling.

    Science.gov (United States)

    Emami-Nemini, Alexander; Gohla, Antje; Urlaub, Henning; Lohse, Martin J; Klenk, Christoph

    2012-08-01

    The parathyroid hormone receptor (PTHR) is a class B G protein-coupled receptor (GPCR) that mediates the endocrine and paracrine effects of parathyroid hormone and related peptides through the activation of phospholipase Cβ-, adenylyl cyclase-, mitogen-activated protein kinase-, and β-arrestin-initiated signaling pathways. It is currently not clear how specificity among these downstream signaling pathways is achieved. A possible mechanism involves adaptor proteins that affect receptor/effector coupling. In a proteomic screen with the PTHR C terminus, we identified vav2, a guanine nucleotide exchange factor (GEF) for Rho GTPases, as a PTHR-interacting protein. The core domains of vav2 bound to the intracellular domains of the PTHR independent of receptor activation. In addition, vav2 specifically interacted with activated Gα(q) but not with Gα(s) subunits, and it competed with PTHR for coupling to Gα(q). Consistent with its specific interaction with Gα(q), vav2 impaired G(q)-mediated inositol phosphate generation but not G(s)-mediated cAMP generation. This inhibition of G(q) signaling was specific for PTHR signaling, compared with other G(q)-coupled GPCRs. Moreover, the benefit for PTHR-mediated inositol phosphate generation in the absence of vav2 required the ezrin binding domain of Na(+)/H(+)-exchanger regulatory factor 1. Our results show that a RhoA GEF can specifically interact with a GPCR and modulate its G protein signaling specificity.

  16. Tolerability of Therapies Recommended for the Treatment of Hormone Receptor-Positive Locally Advanced or Metastatic Breast Cancer.

    Science.gov (United States)

    Ohno, Shinji

    2016-08-01

    For women with hormone receptor-positive advanced breast cancer, endocrine therapies, including the selective estrogen receptor modulator tamoxifen, the aromatase inhibitors anastrozole, letrozole, and exemestane, and the selective estrogen receptor degrader fulvestrant, are recommended in clinical guidelines. The addition of targeted agents such as everolimus or palbociclib to aromatase inhibitors are also recommended as treatment options. Chemotherapy remains an option, although clinical guidelines have recommended these agents be reserved for patients with immediately life-threatening disease or if resistance to endocrine therapy is known or suspected. The present review has consolidated the tolerability profiles of the agents approved for use in the treatment of hormone receptor-positive advanced or metastatic breast cancer based on phase III registration trial data. Endocrine therapies are generally well tolerated, although the addition of targeted therapies to aromatase inhibitors or fulvestrant appears to increase the proportion of patients experiencing adverse events, and palbociclib and chemotherapy appear to be more closely associated with serious adverse events, including neutropenia.

  17. Gender and the use of hormonal contraception in women are not associated with cerebral cortical 5-HT 2A receptor binding

    DEFF Research Database (Denmark)

    Frokjaer, V G; Erritzoe, D; Madsen, J

    2009-01-01

    Gender influences brain function including serotonergic neurotransmission, which may play a role in the well-known gender variations in vulnerability to mood and anxiety disorders. Even though hormonal replacement therapy in menopause is associated with globally increased cerebral 5-HT(2A) receptor...... binding it is not clear if gender or use of hormonal contraception exhibits associations with 5-HT(2A) receptor binding. We found no significant effect of gender on cortical 5-HT(2A) receptor binding (P=0.15, n=132). When adjusting for the personality trait neuroticism, known to be positively correlated...... to frontolimbic 5-HT(2A) receptor binding and to be more pronounced in women, again, the effect of gender was not significant (P=0.42, n=127). Also, the use of hormonal contraception (n=14) within the group of pre-menopausal women (total n=29) was not associated with cortical 5-HT(2A) receptor binding (P=0...

  18. Estrogen receptor hormone agonists limit trauma hemorrhage shock-induced gut and lung injury in rats.

    Directory of Open Access Journals (Sweden)

    Danielle Doucet

    Full Text Available BACKGROUND: Acute lung injury (ALI and the development of the multiple organ dysfunction syndrome (MODS is a major cause of death in trauma patients. Earlier studies in trauma hemorrhagic shock (T/HS have documented that splanchnic ischemia leading to gut inflammation and loss of barrier function is an initial triggering event that leads to gut-induced ARDS and MODS. Since sex hormones have been shown to modulate the response to T/HS and proestrous (PE females are more resistant to T/HS-induced gut and distant organ injury, the goal of our study was to determine the contribution of estrogen receptor (ERalpha and ERbeta in modulating the protective response of female rats to T/HS-induced gut and lung injury. METHODS/PRINCIPAL FINDINGS: The incidence of gut and lung injury was assessed in PE and ovariectomized (OVX female rats subjected to T/HS or trauma sham shock (T/SS as well as OVX rats that were administered estradiol (E2 or agonists for ERalpha or ERbeta immediately prior to resuscitation. Marked gut and lung injury was observed in OVX rats subjected to T/HS as compared to PE rats or E2-treated OVX rats subjected to T/HS. Both ERalpha and ERbeta agonists were equally effective in limiting T/HS-induced morphologic villous injury and bacterial translocation, whereas the ERbeta agonist was more effective than the ERalpha agonist in limiting T/HS-induced lung injury as determined by histology, Evan's blue lung permeability, bronchoalevolar fluid/plasma protein ratio and myeloperoxidase levels. Similarly, treatment with either E2 or the ERbeta agonist attenuated the induction of the intestinal iNOS response in OVX rats subjected to T/HS whereas the ERalpha agonist was only partially protective. CONCLUSIONS/SIGNIFICANCE: Our study demonstrates that estrogen attenuates T/HS-induced gut and lung injury and that its protective effects are mediated by the activation of ERalpha, ERbeta or both receptors.

  19. Hormonal regulation of delta opioid receptor immunoreactivity in interneurons and pyramidal cells in the rat hippocampus.

    Science.gov (United States)

    Williams, Tanya J; Torres-Reveron, Annelyn; Chapleau, Jeanette D; Milner, Teresa A

    2011-02-01

    Clinical and preclinical studies indicate that women and men differ in relapse vulnerability to drug-seeking behavior during abstinence periods. As relapse is frequently triggered by exposure of the recovered addict to objects previously associated with drug use and the formation of these associations requires memory systems engaged by the hippocampal formation (HF), studies exploring ovarian hormone modulation of hippocampal function are warranted. Previous studies revealed that ovarian steroids alter endogenous opioid peptide levels and trafficking of mu opioid receptors in the HF, suggesting cooperative interaction between opioids and estrogens in modulating hippocampal excitability. However, whether ovarian steroids affect the levels or trafficking of delta opioid receptors (DORs) in the HF is unknown. Here, hippocampal sections of adult male and normal cycling female Sprague-Dawley rats were processed for quantitative immunoperoxidase light microscopy and dual label fluorescence or immunoelectron microscopy using antisera directed against the DOR and neuropeptide Y (NPY). Consistent with previous studies in males, DOR-immunoreactivity (-ir) localized to select interneurons and principal cells in the female HF. In comparison to males, females, regardless of estrous cycle phase, show reduced DOR-ir in the granule cell layer of the dentate gyrus and proestrus (high estrogen) females, in particular, display reduced DOR-ir in the CA1 pyramidal cell layer. Ultrastructural analysis of DOR-labeled profiles in CA1 revealed that while females generally show fewer DORs in the distal apical dendrites of pyramidal cells, proestrus females, in particular, exhibit DOR internalization and trafficking towards the soma. Dual label studies revealed that DORs are found in NPY-labeled interneurons in the hilus, CA3, and CA1. While DOR colocalization frequency in NPY-labeled neuron somata was similar between animals in the hilus, proestrus females had fewer NPY-labeled neurons that

  20. [Hormone replacement and selective estrogen receptor modulators (SERMS) in the prevention and treatment of postmenopausal osteoporosis].

    Science.gov (United States)

    Pfeilschifter, J

    2001-07-01

    For many years, hormone replacement therapy (HRT) has been regarded as one of the most reliable means of prophylaxis and treatment for postmenopausal osteoporosis. As HRT ameliorates menopausal symptoms, it is widely prescribed among early postmenopausal women. A variety of different modes of replacement that suit each individual requirement are available in terms of schedule (cyclic or combined application of gestagens) and route of application (oral or transdermal). HRT effectively prevents spinal bone loss and delays bone loss at the hip up to a very old age. With continued use after menopause, HRT might theoretically halve the incidence of vertebral and hip fractures. However, long-term use or use of HRT in old age is rarely practiced, and the actual benefit of a transient use for future fracture prevention remains unclear. Raloxifene is the first member of the novel class of selective estrogen receptor modulators (SERMs) that has been approved for the prophylaxis and treatment of postmenopausal osteoporosis. It combines the positive effects of estrogen on the skeleton with estrogen-antagonistic effects on sex tissues. Thus, raloxifene maintains bone mass and decreases the incidence of vertebral fractures in osteoporotic women, but avoids many of the side effects that are responsible for the poor long-term compliance to HRT such as resumption or continuation of regular menses, breast tenderness, or breast cancer. It even markedly reduces the risk of breast cancer. Both estrogen and raloxifene are characterized by a large number of extraskeletal effects that have to be taken into account when counseling postmenopausal women on the use of these agents for the prevention or treatment of osteoporosis.

  1. Hepatic growth hormone and glucocorticoid receptor signaling in body growth, steatosis and metabolic liver cancer development.

    Science.gov (United States)

    Mueller, Kristina M; Themanns, Madeleine; Friedbichler, Katrin; Kornfeld, Jan-Wilhelm; Esterbauer, Harald; Tuckermann, Jan P; Moriggl, Richard

    2012-09-25

    Growth hormone (GH) and glucocorticoids (GCs) are involved in the control of processes that are essential for the maintenance of vital body functions including energy supply and growth control. GH and GCs have been well characterized to regulate systemic energy homeostasis, particular during certain conditions of physical stress. However, dysfunctional signaling in both pathways is linked to various metabolic disorders associated with aberrant carbohydrate and lipid metabolism. In liver, GH-dependent activation of the transcription factor signal transducer and activator of transcription (STAT) 5 controls a variety of physiologic functions within hepatocytes. Similarly, GCs, through activation of the glucocorticoid receptor (GR), influence many important liver functions such as gluconeogenesis. Studies in hepatic Stat5 or GR knockout mice have revealed that they similarly control liver function on their target gene level and indeed, the GR functions often as a cofactor of STAT5 for GH-induced genes. Gene sets, which require physical STAT5-GR interaction, include those controlling body growth and maturation. More recently, it has become evident that impairment of GH-STAT5 signaling in different experimental models correlates with metabolic liver disease, ranging from hepatic steatosis to hepatocellular carcinoma (HCC). While GH-activated STAT5 has a protective role in chronic liver disease, experimental disruption of GC-GR signaling rather seems to ameliorate metabolic disorders under metabolic challenge. In this review, we focus on the current knowledge about hepatic GH-STAT5 and GC-GR signaling in body growth, metabolism, and protection from fatty liver disease and HCC development.

  2. Calcium-sensing receptor expression and parathyroid hormone secretion in hyperplastic parathyroid glands from humans.

    Science.gov (United States)

    Cañadillas, Sagrario; Canalejo, Antonio; Santamaría, Rafael; Rodríguez, Maria E; Estepa, Jose C; Martín-Malo, Alejandro; Bravo, Juan; Ramos, Blanca; Aguilera-Tejero, Escolastico; Rodríguez, Mariano; Almadén, Yolanda

    2005-07-01

    In uremic patients, severe parathyroid hyperplasia is associated with reduced parathyroid calcium-sensing receptor (CaR) expression. Thus, in these patients, a high serum Ca concentration may be required to inhibit parathyroid hormone (PTH) secretion. This study compares the magnitude of reduction in CaR expression and the degree of the abnormality in Ca-regulated PTH release in vitro. A total of 50 glands from 23 hemodialysis patients with refractory hyperparathyroidism were studied. Tissue slices were incubated in vitro to evaluate (1) the PTH secretory output in a normal Ca concentration (1.25 mM) and (2) the PTH secretory response to high (1.5 mM) and low (0.6 mM) Ca concentration. Tissue aliquots were processed for determination of CaRmRNA expression. The results showed that, corrected for DNA, parathyroid tissue with lowest CaR expression secreted more PTH than that with relatively high CaR expression (146 +/- 23 versus 60 +/- 2 pg/microg DNA; P < 0.01). Furthermore, glands with low CaR expression demonstrated a blunted PTH secretory response to both the inhibitory effect of high Ca and the stimulatory effect of low Ca. The study also showed that the larger the gland, the lower the CaRmRNA expression. Thus, large parathyroid glands produce a large amount of PTH not only as a result of the increased gland size but also because the parathyroid tissue secretory output is increased. These abnormalities in PTH regulation are related to low CaR expression.

  3. Disruption of growth hormone receptor prevents calorie restriction from improving insulin action and longevity.

    Directory of Open Access Journals (Sweden)

    Michael S Bonkowski

    Full Text Available Most mutations that delay aging and prolong lifespan in the mouse are related to somatotropic and/or insulin signaling. Calorie restriction (CR is the only intervention that reliably increases mouse longevity. There is considerable phenotypic overlap between long-lived mutant mice and normal mice on chronic CR. Therefore, we investigated the interactive effects of CR and targeted disruption or knock out of the growth hormone receptor (GHRKO in mice on longevity and the insulin signaling cascade. Every other day feeding corresponds to a mild (i.e. 15% CR which increased median lifespan in normal mice but not in GHRKO mice corroborating our previous findings on the effects of moderate (30% CR on the longevity of these animals. To determine why insulin sensitivity improves in normal but not GHRKO mice in response to 30% CR, we conducted insulin stimulation experiments after one year of CR. In normal mice, CR increased the insulin stimulated activation of the insulin signaling cascade (IR/IRS/PI3K/AKT in liver and muscle. Livers of GHRKO mice responded to insulin by increased activation of the early steps of insulin signaling, which was dissipated by altered PI3K subunit abundance which putatively inhibited AKT activation. In the muscle of GHRKO mice, there was elevated downstream activation of the insulin signaling cascade (IRS/PI3K/AKT in the absence of elevated IR activation. Further, we found a major reduction of inhibitory Ser phosphorylation of IRS-1 seen exclusively in GHRKO muscle which may underpin their elevated insulin sensitivity. Chronic CR failed to further modify the alterations in insulin signaling in GHRKO mice as compared to normal mice, likely explaining or contributing to the absence of CR effects on insulin sensitivity and longevity in these long-lived mice.

  4. Cardioselective Dominant-negative Thyroid Hormone Receptor (Δ337T) Modulates Myocardial Metabolism and Contractile Dfficiency

    Energy Technology Data Exchange (ETDEWEB)

    Hyyti, Outi M.; Olson, Aaron; Ge, Ming; Ning, Xue-Han; Buroker, Norman E.; Chung, Youngran; Jue, Thomas; Portman, Michael A.

    2008-06-03

    Dominant- negative thyroid hormone receptors (TRs) show elevated expression relative to ligand-binding TRs during cardiac hypertrophy. We tested the hypothesis that overexpression of a dominant-negative TR alters cardiac metabolism and contractile efficiency (CE). We used mice expressing the cardioselective dominant-negative TRβ1 mutation Δ337T. Isolated working Δ337T hearts and nontransgenic control (Con) hearts were perfused with 13C-labeled free fatty acids (FFA), acetoacetate (ACAC), lactate, and glucose at physiological concentrations for 30 min. 13C NMR spectroscopy and isotopomer analyses were used to determine substrate flux and fractional contributions (Fc) of acetyl-CoA to the citric acid cycle (CAC). Δ337T hearts exhibited rate depression but higher developed pressure and CE, defined as work per oxygen consumption (MV˙ O2). Unlabeled substrate Fc from endogenous sources was higher in Δ337T, but ACAC Fc was lower. Fluxes through CAC, lactate, ACAC, and FFA were reduced in Δ337T. CE and Fc differences were reversed by pacing Δ337T to Con rates, accompanied by an increase in FFA Fc. Δ337T hearts lacked the ability to increase MV˙ O2. Decreases in protein expression for glucose transporter-4 and hexokinase-2 and increases in pyruvate dehydrogenase kinase-2 and -4 suggest that these hearts are unable to increase carbohydrate oxidation in response to stress. These data show that Δ337T alters the metabolic phenotype in murine heart by reducing substrate flux for multiple pathways. Some of these changes are heart rate dependent, indicating that the substrate shift may represent an accommodation to altered contractile protein kinetics, which can be disrupted by pacing stress.

  5. Two gonadotropin-releasing hormone receptor subtypes with distinct ligand selectivity and differential distribution in brain and pituitary in the goldfish (Carassius auratus)

    OpenAIRE

    Illing, Nicola; Troskie, Brigitte E.; Nahorniak, Carol S.; Janet P Hapgood; Peter, Richard E.; Millar, Robert P.

    1999-01-01

    In the goldfish (Carassius auratus) the two endogenous forms of gonadotropin-releasing hormone (GnRH), namely chicken GnRH II ([His5,Trp7,Tyr8]GnRH) and salmon GnRH ([Trp7,Leu8]GnRH), stimulate the release of both gonadotropins and growth hormone from the pituitary. This control is thought to occur by means of the stimulation of distinct GnRH receptors. These receptors can be distinguished on the basis of differential gonadotropin and growth hormone releasing activities of naturally occurring...

  6. 3,5-Diiodothyronine in vivo maintains euthyroidal expression of type 2 iodothyronine deiodinase, growth hormone, and thyroid hormone receptor beta1 in the killifish.

    Science.gov (United States)

    García-G, C; López-Bojorquez, L; Nuñez, J; Valverde-R, C; Orozco, A

    2007-08-01

    Until recently, 3,5-diiodothyronine (3,5-T(2)) has been considered an inactive by-product of triiodothyronine (T(3)) deiodination. However, studies from several laboratories have shown that 3,5-T(2) has specific, nongenomic effects on mitochondrial oxidative capacity and respiration rate that are distinct from those due to T(3). Nevertheless, little is known about the putative genomic effects of 3,5-T(2). We have previously shown that hyperthyroidism induced by supraphysiological doses of 3,5-T(2) inhibits hepatic iodothyronine deiodinase type 2 (D2) activity and lowers mRNA levels in the killifish in the same manner as T(3) and T(4), suggesting a pretranslational effect of 3,5-T(2) (Garcia-G C, Jeziorski MC, Valverde-R C, Orozco A. Gen Comp Endocrinol 135: 201-209, 2004). The question remains as to whether 3,5-T(2) would have effects under conditions similar to those that are physiological for T(3). To this end, intact killifish were rendered hypothyroid by administering methimazole. Groups of hypothyroid animals simultaneously received 30 nM of either T(3), reverse T(3), or 3,5-T(2). Under these conditions, we expected that, if it were bioactive, 3,5-T(2) would mimic T(3) and thus reverse the compensatory upregulation of D2 and tyroid receptor beta1 and downregulation of growth hormone that characterize hypothyroidism. Our results demonstrate that 3,5-T(2) is indeed bioactive, reversing both hepatic D2 and growth hormone responses during a hypothyroidal state. Furthermore, we observed that 3,5-T(2) and T(3) recruit two distinct populations of transcription factors to typical palindromic and DR4 thyroid hormone response elements. Taken together, these results add further evidence to support the notion that 3,5-T(2) is a bioactive iodothyronine.

  7. Analysis and functional characterization of sequence variations in ligand binding domain of thyroid hormone receptors in autism spectrum disorder (ASD) patients.

    Science.gov (United States)

    Kalikiri, Mahesh Kumar; Mamidala, Madhu Poornima; Rao, Ananth N; Rajesh, Vidya

    2017-08-30

    Autism spectrum disorder (ASD) is a neuro developmental disorder, reported to be on a rise in the past two decades. Thyroid hormone-T3 plays an important role in early embryonic and central nervous system development. T3 mediates its function by binding to thyroid hormone receptors, TRα and TRβ. Alterations in T3 levels and thyroid receptor mutations have been earlier implicated in neuropsychiatric disorders and have been linked to environmental toxins. Limited reports from earlier studies have shown the effectiveness of T3 treatment with promising results in children with ASD and that the thyroid hormone levels in these children was also normal. This necessitates the need to explore the genetic variations in the components of the thyroid hormone pathway in ASD children. To achieve this objective, we performed genetic analysis of ligand binding domain of THRA and THRB receptor genes in 30 ASD subjects and in age matched controls from India. Our study for the first time reports novel single nucleotide polymorphisms in the THRA and THRB receptor genes of ASD individuals. Autism Res 2017. ©2017 International Society for Autism Research, Wiley Periodicals, Inc. Thyroid hormone (T3) and thyroid receptors (TRα and TRβ) are the major components of the thyroid hormone pathway. The link between thyroid pathway and neuronal development is proven in clinical medicine. Since the thyroid hormone levels in Autistic children are normal, variations in their receptors needs to be explored. To achieve this objective, changes in THRA and THRB receptor genes was studied in 30 ASD and normal children from India. The impact of some of these mutations on receptor function was also studied. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

  8. Effect of recombinant growth hormone on expression of growth hormone receptor, insulin-like growth factor mRNA and serum level of leptin in growing pigs

    Institute of Scientific and Technical Information of China (English)

    XU; Qingfu; (胥清富); ZHAO; Zhihui; (赵志辉); NI; Yingdong; (倪迎冬); ZHAO; Ruqian; (赵茹茜); CHEN; Jie; (陈杰)

    2003-01-01

    Sixteen Large White × Landrace castrated male pigs were allotted into treatment and control group. The treatment group was injected intramuscularly with recombinant porcine growth hormone (rpGH, 4 mg@d-1) and the control group with vehicle for 28 days. Animals were slaughtered 4 h after final injection for liver, longissimus dorsi (LD) muscle and blood sampling. Serum concentration of insulin-like growth factor 1 (IGF-I) and leptin were determined by RIA. The total RNA was extracted from tissues to measure the abundance of growth hormone receptor (GHR), IGF-I mRNA by RT-PCR with 18S rRNA internal standard. Results showed that rpGH enhanced the average daily weight gain by 26.1% (P 0.05) and IGF-I mRNA (P > 0.05) in LD between GH treated and control group was found. These results suggest that rpGH can up-regulate hepatic GHR and IGF-I gene expression and improve animal growth. However the effect of rpGH on GHR and IGF-I gene expression are tissue-specific.

  9. Design and characterization of a fluorescent ghrelin analog for imaging the growth hormone secretagogue receptor 1a.

    Science.gov (United States)

    McGirr, Rebecca; McFarland, Mark S; McTavish, Jillian; Luyt, Leonard G; Dhanvantari, Savita

    2011-12-10

    Ghrelin is a 28-amino acid peptide hormone produced in the stomach. It binds to the growth hormone secretagogue receptor 1a (GHS-R1a), a class A G-protein-coupled receptor. In the present study, we describe the design, synthesis and characterization of a truncated, 18-amino acid analog of ghrelin conjugated to a fluorescent molecule, fluorocein isothiocyanate (FITC), through the addition of a lysine at its C terminus ([Dpr(octanoyl)(3), Lys(fluorescein)(19)]ghrelin(1-19)). Receptor binding affinity of this novel fluorescein-ghrelin(1-18) was similar to that of wild-type ghrelin and a synthetic GHS-R1a ligand, hexarelin. Live cell imaging in CHO/GHS-R1a cells demonstrated cell surface receptor labeling and internalization, and agonist activity of fluorescein-ghrelin(1-18) was confirmed by increased phosphorylation of ERK1/2. We also show that GHS-R1a protein is expressed primarily in the heart when compared to all other organs, suggesting high receptor density in the left ventricle. Finally, we demonstrate that fluorescein-ghrelin(1-18) binds specifically to heart tissue in situ, and its binding is displaced by both wt ghrelin and hexarelin. We have therefore developed a novel imaging probe, fluorescein-ghrelin(1-18), that can be used to image GHS-R1a in situ, for the purposes of investigating mechanisms of receptor trafficking or pharmacological agents that target GHS-R1a.

  10. T-Screen as a tool to identify thyroid hormone receptor active compounds

    NARCIS (Netherlands)

    Gutleb, A.C.; Meerts, I.A.T.M.; Bergsma, J.H.; Schriks, M.; Murk, A.J.

    2005-01-01

    The T-Screen represents an in vitro bioassay based on thyroid hormone dependent cell proliferation of a rat pituitary tumour cell line (GH3) in serum-free medium. It can be used to study interference of compounds with thyroid hormone at the cellular level, thus bridging the gap between limitations o

  11. PET imaging of brain sex steroid hormone receptors and the role of estrogen in depression

    NARCIS (Netherlands)

    Khayum, Mohamed Abdul

    2015-01-01

    Androgens and estrogens are steroid hormones that are involved in several neurodegenerative and psychiatric disorders. Decreased levels of steroid hormones are associated with e.g. decreased cognition, anxiety and depression. Androgens and estrogens exert their biological effects through their corre

  12. Activation of GABA B receptors in the anterior pituitary inhibits prolactin and luteinizing hormone secretion.

    Science.gov (United States)

    Lux-Lantos, V; Rey, E; Libertun, C

    1992-11-01

    Previous work from our laboratory showed that baclofen could lower serum prolactin (PRL) levels acting at the central nervous system. The present experiments were designed to evaluate whether the gamma-aminobutyric acid B agonist was also effective in inhibiting hormone release at the pituitary level. In monolayer cultures of adenohypophyseal dispersed cells, baclofen inhibited basal PRL secretion after 1 or 2 h of incubation. This inhibition was significantly abolished by three antagonists: phaclofen, 3-aminopropyl-phosphonic acid and 4-aminobutylphosphonic acid. Furthermore, baclofen inhibited the thyrotropin-releasing hormone-induced PRL release in a concentration-dependent manner. With regard to gonadotropin secretion, baclofen was unable to modify basal luteinizing hormone (LH) secretion, but significantly inhibited the LH-releasing hormone-induced LH release. These results show that baclofen, in addition to its central neuroendocrine effects, inhibits pituitary hormone secretion, under basal and/or stimulated conditions, by direct action at the pituitary level.

  13. The human gonadotropin releasing hormone type I receptor is a functional intracellular GPCR expressed on the nuclear membrane.

    Directory of Open Access Journals (Sweden)

    Michelle Re

    Full Text Available The mammalian type I gonadotropin releasing hormone receptor (GnRH-R is a structurally unique G protein-coupled receptor (GPCR that lacks cytoplasmic tail sequences and displays inefficient plasma membrane expression (PME. Compared to its murine counterparts, the primate type I receptor is inefficiently folded and retained in the endoplasmic reticulum (ER leading to a further reduction in PME. The decrease in PME and concomitant increase in intracellular localization of the mammalian GnRH-RI led us to characterize the spatial distribution of the human and mouse GnRH receptors in two human cell lines, HEK 293 and HTR-8/SVneo. In both human cell lines we found the receptors were expressed in the cytoplasm and were associated with the ER and nuclear membrane. A molecular analysis of the receptor protein sequence led us to identify a putative monopartite nuclear localization sequence (NLS in the first intracellular loop of GnRH-RI. Surprisingly, however, neither the deletion of the NLS nor the addition of the Xenopus GnRH-R cytoplasmic tail sequences to the human receptor altered its spatial distribution. Finally, we demonstrate that GnRH treatment of nuclei isolated from HEK 293 cells expressing exogenous GnRH-RI triggers a significant increase in the acetylation and phosphorylation of histone H3, thereby revealing that the nuclear-localized receptor is functional. Based on our findings, we conclude that the mammalian GnRH-RI is an intracellular GPCR that is expressed on the nuclear membrane. This major and novel discovery causes us to reassess the signaling potential of this physiologically and clinically important receptor.

  14. The human gonadotropin releasing hormone type I receptor is a functional intracellular GPCR expressed on the nuclear membrane.

    Science.gov (United States)

    Re, Michelle; Pampillo, Macarena; Savard, Martin; Dubuc, Céléna; McArdle, Craig A; Millar, Robert P; Conn, P Michael; Gobeil, Fernand; Bhattacharya, Moshmi; Babwah, Andy V

    2010-07-08

    The mammalian type I gonadotropin releasing hormone receptor (GnRH-R) is a structurally unique G protein-coupled receptor (GPCR) that lacks cytoplasmic tail sequences and displays inefficient plasma membrane expression (PME). Compared to its murine counterparts, the primate type I receptor is inefficiently folded and retained in the endoplasmic reticulum (ER) leading to a further reduction in PME. The decrease in PME and concomitant increase in intracellular localization of the mammalian GnRH-RI led us to characterize the spatial distribution of the human and mouse GnRH receptors in two human cell lines, HEK 293 and HTR-8/SVneo. In both human cell lines we found the receptors were expressed in the cytoplasm and were associated with the ER and nuclear membrane. A molecular analysis of the receptor protein sequence led us to identify a putative monopartite nuclear localization sequence (NLS) in the first intracellular loop of GnRH-RI. Surprisingly, however, neither the deletion of the NLS nor the addition of the Xenopus GnRH-R cytoplasmic tail sequences to the human receptor altered its spatial distribution. Finally, we demonstrate that GnRH treatment of nuclei isolated from HEK 293 cells expressing exogenous GnRH-RI triggers a significant increase in the acetylation and phosphorylation of histone H3, thereby revealing that the nuclear-localized receptor is functional. Based on our findings, we conclude that the mammalian GnRH-RI is an intracellular GPCR that is expressed on the nuclear membrane. This major and novel discovery causes us to reassess the signaling potential of this physiologically and clinically important receptor.

  15. Crosstalk between integrin αvβ3 and estrogen receptor-α is involved in thyroid hormone-induced proliferation in human lung carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Ran Meng

    Full Text Available A cell surface receptor for thyroid hormone that activates extracellular regulated kinase (ERK 1/2 has been identified on integrin αvβ3. We have examined the actions of thyroid hormone initiated at the integrin on human NCI-H522 non-small cell lung carcinoma and NCI-H510A small cell lung cancer cells. At a physiologic total hormone concentration (10(-7 M, T(4 significantly increased proliferating cell nuclear antigen (PCNA abundance in these cell lines, as did 3, 5, 3'-triiodo-L-thyronine (T(3 at a supraphysiologic concentration. Neutralizing antibody to integrin αvβ3 and an integrin-binding Arg-Gly-Asp (RGD peptide blocked thyroid hormone-induced PCNA expression. Tetraiodothyroacetic acid (tetrac lacks thyroid hormone function but inhibits binding of T(4 and T(3 to the integrin receptor; tetrac eliminated thyroid hormone-induced lung cancer cell proliferation and ERK1/2 activation. In these estrogen receptor-α (ERα-positive lung cancer cells, thyroid hormone (T(4>T(3 caused phosphorylation of ERα; the specific ERα antagonist ICI 182,780 blocked T(4-induced, but not T(3-induced ERK1/2 activation, as well as ERα phosphorylation, proliferating-cell nuclear antigen (PCNA expression and hormone-dependent thymidine uptake by tumor cells. Thus, in ERα-positive human lung cancer cells, the proliferative action of thyroid hormone initiated at the plasma membrane is at least in part mediated by ERα. In summary, thyroid hormone may be one of several endogenous factors capable of supporting proliferation of lung cancer cells. Activity as an inhibitor of lung cancer cell proliferation induced at the integrin receptor makes tetrac a novel anti-proliferative agent.

  16. Comparative peptidomics of four related hemipteran species: Pyrokinins, myosuppressin, corazonin, adipokinetic hormone, sNPF, and periviscerokinins

    Science.gov (United States)

    We performed the first comprehensive peptidomic analysis of neurohormones from hemipteran insects by analyzing the neuropeptides of two major neurohemal organs, namely the corpora cardiaca and abdominal perisympathetic organs. For the experiments we selected four related species of polyphagous stin...

  17. The N-terminal extracellular domain 23-60 of the calcitonin receptor-like receptor in chimeras with the parathyroid hormone receptor mediates association with receptor activity-modifying protein 1.

    Science.gov (United States)

    Ittner, Lars M; Koller, Daniela; Muff, Roman; Fischer, Jan A; Born, Walter

    2005-04-19

    The calcitonin receptor-like receptor (CLR) requires the associated receptor activity-modifying protein (RAMP)1 to reveal a calcitonin gene-related peptide (CGRP) receptor. Here, the subdomain of the CLR that associates with RAMP1 has been identified in chimeras between the CLR and the parathyroid hormone (PTH) receptor 1 (PTHR). The PTHR alone does not interact with RAMP1. RAMP1 requires the CLR for its transport to the cell surface. Thus, receptor-dependent RAMP1 delivery to the plasma membrane and coimmunoprecipitation from the cell surface were used as measures for receptor/RAMP1 interaction. Several chimeric CLR-PTHR included the N-terminal amino acids 23-60 of the CLR transported RAMP1 to the surface of COS-7 cells much like the intact CLR. Moreover, RAMP1 coimmunoprecipitated with these receptors from the cell surface. A CLR deletion mutant, consisting of the N-terminal extracellular domain, the first transmembrane domain, and the C-terminal intracellular region, revealed the same results. Cyclic AMP was stimulated by CGRP in CLR/RAMP1 expressing cells (58 +/- 19-fold, EC(50) = 0.12 +/- 0.03 nM) and by PTH-related protein in cells expressing the PTHR (50 +/- 10-fold, EC(50) = 0.25 +/- 0.03 nM) or a PTHR with the N-terminal amino acids 23-60 of the CLR (23 +/- 5-fold, EC(50) > 1000 nM). Other chimeric CLR-PTHR were inactive. In conclusion, structural elements in the extreme N-terminus of the CLR between amino acids 23-60 are required and sufficient for CLR/RAMP1 cotransport to the plasma membrane and heterodimerization.

  18. Aromatic anchor at an invariant hormone-receptor interface: function of insulin residue B24 with application to protein design.

    Science.gov (United States)

    Pandyarajan, Vijay; Smith, Brian J; Phillips, Nelson B; Whittaker, Linda; Cox, Gabriella P; Wickramasinghe, Nalinda; Menting, John G; Wan, Zhu-li; Whittaker, Jonathan; Ismail-Beigi, Faramarz; Lawrence, Michael C; Weiss, Michael A

    2014-12-12

    Crystallographic studies of insulin bound to fragments of the insulin receptor have recently defined the topography of the primary hormone-receptor interface. Here, we have investigated the role of Phe(B24), an invariant aromatic anchor at this interface and site of a human mutation causing diabetes mellitus. An extensive set of B24 substitutions has been constructed and tested for effects on receptor binding. Although aromaticity has long been considered a key requirement at this position, Met(B24) was found to confer essentially native affinity and bioactivity. Molecular modeling suggests that this linear side chain can serve as an alternative hydrophobic anchor at the hormone-receptor interface. These findings motivated further substitution of Phe(B24) by cyclohexanylalanine (Cha), which contains a nonplanar aliphatic ring. Contrary to expectations, [Cha(B24)]insulin likewise exhibited high activity. Furthermore, its resistance to fibrillation and the rapid rate of hexamer disassembly, properties of potential therapeutic advantage, were enhanced. The crystal structure of the Cha(B24) analog, determined as an R6 zinc-stabilized hexamer at a resolution of 1.5 Å, closely resembles that of wild-type insulin. The nonplanar aliphatic ring exhibits two chair conformations with partial occupancies, each recapitulating the role of Phe(B24) at the dimer interface. Together, these studies have defined structural requirements of an anchor residue within the B24-binding pocket of the insulin receptor; similar molecular principles are likely to pertain to insulin-related growth factors. Our results highlight in particular the utility of nonaromatic side chains as probes of the B24 pocket and suggest that the nonstandard Cha side chain may have therapeutic utility. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  19. During hormone depletion or tamoxifen treatment of breast cancer cells the estrogen receptor apoprotein supports cell cycling through the retinoic acid receptor α1 apoprotein.

    Science.gov (United States)

    Salazar, Marcela D; Ratnam, Maya; Patki, Mugdha; Kisovic, Ivana; Trumbly, Robert; Iman, Mohamed; Ratnam, Manohar

    2011-02-07

    Current hormonal adjuvant therapies for breast cancer including tamoxifen treatment and estrogen depletion are overall tumoristatic and are severely limited by the frequent recurrence of the tumors. Regardless of the resistance mechanism, development and progression of the resistant tumors requires the persistence of a basal level of cycling cells during the treatment for which the underlying causes are unclear. In estrogen-sensitive breast cancer cells the effects of hormone depletion and treatment with estrogen, tamoxifen, all-trans retinoic acid (ATRA), fulvestrant, estrogen receptor α (ER) siRNA or retinoic acid receptor α (RARα) siRNA were studied by examining cell growth and cycling, apoptosis, various mRNA and protein expression levels, mRNA profiles and known chromatin associations of RAR. RARα subtype expression was also examined in breast cancer cell lines and tumors by competitive PCR. Basal proliferation persisted in estrogen-sensitive breast cancer cells grown in hormone depleted conditioned media without or with 4-hydroxytamoxifen (OH-Tam). Downregulating ER using either siRNA or fulvestrant inhibited basal proliferation by promoting cell cycle arrest, without enrichment for ErbB2/3+ overexpressing cells. The basal expression of RARα1, the only RARα isoform that was expressed in breast cancer cell lines and in most breast tumors, was supported by apo-ER but was unaffected by OH-Tam; RAR-β and -γ were not regulated by apo-ER. Depleting basal RARα1 reproduced the antiproliferative effect of depleting ER whereas its restoration in the ER depleted cells partially rescued the basal cycling. The overlapping tamoxifen-insensitive gene regulation by apo-ER and apo-RARα1 comprised activation of mainly genes promoting cell cycle and mitosis and suppression of genes involved in growth inhibition; these target genes were generally insensitive to ATRA but were enriched in RAR binding sites in associated chromatin regions. In hormone-sensitive breast

  20. Gain-of-Function Alleles in Caenorhabditis elegans Nuclear Hormone Receptor nhr-49 Are Functionally Distinct

    Science.gov (United States)

    Lee, Kayoung; Goh, Grace Ying Shyen; Wong, Marcus Andrew; Klassen, Tara Leah

    2016-01-01

    Nuclear hormone receptors (NHRs) are transcription factors that regulate numerous physiological and developmental processes and represent important drug targets. NHR-49, an ortholog of Hepatocyte Nuclear Factor 4 (HNF4), has emerged as a key regulator of lipid metabolism and life span in the nematode worm Caenorhabditis elegans. However, many aspects of NHR-49 function remain poorly understood, including whether and how it regulates individual sets of target genes and whether its activity is modulated by a ligand. A recent study identified three gain-of-function (gof) missense mutations in nhr-49 (nhr-49(et7), nhr-49(et8), and nhr-49(et13), respectively). These substitutions all affect the ligand-binding domain (LBD), which is critical for ligand binding and protein interactions. Thus, these alleles provide an opportunity to test how three specific residues contribute to NHR-49 dependent gene regulation. We used computational and molecular methods to delineate how these mutations alter NHR-49 activity. We find that despite originating from a screen favoring the activation of specific NHR-49 targets, all three gof alleles cause broad upregulation of NHR-49 regulated genes. Interestingly, nhr-49(et7) and nhr-49(et8) exclusively affect nhr-49 dependent activation, whereas the nhr-49(et13) surprisingly affects both nhr-49 mediated activation and repression, implicating the affected residue as dually important. We also observed phenotypic non-equivalence of these alleles, as they unexpectedly caused a long, short, and normal life span, respectively. Mechanistically, the gof substitutions altered neither protein interactions with the repressive partner NHR-66 and the coactivator MDT-15 nor the subcellular localization or expression of NHR-49. However, in silico structural modeling revealed that NHR-49 likely interacts with small molecule ligands and that the missense mutations might alter ligand binding, providing a possible explanation for increased NHR-49 activity. In

  1. Considerations for payers in managing hormone receptor-positive advanced breast cancer

    Directory of Open Access Journals (Sweden)

    Chitre M

    2014-07-01

    Full Text Available Mona Chitre,1 Kristen M Reimers21Pharmacy Management, Excellus BlueCross BlueShield, Rochester, NY, USA; 2Clinical Drug Programs, Magellan Health/Icore, Orlando, FL, USAAbstract: Breast cancer (BC is the second most common cause of death in women. In 2010, the direct cost associated with BC care in the US was $16.5 billion, the highest among all cancers. By the year 2020, at the current rates of incidence and survival, the cost is projected to increase to approximately $20 billion. Although endocrine therapies to manage hormone receptor-positive (HR+ BC are highly effective, endocrine resistance results in disease progression. Increased understanding of endocrine resistance and the mechanisms of disease progression has led to development and subsequent approval of novel targeted treatments, resulting in the expansion of the therapeutic armamentarium to combat HR+ BC. Clear guidelines based on the safety and efficacy of treatment options exist; however, the optimal sequence of therapy is unknown, and providers, payers, and other key players in the health care system are tasked with identifying cost-effective and evidence-based treatment strategies that will improve patient outcomes and, in time, help curb the staggering increase in cost associated with BC care. Safety and efficacy are key considerations, but there is also a need to consider the impact of a given therapy on patient quality of life, treatment adherence, and productivity. To minimize cost associated with overall management, cost-effectiveness, and financial burden that the therapy can impose on patients, caregivers and managed care plans are also important considerations. To help evaluate and identify the optimal choice of therapy for patients with HR+ advanced BC, the available data on endocrine therapies and novel agents are discussed, specifically with respect to the safety, efficacy, financial impact on patients and the managed care plan, impact on quality of life and

  2. Influence of Music on Steroid Hormones and the Relationship between Receptor Polymorphism and Musical Ability: a Pilot Study

    Directory of Open Access Journals (Sweden)

    Hajime eFukui

    2013-12-01

    Full Text Available Studies have shown that music confers plasticity to the brain. In a preliminary pilot study, we examined the effect of music listening on steroid hormones and the relationship between steroid hormone receptor polymorphisms and musical ability. Twenty-one subjects (10 males and 11 females were recruited and divided into musically talented and control groups. The subjects selected (1 music they preferred (chill-inducing music and (2 music they did not like. Before and after the experiments, saliva was collected to measure the levels of steroid hormones such as testosterone, estradiol, and cortisol. DNA was also isolated from the saliva samples to determine the androgen receptor and arginine vasopressin receptor 1A genotypes. Advanced Measures of Music Audiation (AMMA was used to determine the musical ability of the subjects. With both types of music, the cortisol levels decreased significantly in both sexes. The testosterone (T levels declined in males when they listened to both types of music. In females, the T levels increased in those listening to chill-inducing music but declined when they listened to music they disliked. However, these differences were not significant. The 17-beta estradiol levels increased in males with both types of music, whereas the levels increased with chill-inducing music but declined with disliked music in females. The AMMA scores were higher for the short repeat length-type AR than for the long repeat length-type. Comparisons of AR polymorphisms and T levels before the experiments showed that the T levels were within the low range in the short repeat length-type group and there was a positive relationship with the repeat length, although it was not significant. This is the first study conducted in humans to analyze the relationships between the AR gene, T levels, and musical ability.

  3. Neuropeptide S receptor 1 expression in the intestine and skin--putative role in peptide hormone secretion.

    Science.gov (United States)

    Sundman, L; Saarialho-Kere, U; Vendelin, J; Lindfors, K; Assadi, G; Kaukinen, K; Westerholm-Ormio, M; Savilahti, E; Mäki, M; Alenius, H; D'Amato, M; Pulkkinen, V; Kere, J; Saavalainen, P

    2010-01-01

    Neuropeptide S receptor 1 (NPSR1) was recently found to be genetically associated with inflammatory bowel disease in addition to asthma and related traits. Epithelia of several organs express NPSR1 isoforms A and B, including the intestine and the skin, and NPSR1 appears to be upregulated in inflammation. In this study, we used cell lines and tissue samples to characterize the expression of NPSR1 and its ligand neuropeptide S (NPS) in inflammation. We used polyclonal and monoclonal antibodies to investigate the expression of NPS and NPSR1 in intestinal diseases, such as celiac disease and food allergy, and in cutaneous inflammatory disorders. We found that NPSR1-A was expressed by the enteroendocrine cells of the gut. Overall, the expression pattern of NPS was similar to its receptor suggesting an autocrine mechanism. In an NPSR1-A overexpressing cell model, stimulation with NPS resulted in a dose-dependent upregulation of glycoprotein hormone, alpha polypeptide (CGA), tachykinin 1 (TAC1), neurotensin (NTS) and galanin (GAL) encoding peptide hormones secreted by enteroendocrine cells. Because NPSR1 was also expressed in macrophages, neutrophils, and intraepithelial lymphocytes, we demonstrated that stimulation with the pro-inflammatory cytokines tumour necrosis factor alpha and interferon gamma increased NPSR1 expression in the THP-1 monocytic cells. In conclusion, similar to other neuropeptides and their receptors, NPSR1 signalling might play a dual role along the gut-brain axis. The NPS/NPSR1 pathway may participate in the regulation of the peptide hormone production in enteroendocrine cells of the small intestine.

  4. Predictive value of Ki67 for adjuvant chemotherapy in node-negative, hormone receptor-positive breast cancer.

    Science.gov (United States)

    Sutepvarnon, Apisada; Warnnissorn, Malee; Srimuninnimit, Vichien

    2013-02-01

    Ki67 labeling index (Ki67 LI) is a measure of tumor proliferation. In breast cancer, evidence supporting its prognostic value is clear and its predictive value for response to treatment finds some benefits. However studies of Ki67 LI as a predictive marker in early breast cancer are still limited worldwide and there is no data in Thailand. To assess the predictive value of Ki67 expression for adjuvant chemotherapy in patients with node-negative, hormone receptor-positive breast cancer The authors retrospectively evaluated 127 diagnosed early breast cancer with node-negative, hormone receptor-positive patients and receiving adjuvant systemic treatment at Siriraj hospital. Disease free survival (DFS) was compared with the log-rank test according to Ki67 LI and adjuvant systemic treatment (chemoendocrine therapy and endocrine therapy alone). At a median follow-up of 3.3 years. The 5-year DFS rate was 79% for patients with low Ki67 expression and 75% for patients with high Ki67 expression. Of the 127 patients, 56 (44.1%) received chemoendocrine therapy and 71 (55.9%) were treated with endocrine therapy alone. There was no different effect of DFS among those receiving adjuvant endocrine therapy alone and those receiving adjuvant chemoendocrine therapy depending on Ki67 expression. Among patients with node-negative, hormone receptor-positive breast cancer, a high Ki67 LI had worse DFS trend than a low Ki67 LI but the Ki67 LI did not predict the efficacy of adjuvant chemotherapy.

  5. Follicle-stimulating Hormone (FSH) Induced Internalization of Porcine FSH Receptor in Cultured Porcine Granulosa Cells and Chinese Hamster Ovary Cells Transfected with Recombinant Porcine FSH Receptor cDNA

    Institute of Scientific and Technical Information of China (English)

    ZHU; Changhong; TIAN; Hong; XIONG; Zhongming; XIA; Huizhu

    2001-01-01

    In order to study the fate of human follicle-stimulating hormone (FSH) when hormone binds to its receptor, a quick biochemical method that can differentiate between the surface-bound and internalized hormone was used to determine the internalization induced by FSH in cultured both porcine granulosa cells and Chinese hamster ovary (CHO) cells expressing recombinant porcine FSH receptor. The results showed that FSH was slowly internalized, and the internalized radioactivity (acid resistant) reached a peak 10-12 h after addition of 125I-hFSH. It was suggested that FSHR do not get internalized rapidly under physiological circumstances precisely because the appropriate sequences are absent.

  6. Evaluation of grading and hormone receptor immunostaining on fine needle aspirates in carcinoma breast

    Directory of Open Access Journals (Sweden)

    Uma Handa

    2015-01-01

    Conclusion: The grading along with ER and PR immunostaining of breast carcinoma on smears is advocated because of high concordance between cytology and histology. This allows the patient to be treated with hormonal therapy on the basis of FNAC alone.

  7. Infertility in Female Mice with a Gain-of-Function Mutation in the Luteinizing Hormone Receptor Is Due to Irregular Estrous Cyclicity, Anovulation, Hormonal Alterations, and Polycystic Ovaries.

    Science.gov (United States)

    Hai, Lan; McGee, Stacey R; Rabideau, Amanda C; Paquet, Marilène; Narayan, Prema

    2015-07-01

    The luteinizing hormone receptor, LHCGR, is essential for fertility in males and females, and genetic mutations in the receptor have been identified that result in developmental and reproductive defects. We have previously generated and characterized a mouse model (KiLHR(D582G)) for familial male-limited precocious puberty caused by an activating mutation in the receptor. We demonstrated that the phenotype of the KiLHR(D582G) male mice is an accurate phenocopy of male patients with activating LHCGR mutations. In this study, we observed that unlike women with activating LHCGR mutations who are normal, female KiLHR(D582G) mice are infertile. Mice exhibit irregular estrous cyclicity, anovulation, and precocious puberty. A temporal study from 2-24 wk of age indicated elevated levels of progesterone, androstenedione, testosterone, and estradiol and upregulation of several steroidogenic enzyme genes. Ovaries of KiLHR(D582G) mice exhibited significant pathology with the development of large hemorrhagic cysts as early as 3 wk of age, extensive stromal cell hyperplasia and hypertrophy with luteinization, numerous atretic follicles, and granulosa cell tumors. Ovulation could not be rescued by the addition of exogenous gonadotropins. The body weights of the KiLHR(D582G) mice were higher than wild-type counterparts, but there was no increase in the body fat composition or metabolic abnormalities such as impaired glucose tolerance and insulin resistance. These studies demonstrate that activating LHCGR mutations do not produce the same phenotype in female mice as in humans and clearly illustrate species differences in the expression and regulation of LHCGR in the ovary, but not in the testis. © 2015 by the Society for the Study of Reproduction, Inc.

  8. The Growth Hormone Receptor Gene-Disrupted (GHR-KO) Mouse Fails to Respond to an Intermittent Fasting (IF) Diet

    OpenAIRE

    Arum, Oge; Bonkowski, Michael S.; Rocha, Juliana S.; Bartke, Andrzej

    2009-01-01

    The interaction of longevity-conferring genes with longevity-conferring diets is poorly understood. The growth hormone receptor gene-disrupted (GHR-KO) mouse is long-lived; and this longevity is not responsive to 30% caloric restriction (CR), in contrast to wild-type animals from the same strain. To determine whether this may have been limited to a particular level of dietary restriction (DR), we subjected GHR-KO mice to a different dietary restriction regimen, an intermittent fasting (IF) diet.

  9. Growth hormone response to growth hormone-releasing peptide-2 in growth hormone-deficient Little mice

    OpenAIRE

    PERONI, CIBELE N.; Cesar Y. Hayashida; Nancy Nascimento; LONGUINI, VIVIANE C.; Toledo, Rodrigo A.; Paolo Bartolini; Bowers, Cyril Y.; Toledo,Sergio P. A.

    2012-01-01

    OBJECTIVE: To investigate a possible direct, growth hormone-releasing, hormone-independent action of a growth hormone secretagogue, GHRP-2, in pituitary somatotroph cells in the presence of inactive growth hormone-releasing hormone receptors. MATERIALS AND METHODS: The responses of serum growth hormone to acutely injected growth hormone-releasing P-2 in lit/litmice, which represent a model of GH deficiency arising frommutated growth hormone-releasing hormone-receptors, were compared to those ...

  10. Structural requirements for the interaction of 91 hydroxylated polychlorinated biphenyls with estrogen and thyroid hormone receptors

    National Research Council Canada - National Science Library

    Arulmozhiraja, Sundaram; Shiraishi, Fujio; Okumura, Tameo; Iida, Mitsuru; Takigami, Hidetaka; Edmonds, John S; Morita, Masatoshi

    2005-01-01

    Estrogenic and thyroid activities of 91 monohydroxylated PCBs were measured with two-hybrid assays using yeast cells containing the human estrogen receptor ERalpha or human thyroid receptor TRalpha...

  11. Hormone Binding to Recombinant Estrogen Receptors from Human, Alligator, Quail, Salamander, and Fathead Minnow

    Science.gov (United States)

    In this work, a 96-well plate estrogen receptor binding assay was developed to facilitate the direct comparison of chemical binding to full-length recombinant estrogen receptors across vertebrate classes. Receptors were generated in a baculovirus expression system. This approach ...

  12. Novel mutation involving the translation initiation codon of the growth hormone receptor gene (GHR) in a patient with Laron syndrome.

    Science.gov (United States)

    Quinteiro, Celsa; Castro-Feijoo, Lidia; Loidi, Lourdes; Barreiro, Jesus; de la Fuente, Maria; Dominguez, Fernando; Pombo, Manuel

    2002-01-01

    Laron syndrome (LS) or growth hormone (GH) insensitivity syndrome (GHIS) is an autosomal recessive disease due to molecular defects in the GH receptor gene (GHR). Most of the identified mutations are located on the extracelular domain of the receptor. We studied the GHR gene in a patient with LS and found a homozygous missense mutation in exon 2. The novel mutation is an A-->T transversion (ATG -->TTG) that abolishes the translation initiation codon of the GHR gene. This mutation is expected to prevent the translation of the protein. We present clinical, biochemical and molecular evidence of Laron syndrome as the result of a mutation (ATG-->TTG) in the codon for the initial methionine of the GHR gene.

  13. Comparative metabolomics reveals endogenous ligands of DAF-12, a nuclear hormone receptor, regulating C. elegans development and lifespan.

    Science.gov (United States)

    Mahanti, Parag; Bose, Neelanjan; Bethke, Axel; Judkins, Joshua C; Wollam, Joshua; Dumas, Kathleen J; Zimmerman, Anna M; Campbell, Sydney L; Hu, Patrick J; Antebi, Adam; Schroeder, Frank C

    2014-01-07

    Small-molecule ligands of nuclear hormone receptors (NHRs) govern the transcriptional regulation of metazoan development, cell differentiation, and metabolism. However, the physiological ligands of many NHRs remain poorly characterized, primarily due to lack of robust analytical techniques. Using comparative metabolomics, we identified endogenous steroids that act as ligands of the C. elegans NHR, DAF-12, a vitamin D and liver X receptor homolog regulating larval development, fat metabolism, and lifespan. The identified molecules feature unexpected chemical modifications and include only one of two DAF-12 ligands reported earlier, necessitating a revision of previously proposed ligand biosynthetic pathways. We further show that ligand profiles are regulated by a complex enzymatic network, including the Rieske oxygenase DAF-36, the short-chain dehydrogenase DHS-16, and the hydroxysteroid dehydrogenase HSD-1. Our results demonstrate the advantages of comparative metabolomics over traditional candidate-based approaches and provide a blueprint for the identification of ligands for other C. elegans and mammalian NHRs.

  14. Polymorphisms in luteinizing hormone receptor and hypothalamic gonadotropin-releasing hormone genes and their effects on sperm quality traits in Chinese Holstein bulls.

    Science.gov (United States)

    Sun, Li-Ping; Du, Qing-Zhi; Song, Ya-Pan; Yu, Jun-Na; Wang, Shu-Juan; Sang, Lei; Song, Luo-Wen; Yue, Yao-Min; Lian, Yu-Ze; Zhang, Sheng-Li; Hua, Guo-Hua; Zhang, Shu-Jun; Yang, Li-Guo

    2012-06-01

    Genes of hypothalamic-pituitary-gonadal axis play a key role in male reproductive performance. This study evaluated the polymorphisms of luteinizing hormone receptor (LHR) and hypothalamic gonadotropin-releasing hormone (GnRH) genes and their effects on sperm quality traits including semen volume per ejaculate (VOL), sperm density (SD), fresh sperm motility (FSM), thawed sperm motility (TSM), acrosome integrity rate (AIR), and abnormal sperm rate (ASR) collected from 205 Chinese Hostein bulls. The study bulls consisted of 205 mature Chinese Holstein, 27 Simmental, 28 Charolais, and 14 German yellow cattle. One single nucleotide polymorphism (SNP) (A883G) in exon 2 of GnRH and two SNPs (A51703G and G51656T) in intron 9 of LHR were identified in 274 bulls. Analysis of variance in 205 Chinese Holstein bulls showed that age had significant effect on both SD and FSM (P bulls with AG genotype had higher FSM than bulls with AA and GG genotype in LHR at 51,703 locus (P bulls with GG genotype had higher SD than bulls with TT genotype in LHR at G51656T locus (P < 0.10). Phenotypic correlation among the traits revealed that significant negative correlations were observed between ASR and AIR (r = -0.736, P < 0.01), ASR and AIR (r = -0.500, P < 0.01). There were moderate positive correlations between VOL and SD (r = 0.422, P < 0.01), as well as FSM (r = 0.411, P < 0.01). In conclusion, LHR may be a potential marker for sperm quality of SD and FSM.

  15. Body Mass Index and Breast Cancer Risk According to Postmenopausal Estrogen-Progestin Use and Hormone Receptor Status

    Science.gov (United States)

    Munsell, Mark F.; Sprague, Brian L.; Berry, Donald A.; Chisholm, Gary; Trentham-Dietz, Amy

    2014-01-01

    To assess the joint relationships among body mass index, menopausal status, and breast cancer according to breast cancer subtype and estrogen-progestin medication use, we conducted a meta-analysis of 89 epidemiologic reports published in English during 1980–2012 identified through a systematic search of bibliographic databases. Pooled analysis yielded a summary risk ratio of 0.78 (95% confidence interval (CI): 0.67, 0.92) for hormone receptor–positive premenopausal breast cancer associated with obesity (body mass index (weight (kg)/height (m)2) ≥30 compared with Obesity was associated with a summary risk ratio of 1.39 (95% CI: 1.14, 1.70) for receptor-positive postmenopausal breast cancer. For receptor-negative breast cancer, the summary risk ratios of 1.06 (95% CI: 0.70, 1.60) and 0.98 (95% CI: 0.78, 1.22) associated with obesity were null for both premenopausal and postmenopausal women, respectively. Elevated postmenopausal breast cancer risk ratios associated with obesity were limited to women who never took estrogen-progestin therapy, with risk ratios of 1.42 (95% CI: 1.30, 1.55) among never users and 1.18 (95% CI: 0.98, 1.42) among users; too few studies were available to examine this relationship according to receptor subtype. Future research is needed to confirm whether obesity is unrelated to receptor-negative breast cancer in populations of postmenopausal women with low prevalence of hormone medication use. PMID:24375928

  16. Circulating sex hormones and gene expression of subcutaneous adipose tissue oestrogen and alpha-adrenergic receptors in HIV-lipodystrophy: implications for fat distribution

    DEFF Research Database (Denmark)

    Andersen, Ove; Pedersen, Steen B; Svenstrup, Birgit;

    2007-01-01

    of alpha2A-adrenergic-receptor correlated positively with expression of oestrogen-receptor-alpha. CONCLUSIONS: The results fit the hypothesis that sex hormones play a role in altered fat distribution and insulin sensitivity of male patients with HIV-lipodystrophy. The effect of oestradiol......OBJECTIVE: Circulating oestradiol and testosterone, which have been shown to increase in human immunodeficiency virus (HIV)-infected patients following highly active antiretroviral therapy (HAART), may influence fat distribution and insulin sensitivity. Oestradiol increases subcutaneous adipose...... tissue in humans possibly through binding to oestrogen-receptor-alpha, which in turn activates anti-lipolytic alpha2A-adrenergic-receptor. DESIGN AND METHODS: To address these issues circulating pituitary-gonadal-axis hormones and gene expression of receptors in subcutaneous adipose tissue were...

  17. Polychlorinated biphenyls disturb differentiation of normal human neural progenitor cells: clue for involvement of thyroid hormone receptors.

    Science.gov (United States)

    Fritsche, Ellen; Cline, Jason E; Nguyen, Ngoc-Ha; Scanlan, Thomas S; Abel, Josef

    2005-07-01

    Polychlorinated biphenyls (PCBs) are ubiquitous environmental chemicals that accumulate in adipose tissues over the food chain. Epidemiologic studies have indicated that PCBs influence brain development. Children who are exposed to PCBs during development suffer from neuropsychologic deficits such as a lower full-scale IQ (intelligence quotient), reduced visual recognition memory, and attention and motor deficits. The mechanisms leading to these effects are not fully understood. It has been speculated that PCBs may affect brain development by interfering with thyroid hormone (TH) signaling. Because most of the data are from animal studies, we established a model using primary normal human neural progenitor (NHNP) cells to determine if PCBs interfere with TH-dependent neural differentiation. NHNP cells differentiate into neurons, astrocytes, and oligodendrocytes in culture, and they express a variety of drug metabolism enzymes and nuclear receptors. Like triiodothyronine (T3), treatment with the mono-ortho-substituted PCB-118 (2,3',4,4 ,5-pentachlorobiphenyl; 0.01-1 microM) leads to a dose-dependent increase of oligodendrocyte formation. This effect was congener specific, because the coplanar PCB-126 (3,3',4,4 ,5-pentachlorobiphenyl) had no effect. Similar to the T3 response, the PCB-mediated effect on oligodendrocyte formation was blocked by retinoic acid and the thyroid hormone receptor antagonist NH-3. These results suggest that PCB-118 mimics T3 action via the TH pathway.

  18. Investigating the association between polymorphism of follicle-stimulating hormone receptor gene and ovarian response in controlled ovarian hyperstimulation

    Directory of Open Access Journals (Sweden)

    Mohammad Hasan Sheikhha

    2011-01-01

    Full Text Available Aim : The aim of the study was to investigate the association between follicle-stimulating hormone receptor (FSHR gene polymorphism at Position 680 and the outcomes of controlled ovarian hyperstimulation for in vitro fertilization and embryo transfer (IVF-ET in infertile women. Materials and Methods : One hundred and eight patients under 35 years of age who underwent IVF-ET procedures were included in this study. The hormonal profile and treatment of all patients were analyzed and FSHR polymorphism was examined by polymerase chain reaction-restriction fragment length polymorphism. Women from all groups were classified based on polymorphisms at Position 680, occupied either by asparagines (Asn or serine (Ser as Asn/Asn, Asn/Ser, and Ser/Ser genotype. Result : Our study showed that all patients in the Asn/Asn group were normal responders and in the Asn/Ser group 64.8% were normal responders and 21.1% and 14.1% were poor and hyper responders respectively. In the Ser/Ser group we did not have normal responders and 46.7% of these patients were poor responders and 53.3% were hyper responders. Conclusion : FSH receptor polymorphism is correlated with response to ovarian stimulation.

  19. [Vitamin D hormone system and diabetes mellitus: lessons from selective activators of vitamin D receptor and diabetes mellitus].

    Science.gov (United States)

    Jódar-Gimeno, Esteban; Muñoz-Torres, Manuel

    2013-02-01

    The vitamin D hormone system has significant skeletal and extra-skeletal effects. Vitamin D receptor occurs in different tissues, and several cells other than renal cells are able to locally produce active vitamin D, which is responsible for transcriptional control of hundreds of genes related to its pleiotropic effects. There is increasing evidence relating vitamin D to development and course of type 1 and 2 diabetes mellitus. Specifically, influence of vitamin D on the renin-angiotensin-aldosterone system, inflammatory response, and urinary albumin excretion could explain the relevant impact of vitamin D status on diabetic nephropathy. Selective vitamin D receptor activators are molecules able to reproduce agonistic or antagonistic effects of active vitamin D depending on the tissue or even on the cell type. Specifically, paricalcitol has a beneficial profile because of its potency to reduce parathyroid hormone, with lower effects on serum calcium or phosphate levels. Moreover, in patients with diabetes and renal disease, paricalcitol decreases microalbuminuria, hospitalization rates, and cardiovascular mortality. Therefore, these molecules represent an attractive new option to improve prognosis of renal disease in patients with diabetes.

  20. Characterization of AvaR1, a butenolide-autoregulator receptor for biosynthesis of a Streptomyces hormone in Streptomyces avermitilis.

    Science.gov (United States)

    Sultan, Suandi Pratama; Kitani, Shigeru; Miyamoto, Kiyoko T; Iguchi, Hiroyuki; Atago, Tokitaka; Ikeda, Haruo; Nihira, Takuya

    2016-11-01

    Streptomyces hormones, sometimes called as autoregulators, are important signaling molecules to trigger secondary metabolism across many Streptomyces species. We recently identified a butenolide-type autoregulator (termed avenolide) as a new class of Streptomyces hormone from Streptomyces avermitilis that produces important anthelmintic agent avermectin. Avenolide triggers the production of avermectin with minimum effective concentration of nanomolar. Here, we describe the characterization of avaR1 encoding an avenolide receptor in the regulation of avermectin production and avenolide biosynthesis. The disruption of avaR1 resulted in transcriptional derepression of avenolide biosynthetic gene with an increase in avenolide production, with no change in the avermectin production profile. Moreover, the avaR1 mutant showed increased transcription of avaR1. Together with clear DNA-binding capacity of AvaR1 toward avaR1 upstream region, it suggests that AvaR1 negatively controls the expression of avaR1 through the direct binding to the promoter region of avaR1. These findings revealed that the avenolide receptor AvaR1 functions as a transcriptional repressor for avenolide biosynthesis and its own synthesis.

  1. Sex steroid and thyroid hormone receptor expressions in the thyroid of the American alligator (Alligator mississippiensis) during different life stages.

    Science.gov (United States)

    Bermudez, Dieldrich S; Skotko, Jeremy P; Ohta, Yasuhiko; Boggs, Ashley S P; Iguchi, Taisen; Guillette, Louis J

    2011-06-01

    The expression of estrogen receptors, ESR1 (ERα) and ESR2 (ERβ), and androgen receptors (AR) in the thyroid gland has been reported in few vertebrate species other than a few mammals. This study reports the presence of sex steroid hormone receptors and thyroid receptors (ERα, ERβ, AR, TRα, and TRβ) in the thyroid gland of the American alligator at several life stages. It provides a semiquantification and distribution of ERα in the thyroid follicle cells using an immunohistochemical approach as well as reports quantitative differences in mRNA expression of ERα, ERβ, TRα, TRβ, and AR in the same tissue using quantitative real time-PCR (Q-PCR) with primers designed specifically for alligators. The thyroid tissue of the American alligator expresses ERα, ERβ, and AR at all of the life stages examined here although no statistically significant differences were observed between male and female in thyroid mRNA expression for any of the genes analyzed. No sexual dimorphism was observed in ERα immunostaining. No statistical analysis across life stages were performed due to confounding factor of season. Copyright © 2011 Wiley-Liss, Inc.

  2. Dose-response effects of a new growth hormone receptor antagonist (B2036-PEG) on circulating, hepatic and renal expression of the growth hormone/insulin-like growth factor system in adult mice

    NARCIS (Netherlands)

    J.W. van Neck (Han); N.F. Dits (Natasja); V. Cingel-Ristic; I.A. Hoppenbrouwers (Ilse); S.L.S. Drop (Stenvert); A. Flyvbjerg (Allan)

    2000-01-01

    textabstractThe effects of growth hormone (GH) in regulating the expression of the hepatic and renal GH and insulin-like growth factor (IGF) system were studied by administering a novel GH receptor antagonist (GHRA) (B2036-PEG) at different doses (0, 1.25, 2.5, 5 and 10

  3. Vestigialization of an allosteric switch: genetic and structural mechanisms for the evolution of constitutive activity in a steroid hormone receptor.

    Directory of Open Access Journals (Sweden)

    Jamie T Bridgham

    2014-01-01

    Full Text Available An important goal in molecular evolution is to understand the genetic and physical mechanisms by which protein functions evolve and, in turn, to characterize how a protein's physical architecture influences its evolution. Here we dissect the mechanisms for an evolutionary shift in function in the mollusk ortholog of the steroid hormone receptors (SRs, a family of biologically essential transcription factors. In vertebrates, the activity of SRs allosterically depends on binding a hormonal ligand; in mollusks, however, the SR ortholog (called ER, because of high sequence similarity to vertebrate estrogen receptors activates transcription in the absence of ligand and does not respond to steroid hormones. To understand how this shift in regulation evolved, we combined evolutionary, structural, and functional analyses. We first determined the X-ray crystal structure of the ER of the Pacific oyster Crassostrea gigas (CgER, and found that its ligand pocket is filled with bulky residues that prevent ligand occupancy. To understand the genetic basis for the evolution of mollusk ERs' unique functions, we resurrected an ancient SR progenitor and characterized the effect of historical amino acid replacements on its functions. We found that reintroducing just two ancient replacements from the lineage leading to mollusk ERs recapitulates the evolution of full constitutive activity and the loss of ligand activation. These substitutions stabilize interactions among key helices, causing the allosteric switch to become "stuck" in the active conformation and making activation independent of ligand binding. Subsequent changes filled the ligand pocket without further affecting activity; by degrading the allosteric switch, these substitutions vestigialized elements of the protein's architecture required for ligand regulation and made reversal to the ancestral function more complex. These findings show how the physical architecture of allostery enabled a few large

  4. Distribution of growth hormone-like immunoreactive cells and somatostatin receptors in the nervous system and Hatschek's pit of amphioxus, Branchiostoma belcheri

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Using immunohistochemical method and double staining technique, the localization of growth hormone (GH) and somatostatin receptors in the nervous system and Hatschek's pit of amphioxus has been investigated. The results showed that the growth hormone-like nerve cells and endocrine cells as well as three subtypes-of somatostatin receptors exist in the nervous system and Hatschek's pit, and GH-like nerve cells and endocrine cells co-exist with three subtypes of somatostatin receptors in the brain vesicle and Hatschek's pit. It is suggested that a primitive control system of inhibitory growth hormone secretion in Hatschek's pit could have been developed in amphioxus, as in vertebrates. The present study provides new evidence for the endocrinology and the evolution of Hatschek's pit.

  5. Increase in cell-surface localization of parathyroid hormone receptor by cytoskeletal protein 4.1G.

    Science.gov (United States)

    Saito, Masaki; Sugai, Maki; Katsushima, Yuriko; Yanagisawa, Teruyuki; Sukegawa, Jun; Nakahata, Norimichi

    2005-11-15

    The cell-surface localization of GPCRs (G-protein-coupled receptors) has emerged as one of critical factors of the GPCR-mediated signal transduction. It has been reported that the C-termini of GPCRs contain the sequences for sorting the receptors to cell surface. In the present study, we have searched for proteins that interact with the C-terminus of PTH (parathyroid hormone)/PTH-related protein receptor (PTHR) by using the yeast two-hybrid system, and identified a cytoskeletal protein 4.1G (generaltype 4.1 protein) as an interactant with the C-terminus. Immunohistochemical study revealed that both PTHR and 4.1G were co-localized on plasma membranes, when they were transiently expressed in COS-7 cells. When 4.1G or the C-terminal domain of 4.1G (4.1G-CTD), a dominant-negative form of 4.1G, was co-expressed with PTHR in COS-7 cells, 4.1G, but not 4.1G-CTD, facilitated the cell-surface localization of PTHR, determined by cell-surface biotinylation assay. PTH-(1-34) caused phosphorylation of ERK (extracellular-signal-regulated kinase) 1/2 in PTHR-expressed cells mainly mediated through EGF (epidermal growth factor) receptor. The phosphorylation was enhanced by the expression of 4.1G, but not 4.1G-CTD. PTH-(1-34) elevated [Ca2+]i (intracellular Ca2+ concentration) independent of EGF receptor activation, and the elevation was enhanced by the expression of 4.1G, but not 4.1G-CTD. These data indicate that 4.1G facilitates the cell-surface localization of PTHR through its interaction with the C-terminus of the receptor, resulting in the potentiation of PTHR-mediated signal transduction.

  6. Reproductive parameters of double transgenic zebrafish (Danio rerio) males overexpressing both the growth hormone (GH) and its receptor (GHR).

    Science.gov (United States)

    Silva, Ana Cecilia Gomes; Almeida, Daniela Volcan; Nornberg, Bruna Felix; Pereira, Jessica Ribeiro; Pires, Diego Martins; Corcini, Carine Dahl; Junior, Antonio Sergio Varela; Marins, Luis Fernando

    2017-02-01

    Growth hormone (GH) transgenesis presents a high potential application in aquaculture. However, excess GH may have serious consequences due to pleiotropic actions. In order to study these effects in zebrafish (Danio rerio), two transgenic lines were developed. The first expresses GH ubiquitously and constitutively (F0104 line), while the second expresses the GH receptor in a muscle-specific manner (Myo-GHR line). Results from the F0104 line showed accelerated growth but increased reproductive difficulties, while Myo-GHR did not show the expected increase in muscle mass. Since the two lines appeared to display complementary characteristics, a double transgenic (GH/GHR) was created via crossing between them. This double transgenic displayed accelerated growth, however reproductive parameters remained uncertain. The objective of the present study was to determine the reproductive capacity of males of this new line, by evaluating sperm parameters, expression of spermatogenesis-related genes, and reproductive tests. Double transgenics showed a strong recovery in almost all sperm parameters analyzed when compared to the F0104 line. Gene expression analyses revealed that Anti-Müllerian Hormone gene (amh) appeared to be primarily responsible for this recovery. Reproductive tests showed that double transgenic males did not differ from non-transgenics. It is possible that GHR excess in the muscle tissues of double transgenics may have contributed to lower circulating GH levels and thus reduced the negative effects of this hormone with respect to reproduction. Therefore, it is clear that GH-transgenesis technology should take into account the need to obtain adequate levels of circulating hormone in order to achieve maximum growth with minimal negative side effects.

  7. Parathyroid hormone/parathyroid hormone-related protein receptor signaling is required for maintenance of the growth plate in postnatal life.

    Science.gov (United States)

    Hirai, Takao; Chagin, Andrei S; Kobayashi, Tatsuya; Mackem, Susan; Kronenberg, Henry M

    2011-01-04

    Parathyroid hormone (PTH)-related protein (PTHrP), regulated by Indian hedgehog and acting through the PTH/PTHrP receptor (PPR), is crucial for normal cartilage development. These observations suggest a possible role of PPR signaling in the postnatal growth plate; however, the role of PPR signaling in postnatal chondrocytes is unknown. In this study, we have generated tamoxifen-inducible and cartilage-specific PPR KO mice to evaluate the physiological role of PPR signaling in postnatal chondrocytes. We found that inactivation of the PPR in chondrocytes postnatally leads to accelerated differentiation of chondrocytes, followed by disappearance of the growth plate. We also observed an increase of TUNEL-positive cells and activities of caspase-3 and caspase-9 in the growth plate, along with a decrease in phosphorylation of Bad at Ser155 in postnatal PPR KO mice. Administration of a low-phosphate diet, which prevents apoptosis of chondrocytes, prevented the disappearance of the growth plate. Taken together, these observations suggest that the major consequences of PPR activation are similar in both the fetal and postnatal growth plates. Moreover, chondrocyte apoptosis through the activation of a mitochondrial pathway may be involved in the process of premature disappearance of the growth plate by postnatal inactivation of the PPR in chondrocytes.

  8. Identification and expression of PBAN/diapause hormone and receptors from Aedes aegypti

    Science.gov (United States)

    Neuropeptides control various physiological functions and constitute more than 90% of insect hormones. The pheromone biosynthesis activating neuropeptide (PBAN)/pyrokinin family is a major group of insect neuropeptides and is well conserved in Insecta. This family of peptides has at least two closel...

  9. BINDING OF GONADOTROPHIN-RELEASING HORMONE WITH ITS RECEPTORS ON HUMAN PLACENTAL MEMBRANES

    Institute of Scientific and Technical Information of China (English)

    QIUXiu-Di; WANGHan-Zheng; GONGYue-Ting

    1989-01-01

    Theeffects of gonadotrophin--relensing hormone (GnRH) onthe bindingof125I-labelled GnRH agonist to human placental membranes were studied. The GnRH binding sites of human plaoenta had a high specificity but low affinity. The natural GnRH had a slightly

  10. Switching of G-protein Usage by the Calcium-sensing Receptor Reverses Its Effect on Parathyroid Hormone-related Protein Secretion in Normal Versus Malignant Breast Cells*

    OpenAIRE

    Mamillapalli, Ramanaiah; VanHouten, Joshua; Zawalich, Walter; Wysolmerski, John

    2008-01-01

    The calcium-sensing receptor (CaR) is a G-protein-coupled receptor that signals in response to extracellular calcium and regulates parathyroid hormone secretion. The CaR is also expressed on normal mammary epithelial cells (MMECs), where it has been shown to inhibit secretion of parathyroid hormone-related protein (PTHrP) and participate in the regulation of calcium and bone metabolism during lactation. In contrast to normal breast cells, the CaR has been reported to s...

  11. Disrupting actions of bisphenol A and malachite green on growth hormone receptor gene expression and signal transduction in seabream.

    Science.gov (United States)

    Jiao, Baowei; Cheng, Christopher H K

    2010-06-01

    Environmental estrogen could mimic natural estrogens thereby disrupting the endocrine systems of human and animals. The actions of such endocrine disruptors have been studied mainly on reproduction and development. However, estrogen could also affect the somatotropic axis via multiple targets such as growth hormone (GH). In the present study, two endocrine disruptors were chosen to investigate their effects on the expression level and signal transduction of growth hormone receptor (GHR) in fish. Using real-time PCR, it was found that exposure to both the estrogenic (bisphenol A) and anti-estrogenic (malachite green) compounds could attenuate the expression levels of GHR1 and GHR2 in black seabream (Acanthopagrus schlegeli) hepatocytes. The expression level of IGF-I, the downstream effector of GHR activation in the liver, was decreased by bisphenol A but not by malachite green. Luciferase reporter assay of the beta-casein promoter was used to monitor GHR signaling in transfected cells. In the fish liver cell line Hepa-T1, both GHR1 and GHR2 signaling were attenuated by bisphenol A and malachite green. This attenuation could only occur in the presence of estrogen receptor, indicating that these agents probably produce their actions via the estrogen receptor. Results of the present study demonstrated that estrogenic or anti-estrogenic compounds could down-regulate the somatotropic axis in fish by affecting both the gene expression and signaling of GHR. In view of the increasing prevalence of these compounds in the environment, the impact on fish growth and development both in the wild and in aquaculture would be considerable.

  12. Genetic Evidence for Function of the bHLH-PAS Protein Gce/Met As a Juvenile Hormone Receptor.

    Directory of Open Access Journals (Sweden)

    Marek Jindra

    2015-07-01

    Full Text Available Juvenile hormones (JHs play a major role in controlling development and reproduction in insects and other arthropods. Synthetic JH-mimicking compounds such as methoprene are employed as potent insecticides against significant agricultural, household and disease vector pests. However, a receptor mediating effects of JH and its insecticidal mimics has long been the subject of controversy. The bHLH-PAS protein Methoprene-tolerant (Met, along with its Drosophila melanogaster paralog germ cell-expressed (Gce, has emerged as a prime JH receptor candidate, but critical evidence that this protein must bind JH to fulfill its role in normal insect development has been missing. Here, we show that Gce binds a native D. melanogaster JH, its precursor methyl farnesoate, and some synthetic JH mimics. Conditional on this ligand binding, Gce mediates JH-dependent gene expression and the hormone's vital role during development of the fly. Any one of three different single amino acid mutations in the ligand-binding pocket that prevent binding of JH to the protein block these functions. Only transgenic Gce capable of binding JH can restore sensitivity to JH mimics in D. melanogaster Met-null mutants and rescue viability in flies lacking both Gce and Met that would otherwise die at pupation. Similarly, the absence of Gce and Met can be compensated by expression of wild-type but not mutated transgenic D. melanogaster Met protein. This genetic evidence definitively establishes Gce/Met in a JH receptor role, thus resolving a long-standing question in arthropod biology.

  13. Missense mutations in the growth hormone receptor dimerization region in Laron syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Berg, M.A.; Francke, U. [Howard Hughes Medical Institute, Stanford, CA (United States)]|[Univ. of Stanford, CA (United States); Geffner, M.E.; Bersch, N. [Univ. of California, Los Angeles, CA (United States)] [and others

    1994-09-01

    Laron syndrome (LS) is an autosomal recessively inherited condition characterized by insensitivity to endogenous and exogenous GH. Affected individuals have severe episodes and other characteristic features. GH receptor gene mutations are present in all affected individuals in whom molecular studies have been reported. The GH receptor is a plasma membrane-spanning protein in which the extracellular domain binds circulating GH and the intracellular domain interacts with the JAK-2 kinase and possibly other intracellular signaling molecules. GH receptor dimerization occurs on GH binding and is thought to be required for normal signal transduction. We have studied the GH receptor genes of four unrelated individuals affected with LS from the United States, Italy, Saudi Arabia, and India. We have identified four different missense mutations that alter consecutive amino acids 152 to 155 in or near the dimerization domain of the GH receptor. One of these mutations, D152H, has been reported previously in Asian LS patients and, in in vitro studies, the mutant receptor was unable to dimerize. This report increases to over 20 the number of different GH receptor gene mutations that have been reported in LS patients and defines the first apparent mutational {open_quotes}hotspot{close_quotes} region in this gene. This cluster of mutations in patients with classic LS phenotype provides additional in vivo evidence that receptor dimerization plays an important role in signaling GH`s growth promoting and metabolic effects. Further in vitro studies of the mutations in this region are in progress.

  14. Fibroblast growth factor 21, fibroblast growth factor receptor 1, and β-Klotho expression in bovine growth hormone transgenic and growth hormone receptor knockout mice

    DEFF Research Database (Denmark)

    Brooks, Nicole E; Hjortebjerg, Rikke; Henry, Brooke E;

    2016-01-01

    of Fgf21, Fgfr1, and Klb mRNA in white adipose tissue (AT), brown AT, and liver were evaluated by reverse transcription quantitative PCR. RESULTS: As expected, bGH mice had increased body weight (p=3.70E(-8)) but decreased percent fat mass (p=4.87E(-4)). Likewise, GHR-/- mice had decreased body weight (p...... was to quantify circulating FGF21 and tissue specific expression of Fgf21, Fgfr1, and Klb in mice with modified GH action. Based on previous studies, we hypothesized that bovine GH transgenic (bGH) mice will be FGF21 resistant and GH receptor knockout (GHR-/-) mice will have normal FGF21 action. DESIGN: Seven......-month-old male bGH mice (n=9) and wild type (WT) controls (n=10), and GHR-/- mice (n=8) and WT controls (n=8) were used for all measurements. Body composition was determined before dissection, and tissue weights were measured at the time of dissection. Serum FGF21 levels were evaluated by ELISA. Expression...

  15. Risk of Breast Cancer in Relation to Combined Effects of Hormone Therapy, Body Mass Index, and Alcohol Use, by Hormone-receptor Status

    DEFF Research Database (Denmark)

    Hvidtfeldt, Ulla Arthur; Tjonneland, Anne; Keiding, Niels;

    2015-01-01

    BACKGROUND: Alcohol consumption, increased body mass index (BMI), and hormone therapy are risk factors for postmenopausal breast cancer, but their combined effects are not well understood. Because hormone therapy is effective for the relief of menopausal symptoms, the identification of "high...... therapy users across all BMI strata (P for interaction = 0.003). A markedly higher risk of breast cancer was also observed for alcohol combined with hormone therapy use compared with abstinent nonusers (P for interaction = 0.02). These effects were primarily restricted to ER-positive cases. Combined...... effects of hormone therapy/high BMI and hormone therapy/alcohol on serum estradiol and testosterone supported the hypothesis of a hormonal pathway linking these exposures to breast cancer. CONCLUSION: These analyses suggest an increased risk of breast cancer associated with hormone therapy use-a risk...

  16. Crystal structure of the PAC1R extracellular domain unifies a consensus fold for hormone recognition by class B G-protein coupled receptors.

    Directory of Open Access Journals (Sweden)

    Shiva Kumar

    Full Text Available Pituitary adenylate cyclase activating polypeptide (PACAP is a member of the PACAP/glucagon family of peptide hormones, which controls many physiological functions in the immune, nervous, endocrine, and muscular systems. It activates adenylate cyclase by binding to its receptor, PAC1R, a member of class B G-protein coupled receptors (GPCR. Crystal structures of a number of Class B GPCR extracellular domains (ECD bound to their respective peptide hormones have revealed a consensus mechanism of hormone binding. However, the mechanism of how PACAP binds to its receptor remains controversial as an NMR structure of the PAC1R ECD/PACAP complex reveals a different topology of the ECD and a distinct mode of ligand recognition. Here we report a 1.9 Å crystal structure of the PAC1R ECD, which adopts the same fold as commonly observed for other members of Class B GPCR. Binding studies and cell-based assays with alanine-scanned peptides and mutated receptor support a model that PAC1R uses the same conserved fold of Class B GPCR ECD for PACAP binding, thus unifying the consensus mechanism of hormone binding for this family of receptors.

  17. Crystal Structure of the PAC1R Extracellular Domain Unifies a Consensus Fold for Hormone Recognition by Class B G-Protein Coupled Receptors

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, Shiva; Pioszak, Augen; Zhang, Chenghai; Swaminathan, Kunchithapadam; Xu, H. Eric (Van Andel); (NU Singapore)

    2012-02-21

    Pituitary adenylate cyclase activating polypeptide (PACAP) is a member of the PACAP/glucagon family of peptide hormones, which controls many physiological functions in the immune, nervous, endocrine, and muscular systems. It activates adenylate cyclase by binding to its receptor, PAC1R, a member of class B G-protein coupled receptors (GPCR). Crystal structures of a number of Class B GPCR extracellular domains (ECD) bound to their respective peptide hormones have revealed a consensus mechanism of hormone binding. However, the mechanism of how PACAP binds to its receptor remains controversial as an NMR structure of the PAC1R ECD/PACAP complex reveals a different topology of the ECD and a distinct mode of ligand recognition. Here we report a 1.9 {angstrom} crystal structure of the PAC1R ECD, which adopts the same fold as commonly observed for other members of Class B GPCR. Binding studies and cell-based assays with alanine-scanned peptides and mutated receptor support a model that PAC1R uses the same conserved fold of Class B GPCR ECD for PACAP binding, thus unifying the consensus mechanism of hormone binding for this family of receptors.

  18. Effects of adrenal hormones on the expression of adiponectin and adiponectin receptors in adipose tissue, muscle and liver.

    Science.gov (United States)

    de Oliveira, Cristiane; Iwanaga-Carvalho, Carla; Mota, João F; Oyama, Lila M; Ribeiro, Eliane B; Oller do Nascimento, Cláudia M

    2011-11-01

    Adiponectin, an insulin-sensitive hormone that is primarily synthesized in adipose tissue, exerts its effects by binding to two receptors, adipoR1 and adipoR2. Little is known regarding the effects of glucocorticoids on the expression of adiponectin receptors. Male Wistar rats were bilaterally adrenalectomized and treated with dexamethasone (0.2 mg/100 g) twice daily for 3 days. To analyze the potential effects of glucocorticoids, rats received two daily injections of the glucocorticoid receptor antagonist (RU-486, 5.0 mg) over the course of 3 days. Additionally, 3T3-L1 adipocytes and C2C12 myotubes were treated with dexamethasone, adrenaline or RU-486. The gene expression of adiponectin, adipoR1 and adipoR2 was determined by real-time PCR, and protein secretion was examined by Western blotting using lysates from retroperitoneal, epididymal and subcutaneous adipose tissue depots, liver and muscle. In rats, excess glucocorticoids increased the levels of insulin in serum and decreased serum adiponectin concentrations, whereas adrenalectomy decreased the mRNA expression of adiponectin (3-fold) and adipoR2 (7-fold) in epididymal adipose tissue and increased adipoR2 gene expression in muscle (3-fold) compared to control group sham-operated. Dexamethasone treatment did not reverse the effects of adrenalectomy, and glucocorticoid receptor blockade did not reproduce the effects of adrenalectomy. In 3T3-L1 adipocytes, dexamethasone and adrenaline both increased adipoR2 mRNA levels, but RU-486 reduced adipoR2 gene expression in vitro. Dexamethasone treatment induces a state of insulin resistance but does not affect adiponectin receptor expression in adipose tissue. However, the effects of catecholamines on insulin resistance may be due to their effects on adipoR2. Copyright © 2011 Elsevier Inc. All rights reserved.

  19. Signature motif-guided identification of receptors for peptide hormones essential for root meristem growth.

    Science.gov (United States)

    Song, Wen; Liu, Li; Wang, Jizong; Wu, Zhen; Zhang, Heqiao; Tang, Jiao; Lin, Guangzhong; Wang, Yichuan; Wen, Xing; Li, Wenyang; Han, Zhifu; Guo, Hongwei; Chai, Jijie

    2016-06-01

    Peptide-mediated cell-to-cell signaling has crucial roles in coordination and definition of cellular functions in plants. Peptide-receptor matching is important for understanding the mechanisms underlying peptide-mediated signaling. Here we report the structure-guided identification of root meristem growth factor (RGF) receptors important for plant development. An assay based on a signature ligand recognition motif (Arg-x-Arg) conserved in a subfamily of leucine-rich repeat receptor kinases (LRR-RKs) identified the functionally uncharacterized LRR-RK At4g26540 as a receptor of RGF1 (RGFR1). We further solved the crystal structure of RGF1 in complex with the LRR domain of RGFR1 at a resolution of 2.6 Å, which reveals that the Arg-x-Gly-Gly (RxGG) motif is responsible for specific recognition of the sulfate group of RGF1 by RGFR1. Based on the RxGG motif, we identified additional four RGFRs. Participation of the five RGFRs in RGF-induced signaling is supported by biochemical and genetic data. We also offer evidence showing that SERKs function as co-receptors for RGFs. Taken together, our study identifies RGF receptors and co-receptors that can link RGF signals with their downstream components and provides a proof of principle for structure-based matching of LRR-RKs with their peptide ligands.

  20. The nuclear hormone receptor gene Nr2c1 (Tr2) is a critical regulator of early retina cell patterning.

    Science.gov (United States)

    Olivares, Ana Maria; Han, Yinan; Soto, David; Flattery, Kyle; Marini, Joseph; Molemma, Nissa; Haider, Ali; Escher, Pascal; DeAngelis, Margaret M; Haider, Neena B

    2017-09-01

    Nuclear hormone receptors play a major role in the development of many tissues. This study uncovers a novel role for testicular receptor 2 (Tr2, Nr2c1) in defining the early phase of retinal development and regulating normal retinal cell patterning and topography. The mammalian retina undergoes an overlapping yet biphasic period of development to generate all seven retinal cell types. We discovered that Nr2c1 expression coincides with development of the early retinal cells. Loss of Nr2c1 causes a severe vision deficit and impacts early, but not late retina cell types. Retinal cone cell topography is disrupted with an increase in displaced amacrine cells. Additionally, genetic background significantly impacts phenotypic outcome of cone photoreceptor cells but not amacrine cells. Chromatin-IP experiments reveal NR2C1 regulates early cell transcription factors that regulate retinal progenitor cells during development, including amacrine (Satb2) and cone photoreceptor regulators thyroid and retinoic acid receptors. This study supports a role for Nr2c1 in defining the biphasic period of retinal development and specifically influencing the early phase of retinal cell fate. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  1. Cardiac ACE2/angiotensin 1-7/Mas receptor axis is activated in thyroid hormone-induced cardiac hypertrophy.

    Science.gov (United States)

    Diniz, Gabriela P; Senger, Nathalia; Carneiro-Ramos, Marcela S; Santos, Robson A S; Barreto-Chaves, Maria Luiza M

    2016-08-01

    Thyroid hormone (TH) promotes marked effects on the cardiovascular system, including the development of cardiac hypertrophy. Some studies have demonstrated that the renin-angiotensin system (RAS) is a key mediator of the cardiac growth in response to elevated TH levels. Although some of the main RAS components are changed in cardiac tissue on hyperthyroid state, the potential modulation of the counter regulatory components of the RAS, such as angiotensin-converting enzyme type 2 (ACE2), angiotensin 1-7 (Ang 1-7) levels and Mas receptor induced by hyperthyroidism is unknown. The aim of this study was to investigate the effect of hyperthyroidism on cardiac Ang 1-7, ACE2 and Mas receptor levels. Hyperthyroidism was induced in Wistar rats by daily intraperitoneal injections of T4 for 14 days. Although plasma Ang 1-7 levels were unchanged by hyperthyroidism, cardiac Ang 1-7 levels were increased in TH-induced cardiac hypertrophy. ACE2 enzymatic activity was significantly increased in hearts from hyperthyroid animals, which may be contributing to the higher Ang 1-7 levels observed in the T4 group. Furthermore, elevated cardiac levels of Ang 1-7 levels were accompanied by increased Mas receptor protein levels. The counter-regulatory components of the RAS are activated in hyperthyroidism and may be contributing to modulate the cardiac hypertrophy in response to TH. © The Author(s), 2015.

  2. Na/H Exchanger Regulatory Factors Control Parathyroid Hormone Receptor Signaling by Facilitating Differential Activation of Gα Protein Subunits*

    Science.gov (United States)

    Wang, Bin; Ardura, Juan A.; Romero, Guillermo; Yang, Yanmei; Hall, Randy A.; Friedman, Peter A.

    2010-01-01

    The Na/H exchanger regulatory factors, NHERF1 and NHERF2, are adapter proteins involved in targeting and assembly of protein complexes. The parathyroid hormone receptor (PTHR) interacts with both NHERF1 and NHERF2. The NHERF proteins toggle PTHR signaling from predominantly activation of adenylyl cyclase in the absence of NHERF to principally stimulation of phospholipase C when the NHERF proteins are expressed. We hypothesized that this signaling switch occurs at the level of the G protein. We measured G protein activation by [35S]GTPγS binding and Gα subtype-specific immunoprecipitation using three different cellular models of PTHR signaling. These studies revealed that PTHR interactions with NHERF1 enhance receptor-mediated stimulation of Gαq but have no effect on stimulation of Gαi or Gαs. In contrast, PTHR associations with NHERF2 enhance receptor-mediated stimulation of both Gαq and Gαi but decrease stimulation of Gαs. Consistent with these functional data, NHERF2 formed cellular complexes with both Gαq and Gαi, whereas NHERF1 was found to interact only with Gαq. These findings demonstrate that NHERF interactions regulate PTHR signaling at the level of G proteins and that NHERF1 and NHERF2 exhibit isotype-specific effects on G protein activation. PMID:20562104

  3. Effects of gadolinium-based contrast agents on thyroid hormone receptor action and thyroid hormone-induced cerebellar Purkinje cell morphogenesis

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    Noriyuki Koibuchi

    2016-08-01

    Full Text Available Gadolinium (Gd-based contrast agents (GBCAs are used in diagnostic imaging to enhance the quality of magnetic resonance imaging or angiography. After intravenous injection, GBCAs can accumulate in the brain. Thyroid hormones (THs are critical to the development and functional maintenance of the central nervous system. TH actions in brain are mainly exerted through nuclear TH receptors (TRs. We examined the effects of GBCAs on TR-mediated transcription in CV-1 cells using transient transfection-based reporter assay and thyroid hormone-mediated cerebellar Purkinje cell morphogenesis in primary culture. We also measured the cellular accumulation and viability of Gd after representative GBCA treatments in cultured CV-1 cells. Both linear (Gd-diethylene triamine pentaacetic acid-bis methyl acid, Gd-DTPA-BMA and macrocyclic (Gd-tetraazacyclododecane tetraacetic acid, Gd-DOTA GBCAs were accumulated without inducing cell death in CV-1 cells. In contrast, Gd chloride (GdCl3 treatment induced approximately 100 times higher Gd accumulation and significantly reduced the number of cells. Low doses of Gd-DTPA-BMA (10−8–10−6 M augmented TR-mediated transcription, but the transcription was suppressed at higher dose (10−5 – 10−4 M, with decreased β-galactosidase activity indicating cellular toxicity. TR-mediated transcription was not altered by Gd-DOTA or GdCl3, but the latter induced a significant reduction in β-galactosidase activity at high doses, indicating cellular toxicity. In cerebellar cultures, the dendrite arborization of Purkinje cells induced by 10-9 M T4 was augmented by low-dose Gd-DTPA-BMA (10−7 M but was suppressed by higher dose (10−5 M. Such augmentation by low-dose Gd-DTPA-BMA was not observed with 10-9 M T3, probably because of the greater dendrite arborization by T3; however, the arborization by T3 was suppressed by a higher dose of Gd-DTPA-BMA (10-5 M as seen in T4 treatment. The effect of Gd-DOTA on dendrite arborization

  4. Steroid hormones, receptors, and perceptual and cognitive sex differences in the visual system.

    Science.gov (United States)

    Handa, Robert J; McGivern, Robert F

    2015-02-01

    The actions of gonadal steroid hormones induce morphological sex differences in many tissues in the body, including brain. These occur either during development to organize tissues in a sex-specific pattern and/or in adulthood to activate specific cellular pathways. Cellular and morphological changes in the brain, induced by androgens and estrogens, underlie behavioral sex differences in both reproductive and non-reproductive behaviors, including visual perception. A growing body of evidence indicates that some sex differences related to visual perception arise as the result of the organizational actions of gonadal steroid hormones on cerebral cortical pathways involved in visual processing of objects and movement. This review addresses the influence of gonadal steroids on structural, biochemical and morphological changes in tissues in the brain and body. These effects are extended to consider how gonadal hormone effects may contribute to cognitive sex differences across species that are related to processing within the dorsal and ventral visual streams for motion and objects, respectively. Lastly, this review considers the question of how cognitive sex differences related to processing of movement and objects in humans may be reflective of two types of cognitive style that are only superficially related to gender.

  5. All-atom structural models of insulin binding to the insulin receptor in the presence of a tandem hormone-binding element.

    Science.gov (United States)

    Vashisth, Harish; Abrams, Cameron F

    2013-06-01

    Insulin regulates blood glucose levels in higher organisms by binding to and activating insulin receptor (IR), a constitutively homodimeric glycoprotein of the receptor tyrosine kinase (RTK) superfamily. Therapeutic efforts in treating diabetes have been significantly impeded by the absence of structural information on the activated form of the insulin/IR complex. Mutagenesis and photo-crosslinking experiments and structural information on insulin and apo-IR strongly suggest that the dual-chain insulin molecule, unlike the related single-chain insulin-like growth factors, binds to IR in a very different conformation than what is displayed in storage forms of the hormone. In particular, hydrophobic residues buried in the core of the folded insulin molecule engage the receptor. There is also the possibility of plasticity in the receptor structure based on these data, which may in part be due to rearrangement of the so-called CT-peptide, a tandem hormone-binding element of IR. These possibilities provide opportunity for large-scale molecular modeling to contribute to our understanding of this system. Using various atomistic simulation approaches, we have constructed all-atom structural models of hormone/receptor complexes in the presence of CT in its crystallographic position and a thermodynamically favorable displaced position. In the "displaced-CT" complex, many more insulin-receptor contacts suggested by experiments are satisfied, and our simulations also suggest that R-insulin potentially represents the receptor-bound form of hormone. The results presented in this work have further implications for the design of receptor-specific agonists/antagonists.

  6. Density of mu-opioid receptors in the hippocampus of adult male and female rats is altered by prenatal morphine exposure and gonadal hormone treatment.

    Science.gov (United States)

    Slamberová, Romana; Rimanóczy, Agnes; Bar, Noffar; Schindler, Cheryl J; Vathy, Ilona

    2003-01-01

    The present in vitro autoradiography study demonstrates that prenatal exposure to morphine alters the density of mu-opioid receptors in the hippocampus of adult female but not adult male rats. Prenatal morphine exposure increased the mu-opioid receptor density in the CA1 of ovariectomized (OVX) females and in the CA3 of OVX, estradiol benzoate-plus progesterone (EB+P)-treated females, but decreased it in CA3 of OVX females. There were also hormonal effects on mu-opioid receptor density in adult female rats. In the CA1, only morphine-exposed but not saline-exposed, hormone-treated females (EB, P, or EB+P) had a decrease in mu-opioid receptor density relative to OVX females. Both saline-exposed and morphine-exposed, OVX females after gonadal hormone replacement had a lower density of mu-opioid receptors in the CA3 and in the dentate gyrus (DG) than OVX females. In male rats, there was a decrease in mu-opioid receptor density in the CA1 and CA3 of gonadectomized (GNX), testosterone 17beta-proprionate (TP)-treated males relative to GNX males regardless of prenatal morphine exposure. In the DG, the mu-opioid receptor density was reduced only in morphine-exposed but not in saline-exposed, TP-treated males compared with GNX males. Thus, our data demonstrate that mu-opioid receptor density in the hippocampus is affected by prenatal morphine exposure and by male and female gonadal hormones.

  7. Adjuvant Trastuzumab in HER2-Positive Early Breast Cancer by Age and Hormone Receptor Status: A Cost-Utility Analysis

    Science.gov (United States)

    Leung, William; Kvizhinadze, Giorgi; Nair, Nisha; Blakely, Tony

    2016-01-01

    the same result. A key limitation was a lack of treatment-effect data by hormone receptor subtype. Heterogeneity was restricted to age and hormone receptor status; tumour size/grade heterogeneity could be explored in future work. Conclusions This study highlights how cost-effectiveness can vary greatly by heterogeneity in age and hormone receptor subtype. Resource allocation and licensing of subsidised therapies such as trastuzumab should consider demographic and clinical heterogeneity; there is currently a profound disconnect between how funding decisions are made (largely agnostic to heterogeneity) and the principles of personalised medicine. PMID:27504960

  8. The presence and role of progesterone receptor in the ovaries of postmenopausal women who have not applied hormone replacement therapy.

    Directory of Open Access Journals (Sweden)

    Małgorzata Piasecka

    2008-12-01

    Full Text Available At present, not much is known about progesterone receptor (PR expression and localization in postmenopausal women ovaries. In the ovaries of reproductive age women, PR is localized in internal theca and granulosa cells, corpus luteum, ovary surface epithelium (OSE and in stroma. PR expression depends on the serum concentration of progesterone, estrogen, gonadotropin and androgen. The goal of the conducted studies was to examine PR localization and expression in the ovaries of postmenopausal women who have not applied hormone replacement therapy so far. Also, the correlation was examined between PR expression and localization in the ovaries, steroid and gonadotropin hormone serum concentrations, and influence of the time from the last menstruation. The material came from 50 postmenopausal women who had their ovaries removed due to non-neoplastic diseases. The women were divided into 3 groups (A, B, C depending on the time from the last menstruation. The follitropin (FSH, luteotropin (LH, estradiol (E2, testosterone (T, androstendione (A and dehydroepiandrosterone sulphate (DHEAS concentrations in blood plasma were measured. Monoclonal mouse anti-human PR antibody was used for immunohistochemical detection (examination involved 50 postmenopausal ovaries. Between particular groups, E2 serum concentrations did not differ, but FSH, LH, T, A, DHEAS serum concentrations were significantly different. Immunohistochemical nuclear localization of PR in postmenopausal women ovaries was observed. PR expression was similar in all three groups (A, B, C. PR expression was observed in OSE nuclei and invaginations cysts deriving from the isolation of invaginated epithelium and metaplastic columnar epithelium and in stroma. In the ovaries of postmenopausal women who have not applied hormone replacement therapy so far, PR was detected in all three groups. Its expression did not depend on the time from menopause and was similar in all examined groups. FSH, LH, T, A

  9. Clinical features and growth hormone receptor gene mutations of patients with Laron syndrome from a Chinese family.

    Science.gov (United States)

    Ying, Yan-Qin; Wei, Hong; Cao, Li-Zhi; Lu, Juan-Juan; Luo, Xiao-Ping

    2007-08-01

    Laron syndrome is an autosomal recessive disorder caused by defects of growth hormone receptor (GHR) gene. It is characterized by severe postnatal growth retardation and characteristic facial features as well as high circulating levels of growth hormone (GH) and low levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3). This report described the clinical features and GHR gene mutations in 2 siblings with Laron syndrome in a Chinese family. Their heights and weights were in the normal range at birth, but the growth was retarded after birth. When they presented to the clinic, the heights of the boy (8 years old) and his sister (11 years old) were 80.0 cm (-8.2 SDS) and 96.6 cm (-6.8 SDS) respectively. They had typical appearance features of Laron syndrome such as short stature and obesity, with protruding forehead, saddle nose, large eyes, sparse and thin silky hair and high-pitched voice. They had higher basal serum GH levels and lower serum levels of IGF-I, IGFBP-3 and growth hormone binding protein (GHBP) than normal controls. The peak serum GH level after colonidine and insulin stimulations in the boy was over 350 ng/mL. After one-year rhGH treatment, the boy's height increased from 80.0 cm to 83.3 cm. The gene mutation analysis revealed that two patients had same homozygous mutation of S65H (TCA -->CCA) in exon 4, which is a novel gene mutation. It was concluded that a definite diagnosis of Laron syndrome can be made based on characteristic appearance features and serum levels of GH, IGF-I, IGFBP-3 and GHBP. The S65H mutation might be the cause of Laron syndrome in the two patients.

  10. Association between corticotropin-releasing hormone receptor 1 and 2 (CRHR1 and CRHR2) gene polymorphisms and personality traits.

    Science.gov (United States)

    Ishitobi, Yoshinobu; Nakayama, Shinya; Kanehisa, Masayuki; Higuma, Haruka; Maruyama, Yoshihiro; Okamoto, Shizuko; Inoue, Ayako; Imanaga, Junko; Tanaka, Yoshihiro; Tsuru, Jusen; Hanada, Hiroaki; Akiyoshi, Jotaro

    2013-12-01

    Previous studies have reported that the hypothalamic-pituitary-adrenal axis is involved with personality traits. We examined the association between corticotropin-releasing hormone receptor (CRHR) genes and personality traits. We investigated the 12 single-nucleotide polymorphisms of intron CRHR (six in CRHR1 and six in CRHR2, respectively) in 218 healthy volunteers using TaqMan PCR assays. Personality traits were assessed using the Revised NEO-Personality Inventory, the Temperament and Character Inventory, and the State-Trait Anxiety Inventory. No significant associations were observed between CRHR1 and CRHR2 expression and personality traits. These results fail to provide support for an association of CRHR1 and CRHR2 with personality traits in a Japanese adult population.

  11. Polymorphisms of the bovine luteinizing hormone/choriogonadotropin receptor (LHCGR) gene and its association with superovulation traits.

    Science.gov (United States)

    Yang, Wu-Cai; Tang, Ke-Qiong; Li, Shu-Jing; Chao, Lu-Ming; Yang, Li-Guo

    2012-03-01

    The major limitation to the development of embryo transfer technique in cattle is the highly variable between individuals in ovulatory response to FSH-induced superovulation. The objective of this study was to identify a predictor to forecast superovulation response on the basis of associations between superovulation performance and gene polymorphism, variation in the bovine luteinizing hormone/choriogonadotropin receptor (LHCGR) gene was investigated using PCR-single-strand conformational (PCR-SSCP) and DNA sequencing. Four single nucleotide polymorphisms (SNPs) of G51656T, A51703G, A51726G and G51737A were identified at the intron 9 of the LHCGR gene in 171 Chinese Holstein cows treated for superovulation, and evaluated its associations with superovulatory response. Association analysis showed that these four SNPs had significant effects on the total number of ova (TNO) (P superovulation response and can be used to predict the most appropriate dose of FSH for superovulation in Chinese Holstein cows.

  12. Screening for cardiovascular safety: a structure-activity approach for guiding lead selection of melanin concentrating hormone receptor 1 antagonists.

    Science.gov (United States)

    Kym, Philip R; Souers, Andrew J; Campbell, Thomas J; Lynch, John K; Judd, Andrew S; Iyengar, Rajesh; Vasudevan, Anil; Gao, Ju; Freeman, Jennifer C; Wodka, Dariusz; Mulhern, Mathew; Zhao, Gang; Wagaw, Seble H; Napier, James J; Brodjian, Sevan; Dayton, Brian D; Reilly, Regina M; Segreti, Jason A; Fryer, Ryan M; Preusser, Lee C; Reinhart, Glenn A; Hernandez, Lisa; Marsh, Kennan C; Sham, Hing L; Collins, Christine A; Polakowski, James S

    2006-04-06

    An inactin-anesthetized rat cardiovascular (CV) assay was employed in a screening mode to triage multiple classes of melanin-concentrating hormone receptor 1 (MCHr1) antagonists. Lead identification was based on a compound profile producing high drug concentration in both plasma (>40 microM) and brain (>20 microg/g) with optimization activities on multiple classes of MCHr1 antagonists were terminated. After providing evidence that the cardiovascular liabilities were not a function of MCHr1 antagonism, continued screening identified the chromone-substituted aminopiperidine amides as a class of MCHr1 antagonists that demonstrated a safe cardiovascular profile at high drug concentrations in both plasma and brain. The high incidence of adverse cardiovascular effects associated with an array of MCHr1 antagonists of significant chemical diversity, combined with the stringent safety requirements for antiobesity drugs, highlight the importance of incorporating cardiovascular safety assessment early in the lead selection process.

  13. Age-related and depot-specific changes in white adipose tissue of growth hormone receptor-null mice.

    Science.gov (United States)

    Sackmann-Sala, Lucila; Berryman, Darlene E; Lubbers, Ellen R; Zhang, Han; Vesel, Clare B; Troike, Katie M; Gosney, Elahu S; List, Edward O; Kopchick, John J

    2014-01-01

    Growth hormone receptor-null (GHR(-/-)) mice are dwarf, insulin sensitive, and long-lived in spite of increased adiposity. However, their adiposity is not uniform, with select white adipose tissue (WAT) depots enlarged. To study WAT depot-specific effects on insulin sensitivity and life span, we analyzed individual WAT depots of 12- and 24-month-old GHR(-) (/-) and wild-type (WT) mice, as well as their plasma levels of selected hormones. Adipocyte sizes and plasma insulin, leptin, and adiponectin levels decreased with age in both GHR(-) (/-) and WT mice. Two-dimensional gel electrophoresis proteomes of WAT depots were similar among groups, but several proteins involved in endocytosis and/or cytoskeletal organization (Ehd2, S100A10, actin), anticoagulation (S100A10, annexin A5), and age-related conditions (alpha2-macroglobulin, apolipoprotein A-I, transthyretin) showed significant differences between genotypes. Because Ehd2 may regulate endocytosis of Glut4, we measured Glut4 levels in the WAT depots of GHR(-) (/-) and WT mice. Inguinal WAT of 12-month-old GHR(-) (/-) mice displayed lower levels of Glut4 than WT. Overall, the protein changes detected in this study offer new insights into possible mechanisms contributing to enhanced insulin sensitivity and extended life span in GHR(-) (/-) mice.

  14. Antitumor Responses Stimulated by Dendritic Cells Are Improved by Triiodothyronine Binding to the Thyroid Hormone Receptor β.

    Science.gov (United States)

    Alamino, Vanina A; Mascanfroni, Iván D; Montesinos, María M; Gigena, Nicolás; Donadio, Ana C; Blidner, Ada G; Milotich, Sonia I; Cheng, Sheue-Yann; Masini-Repiso, Ana M; Rabinovich, Gabriel A; Pellizas, Claudia G

    2015-04-01

    Bidirectional cross-talk between the neuroendocrine and immune systems orchestrates immune responses in both physiologic and pathologic settings. In this study, we provide in vivo evidence of a critical role for the thyroid hormone triiodothyronine (T3) in controlling the maturation and antitumor functions of dendritic cells (DC). We used a thyroid hormone receptor (TR) β mutant mouse (TRβPV) to establish the relevance of the T3-TRβ system in vivo. In this model, TRβ signaling endowed DCs with the ability to stimulate antigen-specific cytotoxic T-cell responses during tumor development. T3 binding to TRβ increased DC viability and augmented DC migration to lymph nodes. Moreover, T3 stimulated the ability of DCs to cross-present antigens and to stimulate cytotoxic T-cell responses. In a B16-OVA mouse model of melanoma, vaccination with T3-stimulated DCs inhibited tumor growth and prolonged host survival, in part by promoting the generation of IFNγ-producing CD8(+) T cells. Overall, our results establish an adjuvant effect of T3-TRβ signaling in DCs, suggesting an immediately translatable method to empower DC vaccination approaches for cancer immunotherapy.

  15. Association of a novel single nucleotide polymorphism in growth hormone receptor gene with production traits in Bali cattle

    Directory of Open Access Journals (Sweden)

    Maskur .

    2014-11-01

    Full Text Available The growth hormone (GH is the main regulator of postnatal growth and metabolism in mammals. The action of GH on target cells depends on the growth hormone receptor (GHR. This is mediated through induced transcription of other genes. GHR gene is one of the candidate genes employed in selection strategy using DNA markers (marker assisted selection. This study was designed to identify the novel single nucleotide polymorphisms (SNPs in exon 8 and intron 8 of GHR gene that may affect production traits in Bali cattle. A SNP was identified by the direct sequencing technique. Genotypes of the SNPs were identified using PCR-RFLP. The SNP was located in intron 8 of the GHR gene and was caused by an A/G transition. It was identified using the HpyCH4III restriction enzyme. Polymorphism of GHR/HpyCH4III has a significant influence on weaning weight and average daily gain, but not on birth weight of Bali cattle.

  16. Association between the Growth Hormone Receptor Exon 3 Polymorphism and Metabolic Factors in Korean Patients with Acromegaly

    Directory of Open Access Journals (Sweden)

    Hye Yoon Park

    2015-09-01

    Full Text Available BackgroundThis study investigated the association between the frequency of growth hormone receptor (GHR exon 3 polymorphism (exon 3 deletion; d3-GHR and metabolic factors in patients with acromegaly in Korea.MethodsDNA was extracted from the peripheral blood of 30 unrelated patients with acromegaly. GHR genotypes were evaluated by polymerase chain reaction and correlated with demographic data and laboratory parameters.ResultsNo patient had the d3/d3 genotype, while four (13.3% had the d3/fl genotype, and 26 (86.7% had the fl/fl genotype. Body mass index (BMI in patients with the d3/fl genotype was significantly higher than in those with the fl/fl genotype (P=0.001. Age, gender, blood pressure, insulin-like growth factor-1, growth hormone, fasting plasma glucose, triglycerides, high density lipoprotein cholesterol, and low density lipoprotein cholesterol levels showed no significant differences between the two genotypes.ConclusionThe d3-GHR polymorphism may be associated with high BMI but not with other demographic characteristics or laboratory parameters.

  17. Consolidation of remote fear memories involves Corticotropin-Releasing Hormone (CRH) receptor type 1-mediated enhancement of AMPA receptor GluR1 signaling in the dentate gyrus.

    Science.gov (United States)

    Thoeringer, Christoph K; Henes, Kathrin; Eder, Matthias; Dahlhoff, Maik; Wurst, Wolfgang; Holsboer, Florian; Deussing, Jan M; Moosmang, Sven; Wotjak, Carsten T

    2012-02-01

    Persistent dreadful memories and hyperarousal constitute prominent psychopathological features of posttraumatic stress disorder (PTSD). Here, we used a contextual fear conditioning paradigm to demonstrate that conditional genetic deletion of corticotropin-releasing hormone (CRH) receptor 1 within the limbic forebrain in mice significantly reduced remote, but not recent, associative and non-associative fear memories. Per os treatment with the selective CRHR1 antagonist DMP696 (3 mg/kg) attenuated consolidation of remote fear memories, without affecting their expression and retention. This could be achieved, if DMP696 was administered for 1 week starting as late as 24 h after foot shock. Furthermore, by combining electrophysiological recordings and western blot analyses, we demonstrate a delayed-onset and long-lasting increase in AMPA receptor (AMPAR) GluR1-mediated signaling in the dentate gyrus (DG) of the dorsal hippocampus 1 month after foot shock. These changes were absent from CRHR1-deficient mice and after DMP696 treatment. Inactivation of hippocampal GluR1-containing AMPARs by antisense oligonucleotides or philantotoxin 433 confirmed the behavioral relevance of AMPA-type glutamatergic neurotransmission in maintaining the high levels of remote fear in shocked mice with intact CRHR1 signaling. We conclude that limbic CRHR1 receptors enhance the consolidation of remote fear memories in the first week after foot shock by increasing the expression of Ca(2+)-permeable GluR1-containing AMPARs in the DG. These findings suggest both receptors as rational targets for the prevention and therapy, respectively, of psychopathology associated with exaggerated fear memories, such as PTSD.

  18. Alternative splicing in the fiddler crab cognate ecdysteroid receptor: variation in receptor isoform expression and DNA binding properties in response to hormone.

    Science.gov (United States)

    Durica, David S; Das, Sunetra; Najar, Fares; Roe, Bruce; Phillips, Barret; Kappalli, Sudha; Anilkumar, Gopinathan

    2014-09-15

    RXR cDNA cloning from three Uca species led to the identification of 4 conserved isoforms, indicative of alternative splicing in the hinge and ligand binding domains (LBD). Sequencing of overlapping clones from a Ucapugilator genomic library identified EcR isoforms matching previously identified cDNA variants; in addition, a cryptic exon in the LBD was detected and evidence for expression of this new isoform was obtained from next-generation sequencing. RNA-seq analysis also identified a new amino terminal EcR variant. EcR and RXR transcript abundance increases throughout ovarian maturation in U. pugilator, while cognate receptor transcript abundance remains constant in a related Indo-Pacific species with a different reproductive strategy. To examine if crab RXR LBD isoforms have different physical properties in vitro, electromobility shift assays were performed with different EcR isoforms. The cognate crab and fruit fly receptors differ in their responses to hormone. Ecdysteroids did not increase DNA binding for the crab heterodimers, while ecdysteroids stimulate binding for Drosophilamelanogaster EcR/USP heterodimers. In swapping experiments, UpEcR/USP heterodimers did not show ligand-responsive differences in DNA binding; both crab RXR LBD isoforms, however, conferred ligand-responsive increases in DNA binding with DmEcRs. These data indicate that both UpRXR LBD isoforms can heterodimerize with the heterologous DmEcR receptors and promote ligand and DNA binding. Unresponsiveness of the cognate receptors to ecdysteroid, however, suggest additional factors may be required to mediate endogenous, perhaps isoform-specific, differences in EcR conformation, consistent with previously reported effects of UpRXR isoforms on UpEcR ligand-binding affinities.

  19. Hydroxylated polybrominated diphenyl ethers exhibit different activities on thyroid hormone receptors depending on their degree of bromination

    Energy Technology Data Exchange (ETDEWEB)

    Ren, Xiao-Min, E-mail: rxm200318@gmail.com; Guo, Liang-Hong, E-mail: LHGuo@rcees.ac.cn; Gao, Yu, E-mail: francesscototti@gmail.com; Zhang, Bin-Tian, E-mail: nktianster@gmail.com; Wan, Bin, E-mail: binwan@rcees.ac.cn

    2013-05-01

    Polybrominated diphenyl ethers (PBDEs) have been shown to disrupt thyroid hormone (TH) functions in experimental animals, and one of the proposed disruption mechanisms is direct binding of hydroxylated PBDE (OH-PBDE) to TH receptors (TRs). However, previous data on TH receptor binding and TH activity of OH-PBDEs were very limited and sometimes inconsistent. In the present paper, we examined the binding potency of ten OH-PBDEs with different degrees of bromination to TR using a fluorescence competitive binding assay. The results showed that the ten OH-PBDEs bound to TR with potency that correlated to their bromination level. We further examined their effect on TR using a coactivator binding assay and GH3 cell proliferation assay. Different TR activities of OH-PBDEs were observed depending on their degree of bromination. Four low-brominated OH-PBDEs (2′-OH-BDE-28, 3′-OH-BDE-28, 5-OH-BDE-47, 6-OH-BDE-47) were found to be TR agonists, which recruited the coactivator peptide and enhanced GH3 cell proliferation. However, three high-brominated OH-PBDEs (3-OH-BDE-100, 3′-OH-BDE-154, 4-OH-BDE-188) were tested to be antagonists. Molecular docking was employed to simulate the interactions of OH-PBDEs with TR and identify the structural determinants for TR binding and activity. According to the docking results, low-brominated OH-PBDEs, which are weak binders but TR agonists, bind with TR at the inner side of its binding pocket, whereas high-brominated compounds, which are potent binders but TR antagonists, reside at the outer region. These results indicate that OH-PBDEs have different activities on TR (agonistic or antagonistic), possibly due to their different binding geometries with the receptor. - Highlights: ► Thyroid hormone (TH) activity of OH-PBDEs with different Br number was evaluated. ► Four different experimental approaches were employed to investigate the mechanism. ► Low-brominated OH-PBDEs were agonists, but high-brominated ones were antagonists.

  20. Hormone receptor status of a first primary breast cancer predicts contralateral breast cancer risk in the WECARE study population.

    Science.gov (United States)

    Reiner, Anne S; Lynch, Charles F; Sisti, Julia S; John, Esther M; Brooks, Jennifer D; Bernstein, Leslie; Knight, Julia A; Hsu, Li; Concannon, Patrick; Mellemkjær, Lene; Tischkowitz, Marc; Haile, Robert W; Shen, Ronglai; Malone, Kathleen E; Woods, Meghan; Liang, Xiaolin; Morrow, Monica; Bernstein, Jonine L

    2017-07-19

    Previous population-based studies have described first primary breast cancer tumor characteristics and their association with contralateral breast cancer (CBC) risk. However, information on influential covariates such as treatment, family history of breast cancer, and BRCA1/2 mutation carrier status was not available. In a large, population-based, case-control study, we evaluated whether tumor characteristics of the first primary breast cancer are associated with risk of developing second primary asynchronous CBC, overall and in subgroups of interest, including among BRCA1/2 mutation non-carriers, women who are not treated with tamoxifen, and women without a breast cancer family history. The Women's Environmental Cancer and Radiation Epidemiology Study is a population-based case-control study of 1521 CBC cases and 2212 individually-matched controls with unilateral breast cancer. Detailed information about breast cancer risk factors, treatment for and characteristics of first tumors, including estrogen receptor (ER) and progesterone receptor (PR) status, was obtained by telephone interview and medical record abstraction. Multivariable risk ratios (RRs) and 95% confidence intervals (CIs) were estimated in conditional logistic regression models, adjusting for demographics, treatment, and personal medical and family history. A subset of women was screened for BRCA1/2 mutations. Lobular histology of the first tumor was associated with a 30% increase in CBC risk (95% CI 1.0-1.6). Compared to women with ER+/PR+ first tumors, those with ER-/PR- tumors had increased risk of CBC (RR = 1.4, 95% CI 1.1-1.7). Notably, women with ER-/PR- first tumors were more likely to develop CBC with the ER-/PR- phenotype (RR = 5.4, 95% CI 3.0-9.5), and risk remained elevated in multiple subgroups: BRCA1/2 mutation non-carriers, women younger than 45 years of age, women without a breast cancer family history, and women who were not treated with tamoxifen. Having a hormone receptor

  1. Activation of a cryptic splice site in the growth hormone receptor associated with growth hormone insensitivity syndrome in a genetic isolate of Laron Syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Schiavi, A.; Bartlett, R. [Univ. of Miami, FL (United States); Brown, M. [Emory Univ., Atlanta, GA (United States)] [and others

    1994-09-01

    Laron syndrome (LS) is a rare, autosomal recessive disease found worldwide. Despite various ethnic differences, all patients with LS described display classic dysmorphic features and extreme short stature due to defects in the growth hormone receptor (GHR). The vast majority of these patients are sporadic occurrences resulting from consanguineous matings; however, an Ecuadorian genetic isolate of LS has been reported. Our investigations have identified a genetic isolate of LS of Anglo Saxon origin. Seven individuals, by all clinical and biochemical criteria, have LS. As a result of extensive review of family and medical histories we have constructed a pedigree tracing the lineage of our affected patients through the 17th century. No GHR gross deletions were detected using an exon-specific PCR assay developed in our laboratory. Previous molecular analyses have identified mutations in exons 2-7 in numerous patients with classical LS. Single strand conformational polymorphism (SSCP) analysis was performed on GHR exons 2-7, and a marked conformational shift was noted in exon 7. Cycle sequencing of exon 7 from three affected individuals, and from four first-degree relatives, revealed a C{r_arrow}T transition at position 766 of the cDNA, and a heterozygous C{r_arrow}T transition at the identical position in the obligate carriers studied. This mutation is predicted to activate a cryptic donor splice site 63 base pairs upstream from the 3{prime} end of exon 7, effectively truncating the GHR cDNA without changing the reading frame. The resultant GHR protein is shortened by a proposed 21 amino acids. The identification and conformation of this mutation not only identifies a novel mutation in the GHR, and the first to be described in LS patients of English descent, but also allows for comparisons between genotypes and phenotypes in an inbred population.

  2. NCoR1-independent mechanism plays a role in the action of the unliganded thyroid hormone receptor.

    Science.gov (United States)

    Mendoza, Arturo; Astapova, Inna; Shimizu, Hiroaki; Gallop, Molly R; Al-Sowaimel, Lujain; MacGowan, S M Dileas; Bergmann, Tim; Berg, Anders H; Tenen, Danielle E; Jacobs, Christopher; Lyubetskaya, Anna; Tsai, Linus; Hollenberg, Anthony N

    2017-09-18

    Nuclear receptor corepressor 1 (NCoR1) is considered to be the major corepressor that mediates ligand-independent actions of the thyroid hormone receptor (TR) during development and in hypothyroidism. We tested this by expressing a hypomorphic NCoR1 allele (NCoR1ΔID), which cannot interact with the TR, in Pax8-KO mice, which make no thyroid hormone. Surprisingly, abrogation of NCoR1 function did not reverse the ligand-independent action of the TR on many gene targets and did not fully rescue the high mortality rate due to congenital hypothyroidism in these mice. To further examine NCoR1's role in repression by the unliganded TR, we deleted NCoR1 in the livers of euthyroid and hypothyroid mice and examined the effects on gene expression and enhancer activity measured by histone 3 lysine 27 (H3K27) acetylation. Even in the absence of NCoR1 function, we observed strong repression of more than 43% of positive T3 (3,3',5-triiodothyronine) targets in hypothyroid mice. Regulation of approximately half of those genes correlated with decreased H3K27 acetylation, and nearly 80% of these regions with affected H3K27 acetylation contained a bona fide TRβ1-binding site. Moreover, using liver-specific TRβ1-KO mice, we demonstrate that hypothyroidism-associated changes in gene expression and histone acetylation require TRβ1. Thus, many of the genomic changes mediated by the TR in hypothyroidism are independent of NCoR1, suggesting a role for additional signaling modulators in hypothyroidism.

  3. Human fear acquisition deficits in relation to genetic variants of the corticotropin releasing hormone receptor 1 and the serotonin transporter.

    Directory of Open Access Journals (Sweden)

    Ivo Heitland

    Full Text Available The ability to identify predictors of aversive events allows organisms to appropriately respond to these events, and failure to acquire these fear contingencies can lead to maladaptive contextual anxiety. Recently, preclinical studies demonstrated that the corticotropin-releasing factor and serotonin systems are interactively involved in adaptive fear acquisition. Here, 150 healthy medication-free human subjects completed a cue and context fear conditioning procedure in a virtual reality environment. Fear potentiation of the eyeblink startle reflex (FPS was measured to assess both uninstructed fear acquisition and instructed fear expression. All participants were genotyped for polymorphisms located within regulatory regions of the corticotropin releasing hormone receptor 1 (CRHR1 - rs878886 and the serotonin transporter (5HTTLPR. These polymorphisms have previously been linked to panic disorder and anxious symptomology and personality, respectively. G-allele carriers of CRHR1 (rs878886 showed no acquisition of fear conditioned responses (FPS to the threat cue in the uninstructed phase, whereas fear acquisition was present in C/C homozygotes. Moreover, carrying the risk alleles of both rs878886 (G-allele and 5HTTLPR (short allele was associated with increased FPS to the threat context during this phase. After explicit instructions regarding the threat contingency were given, the cue FPS and context FPS normalized in all genotype groups. The present results indicate that genetic variability in the corticotropin-releasing hormone receptor 1, especially in interaction with the 5HTTLPR, is involved in the acquisition of fear in humans. This translates prior animal findings to the human realm.

  4. p35 regulates the CRM1-dependent nucleocytoplasmic shuttling of nuclear hormone receptor coregulator-interacting factor 1 (NIF-1.

    Directory of Open Access Journals (Sweden)

    Xiao-Su Zhao

    Full Text Available Cyclin-dependent kinase 5 (Cdk5 is a proline-directed serine/threonine kinase, which plays critical roles in a wide spectrum of neuronal functions including neuronal survival, neurite outgrowth, and synapse development and plasticity. Cdk5 activity is controlled by its specific activators: p35 or p39. While knockout studies reveal that Cdk5/p35 is critical for neuronal migration during early brain development, functions of Cdk5/p35 have been unraveled through the identification of the interacting proteins of p35, most of which are Cdk5/p35 substrates. However, it remains unclear whether p35 can regulate neuronal functions independent of Cdk5 activity. Here, we report that a nuclear protein, nuclear hormone receptor coregulator (NRC-interacting factor 1 (NIF-1, is a new interacting partner of p35. Interestingly, p35 regulates the functions of NIF-1 independent of Cdk5 activity. NIF-1 was initially discovered as a transcriptional regulator that enhances the transcriptional activity of nuclear hormone receptors. Our results show that p35 interacts with NIF-1 and regulates its nucleocytoplasmic trafficking via the nuclear export pathway. Furthermore, we identified a nuclear export signal on p35; mutation of this site or blockade of the CRM1/exportin-dependent nuclear export pathway resulted in the nuclear accumulation of p35. Intriguingly, blocking the nuclear export of p35 attenuated the nuclear accumulation of NIF-1. These findings reveal a new p35-dependent mechanism in transcriptional regulation that involves the nucleocytoplasmic shuttling of transcription regulators.

  5. p35 regulates the CRM1-dependent nucleocytoplasmic shuttling of nuclear hormone receptor coregulator-interacting factor 1 (NIF-1).

    Science.gov (United States)

    Zhao, Xiao-Su; Fu, Wing-Yu; Chien, Winnie W Y; Li, Zhen; Fu, Amy K Y; Ip, Nancy Y

    2014-01-01

    Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase, which plays critical roles in a wide spectrum of neuronal functions including neuronal survival, neurite outgrowth, and synapse development and plasticity. Cdk5 activity is controlled by its specific activators: p35 or p39. While knockout studies reveal that Cdk5/p35 is critical for neuronal migration during early brain development, functions of Cdk5/p35 have been unraveled through the identification of the interacting proteins of p35, most of which are Cdk5/p35 substrates. However, it remains unclear whether p35 can regulate neuronal functions independent of Cdk5 activity. Here, we report that a nuclear protein, nuclear hormone receptor coregulator (NRC)-interacting factor 1 (NIF-1), is a new interacting partner of p35. Interestingly, p35 regulates the functions of NIF-1 independent of Cdk5 activity. NIF-1 was initially discovered as a transcriptional regulator that enhances the transcriptional activity of nuclear hormone receptors. Our results show that p35 interacts with NIF-1 and regulates its nucleocytoplasmic trafficking via the nuclear export pathway. Furthermore, we identified a nuclear export signal on p35; mutation of this site or blockade of the CRM1/exportin-dependent nuclear export pathway resulted in the nuclear accumulation of p35. Intriguingly, blocking the nuclear export of p35 attenuated the nuclear accumulation of NIF-1. These findings reveal a new p35-dependent mechanism in transcriptional regulation that involves the nucleocytoplasmic shuttling of transcription regulators.

  6. Evaluating the Survival Benefit Following Ovarian Function Suppression in Premenopausal Patients with Hormone Receptor Positive Early Breast Cancer.

    Science.gov (United States)

    Qiu, Lin; Fu, Fangmeng; Huang, Meng; Lin, Yuxiang; Chen, Yazhen; Chen, Minyan; Wang, Chuan

    2016-05-27

    There are divergent opinions regarding the use of ovarian function suppression or ablation (hereafter, OFS) in hormone receptor positive early breast cancer patients. In order to clarify the survival benefit of OFS, a meta-analysis was performed. The result is that use of OFS was more effective than no OFS on DFS (the pooled relative risk (pRR) = 0.86; 95% CI: 0.75-0.96) and on OS (pRR = 0.79; 95% CI: 0.70-0.89). In subgroup analysis, we found that increased DFS was positively associated with patients who had received chemotherapy (pRR = 0.85; 95% CI: 0.74-0.96), who were lymph node negative (pRR = 0.74; 95% CI: 0.61-0.91) and were less than 40 years old (pRR = 0.71; 95% CI: 0.59-0.83). There was a significant difference in OS between the groups receiving chemotherapy (pRR = 0.73; 95% CI: 0.58-0.89) or for patients less than 40 years old (pRR = 0.52; 95% CI: 0.18-0.87). The use of OFS also produces statistical differences in the occurrence of the side-effects; severe hot flashes (pRR = 2.32; 95% CI: 1.36-3.97), and hypertension (pRR = 1.54; 95% CI: 1.12-2.12). In general, OFS should be considered as one treatment for hormone receptor positive premenopausal early breast cancer patients who have received chemotherapy and are less than 40 years old. We also should pay attention to the side-effects and weigh the advantages and disadvantages before deciding on using OFS.

  7. The nuclear hormone receptor coactivator NRC is a pleiotropic modulator affecting growth, development, apoptosis, reproduction, and wound repair.

    Science.gov (United States)

    Mahajan, Muktar A; Das, Sharmistha; Zhu, Hong; Tomic-Canic, Marjana; Samuels, Herbert H

    2004-06-01

    Nuclear hormone receptor coregulator (NRC) is a 2,063-amino-acid coregulator of nuclear hormone receptors and other transcription factors (e.g., c-Fos, c-Jun, and NF-kappaB). We and others have generated C57BL/6-129S6 hybrid (C57/129) NRC(+/-) mice that appear outwardly normal and grow and reproduce. In contrast, homozygous deletion of the NRC gene is embryonic lethal. NRC(-/-) embryos are always smaller than NRC(+/+) embryos, and NRC(-/-) embryos die between 8.5 and 12.5 days postcoitus (dpc), suggesting that NRC has a pleotrophic effect on growth. To study this, we derived mouse embryonic fibroblasts (MEFs) from 12.5-dpc embryos, which revealed that NRC(-/-) MEFs exhibit a high rate of apoptosis. Furthermore, a small interfering RNA that targets mouse NRC leads to enhanced apoptosis of wild-type MEFs. The finding that C57/129 NRC(+/-) mice exhibit no apparent phenotype prompted us to develop 129S6 NRC(+/-) mice, since the phenotype(s) of certain gene deletions may be strain dependent. In contrast with C57/129 NRC(+/-) females, 20% of 129S6 NRC(+/-) females are infertile while 80% are hypofertile. The 129S6 NRC(+/-) males produce offspring when crossed with wild-type 129S6 females, although fertility is reduced. The 129S6 NRC(+/-) mice tend to be stunted in their growth compared with their wild-type littermates and exhibit increased postnatal mortality. Lastly, both C57/129 NRC(+/-) and 129S6 NRC(+/-) mice exhibit a spontaneous wound healing defect, indicating that NRC plays an important role in that process. Our findings reveal that NRC is a coregulator that controls many cellular and physiologic processes ranging from growth and development to reproduction and wound repair.

  8. Diverse Transcriptional Programs Associated with Environmental Stress and Hormones in the Arabidopsis Receptor-Like Kinase Gene Family

    Institute of Scientific and Technical Information of China (English)

    Lee Chae; Sylvia Sudat; Sandrine Dudoit; Tong Zhu; Sheng Luan

    2009-01-01

    The genome of Arabidopsis thaliana encodes more than 600 receptor-like kinase (RLK) genes, by far the dominant class of receptors found in land plants. Although similar to the mammalian receptor tyrosine kinases, plant RLKs are serine/threonine kinases that represent a novel signaling innovation unique to plants and, consequently, an excellent opportunity to understand how extracellular signaling evolved and functions in plants as opposed to animals. RLKs are predicted to be major components of the signaling pathways that allow plants to respond to environmental and developmental conditions. However, breakthroughs in identifying these processes have been limited to only a handful of individual RLKs. Here, we used a Syngenta custom Arabidopsis GeneChip array to compile a detailed profile of the transcriptional activity of 604 receptor-like kinase genes after exposure to a cross-section of known signaling factors in plants,including abiotic stresses, biotic stresses, and hormones. In the 68 experiments comprising the study, we found that 582 of the 604 RLK genes displayed a two-fold or greater change in expression to at least one of 12 types of treatments, thereby providing a large body of experimental evidence for targeted functional screens of individual RLK genes. We investigated whether particular subfamilies of RLK genes are responsive to specific types of signals and found that each subfamily displayed broad ranges of expression, as opposed to being targeted towards particular signal classes. Finally, by analyzing the divergence of sequence and gene expression among the RLK subfamilies, we present evidence as to the functional basis for the expansion of the RLKs and how this expansion may have affected conservation and divergences in their function. Taken as a whole, our study represents a preliminary, working model of processes and interactions in which the members of the RLK gene family may be involved, where such information has remained elusive for so many

  9. Currently used pesticides and their mixtures affect the function of sex hormone receptors and aromatase enzyme activity

    Energy Technology Data Exchange (ETDEWEB)

    Kjeldsen, Lisbeth Stigaard; Ghisari, Mandana; Bonefeld-Jørgensen, Eva Cecilie, E-mail: ebj@mil.au.dk

    2013-10-15

    . - Highlights: • Currently used pesticides possess endocrine-disrupting (ED) potential in vitro. • ED effects can be mediated via sex hormone receptors and/or the aromatase enzyme. • Additive mixture effects on androgen receptor transactivity were observed.

  10. Effects of sex steroid hormones on neuromedin S and neuromedin U2 receptor expression following experimental traumatic brain injury.

    Science.gov (United States)

    Khaksari, Mohammad; Maghool, Fatemeh; Asadikaram, Gholamreza; Hajializadeh, Zahra

    2016-10-01

    Neuroprotective effects of female gonadal steroids are mediated through several pathways involving multiple peptides and receptors after traumatic brain injury (TBI). Two of these peptides are including the regulatory peptides neuromedin U (NMU) and neuromedin S (NMS), and their common receptor neuromedin U2 receptor (NMUR2). This study investigates the effects of physiological doses of estradiol and progesterone on brain edema, NMS and NMU as well as NMUR2 expression following TBI. Ovariectomized female rats were given high-and low-dose of female sex steroid hormones through implantation of capsules for a week before trauma. The brain NMUR2 expression, prepro-NMS expression, NMU content, and water content (brain edema) were evaluated 24 hr after TBI induced by Marmarou's method. Percentage of brain water content in high- and low-dose estradiol, and in high- and low- dose progesterone was less than vehicle (P<0.01). Results show high expression of prepro-NMS in high dose progesterone (TBI-HP) rats compared to the high dose estrogen (TBI-HE), as well as vehicle (P<0.01). NMU content in low-dose progesterone (TBI-LP) group was more than that of vehicle group (P<0.001). Furthermore a difference in NMU content observed between TBI-HP compared to TBI-HE, and vehicle (P<0.05). The NMUR2 mRNA expression revealed an upregulation in TBI-HP rats compared to the TBI-HE group (P<0.001). Findings indicate that progesterone attenuates brain edema and induces an increase in NMS and its receptor which may mediate the anti-edematous effect of progesterone after TBI.

  11. Is altered expression of hepatic insulin-related genes in growth hormone receptor knockout mice due to GH resistance or a difference in biological life spans?

    Science.gov (United States)

    Panici, Jacob A; Wang, Feiya; Bonkowski, Michael S; Spong, Adam; Bartke, Andrzej; Pawlikowska, Ludmila; Kwok, Pui-Yan; Masternak, Michal M

    2009-11-01

    Growth hormone receptor knockout (GHRKO) mice live about 40%-55% longer than their normal (N) littermates. Previous studies of 21-month-old GHRKO and N mice showed major alterations of the hepatic expression of genes involved in insulin signaling. Differences detected at this age may have been caused by the knockout of the growth hormone receptor (GHR) or by differences in biological age between GHRKO and N mice. To address this question, we compared GHRKO and N mice at ages corresponding to the same percentage of median life span to see if the differences of gene expression persisted. Comparison of GHRKO and N mice at approximately 50% of biological life span showed significant differences in hepatic expression of all 14 analyzed genes. We conclude that these changes are due to disruption of GHR gene and the consequent suppression of growth hormone signaling rather than to differences in "biological age" between mutant and normal animals sampled at the same chronological age.

  12. Dietary fiber intake and risk of hormonal receptor-defined breast cancer in the European Prospective Investigation into Cancer and Nutrition study1,2

    NARCIS (Netherlands)

    Ferrari, P.; Rinaldi, S.; Jenab, M.; Lukanova, A.; Olsen, A.; Tjonneland, A.; Overvad, K.; Clavel-Chapelon, F.; Fagherazzi, G.; Touillaud, M.; Kaaks, R.; Rusten, A. von; Boeing, H.; Trichopoulou, A.; Lagiou, P.; Benetou, V.; Grioni, S.; Panico, S.; Masala, G.; Tumino, R.; Polidoro, S.; Bakker, M.F.; Gils, C.H. van; Ros, M.M.; Bueno-De-Mesquita, H.B.; Krum-Hansen, S.; Engeset, D.; Skeie, G.; Pilar, A.; Sanchez, M.J.; Buckland, G.; Ardanaz, E.; Chirlaque, D.; Rodriguez, L.; Travis, R.; Key, T.; Khaw, K.T.; Wareham, N.J.; Sund, M.; Lenner, P.; Slimani, N.; Norat, T.; Aune, D.; Riboli, E.; Romieu, I.

    2013-01-01

    BACKGROUND: Limited scientific evidence has characterized the association between dietary fiber intake and risk of breast cancer (BC) by menopausal status and hormone receptor expression in tumors. OBJECTIVE: We investigated the relation between total dietary fiber and its main food sources (vegetab

  13. Crystal structure of an affinity-matured prolactin complexed to its dimerized receptor reveals the topology of hormone binding site 2

    DEFF Research Database (Denmark)

    Broutin, Isabelle; Jomain, Jean-Baptiste; Tallet, Estelle;

    2010-01-01

    We report the first crystal structure of a 1:2 hormone.receptor complex that involves prolactin (PRL) as the ligand, at 3.8-A resolution. Stable ternary complexes were obtained by generating affinity-matured PRL variants harboring an N-terminal tail from ovine placental lactogen, a closely relate...

  14. Human fear acquisition deficits in relation to genetic variants of the corticotropin releasing hormone receptor 1 and the serotonin transporter - revisited

    NARCIS (Netherlands)

    Heitland, I; Groenink, L; van Gool, J M; Domschke, K; Reif, A; Baas, J M P

    We recently showed that a genetic polymorphism (rs878886) in the human corticotropin releasing hormone receptor 1 (CRHR1) is associated with reduced fear conditioned responses to a threat cue. This is a potentially important finding considering that the failure to acquire fear contingencies can

  15. CYP19A1 polymorphisms and clinical outcomes in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial

    DEFF Research Database (Denmark)

    Leyland-Jones, Brian; Gray, Kathryn P; Abramovitz, Mark;

    2015-01-01

    To determine whether CYP19A1 polymorphisms are associated with abnormal activity of aromatase and with musculoskeletal and bone side effects of aromatase inhibitors. DNA was isolated from tumor specimens of 4861 postmenopausal women with hormone receptor-positive breast cancer enrolled in the BIG...

  16. Adrenocorticotrophic hormone (ACTH) stimulation of sheep fetal adrenal cortex can occur without increased expression of ACTH receptor (ACTH-R) mRNA

    DEFF Research Database (Denmark)

    Carter, A M; Petersen, Y M; Towstoless, M

    2002-01-01

    In the present study, it was hypothesized that the adrenocorticotrophin hormone receptor (ACTH-R) would be up-regulated in the adrenal gland of the sheep fetus following infusion of physiological amounts of ACTH, as shown for adrenal cortical cells in culture. In chronically catheterized sheep, a...

  17. Dietary fiber intake and risk of hormonal receptor-defined breast cancer in the European Prospective Investigation into Cancer and Nutrition study1,2

    NARCIS (Netherlands)

    Ferrari, P.; Rinaldi, S.; Jenab, M.; Lukanova, A.; Olsen, A.; Tjonneland, A.; Overvad, K.; Clavel-Chapelon, F.; Fagherazzi, G.; Touillaud, M.; Kaaks, R.; Rusten, A. von; Boeing, H.; Trichopoulou, A.; Lagiou, P.; Benetou, V.; Grioni, S.; Panico, S.; Masala, G.; Tumino, R.; Polidoro, S.; Bakker, M.F.; Gils, C.H. van; Ros, M.M.; Bueno-De-Mesquita, H.B.; Krum-Hansen, S.; Engeset, D.; Skeie, G.; Pilar, A.; Sanchez, M.J.; Buckland, G.; Ardanaz, E.; Chirlaque, D.; Rodriguez, L.; Travis, R.; Key, T.; Khaw, K.T.; Wareham, N.J.; Sund, M.; Lenner, P.; Slimani, N.; Norat, T.; Aune, D.; Riboli, E.; Romieu, I.

    2013-01-01

    BACKGROUND: Limited scientific evidence has characterized the association between dietary fiber intake and risk of breast cancer (BC) by menopausal status and hormone receptor expression in tumors. OBJECTIVE: We investigated the relation between total dietary fiber and its main food sources

  18. Modular insulators: genome wide search for composite CTCF/thyroid hormone receptor binding sites.

    Directory of Open Access Journals (Sweden)

    Oliver Weth

    Full Text Available The conserved 11 zinc-finger protein CTCF is involved in several transcriptional mechanisms, including insulation and enhancer blocking. We had previously identified two composite elements consisting of a CTCF and a TR binding site at the chicken lysozyme and the human c-myc genes. Using these it has been demonstrated that thyroid hormone mediates the relief of enhancer blocking even though CTCF remains bound to its binding site. Here we wished to determine whether CTCF and TR combined sites are representative of a general feature of the genome, and whether such sites are functional in regulating enhancer blocking. Genome wide analysis revealed that about 18% of the