Cross-regulation of signaling pathways: An example of nuclear hormone receptors and the canonical Wnt pathway

International Nuclear Information System (INIS)

Beildeck, Marcy E.; Gelmann, Edward P.; Byers, Stephen W.

2010-01-01

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.

Hormonal control of spermatogenesis: expression of FSJH receptor and androgen receptor genes

NARCIS (Netherlands)

L.J. Blok (Leen)

1992-01-01

textabstractFSH and testosterone are the main hormonal regulators of spermatogenesis. The actions of androgens and FSH are mediated by their respective receptors. Receptor gene expression (mRNA and protein). is an important determinant of hormone action. Biochemical aspects of the regulation of

DMPD: NOD-like receptors (NLRs): bona fide intracellular microbial sensors. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 18585455 NOD-like receptors (NLRs): bona fide intracellular microbial sensors. Shaw...tml) (.csml) Show NOD-like receptors (NLRs): bona fide intracellular microbial sensors. PubmedID 18585455 Ti...tle NOD-like receptors (NLRs): bona fide intracellular microbial sensors. Authors

Nuclear Import and Export of the Thyroid Hormone Receptor.

Science.gov (United States)

Zhang, Jibo; Roggero, Vincent R; Allison, Lizabeth A

2018-01-01

The thyroid hormone receptors, TRα1 and TRβ1, are members of the nuclear receptor superfamily that forms one of the most abundant classes of transcription factors in multicellular organisms. Although primarily localized to the nucleus, TRα1 and TRβ1 shuttle rapidly between the nucleus and cytoplasm. The fine balance between nuclear import and export of TRs has emerged as a critical control point for modulating thyroid hormone-responsive gene expression. Mutagenesis studies have defined two nuclear localization signal (NLS) motifs that direct nuclear import of TRα1: NLS-1 in the hinge domain and NLS-2 in the N-terminal A/B domain. Three nuclear export signal (NES) motifs reside in the ligand-binding domain. A combined approach of shRNA-mediated knockdown and coimmunoprecipitation assays revealed that nuclear entry of TRα1 is facilitated by importin 7, likely through interactions with NLS-2, and importin β1 and the adapter importin α1 interacting with both NLS-1 and NLS-2. Interestingly, TRβ1 lacks NLS-2 and nuclear import depends solely on the importin α1/β1 heterodimer. Heterokaryon and fluorescence recovery after photobleaching shuttling assays identified multiple exportins that play a role in nuclear export of TRα1, including CRM1 (exportin 1), and exportins 4, 5, and 7. Even single amino acid changes in TRs dramatically alter their intracellular distribution patterns. We conclude that mutations within NLS and NES motifs affect nuclear shuttling activity, and propose that TR mislocalization contributes to the development of some types of cancer and Resistance to Thyroid Hormone syndrome. © 2018 Elsevier Inc. All rights reserved.

Repeated blockade of mineralocorticoid receptors, but not of glucocorticoid receptors impairs food rewarded spatial learning

NARCIS (Netherlands)

Douma, B. R.; Korte, S. M.; Buwalda, B.; La Fleur, S. E.; Bohus, B.; Luiten, P. G.

1998-01-01

Corticosteroids from the adrenal cortex influence a variety of behaviours including cognition, learning and memory. These hormones act via two intracellular receptors, the mineralo-corticoid receptor (MR) and the glucocorticoid receptor (GR). These two receptor types display a high concentration and

Repeated blockade of mineralocorticoid receptors, but not of glucocorticoid receptors impairs food rewarded spatial learning

NARCIS (Netherlands)

Douma, BRK; Korte, SM; Buwalda, B; la Fleur, SE; Bohus, B; Luiten, PGM

Corticosteroids from the adrenal cortex influence a variety of behaviours including cognition, learning and memory. These hormones act via two intracellular receptors, the mineralo-corticoid receptor (MR) and the glucocorticoid receptor (GR). These two receptor types display a high concentration and

The role of nuclear hormone receptors in cutaneous wound repair.

Science.gov (United States)

Rieger, Sandra; Zhao, Hengguang; Martin, Paige; Abe, Koichiro; Lisse, Thomas S

2015-01-01

The cutaneous wound repair process involves balancing a dynamic series of events ranging from inflammation, oxidative stress, cell migration, proliferation, survival and differentiation. A complex series of secreted trophic factors, cytokines, surface and intracellular proteins are expressed in a temporospatial manner to restore skin integrity after wounding. Impaired initiation, maintenance or termination of the tissue repair processes can lead to perturbed healing, necrosis, fibrosis or even cancer. Nuclear hormone receptors (NHRs) in the cutaneous environment regulate tissue repair processes such as fibroplasia and angiogenesis. Defects in functional NHRs and their ligands are associated with the clinical phenotypes of chronic non-healing wounds and skin endocrine disorders. The functional relationship between NHRs and skin niche cells such as epidermal keratinocytes and dermal fibroblasts is pivotal for successful wound closure and permanent repair. The aim of this review is to delineate the cutaneous effects and cross-talk of various nuclear receptors upon injury towards functional tissue restoration. Copyright © 2014 John Wiley & Sons, Ltd.

Thyroid Stimulating Hormone Receptor

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Murat Tuncel

2017-02-01

Full Text Available Thyroid stimulating hormone receptor (TSHR plays a pivotal role in thyroid hormone metabolism. It is a major controller of thyroid cell function and growth. Mutations in TSHR may lead to several thyroid diseases, most commonly hyperthyroidism. Although its genetic and epigenetic alterations do not directly lead to carcinogenesis, it has a crucial role in tumor growth, which is initiated by several oncogenes. This article will provide a brief review of TSHR and related diseases.

Dependence of calcium on thyroid hormone for the regulation of ...

African Journals Online (AJOL)

concentration by mobilizing intracellular Ca2+. The mobilization of intracellular Ca2+in the absence of transmembrane Ca2+influx has been accepted as evidence for a cell-surface Ca2+ - receptor. The possible role of thyroid hormone in the ...

Hormone receptor expression in male breast cancers | Akosa ...

African Journals Online (AJOL)

Male breast cancers are rare but have been found in higher proportions in Black Africans. Prognostic factors for breast cancers include tumour size, grade and stage, and hormone receptor status. The hormone receptor status is an invaluable guide in the use of adjuvant endocrine therapy, but none of the reports available ...

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.

The interferon response to intracellular DNA: why so many receptors?

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Unterholzner, Leonie

2013-11-01

The detection of intracellular DNA has emerged to be a key event in the innate immune response to viruses and intracellular bacteria, and during conditions of sterile inflammation and autoimmunity. One of the consequences of the detection of DNA as a 'stranger' and a 'danger' signal is the production of type I interferons and pro-inflammatory cytokines. Much work has been dedicated to the elucidation of the signalling cascades that activate this DNA-induced gene expression programme. However, while many proteins have been proposed to act as sensors for intracellular DNA in recent years, none has been met with universal acceptance, and a theory linking all the recent observations is, as yet, lacking. This review presents the evidence for the various interferon-inducing DNA receptors proposed to date, and examines the hypotheses that might explain why so many different receptors appear to be involved in the innate immune recognition of intracellular DNA. Copyright © 2013 Elsevier GmbH. All rights reserved.

Defective membrane expression of human growth hormone (GH) receptor causes Laron-type GH insensitivity syndrome.

Science.gov (United States)

Duquesnoy, P; Sobrier, M L; Amselem, S; Goossens, M

1991-01-01

Mutations in the growth hormone receptor (GHR) gene can cause growth hormone (GH) resistance. Given the sequence homology between the extracellular domain of the GHR and a soluble GH-binding protein (GH-BP), it is remarkable that GH-BP binding activity is absent from the serum of patients with Laron-type GH insensitivity, a hereditary form of severe dwarfism. We have previously identified a mutation within the extracellular domain of this receptor, replacing phenylalanine by serine at position 96 of the mature protein, in a patient with Laron syndrome. We have now investigated the effect of this Phe----Ser substitution on hormone binding activity by expressing the total human GHR cDNA and mutant form in eukaryotic cells. The wild-type protein expressed was able to bind GH but no plasma membrane binding was detectable on cells transfected with the mutant cDNA; this was also the case of cells transfected with a Phe96----Ala mutant cDNA, suggesting that the lack of binding activity is not due to a posttranslational modification of serine. Examination of the variant proteins in subcellular fractions revealed the presence of specific GH binding activity in the lysosomal fraction, whereas immunofluorescence studies located mutant proteins in the cytosol. Our findings suggest that these mutant GHRs fail to follow the correct intracellular transport pathway and underline the potential importance of this phenylalanine residue, which is conserved among the GH, prolactin, and erythropoietin receptors that belong to the same cytokine receptor superfamily. Images PMID:1719554

Efficacy of chemotherapy after hormone therapy for hormone receptor-positive metastatic breast cancer.

Science.gov (United States)

Mori, Ryutaro; Nagao, Yasuko

2014-01-01

According to the guidelines for metastatic breast cancer, hormone therapy for hormone receptor-positive metastatic breast cancer without life-threatening metastasis should be received prior to chemotherapy. Previous trials have investigated the sensitivity of chemotherapy for preoperative breast cancer based on the efficacy of neoadjuvant hormone therapy. In this retrospective study, we investigated the efficacy of chemotherapy for metastatic breast cancer in hormone therapy-effective and hormone therapy-ineffective cases. Patients who received chemotherapy after hormone therapy for metastatic breast cancer between 2006 and 2013 at our institution were investigated. A total of 32 patients received chemotherapy after hormone therapy for metastatic breast cancer. The median patient age was 59 years, and most of the primary tumors exhibited a T2 status. A total of 26 patients had an N(+) status, while 7 patients had human epidermal growth factor receptor 2-positive tumors. A total of 13 patients received clinical benefits from hormone therapy, with a rate of clinical benefit of subsequent chemotherapy of 30.8%, which was not significantly different from that observed in the hormone therapy-ineffective patients (52.6%). A total of 13 patients were able to continue the hormone therapy for more than 1 year, with a rate of clinical benefit of chemotherapy of 38.5%, which was not significantly different from that observed in the short-term hormone therapy patients (47.4%). The luminal A patients were able to continue hormone therapy for a significantly longer period than the non-luminal A patients (median survival time: 17.8 months vs 6.35 months, p = 0.0085). However, there were no significant differences in the response to or duration of chemotherapy. The efficacy of chemotherapy for metastatic breast cancer cannot be predicted based on the efficacy of prior hormone therapy or tumor subtype, and clinicians should administer chemotherapy in all cases of

Identification of an estrogenic hormone receptor in Caenorhabditis elegans

International Nuclear Information System (INIS)

Mimoto, Ai; Fujii, Madoka; Usami, Makoto; Shimamura, Maki; Hirabayashi, Naoko; Kaneko, Takako; Sasagawa, Noboru; Ishiura, Shoichi

2007-01-01

Changes in both behavior and gene expression occur in Caenorhabditis elegans following exposure to sex hormones such as estrogen and progesterone, and to bisphenol A (BPA), an estrogenic endocrine-disrupting compound. However, only one steroid hormone receptor has been identified. Of the 284 known nuclear hormone receptors (NHRs) in C. elegans, we selected nhr-14, nhr-69, and nhr-121 for analysis as potential estrogenic hormone receptors, because they share sequence similarity with the human estrogen receptor. First, the genes were cloned and expressed in Escherichia coli, and then the affinity of each protein for estrogen was determined using a surface plasmon resonance (SPR) biosensor. All three NHRs bound estrogen in a dose-dependent fashion. To evaluate the specificity of the binding, we performed a solution competition assay using an SPR biosensor. According to our results, only NHR-14 was able to interact with estrogen. Therefore, we next examined whether nhr-14 regulates estrogen signaling in vivo. To investigate whether these interactions actually control the response of C. elegans to hormones, we investigated the expression of vitellogenin, an estrogen responsive gene, in an nhr-14 mutant. Semi-quantitative RT-PCR showed that vitellogenin expression was significantly reduced in the mutant. This suggests that NHR-14 is a C. elegans estrogenic hormone receptor and that it controls gene expression in response to estrogen

Revisiting available knowledge on teleostean thyroid hormone receptors.

Science.gov (United States)

Lazcano, Iván; Orozco, Aurea

2018-03-21

Teleosts are the most numerous class of living vertebrates. They exhibit great diversity in terms of morphology, developmental strategies, ecology and adaptation. In spite of this diversity, teleosts conserve similarities at molecular, cellular and endocrine levels. In the context of thyroidal systems, and as in the rest of vertebrates, thyroid hormones in fish regulate development, growth and metabolism by actively entering the nucleus and interacting with thyroid hormone receptors, the final sensors of this endocrine signal, to regulate gene expression. In general terms, vertebrates express the functional thyroid hormone receptors alpha and beta, encoded by two distinct genes (thra and thrb, respectively). However, different species of teleosts express thyroid hormone receptor isoforms with particular structural characteristics that confer singular functional traits to these receptors. For example, teleosts contain two thra genes and in some species also two thrb; some of the expressed isoforms can bind alternative ligands. Also, some identified isoforms contain deletions or large insertions that have not been described in other vertebrates and that have not yet been functionally characterized. As in amphibians, the regulation of some of these teleost isoforms coincides with the climax of metamorphosis and/or life transitions during development and growth. In this review, we aimed to gain further insights into thyroid signaling from a comparative perspective by proposing a systematic nomenclature for teleost thyroid hormone receptor isoforms and summarize their particular functional features when the information was available. Copyright © 2018 Elsevier Inc. All rights reserved.

Application of hormone receptor assay for clinical chemistry

International Nuclear Information System (INIS)

Sato, Seiya

1978-01-01

A conception of hormone receptors was explained to understand radioreceptor assay (RRA), and various problems in the operation of this method were described mainly. The principle of RRA is the same as that of RIA and CPBA, and measured values by RRA resembled to those by bioassay more closely than those by RIA. However, the sensitivity of RRA was inferior to that of RIA. It was important in using this method especially for measurement of peptide hormone not to deactivate biological the base by radioactivation. As the significance of this method in clinical chemistry, it was mentioned that this method was one kind of experiment to observe the biological activity of hormones, and that properties analysis of receptors, studies on action mechanism, the structure and function of hormone, the pathological analysis of endocrine abnormalities, and the development of drugs and treatment methods for receptors may become possible by this method. The other usefulness of this method was also mentioned. (Kanao, N.)

Application of hormone receptor assay for clinical chemistry

Energy Technology Data Exchange (ETDEWEB)

Sato, S [Kitasato Univ. Hospital, Sagamihara, Kanagawa (Japan)

1978-06-01

A conception of hormone receptors was explained to understand radioreceptor assay (RRA), and various problems in the operation of this method were described mainly. The principle of RRA is the same as that of RIA and CPBA, and measured values by RRA resembled to those by bioassay more closely than those by RIA. However, the sensitivity of RRA was inferior to that of RIA. It was important in using this method especially for measurement of peptide hormone not to deactivate biological the base by radioactivation. As the significance of this method in clinical chemistry, it was mentioned that this method was one kind of experiment to observe the biological activity of hormones, and that properties analysis of receptors, studies on action mechanism, the structure and function of hormone, the pathological analysis of endocrine abnormalities, and the development of drugs and treatment methods for receptors may become possible by this method. The other usefulness of this method was also mentioned.

Growth hormone, interferon-gamma, and leukemia inhibitory factor utilize insulin receptor substrate-2 in intracellular signaling

DEFF Research Database (Denmark)

Argetsinger, L S; Norstedt, G; Billestrup, Nils

1996-01-01

In this report, we demonstrate that insulin receptor substrate-2 (IRS-2) is tyrosyl-phosphorylated following stimulation of 3T3-F442A fibroblasts with growth hormone (GH), leukemia inhibitory factor and interferon-gamma. In response to GH and leukemia inhibitory factor, IRS-2 is immediately...... for GH is further demonstrated by the finding that GH stimulates association of IRS-2 with the 85-kDa regulatory subunit of phosphatidylinositol 3'-kinase and with the protein-tyrosine phosphatase SHP2. These results are consistent with the possibility that IRS-2 is a downstream signaling partner...

Thyroid Hormone, Cancer, and Apoptosis.

Science.gov (United States)

Lin, Hung-Yun; Chin, Yu-Tan; Yang, Yu-Chen S H; Lai, Husan-Yu; Wang-Peng, Jacqueline; Liu, Leory F; Tang, Heng-Yuan; Davis, Paul J

2016-06-13

Thyroid hormones play important roles in regulating normal metabolism, development, and growth. They also stimulate cancer cell proliferation. Their metabolic and developmental effects and growth effects in normal tissues are mediated primarily by nuclear hormone receptors. A cell surface receptor for the hormone on integrin [alpha]vβ3 is the initiation site for effects on tumor cells. Clinical hypothyroidism may retard cancer growth, and hyperthyroidism was recently linked to the prevalence of certain cancers. Local levels of thyroid hormones are controlled through activation and deactivation of iodothyronine deiodinases in different organs. The relative activities of different deiodinases that exist in tissues or organs also affect the progression and development of specific types of cancers. In this review, the effects of thyroid hormone on signaling pathways in breast, brain, liver, thyroid, and colon cancers are discussed. The importance of nuclear thyroid hormone receptor isoforms and of the hormone receptor on the extracellular domain of integrin [alpha]vβ3 as potential cancer risk factors and therapeutic targets are addressed. We analyze the intracellular signaling pathways activated by thyroid hormones in cancer progression in hyperthyroidism or at physiological concentrations in the euthyroid state. Determining how to utilize the deaminated thyroid hormone analog (tetrac), and its nanoparticulate derivative to reduce risks of cancer progression, enhance therapeutic outcomes, and prevent cancer recurrence is also deliberated. © 2016 American Physiological Society. Compr Physiol 6:1221-1237, 2016. Copyright © 2016 John Wiley & Sons, Inc.

Generalized resistance to thyroid hormone associated with a mutation in the ligand-binding domain of the human thyroid hormone receptor β

International Nuclear Information System (INIS)

Sakurai, A.; Takeda, K.; Ain, K.; Ceccarelli, P.; Nakai, A.; Seino, S.; Bell, G.I.; Refetoff, S.; DeGroot, L.J.

1989-01-01

The syndrome of generalized resistance to thyroid hormone is characterized by elevated circulating levels of thyroid hormone in the presence of an overall eumetabolic state and failure to respond normally to triiodothyronine. The authors have evaluated a family with inherited generalized resistance to thyroid hormone for abnormalities in the thyroid hormone nuclear receptors. A single guanine → cytosine replacement in the codon for amino acid 340 resulted in a glycine → arginine substitution in the hormone-binding domain of one of two alleles of the patient's thyroid hormone nuclear receptor β gene. In vitro translation products of this mutant human thyroid hormone nuclear receptor β gene did not bind triiodothyronine. Thus, generalized resistance to thyroid hormone can result from expression of an abnormal thyroid hormone nuclear receptor molecule

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

Science.gov (United States)

Grøntved, Lars; Waterfall, Joshua J; Kim, Dong Wook; Baek, Songjoon; Sung, Myong-Hee; Zhao, Li; Park, Jeong Won; Nielsen, Ronni; Walker, Robert L; Zhu, Yuelin J; Meltzer, Paul S; Hager, Gordon L; Cheng, Sheue-yann

2015-04-28

A bimodal switch model is widely used to describe transcriptional regulation by the thyroid hormone receptor (TR). In this model, the unliganded TR forms stable, chromatin-bound complexes with transcriptional co-repressors to repress transcription. Binding of hormone dissociates co-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 gene transcription. Genome-wide footprinting analysis using DNase-seq provides little evidence for TR footprints both in the absence and presence of hormone, suggesting that unliganded TR engagement with repressive complexes on chromatin is, similar to activating receptor complexes, a highly dynamic process. This dynamic and ligand-dependent interaction with chromatin is likely shared by all steroid hormone receptors regardless of their capacity to repress transcription in the absence of ligand.

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...

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...

Ontogenic and sexual differences in pituitary GnRH receptors and intracellular Ca2+ mobilization induced by GnRH.

Science.gov (United States)

Lacau-Mengido, I M; González Iglesias, A; Lux-Lantos, V; Libertun, C; Becú-Villalobos, D

1998-04-01

The present experiments were designed in order to elucidate the participation of the developing hypophysis in determining the changing sensitivity of gonadotrophins to gonadotropin-releasing hormone (GnRH) during ontogeny in the rat. To that end, we chose two well defined developmental ages that differ markedly in sexual and ontogenic characteristics of hypophyseal sensitivity to GnRH, 15 and 30 d. In order to study sex differences and the role of early sexual organization of the hypothalamus, experiments were carried out in males, females, and neonatally androgenized females (TP females). We evaluated (1) the characteristics of pituitary GnRH receptors, and (2) associated changes in GnRH-induced mobilization of intracellular Ca2+ (a second messenger involved in gonadotropins exocytosis). We measured binding characteristics of the GnRH analog D-Ser(TBu)6-des-Gly10-GnRH ethylamide in pituitary homogenates. We found that Kds did not vary among the different sex groups. Total number and concentration of receptors decreased in the female rat from 15-30 d of age, whereas in the male and TP female, receptors/pituitary increased, and the concentration/mg tissue did not change. Also, at 30 days of age, males presented higher content and concentration of receptors than females, and higher content than TP females. In order to evaluate if developmental and sexual differences in pituitary sensitivity to GnRH might be expressed through variations in the intracellular Ca2+ signal, we studied the mobilization of intracellular Ca2+ induced by GnRH (1 x 10(-8) to 1 x 10(-11) M) in a suspension of dispersed pituitary cells in the six groups. In cells from 15-d-old females, Ca2+ response was greater than in 30-d-old females at the doses of 10(-8) to 10(-10) M, indicating that in the infantile female rat activation of highly concentrated GnRH receptors is reflected in an increase in signal transduction mediated by Ca2+. In males and in female rats androgenized at birth, there was also

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.

Structure and proteolysis of the growth hormone receptor on rat hepatocytes

International Nuclear Information System (INIS)

Yamada, K.; Lipson, K.E.; Donner, D.B.

1987-01-01

125 I-Labeled human growth hormone is isolated in high molecular weight (M/sub r/) (300,000, 220,000, and 130,000) and low molecular weight complexes on rat hepatocytes after affinity labeling. The time-dependent formation of low molecular weight complexes occurred at the expense of the higher molecular weight species and was inhibited by low temperature or inhibitors of serine proteinases. Exposure to reducing conditions induced loss of M/sub r/ 300,000 and 220,000 species and augmented the amount of M/sub r/ 130,000 complexes. The molecular weight of growth hormone (22,000) suggests that binding had occurred with species of M/sub r/ 280,000, 200,000, and 100,000. Two-dimensional gel electrophoresis demonstrated that the 100,000-dalton receptor subunit is contained in both the 280,000- and 200-000-dalton species. Reduction of interchain disulfide bonds in the growth hormone receptor did not alter its elution from gel filtration columns, but intact, high molecular weight receptor constituents were separated from lower molecular weight degradation products. Digestion of affinity-labeled growth hormone-receptor complexes with neuraminidase increased the mobility of receptor constituents on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. These observations show that the growth hormone receptor is degraded by hepatic serine proteinases to low molecular weight degradation products which can be separated from intact receptor by gel filtration. Intact hormone-receptor complexes are aggregates of 100,000-dalton sialoglycoprotein subunits held together by interchain disulfide bonds and by noncovalent forces

Emerging Paradigm of Intracellular Targeting of G Protein-Coupled Receptors.

Science.gov (United States)

Chaturvedi, Madhu; Schilling, Justin; Beautrait, Alexandre; Bouvier, Michel; Benovic, Jeffrey L; Shukla, Arun K

2018-05-04

G protein-coupled receptors (GPCRs) recognize a diverse array of extracellular stimuli, and they mediate a broad repertoire of signaling events involved in human physiology. Although the major effort on targeting GPCRs has typically been focused on their extracellular surface, a series of recent developments now unfold the possibility of targeting them from the intracellular side as well. Allosteric modulators binding to the cytoplasmic surface of GPCRs have now been described, and their structural mechanisms are elucidated by high-resolution crystal structures. Furthermore, pepducins, aptamers, and intrabodies targeting the intracellular face of GPCRs have also been successfully utilized to modulate receptor signaling. Moreover, small molecule compounds, aptamers, and synthetic intrabodies targeting β-arrestins have also been discovered to modulate GPCR endocytosis and signaling. Here, we discuss the emerging paradigm of intracellular targeting of GPCRs, and outline the current challenges, potential opportunities, and future outlook in this particular area of GPCR biology. Copyright © 2018 Elsevier Ltd. All rights reserved.

Surveillance for Intracellular Antibody by Cytosolic Fc Receptor TRIM21

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William A. McEwan

2016-11-01

Full Text Available TRIM21 has emerged as an atypical Fc receptor that is broadly conserved and widely expressed in the cytoplasm of mammalian cells. Viruses that traffic surface-bound antibodies into the cell during infection recruit TRIM21 via a high affinity interaction between Fc and TRIM21 PRYSPRY domain. Following binding of intracellular antibody, TRIM21 acts as both antiviral effector and sensor for innate immune signalling. These activities serve to reduce viral replication by orders of magnitude in vitro and contribute to host survival during in vivo infection. Neutralization occurs rapidly after detection and requires the activity of the ubiquitin-proteasome system. The microbial targets of this arm of intracellular immunity are still being identified: TRIM21 activity has been reported following infection by several non-enveloped viruses and intracellular bacteria. These findings extend the sphere of influence of antibodies to the intracellular domain and have broad implications for immunity. TRIM21 has been implicated in the chronic auto-immune condition systemic lupus erythematosus and is itself an auto-antigen in Sjögren’s syndrome. This review summarises our current understanding of TRIM21’s role as a cytosolic Fc receptor and briefly discusses pathological circumstances where intracellular antibodies have been described, or are hypothesized to occur, and may benefit from further investigations of the role of TRIM21.

α-Helical element at the hormone-binding surface of the insulin receptor functions as a signaling element to activate its tyrosine kinase.

Science.gov (United States)

Whittaker, Jonathan; Whittaker, Linda J; Roberts, Charles T; Phillips, Nelson B; Ismail-Beigi, Faramarz; Lawrence, Michael C; Weiss, Michael A

2012-07-10

The primary hormone-binding surface of the insulin receptor spans one face of the N-terminal β-helix of the α-subunit (the L1 domain) and an α-helix in its C-terminal segment (αCT). Crystallographic analysis of the free ectodomain has defined a contiguous dimer-related motif in which the αCT α-helix packs against L1 β-strands 2 and 3. To relate structure to function, we exploited expanded genetic-code technology to insert photo-activatable probes at key sites in L1 and αCT. The pattern of αCT-mediated photo-cross-linking within the free and bound receptor is in accord with the crystal structure and prior mutagenesis. Surprisingly, L1 photo-probes in β-strands 2 and 3, predicted to be shielded by αCT, efficiently cross-link to insulin. Furthermore, anomalous mutations were identified on neighboring surfaces of αCT and insulin that impair hormone-dependent activation of the intracellular receptor tyrosine kinase (contained within the transmembrane β-subunit) disproportionately to their effects on insulin binding. Taken together, these results suggest that αCT, in addition to its hormone-recognition role, provides a signaling element in the mechanism of receptor activation.

The Growth Hormone Receptor: Mechanism of Receptor Activation, Cell Signaling, and Physiological Aspects

Directory of Open Access Journals (Sweden)

Farhad Dehkhoda

2018-02-01

Full Text Available The growth hormone receptor (GHR, although most well known for regulating growth, has many other important biological functions including regulating metabolism and controlling physiological processes related to the hepatobiliary, cardiovascular, renal, gastrointestinal, and reproductive systems. In addition, growth hormone signaling is an important regulator of aging and plays a significant role in cancer development. Growth hormone activates the Janus kinase (JAK–signal transducer and activator of transcription (STAT signaling pathway, and recent studies have provided a new understanding of the mechanism of JAK2 activation by growth hormone binding to its receptor. JAK2 activation is required for growth hormone-mediated activation of STAT1, STAT3, and STAT5, and the negative regulation of JAK–STAT signaling comprises an important step in the control of this signaling pathway. The GHR also activates the Src family kinase signaling pathway independent of JAK2. This review covers the molecular mechanisms of GHR activation and signal transduction as well as the physiological consequences of growth hormone signaling.

Diseases associated with growth hormone-releasing hormone receptor (GHRHR) mutations.

Science.gov (United States)

Martari, Marco; Salvatori, Roberto

2009-01-01

The growth hormone (GH)-releasing hormone (GHRH) receptor (GHRHR) belongs to the G protein-coupled receptors family. It is expressed almost exclusively in the anterior pituitary, where it is necessary for somatotroph cells proliferation and for GH synthesis and secretion. Mutations in the human GHRHR gene (GHRHR) can impair ligand binding and signal transduction, and have been estimated to cause about 10% of autosomal recessive familial isolated growth hormone deficiency (IGHD). Mutations reported to date include five splice donor site mutations, two microdeletions, two nonsense mutations, seven missense mutations, and one mutation in the promoter. These mutations have an autosomal recessive mode of inheritance, and heterozygous individuals do not show signs of IGHD, although the presence of an intermediate phenotype has been hypothesized. Conversely, patients with biallelic mutations have low serum insulin-like growth factor-1 and GH levels (with absent or reduced GH response to exogenous stimuli), resulting--if not treated--in proportionate dwarfism. This chapter reviews the biology of the GHRHR, the mutations that affect its gene and their effects in homozygous and heterozygous individuals. Copyright © 2009 Elsevier Inc. All rights reserved.

LDL Receptors as Gateways for Intracellular Porphyrin Uptake

International Nuclear Information System (INIS)

Novick, S.; Laster, B.; Quastel, M.

2004-01-01

Boronated compounds are currently being studied for possible use in Boron Neutron Capture Therapy (BNCT). We found that one of these agents, BOPP (tetrakis-carborane-carboxylate, esters of 2,4-bis (a,b- dihydroxyethyl) deuteroporphyrin IX), could also be labeled with indium (In-BOPP) and, therefore, could also be used potentially to transport high Z atoms into tumor cell DNA for AET (Auger Electron Therapy). In order to assess the uptake of these agents into cells, the role of the LDL receptor in the intracellular accumulation of BOPP and In-BOPP was investigated. Pre-incubation of V-79 Chinese hamster cells in medium containing delipidized fetal bovine serum (FBS) markedly increased the subsequent uptake of intracellular boron transported by both BOPP and In-BOPP when compared with cells that had been pre-incubated with medium containing 10% normal FBS (lipidized). The increased uptake was characterized by elevated levels of receptor, and greater affinity was shown for both BOPP and In-BOPP, although less marked with the latter. Positive cooperativity was demonstrated by sigmoid saturation curves, Scatchard analysis and Hill plots. Increasing the amount of LDL in the incubation medium had a relatively small effect on the total accumulation of either indium or boron atoms inside the cell. Furthermore, chemical acetylation of LDL did not decrease the intracellular uptake of either boron or indium transported by BOPP or In-BOPP. It is thus concluded that BOPP and In-BOPP preferentially enter the cells directly by way of the LDL receptor and that only a small fraction of these molecules are transported into the cells indirectly using serum LDLs as their carriers. These data suggest a novel way of bringing greater amounts of boron and indium (and perhaps other agents) into tissues. Porphyrins can be used to transport different agents into tumor cells because they are tumor affinic molecules. Tumors express a higher number of LDL receptors than do most normal tissues

Radioreceptor assays: plasma membrane receptors and assays for polypeptide and glycoprotein hormones

International Nuclear Information System (INIS)

Schulster, D.

1977-01-01

Receptors for peptide, protein and glycoprotein hormones, and the catecholamines are located on the plasma membranes of their target cells. Preparations of the receptors may be used as specific, high-affinity binding agents for these hormones in assay methodology akin to that for radioimmunoassay. A particular advantage of the radioreceptor assay is that it has a specificity directed towards the biologically active region of the hormone, rather than to some immunologically active region that may have little (or no) involvement in the expression of hormonal activity. Methods for hormone receptor preparation vary greatly, and range from the use of intact cells (as the source of hormone receptor) to the use of purified or solubilized membrane receptors. Receptors isolated from plasma membranes have proved to be of variable stability, and may be damaged during preparation and/or storage. Moreover, since they are present in relatively low concentration in the cell, their preparation in sufficient quantity for use in a radioreceptor assay may present technical problems. In general, there is good correlation between radioreceptor assays and in-vitro bioassays; differences between results from radioreceptor assays and radioimmunoassays are similar to those noted between in-vitro bioassays and radioimmunoassays. The sensitivity of the method is such that normal plasma concentrations of various hormones have been assayed by this technique. (author)

Dual pathways for the intracellular processing of insulin. Relationship between retroendocytosis of intact hormone and the recycling of insulin receptors

International Nuclear Information System (INIS)

Marshall, S.

1985-01-01

Adipocytes process insulin through either of two pathways: a retroendocytotic pathway that culminates in the release of intact insulin, and a degradative pathway that terminates in the intracellular catabolism and release of degraded ligand. Mechanistically, these pathways were found to differ in several ways. First, temporal differences were found in the rate at which intact and degraded products were extruded. After 125 I-insulin was preloaded into the cell interior, intact ligand was completely released during the first 10 min (t 1/2 = 2 min), whereas degraded insulin was released at a much slower rate over 1 h (t 1/2 greater than 8 min). Secondly, it was found that chloroquine profoundly inhibited the insulin degradative pathway, resulting in the intracellular accumulation of intact ligand and a reduction in the release of degraded products. In contrast, however, chloroquine was without effect on the retroendocytotic processing of insulin. Based on the known actions of chloroquine, it appears that retroendocytosis of insulin does not involve vesicular acidification or dissociation of the insulin-receptor complex and that insulin is most likely carried to the cell exterior in the same vesicles (either receptor-bound or free) as those mediating recycling receptors. Interestingly, accumulation of undergraded insulin within chloroquine-treated cells did not result in the release of additional intact ligand, suggesting that once insulin enters the degradative compartment it is committed to catabolism and cannot exit the cell through the retroendocytotic pathway. A third difference was revealed by the finding that extracellular unlabeled insulin (100 ng/ml) markedly accelerated the rate at which preloaded 125 I-insulin was released from adipocytes (t 1/2 of 3 min versus 7 min in controls cells)

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

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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

Ghrelin increases intracellular Ca²⁺ concentration in the various hormone-producing cell types of the rat pituitary gland.

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Yamazaki, Mami; Aizawa, Sayaka; Tanaka, Toru; Sakai, Takafumi; Sakata, Ichiro

2012-09-20

Ghrelin, isolated from the stomach as an endogenous ligand for the growth hormone secretagogue receptor (GHS-R), has potent growth hormone release ability in vivo and in vitro. Although GHS-R is abundantly expressed in the pituitary gland, there is no direct evidence of a relationship between hormone-producing cells and functional GHS-R in the pituitary gland. The aim of this study was to determine which anterior pituitary cells respond to ghrelin stimulation in male rats. We performed Fura-2 Ca(2+) imaging analysis using isolated pituitary cells, and performed immunocytochemistry to identify the type of pituitary hormone-producing cells. In Fura-2 Ca(2+) imaging analysis, ghrelin administration increased the intracellular Ca(2+) concentration in approximately 50% of total isolated anterior pituitary cells, and 20% of these cells strongly responded to ghrelin. Immunocytochemical analysis revealed that 82.9 ± 1.3% of cells that responded to ghrelin stimulation were GH-immunopositive. On the other hand, PRL-, LH-, and ACTH-immunopositive cells constituted 2.0 ± 0.3%, 12.6 ± 0.3%, and 2.5 ± 0.8% of ghrelin-responding pituitary cells, respectively. TSH-immunopositive cells did not respond to ghrelin treatment. These results suggest that ghrelin directly acts not only on somatotrophs, but also on mammotrophs, gonadotrophs, and corticotrophs in the rat pituitary gland. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Thyroid hormone and retinoic acid nuclear receptors: specific ligand-activated transcription factors

International Nuclear Information System (INIS)

Brtko, J.

1998-01-01

Transcriptional regulation by both the thyroid hormone and the vitamin A-derived 'retinoid hormones' is a critical component in controlling many aspects of higher vertebrate development and metabolism. Their functions are mediated by nuclear receptors, which comprise a large super-family of ligand-inducible transcription factors. Both the thyroid hormone and the retinoids are involved in a complex arrangement of physiological and development responses in many tissues of higher vertebrates. The functions of 3,5,3'-triiodothyronine (T 3 ), the thyromimetically active metabolite of thyroxine as well as all-trans retinoic acid, the biologically active vitamin A metabolite are mediated by nuclear receptor proteins that are members of the steroid/thyroid/retinoid hormone receptor family. The functions of all members of the receptor super family are discussed. (authors)

Killing of intracellular Mycobacterium tuberculosis by receptor-mediated drug delivery

International Nuclear Information System (INIS)

Majumdar, S.; Basu, S.K.

1991-01-01

p-Aminosalicylic acid (PAS) conjugated to maleylated bovine serum albumin (MBSA) was taken up efficiently through high-affinity MBSA-binding sites on macrophages. Binding of the radiolabeled conjugate to cultured mouse peritoneal macrophages at 4 degrees C was competed for by MBSA but not by PAS. At 37 degrees C, the radiolabeled conjugate was rapidly degraded by the macrophages, leading to release of acid-soluble degradation products in the medium. The drug conjugate was nearly 100 times as effective as free PAS in killing the intracellular mycobacteria in mouse peritoneal macrophages infected in culture with Mycobacterium tuberculosis. The killing of intracellular mycobacteria mediated by the drug conjugate was effectively prevented by simultaneous addition of excess MBSA (100 micrograms/ml) or chloroquine (3 microM) to the medium, whereas these agents did not affect the microbicidal action of free PAS. These results suggest that (i) uptake of the PAS-MBSA conjugate was mediated by cell surface receptors on macrophages which recognize MBSA and (ii) lysosomal hydrolysis of the internalized conjugate resulted in intracellular release of a pharmacologically active form of the drug, which led to selective killing of the M. tuberculosis harbored by mouse macrophages infected in culture. This receptor-mediated modality of delivering drugs to macrophages could contribute to greater therapeutic efficacy and minimization of toxic side effects in the management of tuberculosis and other intracellular mycobacterial infections

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.

Facial morphometry of Ecuadorian patients with growth hormone receptor deficiency/Laron syndrome.

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Schaefer, G B; Rosenbloom, A L; Guevara-Aguirre, J; Campbell, E A; Ullrich, F; Patil, K; Frias, J L

1994-01-01

Facial morphometry using computerised image analysis was performed on patients with growth hormone receptor deficiency (Laron syndrome) from an inbred population of southern Ecuador. Morphometrics were compared for 49 patients, 70 unaffected relatives, and 14 unrelated persons. Patients with growth hormone receptor deficiency showed significant decreases in measures of vertical facial growth as compared to unaffected relatives and unrelated persons with short stature from other causes. This report validates and quantifies the clinical impression of foreshortened facies in growth hormone receptor deficiency. Images PMID:7815422

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

DEFF Research Database (Denmark)

Rytved, Klaus A.; Nielsen, Robert

1999-01-01

Antidiuretic hormone; tight epithelium; prostaglandin receptors; sulprostone; misoprostol; cAMP; cellular Ca2+......Antidiuretic hormone; tight epithelium; prostaglandin receptors; sulprostone; misoprostol; cAMP; cellular Ca2+...

Sphingosine-1-phosphate receptors: Zooming in on ligand-induced intracellular trafficking and its functional implications

NARCIS (Netherlands)

Verzijl, Dennis; Peters, Stephan L. M.; Alewijnse, Astrid E.

2010-01-01

Regulatory processes including receptor phosphorylation and intracellular trafficking, also referred to as receptor internalization, are important processes to terminate G protein-coupled receptor (GPCR) signaling. Compelling evidence now indicates that internalization of a receptor is not

Hormone action. Part I. Peptide hormones

International Nuclear Information System (INIS)

Birnbaumer, L.; O'Malley, B.W.

1985-01-01

The major sections of this book on the hormonal action of peptide hormones cover receptor assays, identification of receptor proteins, methods for identification of internalized hormones and hormone receptors, preparation of hormonally responsive cells and cell hybrids, purification of membrane receptors and related techniques, assays of hormonal effects and related functions, and antibodies in hormone action

Thyroid hormone receptor binds to a site in the rat growth hormone promoter required for induction by thyroid hormone

International Nuclear Information System (INIS)

Koenig, R.J.; Brent, G.A.; Warne, R.L.; Larsen, P.R.; Moore, D.D.

1987-01-01

Transcription of the rat growth hormone (rGH) gene in pituitary cells is increased by addition of thyroid hormone (T3). This induction is dependent on the presence of specific sequences just upstream of the rGH promoter. The authors have partially purified T3 receptor from rat liver and examined its interaction with these rGH sequences. They show here that T3 receptor binds specifically to a site just upstream of the basal rGH promoter. This binding site includes two copies of a 7-base-pair direct repeat, the centers of which are separated by 10 base pairs. Deletions that specifically remove the T3 receptor binding site drastically reduce response to T3 in transient transfection experiments. These results demonstrate that T3 receptor can recognize specific DNA sequences and suggest that it can act directly as a positive transcriptional regulatory factor

Structural and functional plasticity of the luteinizing hormone/choriogonadotrophin receptor.

Science.gov (United States)

Troppmann, Britta; Kleinau, Gunnar; Krause, Gerd; Gromoll, Jörg

2013-01-01

BACKGROUND In recent years it became evident that several types of the luteinizing hormone/choriogonadotrophin receptor (LHCGR) exist. In addition to the classical receptor type known in rodents, an LHCGR type containing an additional exon is present in primates and humans. This specific exon 6A introduces a hitherto unknown regulatory pathway of the LHCGR at the transcriptional level which can lead to the expression of an alternative protein covering the extracellular part only. Furthermore, an LHCGR type lacking exon 10 at the mRNA and protein levels has been described in the New World primate lineage, giving rise to an additional receptor type in which amino acids of the extracellular hinge region connecting the leucine-rich repeat domain and transmembrane domain are missing. METHODS Topic-related information was retrieved by systematic searches using Medline/PubMed. Structural homology models were retrieved from a glycoprotein hormone receptors web application and from recent publications. RESULTS In a novel approach, we combine functional aspects with three-dimensional properties of the LHCGR and the different receptor types to deduce causative relationships between these two parameters. On this basis, the physiological impact and patho-physiological consequences of the different LHCGR types are inferred. CONCLUSIONS The complex system of different LHCGR types and two corresponding hormones (LH and CG) represents a major challenge for future studies on selective hormone binding, signal transduction and receptor regulation. The presence of these naturally occurring LHCGR types requires re-examining of our present view on receptor function, experimental set-ups and data interpretation, but also offers new clinical approaches to interfere with LH/CG action in humans.

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

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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.

Hormone receptor densities in relation to 10B neutron capture therapy

International Nuclear Information System (INIS)

Hechter, O.; Schwartz, I.L.

1982-01-01

This presentation is a theoretical discussion of the possibility that appropriate steroid-carborane derivatives might be used to selectively deliver boron-10 ( 10 B) to tumor cells with sex-hormone receptors in sufficient concentration for effective neutron capture theory (NCT) of hormone-dependent mammary and prostatic cancer. The results indicate the concentrations of androgen receptors (AR) and progesterone receptors (PR) in malignant prostatic cells or of estrogen receptors (ER) in malignant mammary cells are two low to achieve nuclear 10 B concentrations of 1 + g per g of tumor by using a steroid ligand coupled to a single carborane cage

Sex Hormones and Their Receptors Regulate Liver Energy Homeostasis

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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.

Microsomal receptor for steroid hormones: functional implications for nuclear activity.

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Muldoon, T G; Watson, G H; Evans, A C; Steinsapir, J

1988-01-01

Target tissues for steroid hormones are responsive by virtue of and to the extent of their content of functional intracellular receptors. Recent years have seen a shift in considerations of the cellular dynamics and distribution of these receptors, with current views favoring predominant intranuclear localization in the intact cell. This paper summarizes our analyses of the microsomal estrogen and androgen binding capability of rat uterine and ventral prostate tissue, respectively; these studies have revealed a set of high affinity sites that may act as a conduit for estrogen traversing the cell en route to the nucleus. These sites have many properties in common with cytosolic receptors, with the salient difference of a failure to activate to a more avid DNA-binding form under conditions which permit such activation of cytosolic receptors. The microsomal estrogen-binding proteins also have appreciable affinity for progesterone, another distinction from other known cellular estrogen receptor species. Various experimental approaches were employed to demonstrate that the microsomal receptors were not simply cytosol contaminants; the most convincing evidence is the recent successful separation of the cytosolic and microsomal forms by differential ammonium sulfate precipitation. Discrete subfractionation of subcellular components on successive sucrose gradients, with simultaneous assessments of binding capability and marker enzyme concentrations, indicates that the major portion of the binding is localized within the vesicles of the endoplasmic reticulum free of significant plasma membrane contamination. The microsomal receptors are readily solubilized by extraction with high- or low-salt-containing buffers or with steroid. The residual microsomes following such extraction have the characteristics of saturable acceptor sites for cytosolic estrogen-receptor complexes. The extent to which these sites will accept the cytosolic complexes is equal to the concentration of

Evolutionary aspects of growth hormones and prolactins and their receptors

International Nuclear Information System (INIS)

Tarpey, J.F.

1986-01-01

The interactions of GH's, PRL's and PL's with receptors for GH and PRL were examined from a comparative and evolutionary viewpoint. The binding of 125 I-bGH to membrane preparations from liver of representatives of the major classes of non-mammalian vertebrates was also studied. Only hepatic membranes from sturgeon and Gillichthys had significant bGH binding and were further characterized and compared with male rabbit liver membranes in terms of time, temperature, pH, and membrane concentration to optimize binding conditions. The binding of several members of the GH, PRL, PL family of hormones to GH receptors from liver of sturgeon, Gillichthys, rabbit, mouse and rat was investigated. in terms of hormonal specificity, the mammalian receptors and the sturgeon binding sites were similar, while Gillichthys receptors had a different pattern of hormonal specificity. The binding of 125 I-oPRL to renal membranes of the turtle, Pseudemys scripta elegans, was characterized and compared to PRL binding sites of kidney membranes of the bullfrog, Rana catesbeiana, and the tiger salamander, Ambystoma tigrinum

A mutation in the receptor Methoprene-tolerant alters juvenile hormone response in insects and crustaceans.

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Miyakawa, Hitoshi; Toyota, Kenji; Hirakawa, Ikumi; Ogino, Yukiko; Miyagawa, Shinichi; Oda, Shigeto; Tatarazako, Norihisa; Miura, Toru; Colbourne, John K; Iguchi, Taisen

2013-01-01

Juvenile hormone is an essential regulator of major developmental and life history events in arthropods. Most of the insects use juvenile hormone III as the innate juvenile hormone ligand. By contrast, crustaceans use methyl farnesoate. Despite this difference that is tied to their deep evolutionary divergence, the process of this ligand transition is unknown. Here we show that a single amino-acid substitution in the receptor Methoprene-tolerant has an important role during evolution of the arthropod juvenile hormone pathway. Microcrustacea Daphnia pulex and D. magna share a juvenile hormone signal transduction pathway with insects, involving Methoprene-tolerant and steroid receptor coactivator proteins that form a heterodimer in response to various juvenoids. Juvenile hormone-binding pockets of the orthologous genes differ by only two amino acids, yet a single substitution within Daphnia Met enhances the receptor's responsiveness to juvenile hormone III. These results indicate that this mutation within an ancestral insect lineage contributed to the evolution of a juvenile hormone III receptor system.

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

A bimodal switch model is widely used to describe transcriptional regulation by the thyroid hormone receptor (TR). In this model, the unliganded TR forms stable, chromatin-bound complexes with transcriptional co-repressors to repress transcription. Binding of hormone dissociates co...

Time-resolved quantitative analysis of CCK1 receptor-induced intracellular calcium increase.

NARCIS (Netherlands)

Staljanssens, D.; Vos, W.H. De; Willems, P.H.; Camp, J. Van; Smagghe, G.

2012-01-01

Cholecystokinin (CCK) is a gastrointestinal hormone, which regulates many physiological functions such as satiety by binding to the CCK receptor (CCKR). Molecules, which recognize this receptor can mimic or block CCK signaling and thereby influence CCKR-mediated processes. We have set up a

Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo

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Hönes, G. Sebastian; Rakov, Helena; Logan, John

2017-01-01

Thyroid hormone (TH) and TH receptors (TRs) α and β act by binding to TH response elements (TREs) in regulatory regions of target genes. This nuclear signaling is established as the canonical or type 1 pathway for TH action. Nevertheless, TRs also rapidly activate intracellular second-messenger s...

Extended hormone binding site of the human thyroid stimulating hormone receptor: distinctive acidic residues in the hinge region are involved in bovine thyroid stimulating hormone binding and receptor activation.

Science.gov (United States)

Mueller, Sandra; Kleinau, Gunnar; Jaeschke, Holger; Paschke, Ralf; Krause, Gerd

2008-06-27

The human thyroid stimulating hormone receptor (hTSHR) belongs to the glycoprotein hormone receptors that bind the hormones at their large extracellular domain. The extracellular hinge region of the TSHR connects the N-terminal leucine-rich repeat domain with the membrane-spanning serpentine domain. From previous studies we reasoned that apart from hormone binding at the leucine-rich repeat domain, additional multiple hormone contacts might exist at the hinge region of the TSHR by complementary charge-charge recognition. Here we investigated highly conserved charged residues in the hinge region of the TSHR by site-directed mutagenesis to identify amino acids interacting with bovine TSH (bTSH). Indeed, the residues Glu-297, Glu-303, and Asp-382 in the TSHR hinge region are essential for bTSH binding and partially for signal transduction. Side chain substitutions showed that the negative charge of Glu-297 and Asp-382 is necessary for recognition of bTSH by the hTSHR. Multiple combinations of alanine mutants of the identified positions revealed an increased negative effect on hormone binding. An assembled model suggests that the deciphered acidic residues form negatively charged patches at the hinge region resulting in an extended binding mode for bTSH on the hTSHR. Our data indicate that certain positively charged residues of bTSH might be involved in interaction with the identified negatively charged amino acids of the hTSHR hinge region. We demonstrate that the hinge region represents an extracellular intermediate connector for both hormone binding and signal transduction of the hTSHR.

Variations in steroid hormone receptor content throughout age and menopausal periods, and menstrual cycle in breast cancer patients

International Nuclear Information System (INIS)

Nikolic-Vukosavljevic, D.; Vasiljevic, N.; Brankovic-Magic, M.; Polic, D.

1996-01-01

Variations in steroid hormone receptor contents throughout age and menopausal periods define three breast carcinoma groups: younger pre-menopausal carcinomas (aged up to 45), middle-aged carcinomas (aged up to 45), middle-aged carcinomas (pre-, peri-, and postmenopausal aged 45-59) and older postmenopausal carcinomas (aged over 59). Age-related steroid hormone receptor contents within pre-menopausal and postmenopausal carcinoma groups are characterized by the important increase of both receptor contents, while menopausal-related steroid hormone receptor contents within middle-aged carcinoma group (aged 45-59) are characterized by the important decrease of progesterone receptor content and estrogen receptor functionality. No variations in steroid hormone receptor contents throughout menstrual cycle within the follicular and the luteal phases were obtained. The important cycle within the follicular and the luteal phases were obtained. The important decrease of estrogen receptor content in the mid-cycle phase versus the peri-menstrual phase was found. Variations in steroid hormone receptor contents throughout age and menopausal periods, as well as throughout menstrual cycle could nod be associated with variations in the blood steroid hormone concentrations. However, important association between steroid hormone receptor contents and the blood steroid hormone concentrations was found within the luteal phase carcinoma group and within older postmenopausal carcinoma group. It is interesting that within carcinoma group with the highest concentration of progesterone, progesterone receptor content increases with an increase of the ration of estradiol and progesterone blood concentrations, while within carcinoma group with the lowest steroid hormone concentration and the highest content of estrogen receptor content, estrogen receptor content decreases with an increase of either the blood estradiol concentration or the ratio of the blood estradiol and progesterone blood

Allosteric activation of the follicle-stimulating hormone (FSH) receptor by selective, nonpeptide agonists.

Science.gov (United States)

Yanofsky, Stephen D; Shen, Emily S; Holden, Frank; Whitehorn, Erik; Aguilar, Barbara; Tate, Emily; Holmes, Christopher P; Scheuerman, Randall; MacLean, Derek; Wu, May M; Frail, Donald E; López, Francisco J; Winneker, Richard; Arey, Brian J; Barrett, Ronald W

2006-05-12

The pituitary glycoprotein hormones, luteinizing hormone and follicle-stimulating hormone (FSH), act through their cognate receptors to initiate a series of coordinated physiological events that results in germ cell maturation. Given the importance of FSH in regulating folliculogenesis and fertility, the development of FSH mimetics has been sought to treat infertility. Currently, purified and recombinant human FSH are the only FSH receptor (FSH-R) agonists available for infertility treatment. By screening unbiased combinatorial chemistry libraries, using a cAMP-responsive luciferase reporter assay, we discovered thiazolidinone agonists (EC50's = 20 microm) of the human FSH-R. Subsequent analog library screening and parallel synthesis optimization resulted in the identification of a potent agonist (EC50 = 2 nm) with full efficacy compared with FSH that was FSH-R-selective and -dependent. The compound mediated progesterone production in Y1 cells transfected with the human FSH-R (EC50 = 980 nm) and estradiol production from primary rat ovarian granulosa cells (EC50 = 10.5 nm). This and related compounds did not compete with FSH for binding to the FSH-R. Use of human FSH/thyroid-stimulating hormone (TSH) receptor chimeras suggested a novel mechanism for receptor activation through a binding site independent of the natural hormone binding site. This study is the first report of a high affinity small molecule agonist that activates a glycoprotein hormone receptor through an allosteric mechanism. The small molecule FSH receptor agonists described here could lead to an oral alternative to the current parenteral FSH treatments used clinically to induce ovarian stimulation for both in vivo and in vitro fertilization therapy.

Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription.

Science.gov (United States)

Stavreva, Diana A; Wiench, Malgorzata; John, Sam; Conway-Campbell, Becky L; McKenna, Mervyn A; Pooley, John R; Johnson, Thomas A; Voss, Ty C; Lightman, Stafford L; Hager, Gordon L

2009-09-01

Studies on glucocorticoid receptor (GR) action typically assess gene responses by long-term stimulation with synthetic hormones. As corticosteroids are released from adrenal glands in a circadian and high-frequency (ultradian) mode, such treatments may not provide an accurate assessment of physiological hormone action. Here we demonstrate that ultradian hormone stimulation induces cyclic GR-mediated transcriptional regulation, or gene pulsing, both in cultured cells and in animal models. Equilibrium receptor-occupancy of regulatory elements precisely tracks the ligand pulses. Nascent RNA transcripts from GR-regulated genes are released in distinct quanta, demonstrating a profound difference between the transcriptional programs induced by ultradian and constant stimulation. Gene pulsing is driven by rapid GR exchange with response elements and by GR recycling through the chaperone machinery, which promotes GR activation and reactivation in response to the ultradian hormone release, thus coupling promoter activity to the naturally occurring fluctuations in hormone levels. The GR signalling pathway has been optimized for a prompt and timely response to fluctuations in hormone levels, indicating that biologically accurate regulation of gene targets by GR requires an ultradian mode of hormone stimulation.

Activation of intracellular angiotensin AT2 receptors induces rapid cell death in human uterine leiomyosarcoma cells

DEFF Research Database (Denmark)

Zhao, Yi; Lützen, Ulf; Fritsch, Jürgen

2015-01-01

The presence of AT2 receptors in mitochondria and their role in NO generation and cell aging were recently demonstrated in various human and mouse non-tumour cells. We investigated the intracellular distribution of AT2 receptors including their presence in mitochondria and the role in the induction...... agonist, Compound 21 (C21) penetrates the cell membrane of quiescent SK-UT-1 cells, activates intracellular AT2 receptors and induces rapid cell death; approximately 70% of cells died within 24 h. The cells, which escaped from the cell death, displayed activation of the mitochondrial apoptotic pathway, i...

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

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, we have transfected ...

Dietary modification of metabolic pathways via nuclear hormone receptors.

Science.gov (United States)

Caiozzi, Gianella; Wong, Brian S; Ricketts, Marie-Louise

2012-10-01

Nuclear hormone receptors (NHRs), as ligand-dependent transcription factors, have emerged as important mediators in the control of whole body metabolism. Because of the promiscuous nature of several members of this superfamily that have been found to bind ligand with lower affinity than the classical steroid NHRs, they consequently display a broader ligand selectivity. This promiscuous nature has facilitated various bioactive dietary components being able to act as agonist ligands for certain members of the NHR superfamily. By binding to these NHRs, bioactive dietary components are able to mediate changes in various metabolic pathways, including, glucose, cholesterol and triglyceride homeostasis among others. This review will provide a general overview of the nuclear hormone receptors that have been shown to be activated by dietary components. The physiological consequences of such receptor activation by these dietary components will then be discussed in more detail. Copyright © 2012 John Wiley & Sons, Ltd.

(−) 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

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...

Role of cysteine residues in the carboxyl-terminus of the follicle-stimulating hormone receptor in intracellular traffic and postendocytic processing

Directory of Open Access Journals (Sweden)

Brenda Melo-Nava

2016-07-01

Full Text Available Posttranslational modifications occurring during the biosynthesis of G protein-coupled receptors include glycosylation and palmitoylation at conserved cysteine residues located in the carboxyl-terminus (Ctail of the receptor. In a number of these receptors, these modifications play an important role in receptor function and particularly, in intracellular trafficking. In the present study, the three cysteine residues present in the carboxyl-terminus of the human FSHR were replaced with glycine by site-directed mutagenesis. Wild-type and mutant (Cys627/629/655Gly FSHRs were then transiently expressed in HEK-293 cells and analyzed for cell-surface plasma membrane expression, agonist-stimulated signaling and internalization, and postendocytic processing in the abscence and presence of lysosome and/or proteasome inhibitors. Compared with the wild-type FSHR, the triple mutant FSHR exhibited ~70% reduction in plasma membrane expression as well as a profound attenuation in agonist-stimulated cAMP production and ERK1/2 phosphorylation. Incubation of HEK-293 cells expressing the wild-type FSHR with 2-bromopalmitate (palmitoylation inhibitor for 6 h, decreased plasma membrane expression of the receptor by ~30%. The internalization kinetics and β-arrestin 1 and 2 recruitment were similar between the wild-type and triple mutant FSHR as disclosed by assays performed in non-equilibrium binding conditions and by confocal microscopy. Cells expressing the mutant FSHR recycled the internalized FSHR back to the plasma membrane less efficiently than those expressing the wild-type FSHR, an effect that was counteracted by proteasome but not by lysosome inhibition. These results indicate that replacement of the cysteine residues present in the carboxyl-terminus of the FSHR, impairs receptor trafficking from the endoplasmic reticulum/Golgi apparatus to the plasma membrane and its recycling from endosomes back to the cell surface following agonist

Sigma-1 receptor: The novel intracellular target of neuropsychotherapeutic drugs

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Teruo Hayashi

2015-01-01

Full Text Available Sigma-1 receptor ligands have been long expected to serve as drugs for treatment of human diseases such as neurodegenerative disorders, depression, idiopathic pain, drug abuse, and cancer. Recent research exploring the molecular function of the sigma-1 receptor started unveiling underlying mechanisms of the therapeutic activity of those ligands. Via the molecular chaperone activity, the sigma-1 receptor regulates protein folding/degradation, ER/oxidative stress, and cell survival. The chaperone activity is activated or inhibited by synthetic sigma-1 receptor ligands in an agonist-antagonist manner. Sigma-1 receptors are localized at the endoplasmic reticulum (ER membranes that are physically associated with the mitochondria (MAM: mitochondria-associated ER membrane. In specific types of neurons (e.g., those at the spinal cord, sigma-1 receptors are also clustered at ER membranes that juxtapose postsynaptic plasma membranes. Recent studies indicate that sigma-1 receptors, partly in sake of its unique subcellular localization, regulate the mitochondria function that involves bioenergetics and free radical generation. The sigma-1 receptor may thus provide an intracellular drug target that enables controlling ER stress and free radical generation under pathological conditions.

Status of sex steroid hormone receptors in large bowel cancer

NARCIS (Netherlands)

Meggouh, F.; Lointier, P.; Pezet, D.; Saez, S.

1991-01-01

To determine the potential role of sex steroid hormones in the development of colorectal tumors in humans, specific androgen (AR), estrogen (ER), and progesterone (PGR) receptors were investigated in normal mucosa (NM) and in tumor (T) paired biopsy specimens from 94 patients. Androgen receptors

β2-Adrenergic receptor activation mobilizes intracellular calcium via a non-canonical cAMP-independent signaling pathway.

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Galaz-Montoya, Monica; Wright, Sara J; Rodriguez, Gustavo J; Lichtarge, Olivier; Wensel, Theodore G

2017-06-16

Beta adrenergic receptors (βARs) are G-protein-coupled receptors essential for physiological responses to the hormones/neurotransmitters epinephrine and norepinephrine which are found in the nervous system and throughout the body. They are the targets of numerous widely used drugs, especially in the case of the most extensively studied βAR, β 2 AR, whose ligands are used for asthma and cardiovascular disease. βARs signal through Gα s G-proteins and via activation of adenylyl cyclase and cAMP-dependent protein kinase, but some alternative downstream pathways have also been proposed that could be important for understanding normal physiological functioning of βAR signaling and its disruption in disease. Using fluorescence-based Ca 2+ flux assays combined with pharmacology and gene knock-out methods, we discovered a previously unrecognized endogenous pathway in HEK-293 cells whereby β 2 AR activation leads to robust Ca 2+ mobilization from intracellular stores via activation of phospholipase C and opening of inositol trisphosphate (InsP 3 ) receptors. This pathway did not involve cAMP, Gα s , or Gα i or the participation of the other members of the canonical β 2 AR signaling cascade and, therefore, constitutes a novel signaling mechanism for this receptor. This newly uncovered mechanism for Ca 2+ mobilization by β 2 AR has broad implications for adrenergic signaling, cross-talk with other signaling pathways, and the effects of βAR-directed drugs. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Specific DNA-binding proteins and DNA sequences involved in steroid hormone regulation of gene expression

International Nuclear Information System (INIS)

Spelsberg, T.; Hora, J.; Horton, M.; Goldberger, A.; Littlefield, B.; Seelke, R.; Toyoda, H.

1987-01-01

Steroid hormones circulate in the blood and are taken by target cells via complexes with intracellular binding proteins termed receptors, that are hormone and tissue specific. Each receptor binds it specific steroid with very high affinity, having an equilibrium dissociation constant (K/sub d/) in the range of 10 -9 to 10 -10 M. Once bound by their specific steroid hormones, the steroid receptors undergo a conformational change which allows them to bind with high affinity to sites on chromatin, termed nuclear acceptor sites. There are estimated 5,000 to 10,000 of these sites expressed with an equal number not expressed (''masked'') in intact chromatin. The result of the binding to nuclear acceptor sites is an alteration of gene transcription or, in some cases, gene expression as measured by the changing levels of specific RNAs and proteins in that target tissue. Each steroid regulates specific effects on the RNA and protein profiles. The chronology of the above mechanism of action after injection of radiolabelled steroid as is follows: Steroid-receptor complex formation (1 minute), nuclear acceptor sites (2 minutes), effects on RNA synthesis (10 to 30 minutes), and finally the changing protein profiles via changes in protein synthesis and protein turnover (1 to 6 hours). Thus steroid receptors represent one of the first identified intracellular gene regulation proteins. The receptor molecules themselves are regulated by the presence or absence of the steroid molecule

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

PURPOSE: The purpose of this study was to determine whether the length of the THRA1 microsatellite, which resides in a noncoding portion of the thyroid hormone receptor-alpha1 gene, affects receptor expression and is linked to clinicopathological parameters in thyroid cancer. EXPERIMENTAL DESIGN......: In 30 cases of surgically resected sporadic thyroid cancer, the length of the THRA1 microsatellite was determined by DNA sequence analysis, and expression of thyroid hormone receptor-alpha1 was assessed immunohistochemically in thin sections cut from tumor blocks. The length of THRA1 and expression...... of thyroid hormone receptor-alpha1 were also assessed in seven cancer cell lines. Regression analysis was used to gauge the correlation between the size of THRA1 and receptor expression. Multivariate analysis was used to test for links to the clinical parameters of gender, age, histology, stage, nodal...

Use of hormone receptors in scintigraphy of the ovaries

International Nuclear Information System (INIS)

Kairento, A.L.; Karonen, S.L.; Adlercreutz, H.

1981-01-01

Based on the mechanism of hormone receptors, luteinizing hormone (LH) labelled with 123-iodine was used as tracer in scintigraphy of rabbit ovaries. The ovaries were visualized in static pictures 6-15 min after injection except in the case where the rabbit was pre-injected with 10 μg of cold LH. 3.1% of the injected activity was found in the ovaries 14 h after injection. (orig.) [de

Hormonal receptors and vascular endothelial growth factor in juvenile nasopharyngeal angiofibroma: immunohistochemical and tissue microarray analysis.

Science.gov (United States)

Liu, Zhuofu; Wang, Jingjing; Wang, Huan; Wang, Dehui; Hu, Li; Liu, Quan; Sun, Xicai

2015-01-01

This work demonstrated that juvenile nasopharyngeal angiofibromas (JNAs) express high levels of hormone receptors and vascular endothelial growth factor (VEGF) compared with normal nasal mucosa. The interaction between hormone receptors and VEGF may be involved in the initiation and growth of JNA. JNA is a rare benign tumor that occurs almost exclusively in male adolescents. Although generally regarded as a hormone-dependent tumor, this has not been proven in previous studies. The aim of this study was to investigate the role of hormone receptors in JNA and the relationship with clinical characteristics. Standard immunohistochemical microarray analysis was performed on 70 JNA samples and 10 turbinate tissue samples. Specific antibodies for androgen receptor (AR), estrogen receptor-α (ER-α), estrogen receptor-β (ER-β), progesterone receptor (PR), and VEGF were examined, and the relationships of receptor expression with age, tumor stage, and bleeding were evaluated. RESULTS showed that JNA expressed ER-α (92.9%), ER-β (91.4%), AR (65.7%), PR (12.8%), and VEGF (95.7%) at different levels. High level of VEGF was linked to elevated ER-α and ER-β. There was no significant relationship between hormonal receptors and age at diagnosis, tumor stage or bleeding. However, overexpression of ER-α was found to be an indicator of poor prognosis (p = 0.031).

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

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...

Growth Hormone Receptor Mutations Related to Individual Dwarfism

Science.gov (United States)

Li, Charles; Zhang, Xiquan

2018-01-01

Growth hormone (GH) promotes body growth by binding with two GH receptors (GHRs) at the cell surface. GHRs interact with Janus kinase, signal transducers, and transcription activators to stimulate metabolic effects and insulin-like growth factor (IGF) synthesis. However, process dysfunctions in the GH–GHR–IGF-1 axis cause animal dwarfism. If, during the GH process, GHR is not successfully recognized and/or bound, or GHR fails to transmit the GH signal to IGF-1, the GH dysfunction occurs. The goal of this review was to focus on the GHR mutations that lead to failures in the GH–GHR–IGF-1 signal transaction process in the dwarf phenotype. Until now, more than 90 GHR mutations relevant to human short stature (Laron syndrome and idiopathic short stature), including deletions, missense, nonsense, frameshift, and splice site mutations, and four GHR defects associated with chicken dwarfism, have been described. Among the 93 identified mutations of human GHR, 68 occur extracellularly, 13 occur in GHR introns, 10 occur intracellularly, and two occur in the transmembrane. These mutations interfere with the interaction between GH and GHRs, GHR dimerization, downstream signaling, and the expression of GHR. These mutations cause aberrant functioning in the GH-GHR-IGF-1 axis, resulting in defects in the number and diameter of muscle fibers as well as bone development. PMID:29748515

Growth Hormone Receptor Mutations Related to Individual Dwarfism

Directory of Open Access Journals (Sweden)

Shudai Lin

2018-05-01

Full Text Available Growth hormone (GH promotes body growth by binding with two GH receptors (GHRs at the cell surface. GHRs interact with Janus kinase, signal transducers, and transcription activators to stimulate metabolic effects and insulin‐like growth factor (IGF synthesis. However, process dysfunctions in the GH–GHR–IGF-1 axis cause animal dwarfism. If, during the GH process, GHR is not successfully recognized and/or bound, or GHR fails to transmit the GH signal to IGF-1, the GH dysfunction occurs. The goal of this review was to focus on the GHR mutations that lead to failures in the GH–GHR–IGF-1 signal transaction process in the dwarf phenotype. Until now, more than 90 GHR mutations relevant to human short stature (Laron syndrome and idiopathic short stature, including deletions, missense, nonsense, frameshift, and splice site mutations, and four GHR defects associated with chicken dwarfism, have been described. Among the 93 identified mutations of human GHR, 68 occur extracellularly, 13 occur in GHR introns, 10 occur intracellularly, and two occur in the transmembrane. These mutations interfere with the interaction between GH and GHRs, GHR dimerization, downstream signaling, and the expression of GHR. These mutations cause aberrant functioning in the GH-GHR-IGF-1 axis, resulting in defects in the number and diameter of muscle fibers as well as bone development.

Expression profile and prognostic role of sex hormone receptors in gastric cancer

International Nuclear Information System (INIS)

Gan, Lu; He, Jian; Zhang, Xia; Zhang, Yong-Jie; Yu, Guan-Zhen; Chen, Ying; Pan, Jun; Wang, Jie-Jun; Wang, Xi

2012-01-01

Increasing interest has been devoted to the expression and possible role of sex hormone receptors in gastric cancer, but most of these findings are controversial. In the present study, the expression profile of sex hormone receptors in gastric cancer and their clinicopathological and prognostic value were determined in a large Chinese cohort. The mRNA and protein expression of estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), progesterone receptor (PR), and androgen receptor (AR) in primary gastric tumors and corresponding adjacent normal tissues from 60 and 866 Chinese gastric cancer patients was detected by real-time quantitative PCR and immunohistochemistry method, respectively. The expression profile of the four receptors was compared and their associations with clinicopathological characteristics were assessed by using Chi-square test. The prognostic value of the four receptors in gastric cancer was evaluated by using univariate and multivariate Cox regression analysis. The presence of ERα, ERβ, PR, and AR in both gastric tumors and normal tissues was confirmed but their expression levels were extremely low except for the predominance of ERβ. The four receptors were expressed independently and showed a decreased expression pattern in gastric tumors compared to adjacent normal tissues. The positive expression of the four receptors all correlated with high tumor grade and intestinal type, and ERα and AR were also associated with early TNM stage and thereby a favorable outcome. However, ERα and AR were not independent prognostic factors for gastric cancer when multivariate survival analysis was performed. Our findings indicate that the sex hormone receptors may be partly involved in gastric carcinogenesis but their clinicopathological and prognostic significance in gastric cancer appears to be limited

A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone.

Science.gov (United States)

Dos Santos, Christine; Essioux, Laurent; Teinturier, Cécile; Tauber, Maïté; Goffin, Vincent; Bougnères, Pierre

2004-07-01

Growth hormone is used to increase height in short children who are not deficient in growth hormone, but its efficacy varies largely across individuals. The genetic factors responsible for this variation are entirely unknown. In two cohorts of short children treated with growth hormone, we found that an isoform of the growth hormone receptor gene that lacks exon 3 (d3-GHR) was associated with 1.7 to 2 times more growth acceleration induced by growth hormone than the full-length isoform (P < 0.0001). In transfection experiments, the transduction of growth hormone signaling through d3-GHR homo- or heterodimers was approximately 30% higher than through full-length GHR homodimers (P < 0.0001). One-half of Europeans are hetero- or homozygous with respect to the allele encoding the d3-GHR isoform, which is dominant over the full-length isoform. These observations suggest that the polymorphism in exon 3 of GHR is important in growth hormone pharmacogenetics.

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

2017-05-01

With increased life expectancy, women will spend over three decades of life postmenopause. 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.

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.

Prolactin receptor, growth hormone receptor, and putative somatolactin receptor in Mozambique tilapia: tissue specific expression and differential regulation by salinity and fasting.

Science.gov (United States)

Pierce, A L; Fox, B K; Davis, L K; Visitacion, N; Kitahashi, T; Hirano, T; Grau, E G

2007-01-01

In fish, pituitary growth hormone family peptide hormones (growth hormone, GH; prolactin, PRL; somatolactin, SL) regulate essential physiological functions including osmoregulation, growth, and metabolism. Teleost GH family hormones have both differential and overlapping effects, which are mediated by plasma membrane receptors. A PRL receptor (PRLR) and two putative GH receptors (GHR1 and GHR2) have been identified in several teleost species. Recent phylogenetic analyses and binding studies suggest that GHR1 is a receptor for SL. However, no studies have compared the tissue distribution and physiological regulation of all three receptors. We sequenced GHR2 from the liver of the Mozambique tilapia (Oreochromis mossambicus), developed quantitative real-time PCR assays for the three receptors, and assessed their tissue distribution and regulation by salinity and fasting. PRLR was highly expressed in the gill, kidney, and intestine, consistent with the osmoregulatory functions of PRL. PRLR expression was very low in the liver. GHR2 was most highly expressed in the muscle, followed by heart, testis, and liver, consistent with this being a GH receptor with functions in growth and metabolism. GHR1 was most highly expressed in fat, liver, and muscle, suggesting a metabolic function. GHR1 expression was also high in skin, consistent with a function of SL in chromatophore regulation. These findings support the hypothesis that GHR1 is a receptor for SL. In a comparison of freshwater (FW)- and seawater (SW)-adapted tilapia, plasma PRL was strongly elevated in FW, whereas plasma GH was slightly elevated in SW. PRLR expression was reduced in the gill in SW, consistent with PRL's function in freshwater adaptation. GHR2 was elevated in the kidney in FW, and correlated negatively with plasma GH, whereas GHR1 was elevated in the gill in SW. Plasma IGF-I, but not GH, was reduced by 4 weeks of fasting. Transcript levels of GHR1 and GHR2 were elevated by fasting in the muscle. However

MEL-18 loss mediates estrogen receptor-α downregulation and hormone independence.

Science.gov (United States)

Lee, Jeong-Yeon; Won, Hee-Young; Park, Ji-Hye; Kim, Hye-Yeon; Choi, Hee-Joo; Shin, Dong-Hui; Kang, Ju-Hee; Woo, Jong-Kyu; Oh, Seung-Hyun; Son, Taekwon; Choi, Jin-Woo; Kim, Sehwan; Kim, Hyung-Yong; Yi, Kijong; Jang, Ki-Seok; Oh, Young-Ha; Kong, Gu

2015-05-01

The polycomb protein MEL-18 has been proposed as a tumor suppressor in breast cancer; however, its functional relevance to the hormonal regulation of breast cancer remains unknown. Here, we demonstrated that MEL-18 loss contributes to the hormone-independent phenotype of breast cancer by modulating hormone receptor expression. In multiple breast cancer cohorts, MEL-18 was markedly downregulated in triple-negative breast cancer (TNBC). MEL-18 expression positively correlated with the expression of luminal markers, including estrogen receptor-α (ER-α, encoded by ESR1). MEL-18 loss was also associated with poor response to antihormonal therapy in ER-α-positive breast cancer. Furthermore, whereas MEL-18 loss in luminal breast cancer cells resulted in the downregulation of expression and activity of ER-α and the progesterone receptor (PR), MEL-18 overexpression restored ER-α expression in TNBC. Consistently, in vivo xenograft experiments demonstrated that MEL-18 loss induces estrogen-independent growth and tamoxifen resistance in luminal breast cancer, and that MEL-18 overexpression confers tamoxifen sensitivity in TNBC. MEL-18 suppressed SUMOylation of the ESR1 transactivators p53 and SP1, thereby driving ESR1 transcription. MEL-18 facilitated the deSUMOylation process by inhibiting BMI-1/RING1B-mediated ubiquitin-proteasomal degradation of SUMO1/sentrin-specific protease 1 (SENP1). These findings demonstrate that MEL-18 is a SUMO-dependent regulator of hormone receptors and suggest MEL-18 expression as a marker for determining the antihormonal therapy response in patients with breast cancer.

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.

How hormones influence composition and physiological function of the brain-blood barrier.

Science.gov (United States)

Hampl, R; Bičíková, M; Sosvorová, L

2015-01-01

Hormones exert many actions in the brain. Their access and effects in the brain are regulated by the blood-brain barrier (BBB). Hormones as other substances may enter the brain and vice versa either by paracellular way requiring breaching tight junctions stitching the endothelial cells composing the BBB, or by passage through the cells (transcellular way). Hormones influence both ways through their receptors, both membrane and intracellular, present on/in the BBB. In the review the main examples are outlined how hormones influence the expression and function of proteins forming the tight junctions, as well as how they regulate expression and function of major protein transporters mediating transport of various substances including hormone themselves.

Enhanced NMDA receptor-mediated intracellular calcium signaling in magnocellular neurosecretory neurons in heart failure rats.

Science.gov (United States)

Stern, Javier E; Potapenko, Evgeniy S

2013-08-15

An enhanced glutamate excitatory function within the hypothalamic supraoptic and paraventricluar nuclei is known to contribute to increased neurosecretory and presympathetic neuronal activity, and hence, neurohumoral activation, during heart failure (HF). Still, the precise mechanisms underlying enhanced glutamate-driven neuronal activity in HF remain to be elucidated. Here, we performed simultaneous electrophysiology and fast confocal Ca²⁺ imaging to determine whether altered N-methyl-d-aspartate (NMDA) receptor-mediated changes in intracellular Ca²⁺ levels (NMDA-ΔCa²⁺) occurred in hypothalamic magnocellular neurosecretory cells (MNCs) in HF rats. We found that activation of NMDA receptors resulted in a larger ΔCa²⁺ in MNCs from HF when compared with sham rats. The enhanced NMDA-ΔCa²⁺ was neither dependent on the magnitude of the NMDA-mediated current (voltage clamp) nor on the degree of membrane depolarization or firing activity evoked by NMDA (current clamp). Differently from NMDA receptor activation, firing activity evoked by direct membrane depolarization resulted in similar changes in intracellular Ca²⁺ in sham and HF rats. Taken together, our results support a relatively selective alteration of intracellular Ca²⁺ homeostasis and signaling following activation of NMDA receptors in MNCs during HF. The downstream functional consequences of such altered ΔCa²⁺ signaling during HF are discussed.

Opposing Roles of Calcium and Intracellular ATP on Gating of the Purinergic P2X2 Receptor Channel

Directory of Open Access Journals (Sweden)

Milos B. Rokic

2018-04-01

Full Text Available P2X2 receptors (P2X2R exhibit a slow desensitization during the initial ATP application and a progressive, calcium-dependent increase in rates of desensitization during repetitive stimulation. This pattern is observed in whole-cell recordings from cells expressing recombinant and native P2X2R. However, desensitization is not observed in perforated-patched cells and in two-electrode voltage clamped oocytes. Addition of ATP, but not ATPγS or GTP, in the pipette solution also abolishes progressive desensitization, whereas intracellular injection of apyrase facilitates receptor desensitization. Experiments with injection of alkaline phosphatase or addition of staurosporine and ATP in the intracellular solution suggest a role for a phosphorylation-dephosphorylation in receptor desensitization. Mutation of residues that are potential phosphorylation sites identified a critical role of the S363 residue in the intracellular ATP action. These findings indicate that intracellular calcium and ATP have opposing effects on P2X2R gating: calcium allosterically facilitates receptor desensitization and ATP covalently prevents the action of calcium. Single cell measurements further revealed that intracellular calcium stays elevated after washout in P2X2R-expressing cells and the blockade of mitochondrial sodium/calcium exchanger lowers calcium concentrations during washout periods to basal levels, suggesting a role of mitochondria in this process. Therefore, the metabolic state of the cell can influence P2X2R gating.

Ligand Receptor-Mediated Regulation of Growth in Plants.

Science.gov (United States)

Haruta, Miyoshi; Sussman, Michael R

2017-01-01

Growth and development of multicellular organisms are coordinately regulated by various signaling pathways involving the communication of inter- and intracellular components. To form the appropriate body patterns, cellular growth and development are modulated by either stimulating or inhibiting these pathways. Hormones and second messengers help to mediate the initiation and/or interaction of the various signaling pathways in all complex multicellular eukaryotes. In plants, hormones include small organic molecules, as well as larger peptides and small proteins, which, as in animals, act as ligands and interact with receptor proteins to trigger rapid biochemical changes and induce the intracellular transcriptional and long-term physiological responses. During the past two decades, the availability of genetic and genomic resources in the model plant species, Arabidopsis thaliana, has greatly helped in the discovery of plant hormone receptors and the components of signal transduction pathways and mechanisms used by these immobile but highly complex organisms. Recently, it has been shown that two of the most important plant hormones, auxin and abscisic acid (ABA), act through signaling pathways that have not yet been recognized in animals. For example, auxins stimulate cell elongation by bringing negatively acting transcriptional repressor proteins to the proteasome to be degraded, thus unleashing the gene expression program required for increasing cell size. The "dormancy" inducing hormone, ABA, binds to soluble receptor proteins and inhibits a specific class of protein phosphatases (PP2C), which activates phosphorylation signaling leading to transcriptional changes needed for the desiccation of the seeds prior to entering dormancy. While these two hormone receptors have no known animal counterparts, there are also many similarities between animal and plant signaling pathways. For example, in plants, the largest single gene family in the genome is the protein kinase

Desensitization of parathyroid hormone receptors on cultured bone cells

International Nuclear Information System (INIS)

Pun, K.K.; Ho, P.W.; Nissenson, R.A.; Arnaud, C.D.

1990-01-01

Administration of excessive amounts of parathyroid hormone (PTH) in the treatment of osteoporosis can reverse the beneficial effects of a low-dose, intermittent regime. To investigate the direct actions and the possible cellular mechanisms of PTH in inducing desensitization of PTH receptors, we studied the effects of desensitization on rat osteoblastic UMR-106 cells. When the osteoblasts were preincubated with bPTH-(1-34), complete refractoriness to a subsequent challenge with the hormone developed within 1 h and at hormone concentrations as low as 5 nM. When osteoblasts thus desensitized were incubated in hormone-free medium, recovery of the cAMP responses began within 2 h and reached maximum after 16 h. Cycloheximide did not affect the process of desensitization. [Nle8,Nle18,Tyr34]bPTH-(3-34)amide significantly impaired the desensitization process by PTH-(1-34) but did not have stimulatory effect on cAMP responses. No significant heterologous desensitization was obvious after preincubation with isoprenaline (50 microM), prostaglandin E1 (50 microM), or prostaglandin E2 (50 microM) for 2 h. Binding experiments with [125I]PLP-(1-36)amide after desensitization revealed that there was an approximate twofold decrease in receptor affinities as analyzed by Scatchard analysis, showing that the decrease in affinity was prominent in the process of desensitization. When the cells were treated with monensin during desensitization, PTH challenge after desensitization produced significantly lower cyclic AMP responses. Recovery after desensitization occurred over a period of 16 h. Inclusion of monensin, but not cycloheximide, impaired the recovery. The results show that homologous desensitization of rat osteoblasts to PTH is brought about by the occupancy of receptors by PTH-(1-34) but not by cAMP generation itself

The Hypercoagulable state in Hyperthyroidism is mediated via the Thyroid Hormone β Receptor pathway

NARCIS (Netherlands)

Elbers, Laura P. B.; Moran, Carla; Gerdes, Victor E. A.; van Zaane, Bregje; Meijers, Joost C. M.; Endert, Erik; Lyons, Greta; Chatterjee, V. Krishna; Bisschop, Peter H.; Fliers, Eric

2016-01-01

Hyperthyroidism is associated with a hypercoagulable state, but the underlying mechanism is unknown. Patients with resistance to thyroid hormone (RTH) due to defective thyroid hormone receptor β (TRβ) exhibit elevated circulating thyroid hormones (TH) with refractoriness to TH action in

Desethylamiodarone is a competitive inhibitor of the binding of thyroid hormone to the thyroid hormone alpha 1-receptor protein

NARCIS (Netherlands)

van Beeren, H. C.; Bakker, O.; Wiersinga, W. M.

1995-01-01

Desethylamiodarone (DEA), the major metabolite of the potent antiarrythmic drug amiodarone, is a non-competitive inhibitor of the binding of thyroid hormone (T3) to the beta 1-thyroid hormone receptor (T3R). In the present study, we investigated whether DEA acts in a similar way with respect to the

17β-estradiol induces non-genomic effects in renal intercalated cells through the G-protein coupled estrogen receptor 1

DEFF Research Database (Denmark)

Hofmeister, Marlene Vind; Damkier, Helle Hasager; Christensen, Birgitte Mønster

2012-01-01

Steroid hormones such as 17β-estradiol (E2) are known to modulate ion transporter expression in the kidney through classic intracellular receptors. Steroid hormones are also known to cause rapid nongenomic responses in a variety of nonrenal tissues. However, little is known about renal short......-term effects of steroid hormones. Here, we studied the acute actions of E2 on intracellular Ca(2+) signaling in isolated distal convoluted tubules (DCT2), connecting tubules (CNT), and initial cortical collecting ducts (iCCD) by fluo 4 fluorometry. Physiological concentrations of E2 induced transient increases...

Analysis of the hormone-binding domain of steroid receptors using chimeras generated by homologous recombination

International Nuclear Information System (INIS)

Martinez, Elisabeth D.; Pattabiraman, Nagarajan; Danielsen, Mark

2005-01-01

The glucocorticoid receptor and the mineralocorticoid receptor are members of the steroid receptor family that exhibit ligand cross-reactivity. Specificity of steroid receptor action is investigated in the present work by the construction and characterization of chimeras between the glucocorticoid receptor and the mineralocorticoid receptor. We used an innovative approach to make novel steroid receptor proteins in vivo that in general, contrary to our expectations, show increased ligand specificity compared to the parental receptors. We describe a receptor that is specific for the potent synthetic glucocorticoid triamcinolone acetonide and does not bind aldosterone. A further set of chimeras has an increased ability to discriminate between ligands, responding potently to mineralocorticoids and only very weakly to synthetic glucocorticoids. A chimera with the fusion site in the hinge highlights the importance of the region between the DNA-binding and the hormone-binding domains since, unlike both the glucocorticoid and mineralocorticoid receptors, it only responds to mineralocorticoids. One chimera has reduced specificity in that it acts as a general corticoid receptor, responding to glucocorticoids and mineralocorticoids with similar potency and efficacy. Our data suggest that regions of the glucocorticoid and mineralocorticoid receptor hormone-binding domains are functionally non-reciprocal. We present transcriptional, hormone-binding, and structure-modeling evidence that suggests that receptor-specific interactions within and across domains mediate aspects of specificity in transcriptional responses to steroids

Intracellular recording from a spider vibration receptor.

Science.gov (United States)

Gingl, Ewald; Burger, Anna-M; Barth, Friedrich G

2006-05-01

The present study introduces a new preparation of a spider vibration receptor that allows intracellular recording of responses to natural mechanical or electrical stimulation of the associated mechanoreceptor cells. The spider vibration receptor is a lyriform slit sense organ made up of 21 cuticular slits located on the distal end of the metatarsus of each walking leg. The organ is stimulated when the tarsus receives substrate vibrations, which it transmits to the organ's cuticular structures, reducing the displacement to about one tenth due to geometrical reasons. Current clamp recording was used to record action potentials generated by electrical or mechanical stimuli. Square pulse stimulation identified two groups of sensory cells, the first being single-spike cells which generated only one or two action potentials and the second being multi-spike cells which produced bursts of action potentials. When the more natural mechanical sinusoidal stimulation was applied, differences in adaptation rate between the two cell types remained. In agreement with prior extracellular recordings, both cell types showed a decrease in the threshold tarsus deflection with increasing stimulus frequency. Off-responses to mechanical stimuli have also been seen in the metatarsal organ for the first time.

Steroid hormone and epidermal growth factor receptors in meningiomas.

Science.gov (United States)

Horsfall, D J; Goldsmith, K G; Ricciardelli, C; Skinner, J M; Tilley, W D; Marshall, V R

1989-11-01

A prospective study of steroid hormone and epidermal growth factor receptor expression in 57 meningiomas is presented. Scatchard analysis of radioligand binding identified 20% of meningiomas as expressing classical oestrogen receptors (ER) at levels below that normally accepted for positivity, the remainder being negative. ER could not be visualized in any meningioma using immunocytochemistry. Alternatively, 74% of meningiomas demonstrated the presence of progesterone receptors (PR) by Scatchard analysis, the specificity of which could not be attributed to glucocorticoid or androgen receptors. Confirmation of classical PR presence was determined by immunocytochemical staining. The presence of epidermal growth factor receptor (EGFR) was demonstrated in 100% of meningiomas using immunocytochemical staining. These data are reviewed in the context of previously reported results and are discussed in relation to the potential for medical therapy as an adjunct to surgery.

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...... of tyrosine kinase activity with cloned liver GH receptor. The level of phosphorylation of the GH receptor was very low, as compared with the endogenous GH receptor in 3T3-F442A cells, suggesting that tyrosine kinase activity is not intrinsic to the cloned GH receptor but rather resides with a kinase present...... in a variety of cell types. The finding that the level of phosphorylation of GH receptor appears to vary with cell type is consistent with the cloned liver GH receptor being a substrate for an associated tyrosine kinase and with the amount of such a GH receptor-associated tyrosine kinase being cell type-specific....

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.

Do unliganded thyroid hormone receptors have physiological functions?

Science.gov (United States)

Chassande, O

2003-08-01

Thyroid hormone (TH) is required for the development of vertebrates and exerts numerous homeostatic functions in adults. TH acts through nuclear receptors which control the transcription of target genes. Unliganded and liganded thyroid hormone receptors (TRs) have been shown to exert opposite effects on the transcription of target genes in vitro. However, the occurance of an aporeceptor activity in vivo and its potential physiological significance has not been clearly addressed. Several data generated using experimental hypothyroidism and thyrotoxicosis in wild type and TR knockout mice support the notion that apoTRs have an intrinsic activity in several tIssues. ApoTRs, and in particular TRalpha1, are predominant during the early stages of vertebrate development and must be turned into holoTRs for post-natal development to proceed normally. However, the absence of striking alterations of embryonic and fetal development in mice devoid of TRs indicates that apoTRs do not play a fundamental role. During development, as well as in adults, apoTRs rather appears as a system which increases the range of transcriptional responses to moderate variations of T3.

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.

Growth hormone receptor deficiency (Laron syndrome) in black ...

African Journals Online (AJOL)

Non-Caucasians with growth honnone receptor (GHR) deficiency/Lamn syndrome among the .... 4,3 cm (-2,4 SOS for bone age 8,5 years at age 12); the girl's height at age 7 years was 77,5 cm (-8,0 SOS, height ... of serum incubated with '25I-labelled human growth hormone and expressed as relative specific binding ...

Study of change of sex hormone receptors in diabetic impotent patients

International Nuclear Information System (INIS)

Zhang Yong; Chen Weizhen; Zhang Zikang; Hu Xiaoke

2002-01-01

To study the relationship between diabetic impotence and sex hormones as well as sex hormone receptors. 32 diabetic impotent patients, 32 diabetic patients with normal sex function, 32 impotent patients without diabetes, and 40 healthy men were enrolled. The plasma sex hormone levels were examined by radioimmunoassay, and sex hormone receptors in white blood cells by radioreceptor assay. Compared with healthy men and impotent patients without diabetes, PRL levels in both diabetic impotent patients and diabetic patients with normal sex function increased markedly, T and AR levels decreased, and the ratio of E 2 /T and ER/AR increased. Compared with diabetic patients with normal sex function, while there was no significant difference in PRL, T and E 2 /T ratio, the AR level of diabetic impotent patients further decreased, and the ER/AR ratio further increased. Negative correlation was found between age and AR as well as T. The decline of AR and the increase of ER/AR ratio might be one main cause of diabetic impotence. And the decline of T and AR might be an important cause of the increase of diabetic impotence incidence with age

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...

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.

Negative regulation of parathyroid hormone-related protein expression by steroid hormones

International Nuclear Information System (INIS)

Kajitani, Takashi; Tamamori-Adachi, Mimi; Okinaga, Hiroko; Chikamori, Minoru; Iizuka, Masayoshi; Okazaki, Tomoki

2011-01-01

Highlights: → Steroid hormones repress expression of PTHrP in the cell lines where the corresponding nuclear receptors are expressed. → Nuclear receptors are required for suppression of PTHrP expression by steroid hormones, except for androgen receptor. → Androgen-induced suppression of PTHrP expression appears to be mediated by estrogen receptor. -- Abstract: Elevated parathyroid hormone-related protein (PTHrP) is responsible for humoral hypercalcemia of malignancy (HHM), which is of clinical significance in treatment of terminal patients with malignancies. Steroid hormones were known to cause suppression of PTHrP expression. However, detailed studies linking multiple steroid hormones to PTHrP expression are lacking. Here we studied PTHrP expression in response to steroid hormones in four cell lines with excessive PTHrP production. Our study established that steroid hormones negatively regulate PTHrP expression. Vitamin D receptor, estrogen receptor α, glucocorticoid receptor, and progesterone receptor, were required for repression of PTHrP expression by the cognate ligands. A notable exception was the androgen receptor, which was dispensable for suppression of PTHrP expression in androgen-treated cells. We propose a pathway(s) involving nuclear receptors to suppress PTHrP expression.

Bicaudal-D1 regulates the intracellular sorting and signalling of neurotrophin receptors.

Science.gov (United States)

Terenzio, Marco; Golding, Matthew; Russell, Matthew R G; Wicher, Krzysztof B; Rosewell, Ian; Spencer-Dene, Bradley; Ish-Horowicz, David; Schiavo, Giampietro

2014-07-17

We have identified a new function for the dynein adaptor Bicaudal D homolog 1 (BICD1) by screening a siRNA library for genes affecting the dynamics of neurotrophin receptor-containing endosomes in motor neurons (MNs). Depleting BICD1 increased the intracellular accumulation of brain-derived neurotrophic factor (BDNF)-activated TrkB and p75 neurotrophin receptor (p75(NTR)) by disrupting the endosomal sorting, reducing lysosomal degradation and increasing the co-localisation of these neurotrophin receptors with retromer-associated sorting nexin 1. The resulting re-routing of active receptors increased their recycling to the plasma membrane and altered the repertoire of signalling-competent TrkB isoforms and p75(NTR) available for ligand binding on the neuronal surface. This resulted in attenuated, but more sustained, AKT activation in response to BDNF stimulation. These data, together with our observation that Bicd1 expression is restricted to the developing nervous system when neurotrophin receptor expression peaks, indicate that BICD1 regulates neurotrophin signalling by modulating the endosomal sorting of internalised ligand-activated receptors. © 2014 The Authors.

Rapid, portable detection of endocrine disrupting chemicals through ligand-nuclear hormone receptor interactions.

Science.gov (United States)

Hunt, J Porter; Schinn, Song-Min; Jones, Matthew D; Bundy, Bradley C

2017-12-04

Endocrine disrupting chemicals (EDC) are structurally diverse compounds that can interact with nuclear hormone receptors, posing significant risk to human and ecological health. Unfortunately, many conventional biosensors have been too structure-specific, labor-intensive or laboratory-oriented to detect broad ranges of EDC effectively. Recently, several technological advances are providing more rapid, portable, and affordable detection of endocrine-disrupting activity through ligand-nuclear hormone receptor interactions. Here, we overview these recent advances applied to EDC biosensors - including cell lyophilization, cell immobilization, cell-free systems, smartphone-based signal detection, and improved competitive binding assays.

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....

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

International Nuclear Information System (INIS)

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

1985-01-01

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

Y1 receptors for neuropeptide Y are coupled to mobilization of intracellular calcium and inhibition of adenylate cyclase

DEFF Research Database (Denmark)

Aakerlund, L; Gether, U; Fuhlendorff, J

1990-01-01

Two types of binding sites have previously been described for neuropeptide Y (NPY), called Y1 and Y2 receptors. The intracellular events following Y1 receptor activation was studied in the human neuroblastoma cell line SK-N-MC. Both NPY and the specific Y1 receptor ligand, [Leu31,Pro34]-NPY, caused...

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.

Radioactive probes for adrenocorticotropic hormone receptors

International Nuclear Information System (INIS)

Hofmann, K.; Romovacek, H.; Stehle, C.J.; Finn, F.M.; Bothner-By, A.A.; Mishra, P.K.

1986-01-01

Our attempts to develop adrenocorticotropic hormone (ACTH) analogues that can be employed for ACTH receptor identification and isolation began with the synthesis of ACTH fragments containing N epsilon-(dethiobiotinyl)lysine (dethiobiocytin) amide in position 25 to be used for affinity chromatographic purification of hormone-receptor complexes on Sepharose-immobilized avidin resins. Because labeling ACTH or ACTH fragments by conventional iodination techniques destroys biological activity due to oxidation of Met4 and incorporation of iodine into Tyr2, we have prepared [Phe2,Nle4]ACTH1-24, [Phe2,Nle4,biocytin25]ACTH1-25 amide, and [Phe2,Nle4,dethiobiocytin25]ACTH1-25 amide by conventional synthetic techniques. The HPLC profiles and amino acid analyses of the final products indicate that the materials are of a high degree of purity. The amount of tertiary butylation of the Trp residue in the peptides was assessed by NMR and was found to be less than 0.5%. All three peptides are equipotent with the standard ACTH1-24 as concerns their ability to stimulate steroidogenesis and cAMP formation in bovine adrenal cortical cells. Iodination of [Phe2,Nle4]ACTH1-24, with iodogen as the oxidizing agent, has been accomplished without any detectable loss of biological activity. The mono- and diiodo derivatives of [Phe2,Nle4]ACTH1-24 have been prepared, separated by HPLC, and assayed for biological activity. Both peptides have the full capacity to stimulate steroidogenesis and cAMP production in bovine adrenal cortical cells

A radioreceptor assay of luteinizing hormone-releasing hormone receptor and characterization of LHRH binding to pituitary receptors in Shao duck

International Nuclear Information System (INIS)

Yang Peixin; Wu Meiwen; Chen Ziyuan

2000-01-01

The properties of Shao duck pituitary luteinizing hormone-releasing hormone (LHRH) receptors were analyzed in pituitary membrane preparation and isolated pituitary cells prepared by enzymatic dispersion with collagenase and trypsin, by using a super-agonist analog of (D-Lys 6 ) LHRH. High binding of 125 I-(D-Lys 6 ) LHRH to 10 6 cultured cells of Shao duck was observed after a 90 minute incubation at 4 degree C, while binding was significantly reduced after a 24h incubation. Binding of the radioligand was a function of tissue concentration of Shao duck pituitary membrane preparation, with a positive correlation over the range of 1-2 pituitary per-tube. Specific binding for 125 I-(D-Lys 6 ) LHRH increased with the increase in the amount of 125 I-(D-Lys 6 ) LHRH. The Scatchard analysis of data revealed a linear relationship between the amount of specific binding and the ratio of specific binding to free 1 '2 5 I(D-Lys 6 )LHRH, indicating a single class of high affinity sites. Equilibrium dissociation constant (Kd) was 0.34 nM in pituitary membrane preparation and 0.43 nM in isolated pituitary cells. Both Kd values were near and the maximum binding capacity (B max ) was great in isolated cells, suggesting no significant loss of the LHRH receptor population caused by the enzymatic procedure employed for cell dispersion in the present study. Addition of 9D-Lys 6 ) LHRH displaced bound 125 I-(D-Lys 6 ) LHRH. These results demonstrated the presence and provided characterization of LHRH receptors in Shao duck pituitary

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.

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

KAUST Repository

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

2009-01-01

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.

Honey bee dopamine and octopamine receptors linked to intracellular calcium signaling have a close phylogenetic and pharmacological relationship.

Directory of Open Access Journals (Sweden)

Kyle T Beggs

Full Text Available BACKGROUND: Three dopamine receptor genes have been identified that are highly conserved among arthropod species. One of these genes, referred to in honey bees as Amdop2, shows a close phylogenetic relationship to the a-adrenergic-like octopamine receptor family. In this study we examined in parallel the functional and pharmacological properties of AmDOP2 and the honey bee octopamine receptor, AmOA1. For comparison, pharmacological properties of the honey bee dopamine receptors AmDOP1 and AmDOP3, and the tyramine receptor AmTYR1, were also examined. METHODOLOGY/PRINCIPAL FINDINGS: Using HEK293 cells heterologously expressing honey bee biogenic amine receptors, we found that activation of AmDOP2 receptors, like AmOA1 receptors, initiates a rapid increase in intracellular calcium levels. We found no evidence of calcium signaling via AmDOP1, AmDOP3 or AmTYR1 receptors. AmDOP2- and AmOA1-mediated increases in intracellular calcium were inhibited by 10 µM edelfosine indicating a requirement for phospholipase C-β activity in this signaling pathway. Edelfosine treatment had no effect on AmDOP2- or AmOA1-mediated increases in intracellular cAMP. The synthetic compounds mianserin and epinastine, like cis-(Z-flupentixol and spiperone, were found to have significant antagonist activity on AmDOP2 receptors. All 4 compounds were effective antagonists also on AmOA1 receptors. Analysis of putative ligand binding sites offers a possible explanation for why epinastine acts as an antagonist at AmDOP2 receptors, but fails to block responses mediated via AmDOP1. CONCLUSIONS/SIGNIFICANCE: Our results indicate that AmDOP2, like AmOA1, is coupled not only to cAMP, but also to calcium-signalling and moreover, that the two signalling pathways are independent upstream of phospholipase C-β activity. The striking similarity between the pharmacological properties of these 2 receptors suggests an underlying conservation of structural properties related to receptor

Interactions between hormones and epilepsy.

Science.gov (United States)

Taubøll, Erik; Sveberg, Line; Svalheim, Sigrid

2015-05-01

There is a complex, bidirectional interdependence between sex steroid hormones and epilepsy; hormones affect seizures, while seizures affect hormones thereby disturbing reproductive endocrine function. Both female and male sex steroid hormones influence brain excitability. For the female sex steroid hormones, progesterone and its metabolites are anticonvulsant, while estrogens are mainly proconvulsant. The monthly fluctuations in hormone levels of estrogen and progesterone are the basis for catamenial epilepsy described elsewhere in this issue. Androgens are mainly anticonvulsant, but the effects are more varied, probably because of its metabolism to, among others, estradiol. The mechanisms for the effects of sex steroid hormones on brain excitability are related to both classical, intracellularly mediated effects, and non-classical membrane effects due to binding to membrane receptors. The latter are considered the most important in relation to epilepsy. The different sex steroids can also be further metabolized within the brain to different neurosteroids, which are even more potent with regard to their effect on excitability. Estrogens potentiate glutamate responses, primarily by potentiating NMDA receptor activity, but also by affecting GABA-ergic mechanisms and altering brain morphology by increasing dendritic spine density. Progesterone and its main metabolite 5α-pregnan-3α-ol-20-one (3α-5α-THP) act mainly to enhance postsynaptic GABA-ergic activity, while androgens enhance GABA-activated currents. Seizures and epileptic discharges also affect sex steroid hormones. There are close anatomical connections between the temporolimbic system and the hypothalamus controlling the endocrine system. Several studies have shown that epileptic activity, especially mediated through the amygdala, alters reproductive function, including reduced ovarian cyclicity in females and altered sex steroid hormone levels in both genders. Furthermore, there is an asymmetric

Sex Hormone Receptor Expression in the Human Vocal Fold Subunits.

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Kirgezen, Tolga; Sunter, Ahmet Volkan; Yigit, Ozgur; Huq, Gulben Erdem

2017-07-01

The study aimed to evaluate the existence of sex hormone receptors in the subunits of vocal fold. This is a cadaver study. The androgen, estrogen, and progesterone receptors were examined in the epithelium (EP), superficial layer of the lamina propria (SLP), vocal ligament (VL), and macula flava (MF) of the vocal folds from 42 human cadavers (21 male, 21 female) by immunohistochemical methods. Their staining ratios were scored and statistically compared. The androgen receptor score was significantly higher for the MF than for the EP and SLP (P vocal fold, mostly in the MF and VLs. Copyright © 2017 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

Pharmacologic management of bone-related complications and bone metastases in postmenopausal women with hormone receptor-positive breast cancer

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Yardley DA

2016-05-01

Full Text Available Denise A Yardley1,2 1Sarah Cannon Research Institute, Nashville, TN, USA; 2Tennessee Oncology, Nashville, TN, USA Abstract: There is a high risk for bone loss and skeletal-related events, including bone metastases, in postmenopausal women with hormone receptor-positive breast cancer. Both the disease itself and its therapeutic treatments can negatively impact bone, resulting in decreases in bone mineral density and increases in bone loss. These negative effects on the bone can significantly impact morbidity and mortality. Effective management and minimization of bone-related complications in postmenopausal women with hormone receptor-positive breast cancer remain essential. This review discusses the current understanding of molecular and biological mechanisms involved in bone turnover and metastases, increased risk for bone-related complications from breast cancer and breast cancer therapy, and current and emerging treatment strategies for managing bone metastases and bone turnover in postmenopausal women with hormone receptor-positive breast cancer. Keywords: breast cancer, bone metastases, hormone receptor-positive, bone-related complications, interventions, management and management strategies, estrogen receptor-positive

Estradiol coupling to human monocyte nitric oxide release is dependent on intracellular calcium transients: evidence for an estrogen surface receptor.

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Stefano, G B; Prevot, V; Beauvillain, J C; Fimiani, C; Welters, I; Cadet, P; Breton, C; Pestel, J; Salzet, M; Bilfinger, T V

1999-10-01

We tested the hypothesis that estrogen acutely stimulates constitutive NO synthase (cNOS) activity in human peripheral monocytes by acting on an estrogen surface receptor. NO release was measured in real time with an amperometric probe. 17beta-estradiol exposure to monocytes stimulated NO release within seconds in a concentration-dependent manner, whereas 17alpha-estradiol had no effect. 17beta-estradiol conjugated to BSA (E2-BSA) also stimulated NO release, suggesting mediation by a membrane surface receptor. Tamoxifen, an estrogen receptor inhibitor, antagonized the action of both 17beta-estradiol and E2-BSA, whereas ICI 182,780, a selective inhibitor of the nuclear estrogen receptor, had no effect. We further showed, using a dual emission microfluorometry in a calcium-free medium, that the 17beta-estradiol-stimulated release of monocyte NO was dependent on the initial stimulation of intracellular calcium transients in a tamoxifen-sensitive process. Leeching out the intracellular calcium stores abolished the effect of 17beta-estradiol on NO release. RT-PCR analysis of RNA obtained from the cells revealed a strong estrogen receptor-alpha amplification signal and a weak beta signal. Taken together, a physiological dose of estrogen acutely stimulates NO release from human monocytes via the activation of an estrogen surface receptor that is coupled to increases in intracellular calcium.

Internalization of G-protein-coupled receptors: Implication in receptor function, physiology and diseases.

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Calebiro, Davide; Godbole, Amod

2018-04-01

G protein-coupled receptors (GPCRs) are the largest family of membrane receptors and mediate the effects of numerous hormones and neurotransmitters. The nearly 1000 GPCRs encoded by the human genome regulate virtually all physiological functions and are implicated in the pathogenesis of prevalent human diseases such as thyroid disorders, hypertension or Parkinson's disease. As a result, 30-50% of all currently prescribed drugs are targeting these receptors. Once activated, GPCRs induce signals at the cell surface. This is often followed by internalization, a process that results in the transfer of receptors from the plasma membrane to membranes of the endosomal compartment. Internalization was initially thought to be mainly implicated in signal desensitization, a mechanism of adaptation to prolonged receptor stimulation. However, several unexpected functions have subsequently emerged. Most notably, accumulating evidence indicates that internalization can induce prolonged receptor signaling on intracellular membranes, which is apparently required for at least some biological effects of hormones like TSH, LH and adrenaline. These findings reveal an even stronger connection between receptor internalization and signaling than previously thought. Whereas new studies are just beginning to reveal an important physiological role for GPCR signaling after internalization and ways to exploit it for therapeutic purposes, future investigations will be required to explore its involvement in human disease. Copyright © 2018 Elsevier Ltd. All rights reserved.

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

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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.

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

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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.

Hormonally-mediated Epigenetic Changes to Steroid Receptors in the Developing Brain: Implications for Sexual Differentiation

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Nugent, Bridget M.; Schwarz, Jaclyn M.; McCarthy, Margaret M.

2010-01-01

The establishment of sex-specific neural morphology, which underlies sex-specific behaviors, occurs during a perinatal sensitive window in which brief exposure to gonadal steroid hormones produces permanent masculinization of the brain. In the rodent, estradiol derived from testicular androgens is a principle organizational hormone. The mechanism by which transient estradiol exposure induces permanent differences in neuronal anatomy has been widely investigated, but remains elusive. Epigenetic changes, such as DNA methylation, allow environmental influences to alter long-term gene expression patterns and therefore may be a potential mediator of estradiol-induced organization of the neonatal brain. Here we review data that demonstrate sex and estradiol-induced differences in DNA methylation on the estrogen receptor α (ERα), estrogen receptor β (ERβ), and progesterone receptor (PR) promoters in sexually dimorphic brain regions across development. Contrary to the overarching view of DNA methylation as a permanent modification directly tied to gene expression, these data demonstrate that methylation patterns on steroid hormone receptors change across the life span and do not necessarily predict expression. Although further exploration into the mechanism and significance of estradiol-induced alterations in DNA methylation patterns in the neonatal brain is necessary, these results provide preliminary evidence that epigenetic alterations can occur in response to early hormone exposure and may mediate estradiol-induced organization of sex differences in the neonatal brain. PMID:20800064

The Dwarfs of Sindh: severe growth hormone (GH) deficiency caused by a mutation in the GH-releasing hormone receptor gene.

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Baumann, G; Maheshwari, H

1997-11-01

We report the discovery of a cluster of severe familial dwarfism in two villages in the Province of Sindh in Pakistan. Dwarfism is proportionate and occurs in members of a kindred with a high degree of consanguinity. Only the last generation is affected, with the oldest dwarf being 28 years old. The mode of inheritance is autosomal recessive. Phenotype analysis and endocrine testing revealed isolated growth hormone deficiency (GHD) as the reason for growth failure. Linkage analysis for the loci of several candidate genes yielded a high lod score for the growth hormone-releasing hormone receptor (GHRH-R) locus on chromosome 7. Amplification and sequencing of the GHRH-R gene in affected subjects demonstrated an amber nonsense mutation (GAG-->TAG; Glu50-->Stop) in exon 3. The mutation, in its homozygous form, segregated 100% with the dwarf phenotype. It predicts a truncation of the GHRH-R in its extracellular domain, which is likely to result in a severely disabled or non-existent receptor protein. Subjects who are heterozygous for the mutation show mild biochemical abnormalities in the growth hormone-releasing hormone (GHRH)--growth hormone--insulin-like growth factor axis, but have only minimal or no growth retardation. The occurrence of an offspring of two dwarfed parents indicates that the GHRH-R is not necessary for fertility in either sex. We conclude that Sindh dwarfism is caused by an inactivating mutation in the GHRH-R gene, resulting in the inability to transmit a GHRH signal and consequent severe isolated GHD.

Specific regulation of thermosensitive lipid droplet fusion by a nuclear hormone receptor pathway.

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Li, Shiwei; Li, Qi; Kong, Yuanyuan; Wu, Shuang; Cui, Qingpo; Zhang, Mingming; Zhang, Shaobing O

2017-08-15

Nuclear receptors play important roles in regulating fat metabolism and energy production in humans. The regulatory functions and endogenous ligands of many nuclear receptors are still unidentified, however. Here, we report that CYP-37A1 (ortholog of human cytochrome P450 CYP4V2), EMB-8 (ortholog of human P450 oxidoreductase POR), and DAF-12 (homolog of human nuclear receptors VDR/LXR) constitute a hormone synthesis and nuclear receptor pathway in Caenorhabditis elegans This pathway specifically regulates the thermosensitive fusion of fat-storing lipid droplets. CYP-37A1, together with EMB-8, synthesizes a lipophilic hormone not identical to Δ7-dafachronic acid, which represses the fusion-promoting function of DAF-12. CYP-37A1 also negatively regulates thermotolerance and lifespan at high temperature in a DAF-12-dependent manner. Human CYP4V2 can substitute for CYP-37A1 in C. elegans This finding suggests the existence of a conserved CYP4V2-POR-nuclear receptor pathway that functions in converting multilocular lipid droplets to unilocular ones in human cells; misregulation of this pathway may lead to pathogenic fat storage.

Thyrotropin-luteinizing hormone/chorionic gonadotropin receptor extracellular domain chimeras as probes for thyrotropin receptor function

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Nagayama, Yuji; Wadsworth, H.L.; Chazenbalk, G.D.; Russo, D.; Seto, Pui; Rapoport, B.

1991-01-01

To define the sites in the extracellular domain of the human thyrotropin (TSH) receptor that are involved in TSH binding and signal transduction the authors constructed chimeric thyrotropin-luteinizing hormone/chorionic gonadotropin (TSH-LH/CG) receptors. The extracellular domain of the human TSH receptor was divided into five regions that were replaced, either singly or in various combinations, with homologous regions of the rat LH/CG receptor. The chimeric receptors were stably expressed in Chinese hamster ovary cells. The data obtained suggest that the carboxyl region of the extracellular domain (amino acid residues 261-418) and particularly the middle region (residues 171-260) play a role in signal transduction. The possibility is also raised of an interaction between the amino and carboxyl regions of the extracellular domain in the process of signal transduction. In summary, these studies suggest that the middle region and carboxyl half of the extracellular domain of the TSH receptor are involved in signal transduction and that the TSH-binding region is likely to span the entire extracellular domain, with multiple discontinuous contact sites

Expression and role of gonadotropin-releasing hormone 2 and its receptor in mammals

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Gonadotropin-releasing hormone (GnRH1) and its receptor (GnRHR1) drive mammalian reproduction via regulation of the gonadotropins. Yet, a second form of GnRH (GnRH2) and its receptor (GnRHR2) also exist in some mammals. GnRH2 has been completely conserved throughout 500 million years of evolution, s...

Thyroid Hormone Receptor Antagonists: From Environmental Pollution to Novel Small Molecules.

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Mackenzie, Louise S

2018-01-01

Thyroid hormone receptors (TRs) are nuclear receptors which control transcription, and thereby have effects in all cells within the body. TRs are an important regulator in many basic physiological processes including development, growth, metabolism, and cardiac function. The hyperthyroid condition results from an over production of thyroid hormones resulting in a continual stimulation of thyroid receptors which is detrimental for the patient. Therapies for hyperthyroidism are available, but there is a need for new small molecules that act as TR antagonists to treat hyperthyroidism. Many compounds exhibit TR antagonism and are considered detrimental to health. Some drugs in the clinic (most importantly, amiodarone) and environmental pollution exhibit TR antagonist properties and thus have the potential to induce hypothyroidism in some people. This chapter provides an overview of novel small molecules that have been specifically designed or screened for their TR antagonist activity as novel treatments for hyperthyroidism. While novel compounds have been identified, to date none have been developed sufficiently to enter clinical trials. Furthermore, a discussion on other sources of TR antagonists is discussed in terms of side effects of current drugs in the clinic as well as environmental pollution. © 2018 Elsevier Inc. All rights reserved.

Increased circulating interleukin-8 in patients with resistance to thyroid hormone receptor α

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Anne H van der Spek

2017-11-01

Full Text Available Innate immune cells have recently been identified as novel thyroid hormone (TH target cells in which intracellular TH levels appear to play an important functional role. The possible involvement of TH receptor alpha (TRα, which is the predominant TR in these cells, has not been studied to date. Studies in TRα0/0 mice suggest a role for this receptor in innate immune function. The aim of this study was to determine whether TRα affects the human innate immune response. We assessed circulating interleukin-8 concentrations in a cohort of 8 patients with resistance to TH due to a mutation of TRα (RTHα and compared these results to healthy controls. In addition, we measured neutrophil and macrophage function in one of these RTHα patients (mutation D211G. Circulating interleukin-8 levels were elevated in 7 out of 8 RTHα patients compared to controls. These patients harbor different mutations, suggesting that this is a general feature of the syndrome of RTHα. Neutrophil spontaneous apoptosis, bacterial killing, NAPDH oxidase activity and chemotaxis were unaltered in cells derived from the RTHαD211G patient. RTHα macrophage phagocytosis and cytokine induction after LPS treatment were similar to results from control cells. The D211G mutation did not result in clinically relevant impairment of neutrophil or pro-inflammatory macrophage function. As elevated circulating IL-8 is also observed in hyperthyroidism, this observation could be due to the high-normal to high levels of circulating T3 found in patients with RTHα.

Intracellular calcium levels determine differential modulation of allosteric interactions within G protein-coupled receptor heteromers.

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Navarro, Gemma; Aguinaga, David; Moreno, Estefania; Hradsky, Johannes; Reddy, Pasham P; Cortés, Antoni; Mallol, Josefa; Casadó, Vicent; Mikhaylova, Marina; Kreutz, Michael R; Lluís, Carme; Canela, Enric I; McCormick, Peter J; Ferré, Sergi

2014-11-20

The pharmacological significance of the adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromer is well established and it is being considered as an important target for the treatment of Parkinson’s disease and other neuropsychiatric disorders. However, the physiological factors that control its distinctive biochemical properties are still unknown. We demonstrate that different intracellular Ca2+ levels exert a differential modulation of A2AR-D2R heteromer-mediated adenylyl-cyclase and MAPK signaling in striatal cells. This depends on the ability of low and high Ca2+ levels to promote a selective interaction of the heteromer with the neuronal Ca2+-binding proteins NCS-1 and calneuron-1, respectively. These Ca2+-binding proteins differentially modulate allosteric interactions within the A2AR-D2R heteromer, which constitutes a unique cellular device that integrates extracellular (adenosine and dopamine) and intracellular (Ca+2) signals to produce a specific functional response.

Interaction between body mass index and hormone-receptor status as a prognostic factor in lymph-node-positive breast cancer.

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Il Yong Chung

Full Text Available The aim of this study was to determine the relationship between the body mass index (BMI at a breast cancer diagnosis and various factors including the hormone-receptor, menopause, and lymph-node status, and identify if there is a specific patient subgroup for which the BMI has an effect on the breast cancer prognosis. We retrospectively analyzed the data of 8,742 patients with non-metastatic invasive breast cancer from the research database of Asan Medical Center. The overall survival (OS and breast-cancer-specific survival (BCSS outcomes were compared among BMI groups using the Kaplan-Meier method and Cox proportional-hazards regression models with an interaction term. There was a significant interaction between BMI and hormone-receptor status for the OS (P = 0.029, and BCSS (P = 0.013 in lymph-node-positive breast cancers. Obesity in hormone-receptor-positive breast cancer showed a poorer OS (adjusted hazard ratio [HR] = 1.51, 95% confidence interval [CI] = 0.92 to 2.48 and significantly poorer BCSS (HR = 1.80, 95% CI = 1.08 to 2.99. In contrast, a high BMI in hormone-receptor-negative breast cancer revealed a better OS (HR = 0.44, 95% CI = 0.16 to 1.19 and BCSS (HR = 0.53, 95% CI = 0.19 to 1.44. Being underweight (BMI < 18.50 kg/m2 with hormone-receptor-negative breast cancer was associated with a significantly worse OS (HR = 1.98, 95% CI = 1.00-3.95 and BCSS (HR = 2.24, 95% CI = 1.12-4.47. There was no significant interaction found between the BMI and hormone-receptor status in the lymph-node-negative setting, and BMI did not interact with the menopause status in any subgroup. In conclusion, BMI interacts with the hormone-receptor status in a lymph-node-positive setting, thereby playing a role in the prognosis of breast cancer.

Analysis and functional characterization of sequence variations in ligand binding domain of thyroid hormone receptors in autism spectrum disorder (ASD) patients.

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Kalikiri, Mahesh Kumar; Mamidala, Madhu Poornima; Rao, Ananth N; Rajesh, Vidya

2017-12-01

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, 10: 1919-1928. ©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.

Vegetable and fruit consumption and the risk of hormone receptor-defined breast cancer in the EPIC cohort.

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Emaus, Marleen J; Peeters, Petra H M; Bakker, Marije F; Overvad, Kim; Tjønneland, Anne; Olsen, Anja; Romieu, Isabelle; Ferrari, Pietro; Dossus, Laure; Boutron-Ruault, Marie Christine; Baglietto, Laura; Fortner, Renée T; Kaaks, Rudolf; Boeing, Heiner; Trichopoulou, Antonia; Lagiou, Pagona; Trichopoulos, Dimitrios; Masala, Giovanna; Pala, Valeria; Panico, Salvatore; Tumino, Rosario; Polidoro, Silvia; Skeie, Guri; Lund, Eiliv; Weiderpass, Elisabete; Quirós, J Ramón; Travier, Noémie; Sánchez, María-José; Chirlaque, Maria-Dolores; Ardanaz, Eva; Dorronsoro, Miren; Winkvist, Anna; Wennberg, Maria; Bueno-de-Mesquita, H Bas; Khaw, Kay-Tee; Travis, Ruth C; Key, Timothy J; Aune, Dagfinn; Gunter, Marc; Riboli, Elio; van Gils, Carla H

2016-01-01

The recent literature indicates that a high vegetable intake and not a high fruit intake could be associated with decreased steroid hormone receptor-negative breast cancer risk. This study aimed to investigate the association between vegetable and fruit intake and steroid hormone receptor-defined breast cancer risk. A total of 335,054 female participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort were included in this study (mean ± SD age: 50.8 ± 9.8 y). Vegetable and fruit intake was measured by country-specific questionnaires filled out at recruitment between 1992 and 2000 with the use of standardized procedures. Cox proportional hazards models were stratified by age at recruitment and study center and were adjusted for breast cancer risk factors. After a median follow-up of 11.5 y (IQR: 10.1-12.3 y), 10,197 incident invasive breast cancers were diagnosed [3479 estrogen and progesterone receptor positive (ER+PR+); 1021 ER and PR negative (ER-PR-)]. Compared with the lowest quintile, the highest quintile of vegetable intake was associated with a lower risk of overall breast cancer (HRquintile 5-quintile 1: 0.87; 95% CI: 0.80, 0.94). Although the inverse association was most apparent for ER-PR- breast cancer (ER-PR-: HRquintile 5-quintile 1: 0.74; 95% CI: 0.57, 0.96; P-trend = 0.03; ER+PR+: HRquintile 5-quintile 1: 0.91; 95% CI: 0.79, 1.05; P-trend = 0.14), the test for heterogeneity by hormone receptor status was not significant (P-heterogeneity = 0.09). Fruit intake was not significantly associated with total and hormone receptor-defined breast cancer risk. This study supports evidence that a high vegetable intake is associated with lower (mainly hormone receptor-negative) breast cancer risk. © 2016 American Society for Nutrition.

Intracellular coexpression of CXC- and CC– chemokine receptors and their ligands in human melanoma cell lines and dynamic variations after xenotransplantation

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Pinto, Sandra; Martínez-Romero, Alicia; O’Connor, José-Enrique; Gil-Benso, Rosario; San-Miguel, Teresa; Terrádez, Liria; Monteagudo, Carlos; Callaghan, Robert C

2014-01-01

Chemokines have been implicated in tumor progression and metastasis. In melanoma, chemokine receptors have been implicated in organ selective metastasis by regulating processes such as chemoattraction, adhesion and survival. In this study we have analyzed, using flow cytometry, the systems formed by the chemokine receptors CXCR3, CXCR4, CXCR7, CCR7 and CCR10 and their ligands in thirteen human melanoma cell lines (five established from primary tumors and eight established from metastasis from different tissues). WM-115 and WM-266.4 melanoma cell lines (obtained from a primary and a metastatic melanoma respectively) were xenografted in nude mice and the tumors and cell lines derived from them were also analyzed. Our results show that the melanoma cell lines do not express or express in a low degree the chemokine receptors on their cell surface. However, melanoma cell lines show intracellular expression of all the aforementioned receptors and most of their respective ligands. When analyzing the xenografts and the cell lines obtained from them we found variations in the intracellular expression of chemokines and chemokine receptors that differed between the primary and metastatic cell lines. However, as well as in the original cell lines, minute or no expression of the chemokine receptors was observed at the cell surface. Coexpression of chemokine receptors and their ligands was found in human melanoma cell lines. However, this expression is intracellular and receptors are not found at the cell membrane nor chemokines are secreted to the cell medium. The levels of expressed chemokine receptors and their ligands show dynamic variations after xenotransplantation that differ depending on the origin of the cell line (from primary tumor or from metastasis)

Fanconi anemia A is a nucleocytoplasmic shuttling molecule required for gonadotropin-releasing hormone (GnRH) transduction of the GnRH receptor.

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Larder, Rachel; Karali, Dimitra; Nelson, Nancy; Brown, Pamela

2006-12-01

GnRH binds its cognate G protein-coupled GnRH receptor (GnRHR) located on pituitary gonadotropes and drives expression of gonadotropin hormones. There are two gonadotropin hormones, comprised of a common alpha- and hormone-specific beta-subunit, which are required for gonadal function. Recently we identified that Fanconi anemia a (Fanca), a DNA damage repair gene, is differentially expressed within the LbetaT2 gonadotrope cell line in response to stimulation with GnRH. FANCA is mutated in more than 60% of cases of Fanconi anemia (FA), a rare genetically heterogeneous autosomal recessive disorder characterized by bone marrow failure, endocrine tissue cancer susceptibility, and infertility. Here we show that induction of FANCA protein is mediated by the GnRHR and that the protein constitutively adopts a nucleocytoplasmic intracellular distribution pattern. Using inhibitors to block nuclear import and export and a GnRHR antagonist, we demonstrated that GnRH induces nuclear accumulation of FANCA and green fluorescent protein (GFP)-FANCA before exporting back to the cytoplasm using the nuclear export receptor CRM1. Using FANCA point mutations that locate GFP-FANCA to the cytoplasm (H1110P) or functionally uncouple GFP-FANCA (Q1128E) from the wild-type nucleocytoplasmic distribution pattern, we demonstrated that wild-type FANCA was required for GnRH-induced activation of gonadotrope cell markers. Cotransfection of H1110P and Q1128E blocked GnRH activation of the alphaGsu and GnRHR but not the beta-subunit gene promoters. We conclude that nucleocytoplasmic shuttling of FANCA is required for GnRH transduction of the alphaGSU and GnRHR gene promoters and propose that FANCA functions as a GnRH-induced signal transducer.

Shaping policy: the Canadian Cancer Society and the Hormone Receptor Testing Inquiry.

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Mathews, M; Newbury, J; Housser, E M

2011-08-01

In 2007, the Government of Newfoundland and Labrador established the Commission of Inquiry on Hormone Receptor Testing to examine problems with estrogen and progesterone hormone receptor tests conducted in the province between 1997 and 2005. Using the Inquiry as a case study, we examine the knowledge transfer activities used by the Canadian Cancer Society - Newfoundland and Labrador Division (CCS-NL) to shape policy and improve cancer control in the province. CCS-NL established a panel to advise its legal counsel and asked academic researchers to prepare papers to submit to the Commission. CCS-NL also interviewed patients to better inform its legal arguments, used its province-wide networks to raise awareness of the Inquiry, and provided a toll-free number that people could call. It also provided basic information, resources, and contact information for people who were affected by the flawed hormone receptor tests. The effectiveness of CCS-NL's activities is reflected by the inclusion of its key messages in the Commission's recommendations, and the investment in cancer care following the Inquiry. The success of the CCS-NL knowledge transfer efforts stemmed from its reputation as an advocate for cancer patients and its long-standing relationship with researchers, especially at the local level. The case illustrates real-world application of knowledge transfer practices in the development of public policy, and describes how community-based non-government organizations can identify and draw attention to important issues that otherwise might not have been addressed.

Selective thyroid hormone receptor modulators

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Girish Raparti

2013-01-01

Full Text Available Thyroid hormone (TH is known to have many beneficial effects on vital organs, but its extrapolation to be used therapeutically has been restricted by the fact that it does have concurrent adverse effects. Recent finding of various thyroid hormone receptors (TR isoforms and their differential pattern of tissue distribution has regained interest in possible use of TH analogues in therapeutics. These findings were followed by search of compounds with isoform-specific or tissue-specific action on TR. Studying the structure-activity relationship of TR led to the development of compounds like GC1 and KB141, which preferentially act on the β1 isoform of TR. More recently, eprotirome was developed and has been studied in humans. It has shown to be effective in dyslipidemia by the lipid-lowering action of TH in the liver and also in obesity. Another compound, 3,5-diiodothyropropionic acid (DITPA, binds to both α- and β-type TRs with relatively low affinity and has been shown to be effective in heart failure (HF. In postinfarction models of HF and in a pilot clinical study, DITPA increased cardiac performance without affecting the heart rate. TR antagonists like NH3 can be used in thyrotoxicosis and cardiac arrhythmias. However, further larger clinical trials on some of these promising compounds and development of newer compounds with increased selectivity is required to achieve higher precision of action and avoid adverse effects seen with TH.

Breast cancer with Her-22 hormone receptor-positive neu: primary systemic treatment, sentinel node biopsy and hormone

International Nuclear Information System (INIS)

Lopez C, Nayara; Sanchez M, Jose Ignacio; De Santiago G, Javier

2013-01-01

Neoadjuvant chemotherapy is an interesting option in the therapy of some breast cancer cases. Cases in which the timing for sentinel lymph node biopsy is controversial. Co-expression of estrogen receptors and Her2/neu (cc-erbB-2) in breast cancer may imply hormone resistance, especially to tamoxifen. We present a clinic case with co-expression of estrogen receptors and Her2/neu that was treated with neoadjuvant chemotherapy and previous sentinel lymph node biopsy followed by breast tumorectomy with axillar lympha- denectomy, radiotherapy and hormonotherapy with letrozol, geserelina and trastuzumab. A good treatment response as found

Internalisation of the protease-activated receptor 1: role of the third intracellular loop and of the cytoplasmic tail.

Science.gov (United States)

Chen, X; Berrou, J; Vigneau, C; Delarue, F; Rondeau, E

2001-06-01

To analyse the mechanisms of PAR-1 internalisation, we constructed several PAR-1 mutants and stably expressed them in CHO cells. Our study shows that the Ser(306)-->Ala mutation (S306A), which eliminates a potential site of phosphorylation by PKC in the third intracellular loop of PAR-1, did not change the rate of phosphorylation but reduced the rate of thrombin-induced internalisation of the PAR-1 mutant (58 versus 78% of membrane PAR-1 in 15 min, pinternalisation upon activation. This deletion also inhibited the PMA-induced and the agonist-independent internalisation of the receptor. The Tyr(371)--> Ala mutation (Y371A), in a NPXXY motif of the seventh transmembrane domain of the receptor had no effect on the receptor behaviour. Our results indicate that both the C-tail and the third intracellular loop are involved in PAR-1 internalisation induced by thrombin while only the C-tail plays a role in the PMA-induced and in the agonist-independent PAR-1 internalisation.

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-5...

Cytoplasmic sequences of the growth hormone receptor necessary for signal transduction

DEFF Research Database (Denmark)

Goujon, L; Allevato, G; Simonin, G

1994-01-01

To study structure-function relationships of the growth hormone (GH) receptor (GHR), two functional systems have been developed. CHO cells were transiently cotransfected with the cDNA encoding the full-length rat GHR and with a construct consisting of the 5' flanking region of one of two GH...

Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors.

Science.gov (United States)

Zhao, Li-Hua; Yin, Yanting; Yang, Dehua; Liu, Bo; Hou, Li; Wang, Xiaoxi; Pal, Kuntal; Jiang, Yi; Feng, Yang; Cai, Xiaoqing; Dai, Antao; Liu, Mingyao; Wang, Ming-Wei; Melcher, Karsten; Xu, H Eric

2016-07-15

G protein-coupled receptors (GPCRs) from the secretin-like (class B) family are key players in hormonal homeostasis and are important drug targets for the treatment of metabolic disorders and neuronal diseases. They consist of a large N-terminal extracellular domain (ECD) and a transmembrane domain (TMD) with the GPCR signature of seven transmembrane helices. Class B GPCRs are activated by peptide hormones with their C termini bound to the receptor ECD and their N termini bound to the TMD. It is thought that the ECD functions as an affinity trap to bind and localize the hormone to the receptor. This in turn would allow the hormone N terminus to insert into the TMD and induce conformational changes of the TMD to activate downstream signaling. In contrast to this prevailing model, we demonstrate that human class B GPCRs vary widely in their requirement of the ECD for activation. In one group, represented by corticotrophin-releasing factor receptor 1 (CRF1R), parathyroid hormone receptor (PTH1R), and pituitary adenylate cyclase activating polypeptide type 1 receptor (PAC1R), the ECD requirement for high affinity hormone binding can be bypassed by induced proximity and mass action effects, whereas in the other group, represented by glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), the ECD is required for signaling even when the hormone is covalently linked to the TMD. Furthermore, the activation of GLP-1R by small molecules that interact with the intracellular side of the receptor is dependent on the presence of its ECD, suggesting a direct role of the ECD in GLP-1R activation. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Molecular characterization of thyroid hormone receptors from the leopard gecko, and their differential expression in the skin.

Science.gov (United States)

Kanaho, Yoh-Ichiro; Endo, Daisuke; Park, Min Kyun

2006-06-01

Thyroid hormones (THs) play crucial roles in various developmental and physiological processes in vertebrates, including squamate reptiles. The effect of THs on shedding frequency is interesting in Squamata, since the effects on lizards are quite the reverse of those in snakes: injection of thyroxine increases shedding frequency in lizards, but decreases it in snakes. However, the mechanism underlying this differential effect remains unclear. To facilitate the investigation of the molecular mechanism of the physiological functions of THs in Squamata, their two specific receptor (TRalpha and beta) cDNAs, which are members of the nuclear hormone receptor superfamily, were cloned from a lizard, the leopard gecko, Eublepharis macularius. This is the first molecular cloning of thyroid hormone receptors (TRs) from reptiles. The deduced amino acid sequences showed high identity with those of other species, especially in the C and E/F domains, which are characteristic domains in nuclear hormone receptors. Expression analysis revealed that TRs were widely expressed in many tissues and organs, as in other animals. To analyze their role in the skin, temporal expression analysis was performed by RT-PCR, revealing that the two TRs had opposing expression patterns: TRalpha was expressed more strongly after than before skin shedding, whereas TRbeta was expressed more strongly before than after skin shedding. This provides good evidence that THs play important roles in the skin, and that the roles of their two receptor isoforms are distinct from each other.

Social information changes stress hormone receptor expression in the songbird brain.

Science.gov (United States)

Cornelius, Jamie M; Perreau, Gillian; Bishop, Valerie R; Krause, Jesse S; Smith, Rachael; Hahn, Thomas P; Meddle, Simone L

2018-01-01

Social information is used by many vertebrate taxa to inform decision-making, including resource-mediated movements, yet the mechanisms whereby social information is integrated physiologically to affect such decisions remain unknown. Social information is known to influence the physiological response to food reduction in captive songbirds. Red crossbills (Loxia curvirostra) that were food reduced for several days showed significant elevations in circulating corticosterone (a "stress" hormone often responsive to food limitation) only if their neighbors were similarly food restricted. Physiological responses to glucocorticoid hormones are enacted through two receptors that may be expressed differentially in target tissues. Therefore, we investigated the influence of social information on the expression of the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA in captive red crossbill brains. Although the role of MR and GR in the response to social information may be highly complex, we specifically predicted social information from food-restricted individuals would reduce MR and GR expression in two brain regions known to regulate hypothalamic-pituitary-adrenal (HPA) activity - given that reduced receptor expression may lessen the efficacy of negative feedback and release inhibitory tone on the HPA. Our results support these predictions - offering one potential mechanism whereby social cues could increase or sustain HPA-activity during stress. The data further suggest different mechanisms by which metabolic stress versus social information influence HPA activity and behavioral outcomes. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Downregulation of transferrin receptor surface expression by intracellular antibody

International Nuclear Information System (INIS)

Peng Jilin; Wu Sha; Zhao Xiaoping; Wang Min; Li Wenhan; Shen Xin; Liu Jing; Lei Ping; Zhu Huifen; Shen Guanxin

2007-01-01

To deplete cellular iron uptake, and consequently inhibit the proliferation of tumor cells, we attempt to block surface expression of transferrin receptor (TfR) by intracellular antibody technology. We constructed two expression plasmids (scFv-HAK and scFv-HA) coding for intracellular single-chain antibody against TfR with or without endoplasmic reticulum (ER) retention signal, respectively. Then they were transfected tumor cells MCF-7 by liposome. Applying RT-PCR, Western blotting, immunofluorescence microscopy and immunoelectron microscope experiments, we insure that scFv-HAK intrabody was successfully expressed and retained in ER contrasted to the secreted expression of scFv-HA. Flow cytometric analysis confirmed that the TfR surface expression was markedly decreased approximately 83.4 ± 2.5% in scFv-HAK transfected cells, while there was not significantly decrease in scFv-HA transfected cells. Further cell growth and apoptosis characteristics were evaluated by cell cycle analysis, nuclei staining and MTT assay. Results indicated that expression of scFv-HAK can dramatically induce cell cycle G1 phase arrest and apoptosis of tumor cells, and consequently significantly suppress proliferation of tumor cells compared with other control groups. For First time this study demonstrates the potential usage of anti-TfR scFv-intrabody as a growth inhibitor of TfR overexpressing tumors

Vitamin D receptor displays DNA binding and transactivation as a heterodimer with the retinoid X receptor, but not with the thyroid hormone receptor.

Science.gov (United States)

Thompson, P D; Hsieh, J C; Whitfield, G K; Haussler, C A; Jurutka, P W; Galligan, M A; Tillman, J B; Spindler, S R; Haussler, M R

1999-12-01

The vitamin D receptor (VDR) is a transcription factor believed to function as a heterodimer with the retinoid X receptor (RXR). However, it was reported [Schräder et al., 1994] that, on putative vitamin D response elements (VDREs) within the rat 9k and mouse 28k calcium binding protein genes (rCaBP 9k and mCaBP 28k), VDR and thyroid hormone receptor (TR) form heterodimers that transactivate in response to both 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) and triiodothyronine (T(3)). We, therefore, examined associations of these receptors on the putative rCaBP 9k and mCaBP 28k VDREs, as well as on established VDREs from the rat osteocalcin (rOC) and mouse osteopontin (mOP) genes, plus the thyroid hormone response element (TRE) from the rat myosin heavy chain (rMHC) gene. In gel mobility shift assays, we found no evidence for VDR-TR heterodimer interaction with any tested element. Further, employing these hormone response elements linked to reporter genes in transfected cells, VDR and TR mediated responses to their cognate ligands only from the rOC/mOP and rMHC elements, respectively, while the CaBP elements were unresponsive to any combination of ligand(s). Utilizing the rOC and mOP VDREs, two distinct repressive actions of TR on VDR-mediated signaling were demonstrated: a T(3)-independent action, presumably via direct TR-RXR competition for DNA binding, and a T(3)-dependent repression, likely by diversion of limiting RXR from VDR-RXR toward the formation of TR-RXR heterodimers. The relative importance of these two mechanisms differed in a response element-specific manner. These results may provide a partial explanation for the observed association between hyperthyroidism and bone demineralization/osteoporosis. Copyright 1999 Wiley-Liss, Inc.

Flow cytometric measurement of DNA level and steroid hormone receptor assay in breast cancer

International Nuclear Information System (INIS)

Zubrikhina, G.N.; Kuz'mina, Eh.V.; Bassalyk, L.S.; Murav'eva, N.I.

1989-01-01

DNA level measured by flow cytometry and estrogen and progesteron receptors assayed in tissue samples obtained from 85 malignant and 16 benign lesions of the breast. All the benign tumors revealed 2c DNA content and most of them were receptor-negative, while 74.1% of breast carcinomas displayed aneuploidy. Three patients (3.5%) had two lines of aneuploid cells. Many aneuploid tumors were receptor-negative. Preoperative radiation treatmet (14-20 Gy) did not significantly influence the level of steroid hormone receptors in tumors. Estrogen receptor level was higher in menopausal patients than in premenopausal ones

Ghrelin: ghrelin as a regulatory Peptide in growth hormone secretion.

Science.gov (United States)

Khatib, Nazli; Gaidhane, Shilpa; Gaidhane, Abhay M; Khatib, Mahanaaz; Simkhada, Padam; Gode, Dilip; Zahiruddin, Quazi Syed

2014-08-01

Ghrelin is a type of growth hormone (GH) secretagogue that stimulates the release of GH. It is a first hormone linking gastrointestinal-pituitary axis. This review highlights the interaction of ghrelin with GHRH and somatostatin to regulate the secretion of GH and intends to explore the possible physiological role of the ghrelin-pituitary-GH axis linkage system. Ghrelin is highly conserved among species and is classified into octanoylated (C8:0), decanoylated (C10:0), decenoylated (C10:1) and nonacylated,ghrelin. Acylated ghrelin is the major active form of human ghrelin. The primary production site of ghrelin is the stomach, and it interacts with stomach ghrelin as well as hypothalamic GHRH and somatostatin in the regulation of pituitary GH secretion. Ghrelin stimulate GH release through the GHS receptor to increase intracellular Ca2+ ([Ca2+] levels via IP3 signal transduction pathway. Ghrelin is a specific endogenous ligand for the GHS receptor and provides a definitive proof of the occurance of a GHS-GHS receptor signalling system in the regulation of GH secretion. Studies suggests that ghrelin is a powerful pharmacological agent that exerts a potent, time-dependent stimulation of pulsatile secretion of GH.

THYROID HORMONE RECEPTOR BETA GENE MUTATION (P453A) IN A TURKISH FAMILY PRODUCING RESISTANCE TO THYROID HORMONE

Science.gov (United States)

Bayraktaroglu, Taner; Noel, Janet; Mukaddes, Nahit Motavalli; Refetoff, Samuel

2018-01-01

Two members of a Turkish family, a mother and son, had thyroid function tests suggestive of resistance to thyroid hormone (RTH). The clinical presentation was, however, different. The mother (proposita) had palpitation, weakness, tiredness, nervousness, dry mouth and was misdiagnosed as having multinodular toxic goiter which was treated with antithyroid drugs and partial thyroidectomy. Her younger son had attention deficit hyperactivity disorder and primary encopresis, but normal intellectual quotient. Both had elevated serum iodothyronine levels with nonsuppressed thyrotropin. A mutation in one allele of the thyroid hormone receptor beta gene (P453A) was identified, providing a genetic confirmation for the diagnosis of RTH. PMID:18561095

Hepatic receptors for homologous growth hormone in the eel

International Nuclear Information System (INIS)

Hirano, T.

1991-01-01

The specific binding of 125I-labeled eel growth hormone (eGH) to liver membranes of the eel was examined. The specific binding to the 10,000g pellet was greater than that to the 600g pellet. The specific binding was linear up to about 100 mg fresh tissue, and was saturable with increasing amounts of membrane. The specific binding was pH-, temperature-, and time-dependent, with the optimum pH at 7.4, and greater specific binding was obtained at 15 and 25 degrees than at 35 degrees. Scatchard analysis of liver binding gave an association constant of 1.1 x 10(9) M-1 and a capacity of 105 fmol/mg protein. The receptor preparation was highly specific for GHs. Natural and recombinant eel GHs as well as recombinant salmon GH competed equally with 125I-eGH for the receptor sites of the 10,000g liver membrane. Ovine GH was more potent in displacing the labeled eGH than the homologous eel hormone. Tilapia GH and ovine prolactin (PRL) were needed in greater amounts (40 times) than eGH to displace the labeled eGH. Salmon and tilapia PRLs were still less potent (500 times) than eGH. There was no displacement with eel PRL. No significant change in the specific binding was seen 1 week after hypophysectomy, whereas injection of eGH into the hypophysectomized eel caused a significant reduction after 24 hr. The binding to the membrane fractions from gills, kidney, muscle, intestine, and brain was low and exclusively nonspecific, indicating the presence of specific GH receptors predominantly in the liver

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...

UV filters induce transcriptional changes of different hormonal receptors in Chironomus riparius embryos and larvae.

Science.gov (United States)

Ozáez, Irene; Aquilino, Mónica; Morcillo, Gloria; Martínez-Guitarte, José-Luis

2016-07-01

Organic ultraviolet (UV) filters are emerging contaminants that are ubiquitous in fresh and marine aquatic systems due to their extensive use in cosmetics, plastics, paints, textiles, and many other industrial products. The estrogenic effects of organic UV filters have been long demonstrated in vertebrates, and other hormonal activities may be altered, according to more recent reports. The impact of UV filters on the endocrine system of invertebrates is largely unknown. We have previously reported that some UV filters may affect ecdysone-related genes in the aquatic insect Chironomus riparius, an ecotoxicologically important model organism. To further analyze other possible effects on endocrine pathways, we first characterized four pivotal genes related with hormonal pathways in insects; thereafter, these genes were assessed for alterations in transcriptional activity after exposure to 4-methylbenzylidene camphor (4MBC) or benzophenone-3 (BP-3), two extensively used sunscreens. We found that both chemicals disturbed the expression of all four genes analyzed: hormonal receptor 38 (HR38), methoprene-tolerant (Met), membrane-associate progesterone receptor (MAPR) and insulin-like receptor (INSR), measured by changes in mRNA levels by real-time PCR. An upregulatory effect at the genomic level was detected in different developmental stages. Interestingly, embryos appeared to be more sensitive to the action of the UV filters than larvae. Our results suggest that the risk of disruption through different endocrine routes is not negligible, considering the significant effects of UV filters on key hormonal receptor and regulatory genes. Further effort is needed to develop environmental risk assessment studies on these pollutants, particularly for aquatic invertebrate model organisms. Copyright © 2016 Elsevier Ltd. All rights reserved.

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.

Machine learning approaches to decipher hormone and HER2 receptor status phenotypes in breast cancer.

Science.gov (United States)

Adabor, Emmanuel S; Acquaah-Mensah, George K

2017-10-16

Breast cancer prognosis and administration of therapies are aided by knowledge of hormonal and HER2 receptor status. Breast cancer lacking estrogen receptors, progesterone receptors and HER2 receptors are difficult to treat. Regarding large data repositories such as The Cancer Genome Atlas, available wet-lab methods for establishing the presence of these receptors do not always conclusively cover all available samples. To this end, we introduce median-supplement methods to identify hormonal and HER2 receptor status phenotypes of breast cancer patients using gene expression profiles. In these approaches, supplementary instances based on median patient gene expression are introduced to balance a training set from which we build simple models to identify the receptor expression status of patients. In addition, for the purpose of benchmarking, we examine major machine learning approaches that are also applicable to the problem of finding receptor status in breast cancer. We show that our methods are robust and have high sensitivity with extremely low false-positive rates compared with the well-established methods. A successful application of these methods will permit the simultaneous study of large collections of samples of breast cancer patients as well as save time and cost while standardizing interpretation of outcomes of such studies. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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 ...

Intracellular signaling of the Ufo/Axl receptor tyrosine kinase is mediated mainly by a multi-substrate docking-site.

Science.gov (United States)

Braunger, J; Schleithoff, L; Schulz, A S; Kessler, H; Lammers, R; Ullrich, A; Bartram, C R; Janssen, J W

1997-06-05

Ufo/Axl belongs to a new family of receptor tyrosine kinases with an extracellular structure similar to that of neural cell adhesion molecules. In order to elucidate intracellular signaling, the cytoplasmic moiety of Ufo/Axl was used to screen an expression library according to the CORT (cloning of receptor targets) method. Three putative Ufo substrates were identified: phospholipase Cgamma1 (PLCgamma), as well as p85alpha and p85beta subunits of phosphatidylinositol 3'-kinase (PI3-kinase). Subsequently, chimeric EGFR/Ufo receptors consisting of the extracellular domains of the epidermal growth factor receptor (EGFR) and the transmembrane and intracellular moiety of Ufo were engineered. Using different far-Western blot analyses and coimmunoprecipitation assays, receptor binding of PLCgamma and p85 proteins as well as GRB2, c-src and lck was examined in vitro and in vivo. Competitive inhibition of substrate binding and mutagenesis experiments with EGFR/Ufo constructs revealed C-terminal tyrosine 821 (EILpYVNMDEG) as a docking site for multiple effectors, namely PLCgamma, p85 proteins, GRB2, c-src and lck. Tyrosine 779 (DGLpYALMSRC) demonstrated an additional, but lower binding affinity for the p85 proteins in vitro. In addition, binding of PLCgamma occurred through tyrosine 866 (AGRpYVLCPST). Moreover, our in vivo data indicate that further direct or indirect binding sites for PLCgamma, GRB2, c-src and lck on the human Ufo receptor may exist.

Expression of Sex Steroid Hormone Receptors in Vagal Motor Neurons Innervating the Trachea and Esophagus in Mouse

International Nuclear Information System (INIS)

Mukudai, Shigeyuki; Ichi Matsuda, Ken; Bando, Hideki; Takanami, Keiko; Nishio, Takeshi; Sugiyama, Yoichiro; Hisa, Yasuo; Kawata, Mitsuhiro

2016-01-01

The medullary vagal motor nuclei, the nucleus ambiguus (NA) and dorsal motor nucleus of the vagus (DMV), innervate the respiratory and gastrointestinal tracts. We conducted immunohistochemical analysis of expression of the androgen receptor (AR) and estrogen receptor α (ERα), in relation to innervation of the trachea and esophagus via vagal motor nuclei in mice. AR and ERα were expressed in the rostral NA and in part of the DMV. Tracing experiments using cholera toxin B subunit demonstrated that neurons of vagal motor nuclei that innervate the trachea and esophagus express AR and ERα. There was no difference in expression of sex steroid hormone receptors between trachea- and esophagus-innervating neurons. These results suggest that sex steroid hormones may act on vagal motor nuclei via their receptors, thereby regulating functions of the trachea and esophagus

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

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.......31). In conclusion, neither gender, nor the use of hormonal contraception in premenopausal women was associated with cortical 5-HT(2A) receptor binding....... 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...

Imaging of persistent cAMP signaling by internalized G protein-coupled receptors.

Science.gov (United States)

Calebiro, Davide; Nikolaev, Viacheslav O; Lohse, Martin J

2010-07-01

G protein-coupled receptors (GPCRs) are the largest family of plasma membrane receptors. They mediate the effects of several endogenous cues and serve as important pharmacological targets. Although many biochemical events involved in GPCR signaling have been characterized in great detail, little is known about their spatiotemporal dynamics in living cells. The recent advent of optical methods based on fluorescent resonance energy transfer allows, for the first time, to directly monitor GPCR signaling in living cells. Utilizing these methods, it has been recently possible to show that the receptors for two protein/peptide hormones, the TSH and the parathyroid hormone, continue signaling to cAMP after their internalization into endosomes. This type of intracellular signaling is persistent and apparently triggers specific cellular outcomes. Here, we review these recent data and explain the optical methods used for such studies. Based on these findings, we propose a revision of the current model of the GPCR-cAMP signaling pathway to accommodate receptor signaling at endosomes.

Molecular Cloning, Genomic Organization and Developmental Regulation of a Novel Receptor from Drosophila melanogaster Structurally Related to Gonadotropin-Releasing Hormone Receptors from Vertebrates

DEFF Research Database (Denmark)

Hauser, Frank; Søndergaard, Leif; Grimmelikhuijzen, Cornelis J.P.

1998-01-01

After screening the data base of the BerkeleyDrosophilaGenome Project with a sequence coding for the transmembrane region of a G protein-coupled receptor, we found thatDrosophilamight contain a gene coding for a receptor that is structurally related to the Gonadotropin-Releasing Hormone (GnRH) re...

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.

L-tyrosine and L-DOPA as hormone-like regulators of melanocytes functions

Science.gov (United States)

Slominski, Andrzej; Zmijewski, Michal; Pawelek, John

2011-01-01

Summary Evidence reveals that L-tyrosine and L-DOPA, besides serving as substrates and intermediates of melanogenesis, are also bioregulatory agents acting not only as inducers and positive regulators of melanogenesis but also as regulators of other cellular functions. These can be mediated through action on specific receptors or through non-receptor mediated mechanisms. The substrate induced (L-tyrosine and/or L-DOPA) melanogenic pathway would autoregulate itself as well as it would regulate the melanocyte functions through activity of its structural or regulatory proteins and through intermediates of melanogenesis and melanin itself. Dissection of regulatory and autoregulatory elements of this process may elucidate how substrate induced autoregulatory pathways have evolved from prokaryotic or simple eukaryotic organisms to complex systems in vertebrates. This could substantiate older theory proposing that receptors for amino-acid derived hormones arose from the receptors for those amino acids, and that nuclear receptors evolved from primitive intracellular receptors binding nutritional factors or metabolic intermediates. PMID:21834848

Triazolophostins: a library of novel and potent agonists of IP3 receptors

OpenAIRE

Vibhute, Amol M; Konieczny, Vera; Taylor, Colin William; Sureshan, Kana M

2015-01-01

IP3 receptors are channels that mediate the release of Ca2+ from the intracellular stores of cells stimulated by hormones or neurotransmitters. Adenophostin A (AdA) is the most potent agonist of IP3 receptors, with the β-anomeric adenine contributing to the increased potency. The potency of AdA and its stability towards the enzymes that degrade IP3 have aroused interest in AdA analogs for biological studies. The complex structure of AdA poses problems that have necessitated optimization of sy...

Alpha-2 adrenoceptors and imidazoline receptors in cardiomyocytes mediate counterbalancing effect of agmatine on NO synthesis and intracellular calcium handling.

Science.gov (United States)

Maltsev, Alexander V; Kokoz, Yuri M; Evdokimovskii, Edward V; Pimenov, Oleg Y; Reyes, Santiago; Alekseev, Alexey E

2014-03-01

Evidence suggests that intracellular Ca(2+) levels and contractility of cardiomyocytes can be modulated by targeting receptors other than already identified adrenergic or non-adrenergic sarcolemmal receptors. This study uncovers the presence in myocardial cells of adrenergic α2 (α2-AR) and imidazoline I1 (I1R) receptors. In isolated left ventricular myocytes generating stationary spontaneous Ca(2+) transients in the absence of triggered action potentials, the prototypic agonist of both receptors agmatine can activate corresponding signaling cascades with opposing outcomes on nitric oxide (NO) synthesis and intracellular Ca(2+) handling. Specifically, activation of α2-AR signaling through PI3 kinase and Akt/protein kinase B stimulates NO production and abolishes Ca(2+) transients, while targeting of I1R signaling via phosphatidylcholine-specific phospholipase C (PC-PLC) and protein kinase C (PKC) suppresses NO synthesis and elevates averaged intracellular Ca(2+). We identified that endothelial NO synthase (eNOS) is a major effector for both signaling cascades. According to the established eNOS transitions between active (Akt-dependent) and inactive (PKC-dependent) conformations, we suggest that balance between α2-AR and I1R signaling pathways sets eNOS activity, which by defining operational states of myocellular sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) can adjust Ca(2+) re-uptake and thereby cardiac inotropy. These results indicate that the conventional catalog of cardiomyocyte sarcolemmal receptors should be expanded by the α2-AR and I1R populations, unveiling previously unrecognized targets for endogenous ligands as well as for existing and potential pharmacological agents in cardiovascular medicine. Copyright © 2014 Elsevier Ltd. All rights reserved.

The Orphan Nuclear Receptor TLX Is an Enhancer of STAT1-Mediated Transcription and Immunity to Toxoplasma gondii.

Directory of Open Access Journals (Sweden)

Daniel P Beiting

2015-07-01

Full Text Available The protozoan parasite, Toxoplasma, like many intracellular pathogens, suppresses interferon gamma (IFN-γ-induced signal transducer and activator of transcription 1 (STAT1 activity. We exploited this well-defined host-pathogen interaction as the basis for a high-throughput screen, identifying nine transcription factors that enhance STAT1 function in the nucleus, including the orphan nuclear hormone receptor TLX. Expression profiling revealed that upon IFN-γ treatment TLX enhances the output of a subset of IFN-γ target genes, which we found is dependent on TLX binding at those loci. Moreover, infection of TLX deficient mice with the intracellular parasite Toxoplasma results in impaired production of the STAT1-dependent cytokine interleukin-12 by dendritic cells and increased parasite burden in the brain during chronic infection. These results demonstrate a previously unrecognized role for this orphan nuclear hormone receptor in regulating STAT1 signaling and host defense and reveal that STAT1 activity can be modulated in a context-specific manner by such "modifiers."

The Orphan Nuclear Receptor TLX Is an Enhancer of STAT1-Mediated Transcription and Immunity to Toxoplasma gondii.

Science.gov (United States)

Beiting, Daniel P; Hidano, Shinya; Baggs, Julie E; Geskes, Jeanne M; Fang, Qun; Wherry, E John; Hunter, Christopher A; Roos, David S; Cherry, Sara

2015-07-01

The protozoan parasite, Toxoplasma, like many intracellular pathogens, suppresses interferon gamma (IFN-γ)-induced signal transducer and activator of transcription 1 (STAT1) activity. We exploited this well-defined host-pathogen interaction as the basis for a high-throughput screen, identifying nine transcription factors that enhance STAT1 function in the nucleus, including the orphan nuclear hormone receptor TLX. Expression profiling revealed that upon IFN-γ treatment TLX enhances the output of a subset of IFN-γ target genes, which we found is dependent on TLX binding at those loci. Moreover, infection of TLX deficient mice with the intracellular parasite Toxoplasma results in impaired production of the STAT1-dependent cytokine interleukin-12 by dendritic cells and increased parasite burden in the brain during chronic infection. These results demonstrate a previously unrecognized role for this orphan nuclear hormone receptor in regulating STAT1 signaling and host defense and reveal that STAT1 activity can be modulated in a context-specific manner by such "modifiers."

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

Changes in amount and intracellular distribution of androgen receptor in human foreskin as a function of age.

Science.gov (United States)

Roehrborn, C G; Lange, J L; George, F W; Wilson, J D

1987-01-01

To provide insight into the factors that control growth of the penis we measured the amount and intracellular distribution of specific high affinity androgen receptor in foreskins obtained at circumcision from 49 males varying in age from newborn to 59 yr. Total (cytosolic plus nuclear extract) androgen receptor decreased from approximately 40 fmol/g tissue weight in newborn foreskins to approximately 25 fmol/g by 1 yr of age. The amount of receptor rose in childhood to approximately 180 fmol/g in the late teenage years and fell thereafter to approximately 20-40 fmol/g in men older than 40 yr. The amount of receptor in the nuclear fraction increased at the time of puberty and subsequently decreased in parallel with the decline in total receptor level. These changes in androgen-receptor amount are similar when expressed per milligram DNA or per milligram protein. Images PMID:3491838

Solubilization and molecular size of atrial natriuretic hormone (ANH) receptors from rabbit aorta, renal cortex and adrenal

International Nuclear Information System (INIS)

Budzik, G.P.; Bush, E.N.; Holleman, W.H.

1986-01-01

ANH(1-28) is presumed to regulate blood pressure and fluid balance via membrane receptors coupled to particulate guanylate cyclase. ANH receptors were solubilized from rabbit aorta, renal cortex and adrenal, primary ANH targets. Plasma membranes extracted with 3-[(3-cholamidopropyl)dimethylammonio]-1-propane sulfonate(CHAPS) yield solubilized receptors with high affinity binding of 125 I-Tyr 28 -ANH. Degradation of hormone was minimized with a broad spectrum of protease inhibitors. 125 I-ANH binding reached maximum by 1 hr at 0 0 C and was stable for at least an additional 2 hrs. Bound was separated from free ligand by HPLC gel filtration on TSK-3000SW in PBS/CHAPS. Bound hormone eluted at a MW of ∼ 200KD in each tissue preparation and was displaced by unlabelled ANH. The concentration of solubilized binding sites was proportional to densities in intact plasma membranes, i.e., adrenal > renal > aorta. Following separation of free hormone, 125 I-ANH-receptors complexes were coupled using bifunctional crosslinking reagents. SDS-PAGE analysis and autoradiography indicated a major labelled band at ∼ 150KD in each tissue preparation. The mobility of this labelled band was not sensitive to reduction before SDS-PAGE. Although these results suggest that solubilized ANH receptors from primary target tissues are very similar, microheterogeneity affecting binding affinity or signal transduction cannot as yet be excluded

In vitro binding and receptor-mediated activity of terlipressin at vasopressin receptors V1 and V2.

Science.gov (United States)

Jamil, Khurram; Pappas, Stephen Chris; Devarakonda, Krishna R

2018-01-01

Terlipressin, a synthetic, systemic vasoconstrictor with selective activity at vasopressin-1 (V 1 ) receptors, is a pro-drug for the endogenous/natural porcine hormone [Lys 8 ]-vasopressin (LVP). We investigated binding and receptor-mediated cellular activities of terlipressin, LVP, and endogenous human hormone [Arg 8 ]-vasopressin (AVP) at V 1 and vasopressin-2 (V 2 ) receptors. Cell membrane homogenates of Chinese hamster ovary cells expressing human V 1 and V 2 receptors were used in competitive binding assays to measure receptor-binding activity. These cells were used in functional assays to measure receptor-mediated cellular activity of terlipressin, LVP, and AVP. Binding was measured by [ 3 H]AVP counts, and the activity was measured by fluorometric detection of intracellular calcium mobilization (V 1 ) and cyclic adenosine monophosphate (V 2 ). Binding potency at V 1 and V 2 was AVP>LVP>terlipressin. LVP and terlipressin had approximately sixfold higher affinity for V 1 than for V 2 . Cellular activity potency was also AVP>LVP>terlipressin. Terlipressin was a partial agonist at V 1 and a full agonist at V 2 ; LVP was a full agonist at both V 1 and V 2 . The in vivo response to terlipressin is likely due to the partial V 1 agonist activity of terlipressin and full V 1 agonist activity of its metabolite, LVP. These results provide supportive evidence for previous findings and further establish terlipressin pharmacology for vasopressin receptors.

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 (...

Enhanced thyroid hormone breakdown in hepatocytes by mutual induction of the constitutive androstane receptor (CAR, NR1I3) and arylhydrocarbon receptor by benzo[a]pyrene and phenobarbital

International Nuclear Information System (INIS)

Schraplau, Anne; Schewe, Bettina; Neuschäfer-Rube, Frank; Ringel, Sebastian; Neuber, Corinna; Kleuser, Burkhard; Püschel, Gerhard P.

2015-01-01

Xenobiotics may interfere with the hypothalamic-pituitary-thyroid endocrine axis by inducing enzymes that inactivate thyroid hormones and thereby reduce the metabolic rate. This induction results from an activation of xeno-sensing nuclear receptors. The current study shows that benzo[a]pyrene, a frequent contaminant of processed food and activator of the arylhydrocarbon receptor (AhR) activated the promoter and induced the transcription of the nuclear receptor constitutive androstane receptor (CAR, NR1I3) in rat hepatocytes. Likewise, phenobarbital induced the AhR transcription. This mutual induction of the nuclear receptors enhanced the phenobarbital-dependent induction of the prototypic CAR target gene Cyp2b1 as well as the AhR-dependent induction of UDP-glucuronosyltransferases. In both cases, the induction by the combination of both xenobiotics was more than the sum of the induction by either substance alone. By inducing the AhR, phenobarbital enhanced the benzo[a]pyrene-dependent reduction of thyroid hormone half-life and the benzo[a]pyrene-dependent increase in the rate of thyroid hormone glucuronide formation in hepatocyte cultures. CAR ligands might thus augment the endocrine disrupting potential of AhR activators by an induction of the AhR

Hormone response element binding proteins: novel regulators of vitamin D and estrogen signaling.

Science.gov (United States)

Lisse, Thomas S; Hewison, Martin; Adams, John S

2011-03-01

Insights from vitamin D-resistant New World primates and their human homologues as models of natural and pathological insensitivity to sterol/steroid action have uncovered a family of novel intracellular vitamin D and estrogen regulatory proteins involved in hormone action. The proteins, known as "vitamin D or estrogen response element-binding proteins", behave as potent cis-acting, transdominant regulators to inhibit steroid receptor binding to DNA response elements and is responsible for vitamin D and estrogen resistances. This set of interactors belongs to the heterogeneous nuclear ribonucleoprotein (hnRNP) family of previously known pre-mRNA-interacting proteins. This review provides new insights into the mechanism by which these novel regulators of signaling and metabolism can act to regulate responses to vitamin D and estrogen. In addition the review also describes other molecules that are known to influence nuclear receptor signaling through interaction with hormone response elements. Copyright © 2011 Elsevier Inc. All rights reserved.

Estrogen enhances expression of the complement C5a receptor and the C5a-agonist evoked calcium influx in hormone secreting neurons of the hypothalamus.

Science.gov (United States)

Farkas, Imre; Varju, Patricia; Szabo, Emese; Hrabovszky, Erik; Okada, Noriko; Okada, Hidechika; Liposits, Zsolt

2008-01-01

In the present study we examined presence of the complement C5a receptor (C5aR) in hypothalamic neurosecretory neurons of the rodent brain and effect of estrogen on C5aR expression. Whole cell patch clamp measurements revealed that magnocellular neurons in the supraoptic and paraventricular nuclei of hypothalamic slices of the rats responded to the C5aR-agonist PL37-MAP peptide with calcium ion current pulses. Gonadotropin-releasing hormone (GnRH) producing neurons in slices of the preoptic area of the mice also reacted to the peptide treatment with inward calcium current. PL37-MAP was able to evoke the inward ion current of GnRH neurons in slices from ovariectomized animals. The amplitude of the inward pulses became higher in slices obtained from 17beta-estradiol (E2) substituted mice. Calcium imaging experiments demonstrated that PL37-MAP increased the intracellular calcium content in the culture of the GnRH-producing GT1-7 cell line in a concentration-dependent manner. Calcium imaging also showed that E2 pretreatment elevated the PL37-MAP evoked increase of the intracellular calcium content in the GT1-7 cells. The estrogen receptor blocker Faslodex in the medium prevented the E2-evoked increase of the PL37-MAP-triggered elevation of the intracellular calcium content in the GT1-7 cells demonstrating that the effect of E2 might be related to the presence of estrogen receptor. Real-time PCR experiments revealed that E2 increased the expression of C5aR mRNA in GT1-7 neurons, suggesting that an increased C5aR synthesis could be involved in the estrogenic modulation of calcium response. These data indicate that hypothalamic neuroendocrine neurons can integrate immune and neuroendocrine functions. Our results may serve a better understanding of the inflammatory and neurodegeneratory diseases of the hypothalamus and the related neuroendocrine and autonomic compensatory responses.

Study of goldfish (Carassius auratus) growth hormone structure-function relationship by domain swapping.

Science.gov (United States)

Chan, Y H; Cheng, C H K; Chan, K M

2007-03-01

Using goldfish as a model, the structure-function relationship of goldfish growth hormone was studied using the strategy of homologous domain swapping. Chimeric mutants were constructed by exchanging homologous regions between goldfish growth hormone (gfGH II) and goldfish prolactin (gfPRL) with their cloned complementary DNAs. Six mutants, with their domain-swapped, were generated to have different combinations of three target regions, including the helix a, helix d and the large section in between these helices (possess the helices b, c and other random coiled regions). After expression in E. coli and refolding, these mutants were characterized by using competitive receptor binding assay (RRA) and growth hormone responding promoter activation assay. The different activity profiles of mutants in Spi 2.1 gene promoter assays from that in RRA shows that, for gfGH, receptor binding dose not confer receptor signal activations. When either helices a or d of gfGH was maintained with other helices replaced by their gfPRL counterparts, both receptor binding and hence gene activation activities are reduced. In mutants with helices b and c in gfGH maintained, containing the gfGH middle section, and helices a and d swapped with gfPRL, the had reduced RRA activities but the promoter activation activities retained. In conclusion, as in the case of human GH, the gfGH molecule possesses two functional sites: one of them is composed of discontinuous epitopes located on the target regions of this study and is for receptor binding; another site is located on the middle section of the molecule that helices a and d are not involved, and it is for activation of GH receptor and intracellular signals.

ARF6 and GASP-1 are post-endocytic sorting proteins selectively involved in the intracellular trafficking of dopamine D2 receptors mediated by GRK and PKC in transfected cells

Science.gov (United States)

Cho, DI; Zheng, M; Min, C; Kwon, KJ; Shin, CY; Choi, HK; Kim, KM

2013-01-01

Background and Purpose GPCRs undergo both homologous and heterologous regulatory processes in which receptor phosphorylation plays a critical role. The protein kinases responsible for each pathway are well established; however, other molecular details that characterize each pathway remain unclear. In this study, the molecular mechanisms that determine the differences in the functional roles and intracellular trafficking between homologous and PKC-mediated heterologous internalization pathways for the dopamine D2 receptor were investigated. Experimental Approach All of the S/T residues located within the intracellular loops of D2 receptor were mutated, and the residues responsible for GRK- and PKC-mediated internalization were determined in HEK-293 cells and SH-SY5Y cells. The functional role of receptor internalization and the cellular components that determine the post-endocytic fate of internalized D2 receptors were investigated in the transfected cells. Key Results T134, T225/S228/S229 and S325 were involved in PKC-mediated D2 receptor desensitization. S229 and adjacent S/T residues mediated the PKC-dependent internalization of D2 receptors, which induced down-regulation and desensitization. S/T residues within the second intracellular loop and T225 were the major residues involved in GRK-mediated internalization of D2 receptors, which induced receptor resensitization. ARF6 mediated the recycling of D2 receptors internalized in response to agonist stimulation. In contrast, GASP-1 mediated the down-regulation of D2 receptors internalized in a PKC-dependent manner. Conclusions and Implications GRK- and PKC-mediated internalizations of D2 receptors occur through different intracellular trafficking pathways and mediate distinct functional roles. Distinct S/T residues within D2 receptors and different sorting proteins are involved in the dissimilar regulation of D2 receptors by GRK2 and PKC. PMID:23082996

Hyperactivity and Learning Deficits in Transgenic Mice Bearing a Human Mutant Thyroid Hormone β1 Receptor Gene

OpenAIRE

McDonald, Michael P.; Wong, Rosemary; Goldstein, Gregory; Weintraub, Bruce; Cheng, Sheue-yann; Crawley, Jacqueline N.

1998-01-01

Resistance to thyroid hormone (RTH) is a human syndrome mapped to the thyroid receptor β (TRβ) gene on chromosome 3, representing a mutation of the ligandbinding domain of the TRβ gene. The syndrome is characterized by reduced tissue responsiveness to thyroid hormone and elevated serum levels of thyroid hormones. A common behavioral phenotype associated with RTH is attention deficit hyperactivity disorder (ADHD). To test the hypothesis that RTH produces attention deficits and/or hyperactivity...

The liver taxis of receptor mediated lactosaminated human growth hormone

International Nuclear Information System (INIS)

Chen Zelian; Shi Lin; Li Tongling; Pang Qijie; He Juying; Guan Changtian

2002-01-01

Radiography imaging is used to assess liver taxis mechanism of anti-dwarfism drug lactosaminated human growth hormone (L-rhGH). Both L-rhGH and rhGH labelled with 131 I are used to study their biodistribution in animals (including rabbits, cocks and rats). The results show that L-rhGH is of specific hepatic targeting property, and the maximum hepatic concentration rate is 76.8%, which is two times of rhGH. Its hepatic binding is receptor mediated

The polymorphic insertion of the luteinizing hormone receptor "insLQ" show a negative association to LHR gene expression and to the follicular fluid hormonal profile in human small antral follicles

DEFF Research Database (Denmark)

Borgbo, T; Chrudimska, J; Macek, M

2018-01-01

(AMHR2) and LHCGR, respectively, were observed for insLQ/insLQ compared to -/insLQ and the -/- genotypes. Moreover, LHCGR and CYP19a1 together with oestradiol and inhibin-B were significantly increased in -/insLQ compared to the -/- genotype. The homozygous insLQ genotype showed strong significant......The luteinizing hormone receptor (LHCGR) has a little studied polymorphic 6 bp insertion (rs4539842/insLQ). This study has evaluated the insLQ polymorphism in relation to potential associations with hormonal characteristics of human small antral follicles (hSAFs). In total, 310 hSAFs were collected...... from 86 women undergoing fertility preservation. Analysis included hormonal profile of 297 follicular fluid (FF) samples and 148 corresponding granulosa cells samples were evaluated by qPCR for selected genes. Significantly reduced and non-detectable mRNA levels of anti-Müllerian hormone receptor II...

Growth hormone receptor C-terminal domains required for growth hormone-induced intracellular free Ca2+ oscillations and gene transcription

DEFF Research Database (Denmark)

Billestrup, N; Bouchelouche, P; Allevato, G

1995-01-01

of varying frequency and amplitude. GH-induced transcription of the serine protease inhibitor 2.1 gene required the same C-terminal 52-amino acid domain of the receptor as for Ca2+ signaling. Mutation of the four proline residues in the conserved box 1 region of the GHR, which is responsible for binding...

Effects of growth hormone treatment on the pituitary expression of GHRH receptor mRNA in uremic rats.

Science.gov (United States)

Ferrando, Susana; Rodríguez, Julián; Santos, Fernando; Weruaga, Ana; Fernández, Marta; Carbajo, Eduardo; García, Enrique

2002-09-01

A decreased ability of pituitary cells to secrete growth hormone (GH) in response to growth hormone releasing hormone (GHRH) stimulation has been shown in young uremic rats. The aim of the current study was to examine the effect of uremia and GH treatment on pituitary GHRH receptor expression. Pituitary GHRH receptor mRNA levels were analyzed by RNase protection assay in young female rats made uremic by subtotal nephrectomy, either untreated (UREM) or treated with 10 IU/kg/day of GH (UREM-GH), and normal renal function animals fed ad libitum (SAL) or pair-fed with the UREM group (SPF). Rats were sacrificed 14 days after the second stage nephrectomy. Renal failure was confirmed by concentrations (X +/- SEM) of serum urea nitrogen (mmol/L) and creatinine (micromol/L) in UREM (20 +/- 1 and 89.4 +/- 4.5) and UREM-GH (16 +/- 1 and 91.4 +/- 6.9) that were much higher (P growth retarded as shown by a daily longitudinal tibia growth rate below (P growth rate acceleration (213 +/- 6 microm/day). GHRH receptor mRNA levels were no different among the SAL (0.43 +/- 0.03), SPF (0.43 +/- 0.08) and UREM (0.44 +/- 0.04) groups, whereas UREM-GH rats had significantly higher values (0.72 +/- 0.07). The status of pituitary GHRH receptor is not modified by nutritional deficit or by severe uremia causing growth retardation. By contrast, the growth promoting effect of GH administration is associated with stimulated GHRH receptor gene expression.

Discrepancy between molecular structure and ligand selectivity of a testicular follicle-stimulating hormone receptor of the African catfish (Clarias gariepinus)

NARCIS (Netherlands)

Bogerd, J.; Blomenröhr, M.; Andersson, E.; van der Putten, H.; Tensen, C.P.; Vischer, H F; Granneman, Joke C M; Janssen-Dommerholt, C; Goos, H.J.; Schulz, Rüdiger W

A putative FSH receptor (FSH-R) cDNA was cloned from African catfish testis. Alignment of the deduced amino acid sequence with other (putative) glycoprotein hormone receptors and analysis of the African catfish gene indicated that the cloned receptor belonged to the FSH receptor subfamily. Catfish

Triiodothyronine affects the alternative splicing of thyroid hormone receptor alpha mRNA

NARCIS (Netherlands)

Timmer, D. C.; Bakker, O.; Wiersinga, W. M.

2003-01-01

The c-erbAalpha gene encodes two thyroid hormone receptors, TRalpha1 and TRalpha2, that arise from alternative splicing of the TRalpha pre-mRNA. TRalpha2 is not able to bind triiodothyronine (T-3) and acts as a weak antagonist of TRs. It has been suggested that the balance of TRalpha1 to TRalpha2 is

Structural–Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work

Directory of Open Access Journals (Sweden)

Gerd Krause

2017-04-01

Full Text Available The thyroid-stimulating hormone receptor (TSHR is a member of the glycoprotein hormone receptors, a sub-group of class A G-protein-coupled receptors (GPCRs. TSHR and its endogenous ligand thyrotropin (TSH are of essential importance for growth and function of the thyroid gland and proper function of the TSH/TSHR system is pivotal for production and release of thyroid hormones. This receptor is also important with respect to pathophysiology, such as autoimmune (including ophthalmopathy or non-autoimmune thyroid dysfunctions and cancer development. Pharmacological interventions directly targeting the TSHR should provide benefits to disease treatment compared to currently available therapies of dysfunctions associated with the TSHR or the thyroid gland. Upon TSHR activation, the molecular events conveying conformational changes from the extra- to the intracellular side of the cell across the membrane comprise reception, conversion, and amplification of the signal. These steps are highly dependent on structural features of this receptor and its intermolecular interaction partners, e.g., TSH, antibodies, small molecules, G-proteins, or arrestin. For better understanding of signal transduction, pathogenic mechanisms such as autoantibody action and mutational modifications or for developing new pharmacological strategies, it is essential to combine available structural data with functional information to generate homology models of the entire receptor. Although so far these insights are fragmental, in the past few decades essential contributions have been made to investigate in-depth the involved determinants, such as by structure determination via X-ray crystallography. This review summarizes available knowledge (as of December 2016 concerning the TSHR protein structure, associated functional aspects, and based on these insights we suggest several receptor complex models. Moreover, distinct TSHR properties will be highlighted in comparison to other

Structural-Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work.

Science.gov (United States)

Kleinau, Gunnar; Worth, Catherine L; Kreuchwig, Annika; Biebermann, Heike; Marcinkowski, Patrick; Scheerer, Patrick; Krause, Gerd

2017-01-01

The thyroid-stimulating hormone receptor (TSHR) is a member of the glycoprotein hormone receptors, a sub-group of class A G-protein-coupled receptors (GPCRs). TSHR and its endogenous ligand thyrotropin (TSH) are of essential importance for growth and function of the thyroid gland and proper function of the TSH/TSHR system is pivotal for production and release of thyroid hormones. This receptor is also important with respect to pathophysiology, such as autoimmune (including ophthalmopathy) or non-autoimmune thyroid dysfunctions and cancer development. Pharmacological interventions directly targeting the TSHR should provide benefits to disease treatment compared to currently available therapies of dysfunctions associated with the TSHR or the thyroid gland. Upon TSHR activation, the molecular events conveying conformational changes from the extra- to the intracellular side of the cell across the membrane comprise reception, conversion, and amplification of the signal. These steps are highly dependent on structural features of this receptor and its intermolecular interaction partners, e.g., TSH, antibodies, small molecules, G-proteins, or arrestin. For better understanding of signal transduction, pathogenic mechanisms such as autoantibody action and mutational modifications or for developing new pharmacological strategies, it is essential to combine available structural data with functional information to generate homology models of the entire receptor. Although so far these insights are fragmental, in the past few decades essential contributions have been made to investigate in-depth the involved determinants, such as by structure determination via X-ray crystallography. This review summarizes available knowledge (as of December 2016) concerning the TSHR protein structure, associated functional aspects, and based on these insights we suggest several receptor complex models. Moreover, distinct TSHR properties will be highlighted in comparison to other class A GPCRs to

Structural–Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work

Science.gov (United States)

Kleinau, Gunnar; Worth, Catherine L.; Kreuchwig, Annika; Biebermann, Heike; Marcinkowski, Patrick; Scheerer, Patrick; Krause, Gerd

2017-01-01

The thyroid-stimulating hormone receptor (TSHR) is a member of the glycoprotein hormone receptors, a sub-group of class A G-protein-coupled receptors (GPCRs). TSHR and its endogenous ligand thyrotropin (TSH) are of essential importance for growth and function of the thyroid gland and proper function of the TSH/TSHR system is pivotal for production and release of thyroid hormones. This receptor is also important with respect to pathophysiology, such as autoimmune (including ophthalmopathy) or non-autoimmune thyroid dysfunctions and cancer development. Pharmacological interventions directly targeting the TSHR should provide benefits to disease treatment compared to currently available therapies of dysfunctions associated with the TSHR or the thyroid gland. Upon TSHR activation, the molecular events conveying conformational changes from the extra- to the intracellular side of the cell across the membrane comprise reception, conversion, and amplification of the signal. These steps are highly dependent on structural features of this receptor and its intermolecular interaction partners, e.g., TSH, antibodies, small molecules, G-proteins, or arrestin. For better understanding of signal transduction, pathogenic mechanisms such as autoantibody action and mutational modifications or for developing new pharmacological strategies, it is essential to combine available structural data with functional information to generate homology models of the entire receptor. Although so far these insights are fragmental, in the past few decades essential contributions have been made to investigate in-depth the involved determinants, such as by structure determination via X-ray crystallography. This review summarizes available knowledge (as of December 2016) concerning the TSHR protein structure, associated functional aspects, and based on these insights we suggest several receptor complex models. Moreover, distinct TSHR properties will be highlighted in comparison to other class A GPCRs to

Screening of hormone-like activities in bottled waters available in Southern Spain using receptor-specific bioassays.

Science.gov (United States)

Real, Macarena; Molina-Molina, José-Manuel; Jiménez-Díaz, Inmaculada; Arrebola, Juan Pedro; Sáenz, José-María; Fernández, Mariana F; Olea, Nicolás

2015-01-01

Bottled water consumption is a putative source of human exposure to endocrine-disrupting chemicals (EDCs). Research has been conducted on the presence of chemicals with estrogen-like activity in bottled waters and on their estrogenicity, but few data are available on the presence of hormonal activities associated with other nuclear receptors (NRs). The aim of this study was to determine the presence of endocrine activities dependent on the activation of human estrogen receptor alpha (hERa) and/or androgen receptor (hAR) in water in glass or plastic bottles sold to consumers in Southern Spain. Hormone-like activities were evaluated in 29 bottled waters using receptor-specific bioassays based on reporter gene expression in PALM cells [(anti-)androgenicity] and cell proliferation assessment in MCF-7 cells [(anti-)estrogenicity] after optimized solid phase extraction (SPE). All of the water samples analyzed showed hormonal activity. This was estrogenic in 79.3% and anti-estrogenic in 37.9% of samples and was androgenic in 27.5% and anti-androgenic in 41.3%, with mean concentrations per liter of 0.113pM 17β-estradiol (E2) equivalent units (E2Eq), 11.01pM anti-estrogen (ICI 182780) equivalent units (ICI 182780Eq), 0.33pM methyltrienolone (R1881) equivalent units (R1881Eq), and 0.18nM procymidone equivalent units (ProcEq). Bottled water consumption contributes to EDC exposure. Hormone-like activities observed in waters from both plastic and glass bottles suggest that plastic packaging is not the sole source of contamination and that the source of the water and bottling process may play a role, among other factors. Further research is warranted on the cumulative effects of long-term exposure to low doses of EDCs. Copyright © 2014 Elsevier Ltd. All rights reserved.

[Clinical relevance of ESR1 circulating mutations detection in hormone receptor positive metastatic breast cancer].

Science.gov (United States)

Clatot, Florian; Perdrix, Anne; Sefrioui, David; Sarafan-Vasseur, Nasrin; Di Fiore, Frédéric

2018-01-01

If hormone therapy is a key treatment for hormone receptor positive advanced breast cancers, secondary resistance occurs as a rule. Recently, acquired alterations of the ESR1 gene have been identified as a mechanism of resistance on aromatase inhibitor (AI) treatment. The selective pressure by AI exposure during the metastatic setting triggers the emergence of ESR1 activating mutations. In that context, the "liquid biopsy" concept has been used to detect this molecular resistance before progression. Thus, the ESR1 circulating mutation detection will soon be used in daily practice to help monitoring patients on AI treatment and provide an early change for specific therapies that still have to be determined in prospective clinical trials. This review will present the acquired ESR1 mutations, as well as the methods used for their detection in blood and the potential clinical impact of this approach for hormone receptor positive breast cancer management. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Enhanced thyroid hormone breakdown in hepatocytes by mutual induction of the constitutive androstane receptor (CAR, NR1I3) and arylhydrocarbon receptor by benzo[a]pyrene and phenobarbital.

Science.gov (United States)

Schraplau, Anne; Schewe, Bettina; Neuschäfer-Rube, Frank; Ringel, Sebastian; Neuber, Corinna; Kleuser, Burkhard; Püschel, Gerhard P

2015-02-03

Xenobiotics may interfere with the hypothalamic-pituitary-thyroid endocrine axis by inducing enzymes that inactivate thyroid hormones and thereby reduce the metabolic rate. This induction results from an activation of xeno-sensing nuclear receptors. The current study shows that benzo[a]pyrene, a frequent contaminant of processed food and activator of the arylhydrocarbon receptor (AhR) activated the promoter and induced the transcription of the nuclear receptor constitutive androstane receptor (CAR, NR1I3) in rat hepatocytes. Likewise, phenobarbital induced the AhR transcription. This mutual induction of the nuclear receptors enhanced the phenobarbital-dependent induction of the prototypic CAR target gene Cyp2b1 as well as the AhR-dependent induction of UDP-glucuronosyltransferases. In both cases, the induction by the combination of both xenobiotics was more than the sum of the induction by either substance alone. By inducing the AhR, phenobarbital enhanced the benzo[a]pyrene-dependent reduction of thyroid hormone half-life and the benzo[a]pyrene-dependent increase in the rate of thyroid hormone glucuronide formation in hepatocyte cultures. CAR ligands might thus augment the endocrine disrupting potential of AhR activators by an induction of the AhR. Copyright © 2014. Published by Elsevier Ireland Ltd.

Identification of phenylalanine 346 in the rat growth hormone receptor as being critical for ligand-mediated internalization and down-regulation

DEFF Research Database (Denmark)

Allevato, G; Billestrup, N; Goujon, L

1995-01-01

The functional significance of growth hormone (GH) receptor (GHR) internalization is unknown; therefore, we have analyzed domains and individual amino acids in the cytoplasmic region of the rat GHR required for ligand-mediated receptor internalization, receptor down-regulation, and transcriptiona...

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

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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.

Putative thyroid hormone receptors in red blood cells of some reptiles.

Science.gov (United States)

Wong, C C; Chiu, K W

1987-06-01

Putative triiodothyronine (T3) receptors have been detected in the nuclei of red blood cells (RBC) in a number of reptile species. The binding characteristics of T3 receptors in vitro were dissociation constant (Kd) 9.1 to 28.58, 36.8 and 40, and 11.12 and 11.36 pM, and binding capacity (Bmax) 0.12 to 0.37, 0.17 and 0.24, and 0.19 and 0.28 fmol per million cells in the rat snake (Ptyas korros), soft-shelled turtle (Trionyx sinensis), and tokay gecko (Gekko gecko), respectively. These data were obtained in all species using in vitro incubation of whole cell according to current receptor studies on living cells. With modified technique in subsequent experiments, these values of the binding characteristics were seemingly low. The discrepancy was ascribed to the assessment of "free" fraction of hormone which would be used in subsequent calculation.

Diverse growth hormone receptor gene mutations in Laron syndrome.

Science.gov (United States)

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 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, we 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 we identified are unique to patients from particular geographic regions. Ten GHR gene mutations have now been described in this disorder. We 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. Images Figure 1 Figure 2 PMID:8488849

Coiled-coil domain-dependent homodimerization of intracellular barley immune receptors defines a minimal functional module for triggering cell death

NARCIS (Netherlands)

Maekawa, T.; Cheng, W.; Spiridon, L.N.; Töller, A.; Lukasik, E.; Saijo, Y.; Liu, P.; Shen, Q.H.; Micluta, M.A.; Somssich, I.E.; Takken, F.L.W.; Petrescu, A.J.; Chai, J.; Schulze-Lefert, P.

2011-01-01

Plants and animals have evolved structurally related innate immune sensors, designated NLRs, to detect intracellular nonself molecules. NLRs are modular, consisting of N-terminal coiled-coil (CC) or TOLL/interleukin-1 receptor (TIR) domains, a central nucleotide-binding (NB) domain, and C-terminal

Ghrelin: much more than a hunger hormone

Science.gov (United States)

Ghrelin is a multifaceted gut hormone that activates its receptor, growth hormone secretagogue receptor (GHS-R). Ghrelin's hallmark functions are its stimulatory effects on growth hormone release, food intake and fat deposition. Ghrelin is famously known as the 'hunger hormone'. However, ample recen...

Thyroid hormone action: Astrocyte-neuron communication.

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Beatriz eMorte

2014-05-01

Full Text Available Thyroid hormone action is exerted mainly through regulation of gene expression by binding of T3 to the nuclear receptors. T4 plays an important role as a source of intracellular T3 in the central nervous system via the action of the type 2 deiodinase, expressed in the astrocytes. A model of T3 availability to neural cells has been proposed and validated. The model contemplates that brain T3 has a double origin: a fraction is available directly from the circulation, and another is produced locally from T4 in the astrocytes by type 2 deiodinase. The fetal brain depends almost entirely on the T3 generated locally. The contribution of systemic T3 increases subsequently during development to account for approximately 50% of total brain T3 in the late postnatal and adult stages. In this article we review the experimental data in support of this model, and how the factors affecting T3 availability in the brain, such as deiodinases and transporters, play a decisive role in modulating local thyroid hormone action during development.

Crystal structure of the PAC1R extracellular domain unifies a consensus fold for hormone recognition by class B G-protein coupled receptors.

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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.

Thyroid hormones and the central nervous system of mammals (Review).

Science.gov (United States)

Di Liegro, Italia

2008-01-01

The thyroid hormones (THs) L-thyroxine (T4) and L-triiodothyronine (T3) have a profound influence on the development and maturation of the mammalian brain, both before and after birth. Any impairment in the supply of THs to the developing nervous system leads to severe and irreversible changes in both the overall architecture and functions of the brain and causes, in humans, neurological and motor deficits known as cretinism. Pronounced neurological symptoms are also commonly observed in adult patients suffering from both hyperthyroidism and hypothyroidism, and it has recently emerged that certain symptoms might result from the reduced brain uptake, rather than the insufficient production, of THs. Most of the effects of THs are mediated by two classes of nuclear receptors (α and β isoforms), which belong to the c-erbA superfamily of transcriptional regulators and are expressed in a tissue-specific and developmentally regulated manner. Interestingly, the nuclear TH receptors (nTRs) act as both ligand-independent gene repressors and ligand-dependent gene activators. On the other hand, negatively-regulated genes, which can be stimulated in the absence of THs and repressed by THs, have also been observed. Due to this complex pattern of regulation, the effects of receptor dysfunction do not exactly overlap the effects of hormone deficiency or excess. Moreover, non-genomic mechanisms of TH action have been described in many tissues, including the brain, some of which seem to be mediated by integrins and to be calcium-dependent. Intracellular receptors, distinct from nTRs, are present in the mitochondria, where a matrix-associated, T3-dependent transcriptional regulator of approximately 43 kDa has been described. Finally, complex patterns of pituitary and/or peripheral resistance to thyroid hormones (RTH), characterized by elevated plasma levels of THs and non-suppressible thyroid-stimulating hormone (TSH), have been identified. This review summarizes the major advances

Molecular conformation, receptor binding, and hormone action of natural and synthetic estrogens and antiestrogens.

Science.gov (United States)

Duax, W L; Griffin, J F; Weeks, C M; Korach, K S

1985-01-01

The X-ray crystallographic structural determinations of synthetic estrogens and antiestrogens provide reliable information on the global minimum energy conformation of these molecules or a local minimum energy conformation that is within 1 or 2 kcal/mole of the global minimum. In favorable cases, state-of-the-art molecular mechanics calculations provide quantitative agreement with X-ray results and information on the relative energy of other local minimum energy conformations not observed crystallographically. Because the conformation of diethylstilbestrol (DES) observed in solvated crystals has an overall conformation and dipole moment more similar to estradiol it is the form more likely to bind to the receptor and produce hormone activity. Either phenol ring of DES can successfully mimic the estradiol A-ring in binding to the receptor. Indenestrol A (INDA) and indenestrol B (INDB) have nearly identical fully extended planar conformations. Either the alpha or gamma rings of these compounds may mimic the A ring of estradiol and compete for the estrogen receptor. Although there are eight distinct ways in which molecules of a racemic mixture of INDA or INDB can bind to the receptor, not all of them may be able to elicit a hormonal response. This may account for the reduced biological activity of the compounds despite their successful competition for receptor binding. The minimum energy conformations of Z-pseudodiethylstilbestrol (ZPD) and E-pseudodiethylstilbestrol (EPD) are bent in a fashion similar to that of indanestrol (INDC). These molecules have good binding affinity suggesting that the receptor does not require a flat molecule. Therefore these conformations would appear to be compatible with receptor binding, but only the Z isomer has an energetically allowed extended conformation that accounts for its observed biological activity relative to DES. PMID:3905370

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

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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.

Molecular analysis of the interaction between the intracellular loops of the human serotonin receptor type 6 (5-HT6) and the α subunit of GS protein

International Nuclear Information System (INIS)

Kang, Hatan; Lee, Won Kyu; Choi, Yun Hui; Vukoti, Krishna Moorthy; Bang, Won Gi; Yu, Yeon Gyu

2005-01-01

The serotonin type 6 (5-HT 6 ) receptor is a G-protein coupled receptor (GPCR) coupled to a stimulatory G-protein (G S ). To identify the structural basis for the interaction of the 5-HT 6 receptor with the G S protein, we have dissected the interaction between GST-fusion proteins containing the second intracellular loop (iL2), the third intracellular loop (iL3), or the C-terminal tail of the 5-HT 6 receptor and the α subunit of G S (Gα S ). The direct interaction of iL3 and Gα S was demonstrated by co-immunoprecipitation. Furthermore, the kinetic parameters of the interaction between iL3 and Gα S were measured by surface plasmon resonance, and the apparent dissociation constant was determined to be 0.9 x 10 -6 M. In contrast, the second intracellular loop and C-terminal tail regions showed negligible affinity to Gα S . The critical residues within the iL3 region for the interaction with Gα S were identified as conserved positively charged residues near the C-terminus of iL3 by measuring the cellular levels of cAMP produced in response to 5-HT stimulation of cells transfected with 5-HT 6 receptor mutants

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...... americana. This receptor is only activated by various insect AKHs (we tested eight) and not by a library of 29 other insect or invertebrate neuropeptides and nine biogenic amines. Periplaneta has two intrinsic AKHs, Pea-AKH-1, and Pea-AKH-2. The Periplaneta AKH receptor is activated by low concentrations...... of both Pea-AKH-1 (EC50, 5 x 10(-9)M), and Pea-AKH-2 (EC50, 2 x 10(-9)M). Insects can be subdivided into two evolutionary lineages, holometabola (insects with a complete metamorphosis during development) and hemimetabola (incomplete metamorphosis). This paper describes the first AKH receptor from...

Spatiotemporal intracellular dynamics of neurotrophin and its receptors. Implications for neurotrophin signaling and neuronal function.

Science.gov (United States)

Bronfman, F C; Lazo, O M; Flores, C; Escudero, C A

2014-01-01

Neurons possess a polarized morphology specialized to contribute to neuronal networks, and this morphology imposes an important challenge for neuronal signaling and communication. The physiology of the network is regulated by neurotrophic factors that are secreted in an activity-dependent manner modulating neuronal connectivity. Neurotrophins are a well-known family of neurotrophic factors that, together with their cognate receptors, the Trks and the p75 neurotrophin receptor, regulate neuronal plasticity and survival and determine the neuronal phenotype in healthy and regenerating neurons. Is it now becoming clear that neurotrophin signaling and vesicular transport are coordinated to modify neuronal function because disturbances of vesicular transport mechanisms lead to disturbed neurotrophin signaling and to diseases of the nervous system. This chapter summarizes our current understanding of how the regulated secretion of neurotrophin, the distribution of neurotrophin receptors in different locations of neurons, and the intracellular transport of neurotrophin-induced signaling in distal processes are achieved to allow coordinated neurotrophin signaling in the cell body and axons.

Highly potent analogues of luteinizing hormone-releasing hormone containing D-phenylalanine nitrogen mustard in position 6.

Science.gov (United States)

Bajusz, S; Janaky, T; Csernus, V J; Bokser, L; Fekete, M; Srkalovic, G; Redding, T W; Schally, A V

1989-08-01

The nitrogen mustard derivatives of 4-phenylbutyric acid and L-phenylalanine, called chlorambucil (Chl) and melphalan (Mel), respectively, have been incorporated into several peptide hormones, including luteinizing hormone-releasing hormone (LH-RH). The alkylating analogues of LH-RH were prepared by linking Chl, as an N-acyl moiety, to the complete amino acid sequence of agonistic and antagonistic analogues. These compounds, in particular the antagonistic analogues, showed much lower potency than their congeners carrying other acyl groups. To obtain highly potent alkylating analogues of LH-RH, the D enantiomer of Mel was incorporated into position 6 of the native hormone and some of its antagonistic analogues. Of the peptides prepared, [D-Mel6]LH-RH (SB-05) and [Ac-D-Nal(2)1,D-Phe(pCl)2,D-Pal(3)3,Arg5,D-Mel6,D-Ala10++ +]LH-RH [SB-86, where Nal(2) is 3-(2-naphthyl)alanine and Pal(3) is 3-(3-pyridyl)alanine] possessed the expected high agonistic and antagonistic activities, respectively, and also showed high affinities for the membrane receptors of rat pituitary cells, human breast cancer cells, human prostate cancer cells, and rat Dunning R-3327 prostate tumor cells. These two analogues exerted cytotoxic effects on human and rat mammary cancer cells in vitro. Thus these two D-Mel6 analogues seem to be particularly suitable for the study of how alkylating analogues of LH-RH could interfere with intracellular events in certain cancer cells.

Highly potent analogues of luteinizing hormone-releasing hormone containing D-phenylalanine nitrogen mustard in position 6

International Nuclear Information System (INIS)

Bajusz, S.; Janaky, T.; Csernus, V.J.; Bokser, L.; Fekete, M.; Srkalovic, G.; Redding, T.W.; Schally, A.V.

1989-01-01

The nitrogen mustard derivatives of 4-phenylbutyric acid and L-phenylalanine, called chlorambucil (Chl) and melphalan (Mel), respectively, have been incorporated into several peptide hormones, including luteinizing hormone-releasing hormone (LH-RH). The alkylating analogues of LH-RH were prepared by linking Chl, as an N-acyl moiety, to the complete amino acid sequence of agonistic and antagonistic analogues. These compounds, in particular the antagonistic analogues, showed much lower potency than their congeners carrying other acyl groups. To obtain highly potent alkylating analogues of LH-RH, the D enantiomer of Mel was incorporated into position 6 of the native hormone and some of its antagonistic analogues. Of the peptides prepared, [D-Mel 6 ]LH-RH (SB-05) and [Ac-D-Nal(2) 1 ,D-Phe(pCl) 2 ,D-Pal(3) 3 ,Arg 5 ,D-Mel 6 ,D-Ala 10 ]LH-RH [SB-86, where Nal(2) is 3-(2-naphthyl)alanine and Pal(3) is 3-(3-pyridyl)alanine] possessed the expected high agonistic and antagonistic activities, respectively, and also showed high affinities for the membrane receptors of rat pituitary cells, human breast cancer cells, human prostate cancer cells, and rat Dunning R-3327 prostate tumor cells. These two analogues exerted cytotoxic effects on human and rat mammary cancer cells in vitro. Thus these two D-Mel 6 analogues seem to be particularly suitable for the study of how alkylating analogues of LH-RH could interfere with intracellular events in certain cancer cells

Prognostic value of sex-hormone receptor expression in non-muscle-invasive bladder cancer.

Science.gov (United States)

Nam, Jong Kil; Park, Sung Woo; Lee, Sang Don; Chung, Moon Kee

2014-09-01

We investigated sex-hormone receptor expression as predicting factor of recurrence and progression in patients with non-muscle invasive bladder cancer. We retrospectively evaluated tumor specimens from patients treated for transitional cell carcinoma of the bladder at our institution between January 2006 and January 2011. Performing immunohistochemistry using a monoclonal androgen receptor antibody and monoclonal estrogen receptor-beta antibody on paraffin-embedded tissue sections, we assessed the relationship of immunohistochemistry results and prognostic factors such as recurrence and progression. A total of 169 patients with bladder cancer were evaluated in this study. Sixty-threepatients had expressed androgen receptors and 52 patients had estrogen receptor beta. On univariable analysis, androgen receptor expression was significant lower in recurrence rates (p=0.001), and estrogen receptor beta expression was significant higher in progression rates (p=0.004). On multivariable analysis, significant association was found between androgen receptor expression and lower recurrence rates (hazard ratio=0.500; 95% confidence interval, 0.294 to 0.852; p=0.011), but estrogen receptor beta expression was not significantly associated with progression rates. We concluded that the possibility of recurrence was low when the androgen receptor was expressed in the bladder cancer specimen and it could be the predicting factor of the stage, number of tumors, carcinoma in situ lesion and recurrence.

Treatment challenges for community oncologists treating postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer

International Nuclear Information System (INIS)

Gradishar, William J

2016-01-01

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

Highly specific detection of muscarinic M3 receptor, G protein interaction and intracellular trafficking in human detrusor using Proximity Ligation Assay (PLA).

Science.gov (United States)

Berndt-Paetz, Mandy; Herbst, Luise; Weimann, Annett; Gonsior, Andreas; Stolzenburg, Jens-Uwe; Neuhaus, Jochen

2018-05-01

Muscarinic acetylcholine receptors (mAChRs) regulate a number of important physiological functions. Alteration of mAChR expression or function has been associated in the etiology of several pathologies including functional bladder disorders (e.g bladder pain syndrome/interstitial cystitis - BPS/IC). In a previous study we found specific mAChR expression patterns associated with BPS/IC, while correlation between protein and gene expression was lacking. Posttranslational regulatory mechanisms, e.g. altered intracellular receptor trafficking, could explain those differences. In addition, alternative G protein (GP) coupling could add to the pathophysiology via modulation of muscarinic signaling. In our proof-of-principle study, we addressed these questions in situ. We established PLA in combination with confocal laserscanning microscopy (CLSM) and 3D object reconstruction for highly specific detection and analysis of muscarinic 3 receptors (M3), G protein (GP) coupling and intracellular trafficking in human detrusor samples. Paraffin sections of formalin-fixed bladder tissue (FFPE) of BPS/IC patients receiving transurethral biopsy were examined by Cy3-PLA for M3 expression, coupling of M3 to GPs (G αq/11 , G αs , G αi ) and interaction of M3 with endocytic regulator proteins. Membranes were labeled with wheat germ agglutinin-Alexa Fluor ® 488, nuclei were stained with DAPI. Object density and co-localization were analyzed in 3D-reconstruction of high resolution confocal z-stacks. Confocal image stack processing resulted in well demarcated objects. Calculated receptor densities correlated significantly with existing confocal expression data, while significantly improved specificity of M3 detection by PLA was verified using bladder tissue samples from transgenic mice. 50-60% of the M3 receptor complexes were plasma membrane associated in human bladder detrusor. Application of PLA for M3 and GPs allowed visualization of M3-GP interactions and revealed individual GP

Autoradiographic localization of thyrotropin releasing hormone (TRH) receptors in the central nervous system

International Nuclear Information System (INIS)

Manaker, S.

1985-01-01

Quantitative autoradiography was used to examine the distribution of thyrotropin-releasing hormone (TRH) receptors in the rat and human central nervous system (CNS). The binding of [ 3 H]-3-methyl-histidine 2 -TRH ([ 3 H]-MeTRH) to TRH receptors was saturable, of a high affinity (K/sub d/ = 5 nM), and specific for TRH analogs. Studies with neurotoxins ibotenic acid and 6-hydroxydopamine (6-OHDA) suggest that TRH receptors within the amygdala are predominantly located on cell bodies, and not nerve terminals. Finally, an examination was made of the concentrations of TRH receptors in spinal cords of patients with amyotrophic lateral sclerosis (ALS), a degenerative disease of the motor neurons located in Lamina IX. Large decreases in TRH receptors were noted in ALS spinal cords, when compared to non-neurological controls, probably reflecting the loss of motor neurons. In addition, decreases in the TRH receptor concentration of Lamina II were observed. This finding may reflect the sensitivity of neurons throughout the CNS to the pathophysiologic mechanisms of neuronal degeneration which cause ALS

Preparation and Characterization of an Antibody Antagonist That Targets the Porcine Growth Hormone Receptor

Directory of Open Access Journals (Sweden)

Huanzhong Cui

2016-10-01

Full Text Available A series of antagonists specifically targeting growth hormone receptors (GHR in different species, such as humans, rats, bovines, and mice, have been designed; however, there are currently no antagonists that target the porcine growth hormone (GH. Therefore, in this study, we developed and characterized a porcine GHR (pGHR antibody antagonist (denoted by AN98 via the hybridoma technique. The results from enzyme-linked immunosorbent assay, fluorescence activated cell sorter, indirect immunoinfluscent assay, and competitive receptor binding analysis showed that AN98 could specifically recognize pGHR, and further experiments indicated that AN98 could effectively inhibit pGH-induced signalling in CHO-pGHR cells and porcine hepatocytes. In addition, AN98 also inhibited GH-induced insulin-like growth factor-1 (IGF-1 secretion in porcine hepatocytes. In summary, these findings indicated that AN98, as a pGHR-specific antagonist, has potential applications in pGH-pGHR-related research on domestic pigs.

Seasonal Relationship between Gonadotropin, Growth Hormone, and Estrogen Receptor mRNA Expression in the Pituitary Gland of Largemouth Bass

OpenAIRE

Martyniuk, Christopher J; Kroll, Kevin J.; Porak, Wesley F.; Steward, Cheree; Grier, Harry J.; Denslow, Nancy D.

2009-01-01

The objectives of this study were to investigate the seasonal changes in pituitary gonadotropins, growth hormone (GH), and estrogen receptor (ER) isoform mRNA in wild female and male largemouth bass (LMB) (Micropterus salmoides) from an unpolluted habitat to better understand reproductive physiology in this ecologically important species. Female pituitary luteinizing hormone (LH) β subunit and follicle-stimulating hormone (FSH) β subunit mRNA showed significant seasonal variation with levels ...

Radioanalytical methods for the measurement of melanin concentrating hormone (MCH) and detection its receptor in rat tissues

International Nuclear Information System (INIS)

Lelesz, B.; Szilvassy, Z.; Varga, A.; Juhasz, B.; Nemeth, J.; Toth, G.K.; Toth, A.; Enyedi, A.; Felszeghy, E.

2016-01-01

In the present paper the development and application of a novel melanin concentrating hormone radioimmunoassay and receptor-binding assay are described. 125 I-labeling of melanin concentrating hormone (MCH) was performed by iodogen and the mono-iodinated peptide was separated by reversed-phase high performance liquid chromatography. Detection limit of the MCH specific assay was 0.2 fmol/ml. As a practical application of the novel radioimmunoassay, we measured the MCH concentration in different rat organs. High MCH concentrations were detected in the small intestine, pancreas, kidney, liver, trachea, hypothalamus and spinal cord. 125 I-MCH was also suitable for RBA to demonstrate the presence of MCH receptors in the rat brain. (author)

Tissue architecture and function: dynamic reciprocity via extra- and intra-cellular matrices

Energy Technology Data Exchange (ETDEWEB)

Xu, Ren; Boudreau, Aaron; Bissell, Mina J

2008-12-23

Mammary gland development, functional differentiation, and homeostasis are orchestrated and sustained by a balance of biochemical and biophysical cues from the organ's microenvironment. The three-dimensional microenvironment of the mammary gland, predominantly 'encoded' by a collaboration between the extracellular matrix (ECM), hormones, and growth factors, sends signals from ECM receptors through the cytoskeletal intracellular matrix to nuclear and chromatin structures resulting in gene expression; the ECM in turn is regulated and remodeled by signals from the nucleus. In this chapter, we discuss how coordinated ECM deposition and remodeling is necessary for mammary gland development, how the ECM provides structural and biochemical cues necessary for tissue-specific function, and the role of the cytoskeleton in mediating the extra - to intracellular dialogue occurring between the nucleus and the microenvironment. When operating normally, the cytoskeletal-mediated dynamic and reciprocal integration of tissue architecture and function directs mammary gland development, tissue polarity, and ultimately, tissue-specific gene expression. Cancer occurs when these dynamic interactions go awry for an extended time.

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...

Investigating Internalization and Intracellular Trafficking of GPCRs

DEFF Research Database (Denmark)

Foster, Simon R; Bräuner-Osborne, Hans

2017-01-01

for signal transduction. One of the major mechanisms for GPCR regulation involves their endocytic trafficking, which serves to internalize the receptors from the plasma membrane and thereby attenuate G protein-dependent signaling. However, there is accumulating evidence to suggest that GPCRs can signal...... independently of G proteins, as well as from intracellular compartments including endosomes. It is in this context that receptor internalization and intracellular trafficking have attracted renewed interest within the GPCR field. In this chapter, we will review the current understanding and methodologies...

Absence of serum growth hormone binding protein in patients with growth hormone receptor deficiency (Laron dwarfism)

Energy Technology Data Exchange (ETDEWEB)

Daughaday, W.H.; Trivedi, B.

1987-07-01

It has recently been recognized that human serum contains a protein that specifically binds human growth hormone (hGH). This protein has the same restricted specificity for hGH as the membrane-bound GH receptor. To determine whether the GH-binding protein is a derivative of, or otherwise related to, the GH receptor, the authors have examined the serum of three patients with Laron-type dwarfism, a condition in which GH refractoriness has been attributed to a defect in the GH receptor. The binding of /sup 125/I-labeled hGH incubated with serum has been measured after gel filtration of the serum through an Ultrogel AcA 44 minicolumn. Results are expressed as percent of specifically bound /sup 125/I-hGH and as specific binding relative to that of a reference serum after correction is made for endogenous GH. The mean +/- SEM of specific binding of sera from eight normal adults (26-46 years of age) was 21.6 +/- 0.45%, and the relative specific binding was 101.1 +/- 8.6%. Sera from 11 normal children had lower specific binding of 12.5 +/- 1.95% and relative specific binding of 56.6 +/- 9.1%. Sera from three children with Laron-type dwarfism lacked any demonstrable GH binding, whereas sera from 10 other children with other types of nonpituitary short stature had normal relative specific binding. They suggest that the serum GH-binding protein is a soluble derivative of the GH receptor. Measurement of the serum GH-binding protein may permit recognition of other abnormalities of the GH receptor.

Absence of serum growth hormone binding protein in patients with growth hormone receptor deficiency (Laron dwarfism)

International Nuclear Information System (INIS)

Daughaday, W.H.; Trivedi, B.

1987-01-01

It has recently been recognized that human serum contains a protein that specifically binds human growth hormone (hGH). This protein has the same restricted specificity for hGH as the membrane-bound GH receptor. To determine whether the GH-binding protein is a derivative of, or otherwise related to, the GH receptor, the authors have examined the serum of three patients with Laron-type dwarfism, a condition in which GH refractoriness has been attributed to a defect in the GH receptor. The binding of 125 I-labeled hGH incubated with serum has been measured after gel filtration of the serum through an Ultrogel AcA 44 minicolumn. Results are expressed as percent of specifically bound 125 I-hGH and as specific binding relative to that of a reference serum after correction is made for endogenous GH. The mean +/- SEM of specific binding of sera from eight normal adults (26-46 years of age) was 21.6 +/- 0.45%, and the relative specific binding was 101.1 +/- 8.6%. Sera from 11 normal children had lower specific binding of 12.5 +/- 1.95% and relative specific binding of 56.6 +/- 9.1%. Sera from three children with Laron-type dwarfism lacked any demonstrable GH binding, whereas sera from 10 other children with other types of nonpituitary short stature had normal relative specific binding. They suggest that the serum GH-binding protein is a soluble derivative of the GH receptor. Measurement of the serum GH-binding protein may permit recognition of other abnormalities of the GH receptor

Prostate-Derived Ets Transcription Factor Overexpression is Associated with Nodal Metastasis, Hormone Receptor Positivity in Invasive Breast Cancer

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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.

Corticotropin-Releasing Hormone Receptor Type 1 (CRHR1 Clustering with MAGUKs Is Mediated via Its C-Terminal PDZ Binding Motif.

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Julia Bender

Full Text Available The corticotropin-releasing hormone receptor type 1 (CRHR1 plays an important role in orchestrating neuroendocrine, behavioral, and autonomic responses to stress. To identify molecules capable of directly modulating CRHR1 signaling, we performed a yeast-two-hybrid screen using the C-terminal intracellular tail of the receptor as bait. We identified several members of the membrane-associated guanylate kinase (MAGUK family: postsynaptic density protein 95 (PSD95, synapse-associated protein 97 (SAP97, SAP102 and membrane associated guanylate kinase, WW and PDZ domain containing 2 (MAGI2. CRHR1 is co-expressed with the identified MAGUKs and with the additionally investigated PSD93 in neurons of the adult mouse brain and in primary hippocampal neurons, supporting the probability of a physiological interaction in vivo. The C-terminal PDZ (PSD-95, discs large, zona occludens 1 binding motif of CRHR1 is essential for its physical interaction with MAGUKs, as revealed by the CRHR1-STAVA mutant, which harbors a functionally impaired PDZ binding motif. The imitation of a phosphorylation at Thr413 within the PDZ binding motif also disrupted the interaction with MAGUKs. In contrast, distinct PDZ domains within the identified MAGUKs are involved in the interactions. Expression of CRHR1 in primary neurons demonstrated its localization throughout the neuronal plasma membrane, including the excitatory post synapse, where the receptor co-localized with PSD95 and SAP97. The co-expression of CRHR1 and respective interacting MAGUKs in HEK293 cells resulted in a clustered subcellular co-localization which required an intact PDZ binding motif. In conclusion, our study characterized the PDZ binding motif-mediated interaction of CRHR1 with multiple MAGUKs, which directly affects receptor function.

Extracellular and intracellular steroid binding proteins

International Nuclear Information System (INIS)

Wagner, R.K.

1978-01-01

Steroid hormone binding proteins can be measured, after the removal of endogenous steroids, as specific complexes with radio-labelled hormones. In this study all the requirements for a quantitative determination of steroid hormone binding proteins are defined. For different methods, agargel electrophoresis, density gradient centrifugation, equilibrium dialysis and polyacrylamide electrophoresis have been evaluated. Agar electrophoresis at low temperature was found to be the simplest and most useful procedure. With this method the dissociation rates of high affinity complexes can be assessed and absolute binding protein concentrations can be determined. The dissociation rates of the oestradiol-oestrogen receptor complex and the R-5020-progestin receptor complex are low (1-2% per h run time.) In contrast, that of complexes between androgen receptor and dihydrotestosterone (17β-hydroxy-5α-androstan-3-one (DHT), progestin receptor and progesterone, corticosteroid binding globulin (CBG) and cortisol or progesterone and sex hormone binding globulin (SHBG) and DHT were hign (16-27% per h run time). Target tissue extracts (cytosols) contain, besides soluble tissue proteins, large amounts of plasma proteins. The extent of this plasma contamination can be determined by measuring the albumin concentration in cytosols by immunodiffusion. In cytosols of 4 different human target tissues the albumin content varied from 20-30% corresponding to an even higher whole plasma concentration. Steroid binding plasma proteins, such as CBG and SHBG are constituents of this containment. (author)

A hormone pulse induces transient changes in the subcellular distribution and leads to a lysosomal accumulation of the estradiol receptor alpha in target tissues.

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Qualmann, B; Kessels, M M; Thole, H H; Sierralta, W D

2000-06-01

An intrauterine pulse-stimulation with estradiol induced changes in the subcellular localization of estrogen receptor alpha in porcine endometrium, as detected with F(ab') fragments of various anti-receptor antibodies covalently linked to nanogold. The low-sterically hindered immunoreagents--recognizing different epitopes within the hormone binding domain--allowed for an efficient immunolabeling of estradiol receptor alpha, detecting it both in the cytoplasm and the nucleus of nonstimulated epithelium cells. In the cytoplasm, the receptor often seemed to be associated with actin filaments and the endoplasmatic reticulum. After the stimulation with estradiol, a predominantly nuclear localization and a labeling of nucleoli was observed. Our immunoelectron microscopy study demonstrates a localization of the receptor in cytoplasmic organelles that increased after the hormone pulse. These organelles exhibited the morphological properties of lysosomes and relocated to the perinuclear area. In analogous cytoplasmic organelles, the presence of cathepsin D was detected via indirect immunogold labeling, justifying their classification as lysosomes. Quantitative examinations revealed that not only the number of lysosomes in the proximity of the nucleus but also their immunostaining for estradiol receptor alpha increased significantly after the hormone pulse. Thus, estradiol induces both the rapid shift of receptor into the nucleus, a slower perinuclear accumulation of lysosomes and an increase of lysosomal ERalpha-immunoreactivity. These results suggest a role for lysosomes in the degradation of receptor shuttling out of the nucleus. This could serve as termination of the estradiol receptor alpha-dependent activation of target cells. This hypothesis is strengthened by the fact that the receptor content in uterine tissue declined drastically few hours after the hormone pulse.

Luteinizing hormone-releasing hormone inactivation by purified pituitary plasma membranes: effects of receptor-binding studies.

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Clayton, R N; Shakespear, R A; Duncan, J A; Marshall, J C

1979-05-01

Inactivation of LHRH by purified bovine pituitary plasma membranes was studied in vitro. After incubation of [125I]iodo-LHRH with plasma membranes, the amount of tracer bound to the pellet was measured, and the integrity of the unbound tracer in the supernatant was assessed. Reduction in ability to bind to anti-LHRH serum and to rebind to plasma membranes together with altered electrophoretic mobility on polyacrylamide gels showed that the unbound [125I]iodo-LHRH was inactivated. LHRH inactivation occurred rapidly and was dependent upon membrane concentration and incubation temperature. These results indicate that hormone inactivation must be taken into account in the interpretation of LHRH-receptor interactions. During 37 C incubations, the apparent absence of specific LHRH binding can be explained by inactivation of tracer hormone. Significant LHRH inactivation also occurred at 0 C, which in part explains the insensitivity of LHRH receptor assays. Assessment of LHRH inactivation by different particulate subcellular fractions of pituitary tissue showed that the inactivating enzyme was associated with the plasma membranes; other organelles did not alter LHRH. The enzyme appeared to be an integral part of the plasma membrane structure, since enzymic activity could not be removed by washing without reducing specific LHRH binding. Additionally, reduction of LHRH inactivation by the inhibitors Bacitracin and Trasylol and by magnesium was also accompanied by reduced LHRH binding. Previous studies have shown that the majority of LHRH binding to pituitary plasma membranes is to the low affinity site (approximately 10(-6) M), but the significance of this binding has been uncertain. Our findings indicate that low affinity binding probably represents binding of LHRH to the inactivating enzyme. The LHRH analog, D-Ser6(TBu), des Gly10, ethylamide, has greater biological activity than LHRH and is not inactivated to a significant extent by pituitary plasma membranes. The

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

International Nuclear Information System (INIS)

Sheng, Zhi-Guo; Tang, Yuan; Liu, Yu-Xiang; Yuan, Ye; Zhao, Bao-Quan; Chao, Xi-Juan; Zhu, Ben-Zhan

2012-01-01

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 −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.

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.

The C'-terminal interaction domain of the thyroid hormone receptor confers the ability of the DNA site to dictate positive or negative transcriptional activity

International Nuclear Information System (INIS)

Holloway, J.M.; Glass, C.K.; Adler, S.; Nelson, C.A.; Rosenfeld, M.G.

1990-01-01

To investigate mechanisms responsible for positive and negative transcriptional control, the authors have utilized two types of promoters that are diffferentially regulated by thyroid hormone (T 3 ) receptors. Promoters containing the palindromic T 3 response element TCAGGTCA TGACCTGA are positively regulated by the T 3 receptor after the administration of T 3 , whereas otherwise identical promoters containing the estrogen response element TCAGGTCA CTG TGACCTGA can be regulated negatively; converse effects are observed with the estrogen receptor. They describe evidence that the transcriptional inhibitory effects of the T 3 or estrogen receptors on the estrogen or T 3 response elements, respectively, are imposed by amino acid sequences in the C'-terminal region that colocalize with dimerization and hormone-binding domains and that these sequences can transfer inhibitory functions to other classes of transcription factors. Removal of the C'-terminal dimerization and hormone-binding domains of either the αT 3 or estrogen receptors permits each receptor to act constitutively to enhance transcription on both T 3 and estrogen response elements. It is, therefore, suggested that protein-protein interactions between receptor C' termini limit the subset of DNA binding sites on which transcriptional activation occurs

Action of Specific Thyroid Hormone Receptor alpha(1) and beta(1) Antagonists in the Central and Peripheral Regulation of Thyroid Hormone Metabolism in the Rat

NARCIS (Netherlands)

van Beeren, Hermina C.; Kwakkel, Joan; Ackermans, Mariëtte T.; Wiersinga, Wilmar M.; Fliers, Eric; Boelen, Anita

2012-01-01

Background: The iodine-containing drug amiodarone (Amio) and its noniodine containing analogue dronedarone (Dron) are potent antiarrhythmic drugs. Previous in vivo and in vitro studies have shown that the major metabolite of Amio, desethylamiodarone, acts as a thyroid hormone receptor (TR) alpha(1)

14-3-3 Proteins Buffer Intracellular Calcium Sensing Receptors to Constrain Signaling.

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Michael P Grant

Full Text Available Calcium sensing receptors (CaSR interact with 14-3-3 binding proteins at a carboxyl terminal arginine-rich motif. Mutations identified in patients with familial hypocalciuric hypercalcemia, autosomal dominant hypocalcemia, pancreatitis or idiopathic epilepsy support the functional importance of this motif. We combined total internal reflection fluorescence microscopy and biochemical approaches to determine the mechanism of 14-3-3 protein regulation of CaSR signaling. Loss of 14-3-3 binding caused increased basal CaSR signaling and plasma membrane levels, and a significantly larger signaling-evoked increase in plasma membrane receptors. Block of core glycosylation with tunicamycin demonstrated that changes in plasma membrane CaSR levels were due to differences in exocytic rate. Western blotting to quantify time-dependent changes in maturation of expressed wt CaSR and a 14-3-3 protein binding-defective mutant demonstrated that signaling increases synthesis to maintain constant levels of the immaturely and maturely glycosylated forms. CaSR thus operates by a feed-forward mechanism, whereby signaling not only induces anterograde trafficking of nascent receptors but also increases biosynthesis to maintain steady state levels of net cellular CaSR. Overall, these studies suggest that 14-3-3 binding at the carboxyl terminus provides an important buffering mechanism to increase the intracellular pool of CaSR available for signaling-evoked trafficking, but attenuates trafficking to control the dynamic range of responses to extracellular calcium.

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. Copyright © 2013 Elsevier B.V. All rights reserved.

Quantification of three steroid hormone receptors of the leopard gecko (Eublepharis macularius), a lizard with temperature-dependent sex determination: their tissue distributions and the effect of environmental change on their expressions.

Science.gov (United States)

Endo, Daisuke; Park, Min Kyun

2003-12-01

Sex steroid hormones play a central role in the reproduction of all vertebrates. These hormones function through their specific receptors, so the expression levels of the receptors may reflect the responsibility of target organs. However, there was no effective method to quantify the expression levels of these receptors in reptilian species. In this study, we established the competitive-PCR assay systems for the quantification of the mRNA expression levels of three sex steroid hormone receptors in the leopard gecko. These assay systems were successfully able to detect the mRNA expression level of each receptor in various organs of male adult leopard geckoes. The expression levels of mRNA of these receptors were highly various depending on the organs assayed. This is the first report regarding the tissue distributions of sex steroid hormone receptor expressions in reptile. The effects of environmental conditions on these hormone receptor expressions were also examined. After the low temperature and short photoperiod treatment for 6 weeks, only the androgen receptor expression was significantly increased in the testes. The competitive-PCR assay systems established in this report should be applicable for various studies of the molecular mechanism underlying the reproductive activity of the leopard gecko.

Expression of orphan G-protein coupled receptor GPR174 in CHO cells induced morphological changes and proliferation delay via increasing intracellular cAMP

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Sugita, Kazuya; Yamamura, Chiaki; Tabata, Ken-ichi [Laboratory of Pharmacoinformatics, Graduate School of Ritsumeikan University, Kusatsu, Shiga 525-8577 (Japan); Fujita, Norihisa, E-mail: nori@ph.ritsumei.ac.jp [Laboratory of Pharmacoinformatics, Graduate School of Ritsumeikan University, Kusatsu, Shiga 525-8577 (Japan); School of Pharmacy, Ristumeikan University, Kusatsu, Shiga 525-8577 (Japan)

2013-01-04

Highlights: Black-Right-Pointing-Pointer Expression of GPR174 in CHO cells induces morphological changes and proliferation delay. Black-Right-Pointing-Pointer These are due to increase in intracellular cAMP concentration. Black-Right-Pointing-Pointer Lysophosphatidylserine was identified to stimulate GPR174 leading to activate ACase. Black-Right-Pointing-Pointer The potencies of fatty acid moiety on LysoPS were oleoyl Greater-Than-Or-Slanted-Equal-To stearoyl > palmitoyl. Black-Right-Pointing-Pointer We propose that GPR174 is a lysophosphatidylserine receptor. -- Abstract: We established cell lines that stably express orphan GPCR GPR174 using CHO cells, and studied physiological and pharmacological features of the receptor. GPR174-expressing cells showed cell-cell adhesion with localization of actin filaments to cell membrane, and revealed significant delay of cell proliferation. Since the morphological changes of GPR174-cells were very similar to mock CHO cells treated with cholera toxin, we measured the concentration of intracellular cAMP. The results showed the concentration was significantly elevated in GPR174-cells. By measuring intracellular cAMP concentration in GPR174-cells, we screened lipids and nucleotides to identify ligands for GPR174. We found that lysophosphatidylserine (LysoPS) stimulated increase in intracellular cAMP in a dose-dependent manner. Moreover, phosphorylation of Erk was elevated by LysoPS in GPR174 cells. These LysoPS responses were inhibited by NF449, an inhibitor of G{alpha}{sub s} protein. These results suggested that GPR174 was a putative LysoPS receptor conjugating with G{alpha}{sub s}, and its expression induced morphological changes in CHO cells by constitutively activating adenylyl cycles accompanied with cell conjunctions and delay of proliferation.

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

A novel growth hormone receptor gene deletion mutation in a patient with primary growth hormone insensitivity syndrome (Laron syndrome).

Science.gov (United States)

Yamamoto, Hiroyasu; Kouhara, Haruhiko; Iida, Keiji; Chihara, Kazuo; Kasayama, Soji

2008-04-01

Growth hormone (GH) insensitivity syndrome (Laron syndrome) is known to be caused by genetic disorders of the GH-IGF-1 axis. Although many mutations in the GH receptor have been identified, there have been only a few reports of deletions of the GH receptor gene. A Japanese adult female patient with Laron syndrome was subjected to chromosome analysis with basic G-banding and also with a high accuracy technique. Each exon of the GH receptor gene was amplified by means of PCR. Since this patient was diagnosed with osteoporosis, the effects of alendronate on bone mineral density (BMD) were also examined. The chromosome analysis with the high accuracy technique demonstrated a large deletion of the short arm in one allele of chromosome 5 from p11 to p13.1 [46, XX, del (5) (p11-p13.1)]. PCR amplification of exons of the GH receptor gene showed that only exons 2 and 3 were amplified. Low-dose IGF-1 administration (30microg/kg body weight) failed to increase her BMD, whereas alendronate administration resulted in an increase associated with a decrease in urinary deoxypyridinoline (DPD) and serum osteocalcin concentrations. The GH receptor gene of the patient was shown to lack exons 4-10. To the best of our knowledge, this is the third case report of Laron syndrome with large GH receptor deletion. Alendronate was effective for the enhancement of BMD.

Melanin-concentrating hormone and its receptor are expressed and functional in human skin.

Science.gov (United States)

Hoogduijn, Martin J; Ancans, Janis; Suzuki, Itaru; Estdale, Siân; Thody, Anthony J

2002-08-23

In this study, we have demonstrated the presence of melanin-concentrating hormone (MCH) and melanin-concentrating hormone receptor (MCHR1) transcripts in human skin. Sequence analysis confirmed that the transcripts of both genes were identical to those previously found in human brain. In culture, endothelial cells showed pro-MCH expression whereas no signal was found in keratinocytes, melanocytes, and fibroblasts. MCHR1 expression was restricted to melanocytes and melanoma cells. Stimulation of cultured human melanocytes with MCH reduced the alpha-MSH-induced increase in cAMP production. Furthermore, the melanogenic actions of alpha-MSH were inhibited by MCH. We propose that the MCH/MCHR1 signalling system is present in human skin and may have a role with the melanocortins in regulating the melanocyte.

Neurotrophins and their receptors in the rat pituitary gland: regulation of BDNF and trkB mRNA levels by adrenal hormones.

Science.gov (United States)

Kononen, J; Soinila, S; Persson, H; Honkaniemi, J; Hökfelt, T; Pelto-Huikko, M

1994-12-01

We studied the expression of messenger ribonucleic acids (mRNAs) for neurotrophins and neurotrophin receptors in the rat pituitary gland and examined the influence of adrenal hormones on their mRNA levels, using in situ hybridization and Northern blot analysis. The only neurotrophin present at detectable levels in the pituitary was brain-derived neurotrophic factor (BDNF), which was observed in the anterior and intermediate lobes. Several transcripts of the putative receptor for BDNF, trkB, were present in the anterior and posterior lobes of the pituitary. A low amount of trkC mRNA was found in both the anterior and the intermediate lobe. Dexamethasone treatment decreased both BDNF and trkB mRNA levels in the anterior lobe of the pituitary. Adrenalectomy had no effect on trkB expression, but it decreased BDNF mRNA levels in comparison to the control animals. This effect could not be reversed by dexamethasone substitution, suggesting that BDNF, mRNA levels may be regulated not only by glucocorticoids but also by other adrenal hormones. These results demonstrate that BDNF, trkB and trkC are expressed in the pituitary gland and that glucocorticoids and possibly other adrenal hormones may modulate pituitary functions by regulating the expression of neurotrophic factors and their receptors. Whether BDNF acts as a secreted hormone, a trophic factor, or has autocrine/paracrine functions within the pituitary through its receptor, trkB, remains to be studied.

The Neuroendocrine Functions of the Parathyroid Hormone 2 Receptor

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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

Characterization of hormonal receptors and human epidermal growth factor receptor-2 in tissues of women with breast cancer at Muhimbili National Hospital, Dar es salaam, Tanzania.

Science.gov (United States)

Mwakigonja, Amos Rodger; Lushina, Nyanda Elias; Mwanga, Ally

2017-01-01

Breast cancer is a leading cause of morbidity and deaths among women worldwide. In Tanzania there is no published data on human epidermal growth receptor-2 (HER2/neu) expression in breast carcinoma. Hormonal receptors and HER2/neu status reportedly influence post-mastectomy adjuvant therapy and predict treatment outcome and prognosis. Here we evaluate hormonal receptors and HER-2 status in biopsies of women with breast cancer at Muhimbili National Hospital (MNH). A cross-sectional study of female breast post-modified radical mastectomy (MRM)/incisional biopsies confirmed to be carcinoma at the Histopathology Unit (January-December 2013). Tissue blocks having poor morphology, without tumor, secondary tumors, cases outside the study period and male patients were excluded. Routine staining was done followed by immunohistochemistry for estrogen (ER), and progesterone (PgR) receptors and HER2. Data analyzed using Statistical Package for Social Sciences (SPSS). A total of 218 cases were confirmed to be carcinoma including 70 meeting inclusion criteria. Age at diagnosis ranged 18-75 years and mean age was 48.36 years. Majority (64.3%) were in the 36-55 years age-group. Histologically, most (88.6%) women had invasive ductal carcinoma including 43.1% of intermediate grade. A great majority (78%) were stage three. Due to logistical constrains, 75.7% ( n  = 53/70) cases where immunostained for hormones including 43.4% (ER+), 26.4% (PgR+), and 28% (ER+/PgR+). Furthermore, 65.7% ( n  = 46/70) cases were immunostained for HER-2 and 15.2% ( n  = 7/46) were positive, 45.6% were triple negative (ER-,PgR-,HER2-), 23.9% (ER+,PgR+,HER2-) or luminal B, 2.2% (ER+,PgR-,HER2+),13% (ER-,PgR-,HER2+) and 15% (ER+,PgR-,HER2-) with none being triple positive. Hormonal receptors and HER2 expression at MNH appears to be comparable to previous Africans/African Americans reports but not with studies among Caucasians and the current proportion of triple negative breast carcinomas (TNBC) is

Characterization of hormonal receptors and human epidermal growth factor receptor-2 in tissues of women with breast cancer at Muhimbili National Hospital, Dar es salaam, Tanzania

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Amos Rodger Mwakigonja

2017-11-01

Full Text Available Abstract Background Breast cancer is a leading cause of morbidity and deaths among women worldwide. In Tanzania there is no published data on human epidermal growth receptor-2 (HER2/neu expression in breast carcinoma. Hormonal receptors and HER2/neu status reportedly influence post-mastectomy adjuvant therapy and predict treatment outcome and prognosis. Here we evaluate hormonal receptors and HER-2 status in biopsies of women with breast cancer at Muhimbili National Hospital (MNH. Methods A cross-sectional study of female breast post-modified radical mastectomy (MRM/incisional biopsies confirmed to be carcinoma at the Histopathology Unit (January–December 2013. Tissue blocks having poor morphology, without tumor, secondary tumors, cases outside the study period and male patients were excluded. Routine staining was done followed by immunohistochemistry for estrogen (ER, and progesterone (PgR receptors and HER2. Data analyzed using Statistical Package for Social Sciences (SPSS. Results A total of 218 cases were confirmed to be carcinoma including 70 meeting inclusion criteria. Age at diagnosis ranged 18–75 years and mean age was 48.36 years. Majority (64.3% were in the 36–55 years age-group. Histologically, most (88.6% women had invasive ductal carcinoma including 43.1% of intermediate grade. A great majority (78% were stage three. Due to logistical constrains, 75.7% (n = 53/70 cases where immunostained for hormones including 43.4% (ER+, 26.4% (PgR+, and 28% (ER+/PgR+. Furthermore, 65.7% (n = 46/70 cases were immunostained for HER-2 and 15.2% (n = 7/46 were positive, 45.6% were triple negative (ER-,PgR-,HER2-, 23.9% (ER+,PgR+,HER2- or luminal B, 2.2% (ER+,PgR-,HER2+,13% (ER-,PgR-,HER2+ and 15% (ER+,PgR-,HER2- with none being triple positive. Conclusions Hormonal receptors and HER2 expression at MNH appears to be comparable to previous Africans/African Americans reports but not with studies among Caucasians and the current proportion

Synthesis and in vitro anti-cancer evaluation of luteinizing hormone-releasing hormone-conjugated peptide.

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Deng, Xin; Qiu, Qianqian; Ma, Ke; Huang, Wenlong; Qian, Hai

2015-11-01

Luteinizing hormone-releasing hormone (LHRH) is a decapeptide hormone released from the hypothalamus and shows high affinity binding to the LHRH receptors. It is reported that several cancer cells also express LHRH receptors such as breast, ovarian, prostatic, bladder and others. In this study, we linked B1, an anti-cancer peptide, to LHRH and its analogs to improve the activity against cancer cells with LHRH receptor. Biological evaluation revealed that TB1, the peptide contains triptorelin sequence, present favorable anti-cancer activity as well as plasma stability. Further investigations disclosed that TB1 trigger apoptosis by activating the mitochondria-cytochrome c-caspase apoptotic pathway, it also exhibited the anti-migratory effect on cancer cells.

The effect of the intracervical application of follicle-stimulating hormone or luteinizing hormone on the pattern of expression of gonadotrophin receptors in the cervix of non-pregnant ewes.

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Leethongdee, S; Khalid, M; Scaramuzzi, R J

2014-08-01

During the periovulatory period, the cervix relaxes in response to changes in circulating concentrations of reproductive hormones. The present study investigated the role of gonadotrophins in cervical function by examining the expression of follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) and their mRNAs following intracervical treatment with either FSH or LH. Eighteen ewes were assigned to four groups, and they were then treated with progestagen sponges and PMSG to synchronize their oestrous cycles. Intracervical treatments were given 24 h after sponge removal as follows: Group 1: FSH 2 mg; Group 2: LH 2 mg; Group 3: Vehicle and Group 4: Control. Cervices were collected 54 h after sponge removal and then divided into three regions. The expression of FSHR and LHR was determined by immunohistochemistry and FSHR mRNA and LH mRNA by in situ hybridization. The expression of LHR, FSHR and their respective mRNAs was compared in six tissue layers (luminal epithelium, subepithelial stroma, circular, longitudinal and transverse muscle and serosa) and in three cervical regions (vaginal, mid and uterine). The results showed that FSH increased transcription of the FSHR gene and the levels of its receptor, but only in subepithelial stroma of the cervix. FSH also increased the levels of LHR in the cervix, but only in the muscle layers. LH had no effect on the levels of FSHR despite the fact that it did increase the level of transcription of the FSHR gene and LH also increased the levels of its own receptor in the cervix, but only in the muscle layers, and this action was independent of increased levels of transcription of the LHR gene. These findings suggest multiple levels of regulation of cervical LH and FSH receptors and that the gonadotrophins may have a role in relaxation of the cervix during oestrus by regulating their own receptors. © 2014 Blackwell Verlag GmbH.

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

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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. Copyright © 2014 Elsevier Inc. All rights reserved.

Binding domain-driven intracellular trafficking of sterols for synthesis of steroid hormones, bile acids and oxysterols.

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Midzak, Andrew; Papadopoulos, Vassilios

2014-09-01

Steroid hormones, bioactive oxysterols and bile acids are all derived from the biological metabolism of lipid cholesterol. The enzymatic pathways generating these compounds have been an area of intense research for almost a century, as cholesterol and its metabolites have substantial impacts on human health. Owing to its high degree of hydrophobicity and the chemical properties that it confers to biological membranes, the distribution of cholesterol in cells is tightly controlled, with subcellular organelles exhibiting highly divergent levels of cholesterol. The manners in which cells maintain such sterol distributions are of great interest in the study of steroid and bile acid synthesis, as limiting cholesterol substrate to the enzymatic pathways is the principal mechanism by which production of steroids and bile acids is regulated. The mechanisms by which cholesterol moves within cells, however, remain poorly understood. In this review, we examine the subcellular machinery involved in cholesterol metabolism to steroid hormones and bile acid, relating it to both lipid- and protein-based mechanisms facilitating intracellular and intraorganellar cholesterol movement and delivery to these pathways. In particular, we examine evidence for the involvement of specific protein domains involved in cholesterol binding, which impact cholesterol movement and metabolism in steroidogenesis and bile acid synthesis. A better understanding of the physical mechanisms by which these protein- and lipid-based systems function is of fundamental importance to understanding physiological homeostasis and its perturbation. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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

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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.

Heart, lipids and hormones

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Peter Wolf

2017-05-01

Full Text Available Cardiovascular disease is the leading cause of death in general population. Besides well-known risk factors such as hypertension, impaired glucose tolerance and dyslipidemia, growing evidence suggests that hormonal changes in various endocrine diseases also impact the cardiac morphology and function. Recent studies highlight the importance of ectopic intracellular myocardial and pericardial lipid deposition, since even slight changes of these fat depots are associated with alterations in cardiac performance. In this review, we overview the effects of hormones, including insulin, thyroid hormones, growth hormone and cortisol, on heart function, focusing on their impact on myocardial lipid metabolism, cardiac substrate utilization and ectopic lipid deposition, in order to highlight the important role of even subtle hormonal changes for heart function in various endocrine and metabolic diseases.

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.

Growth hormone secretagogue receptor (GHS-R1a) knockout mice exhibit improved spatial memory and deficits in contextual memory.

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Albarran-Zeckler, Rosie G; Brantley, Alicia Faruzzi; Smith, Roy G

2012-06-15

Although the hormone ghrelin is best known for its stimulatory effect on appetite and regulation of growth hormone release, it is also reported to have beneficial effects on learning and memory formation in mice. Nevertheless, controversy exists about whether endogenous ghrelin acts on its receptors in extra-hypothalamic areas of the brain. The ghrelin receptor (GHS-R1a) is co-expressed in neurons that express dopamine receptor type-1 (DRD1a) and type-2 (DRD2), and we have shown that a subset of GHS-R1a, which are not occupied by the agonist (apo-GHSR1a), heterodimerize with these two receptors to regulate dopamine signaling in vitro and in vivo. To determine the consequences of ghsr ablation on brain function, congenic ghsr -/- mice on the C57BL6/J background were subjected to a battery of behavioral tests. We show that the ghsr -/- mice exhibit normal balance, movement, coordination, and pain sensation, outperform ghsr +/+ mice in the Morris water maze, but show deficits in contextual fear conditioning. Copyright © 2012 Elsevier B.V. All rights reserved.

[Advanced luminal breast cancer (hormone receptor-positive, HER2 negative): New therapeutic options in 2015].

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Vanacker, Hélène; Bally, Olivia; Kassem, Loay; Tredan, Olivier; Heudel, Pierre; Bachelot, Thomas

2015-06-01

Despite improvements in early detection, surgery and systemic therapy, metastatic breast cancer remains a major cause of death. Luminal type breast cancers expressing hormone estrogen receptor (ER) or progesterone (PR) and without HER2 overexpression are generally sensitive to endocrine therapy, but raise the issue of the occurrence of resistance to treatment, particularly at metastatic stage. A better understanding of hormone resistance may guide the development of new therapeutics. New strategies aim at enhancing and prolonging of endocrine sensitivity, by optimizing existing schemes, or by combining an endocrine therapy with a targeted therapies specific to hormone resistance pathways: ER signaling, PI3K/AKT/mTOR and Cyclin Dependent Kinase (CDK). Key corners of 2014 include confirmation of benefit of high dose fulvestrant, and commercialization of everolimus as the first mTOR inhibitor in this indication. Other strategies are being tested dealing with new endocrine therapies or new molecular targets such as PI3K inhibitors, insulin-like growth factor receptor (IGF-R) and histone deacetylase (HDAC) inhibitors. Coming years may be fruitful and might radically change our way to treat these patients. Copyright © 2015 Société Françise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS. All rights reserved.

Role of corticosteroid hormones in the dentate gyrus.

NARCIS (Netherlands)

Joëls, M.

2007-01-01

Dentate granule cells are enriched with receptors for the stress hormone corticosterone, i.e., the high-affinity mineralocorticoid receptor (MR), which is already extensively occupied with low levels of the hormone, and the glucocorticoid receptor (GR), which is particularly activated after stress.

Increased melanin concentrating hormone receptor type I in the human hypothalamic infundibular nucleus in cachexia

NARCIS (Netherlands)

Unmehopa, Unga A.; van Heerikhuize, Joop J.; Spijkstra, Wenda; Woods, John W.; Howard, Andrew D.; Zycband, Emanuel; Feighner, Scott D.; Hreniuk, Donna L.; Palyha, Oksana C.; Guan, Xiao-Ming; Macneil, Douglas J.; van der Ploeg, Lex H. T.; Swaab, Dick F.

2005-01-01

Melanin-concentrating hormone (MCH) exerts a positive regulation on appetite and binds to the G protein-coupled receptors, MCH1R and MCH2R. In rodents, MCH is produced by neurons in the lateral hypothalamus with projections to various hypothalamic and other brain sites. In the present study, MCH1R

Increased melanin concentrating hormone receptor type I in the human hypothalamic infundibular nucleus in cachexia.

NARCIS (Netherlands)

Unmehopa, U.A.; Heerikhuize, J.J. van; Spijkstra, W.; Woods, J.W.; Howard, A.D.; Zycband, E.; Feighner, S.D.; Hreniuk, D.L.; Palyha, O.C.; Guan, X.-M.; MacNeil, D.J.; Ploeg, L.H.T.; Swaab, D.F.

2005-01-01

Melanin-concentrating hormone (MCH) exerts a positive regulation on appetite and binds to the G protein-coupled receptors, MCH1R and MCH2R. In rodents, MCH is produced by neurons in the lateral hypothalamus with projections to various hypothalamic and other brain sites. In the present study, MCH1R

Hormone Receptor Expression Analyses in Neoplastic and Non-Neoplastic Canine Mammary Tissue by a Bead Based Multiplex Branched DNA Assay: A Gene Expression Study in Fresh Frozen and Formalin-Fixed, Paraffin-Embedded Samples.

Directory of Open Access Journals (Sweden)

Annika Mohr

Full Text Available Immunohistochemistry (IHC is currently considered the method of choice for steroid hormone receptor status evaluation in human breast cancer and, therefore, it is commonly utilized for assessing canine mammary tumors. In case of low hormone receptor expression, IHC is limited and thus is complemented by molecular analyses. In the present study, a multiplex bDNA assay was evaluated as a method for hormone receptor gene expression detection in canine mammary tissues. Estrogen receptor (ESR1, progesterone receptor (PGR, prolactin receptor (PRLR and growth hormone receptor (GHR gene expressions were evaluated in neoplastic and non-neoplastic canine mammary tissues. A set of 119 fresh frozen and 180 formalin-fixed, paraffin-embedded (FFPE was comparatively analyzed and used for assay evaluation. Furthermore, a possible association between the hormone receptor expression in different histological subtypes of canine malignant mammary tumors and the castration status, breed and invasive growth of the tumor were analyzed. The multiplex bDNA assay proved to be more sensitive for fresh frozen specimens. Hormone receptor expression found was significantly decreased in malignant mammary tumors in comparison to non-neoplastic tissue and benign mammary tumors. Among the histological subtypes the lowest gene expression levels of ESR1, PGR and PRLR were found in solid, anaplastic and ductal carcinomas. In summary, the evaluation showed that the measurement of hormone receptors with the multiplex bDNA assay represents a practicable method for obtaining detailed quantitative information about gene expression in canine mammary tissue for future studies. Still, comparison with IHC or quantitative real-time PCR is needed for further validation of the present method.

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.

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.

Transcriptomic and phenotypic profiling in developing zebrafish exposed to thyroid hormone receptor agonists

Energy Technology Data Exchange (ETDEWEB)

Haggard, Derik E.; Noyes, Pamela D.; Waters, Katrina M.; Tanguay, Robert L.

2018-04-01

There is a need to develop novel, high-throughput screening and prioritization methods to identify chemicals with adverse estrogen, androgen, and thyroid activity to protect human health and the environment and is of interest to the Endocrine Disruptor Screening Program. The current aim is to explore the utility of zebrafish as a testing paradigm to classify endocrine activity using phenotypically anchored transcriptome profiling. Transcriptome analysis was conducted on embryos exposed to 25 estrogen-, androgen-, or thyroid-active chemicals at a concentration that elicited adverse malformations or mortality at 120 hours post-fertilization in 80% of the animals exposed. Analysis of the top 1000 significant differentially expressed transcripts across all treatments identified a unique transcriptional and phenotypic profile for thyroid hormone receptor agonists, which can be used as a biomarker screen for potential thyroid hormone agonists.

Molecular and functional characterization of a novel gonadotropin-releasing-hormone receptor isolated from the common octopus (Octopus vulgaris)

OpenAIRE

Kanda, Atsuhiro; Takahashi, Toshio; Satake, Honoo; Minakata, Hiroyuki

2006-01-01

GnRH (gonadotropin-releasing hormone) plays a pivotal role in the regulation of reproduction in vertebrates through interaction with a specific receptor. Previously, we isolated a GnRH homo-logue, oct-GnRH, from the common octopus (Octopus vulgaris). In the present study, we have identified a GnRH receptor (oct-GnRHR) specific for oct-GnRH from Octopus brain. Oct-GnRHR includes domains and motifs typical of vertebrate GnRH receptors. The intron-inserted positions are conserved between oct-GnR...

Agonist-mediated activation of Bombyx mori diapause hormone receptor signals to extracellular signal-regulated kinases 1 and 2 through Gq-PLC-PKC-dependent cascade.

Science.gov (United States)

Jiang, Xue; Yang, Jingwen; Shen, Zhangfei; Chen, Yajie; Shi, Liangen; Zhou, Naiming

2016-08-01

Diapause is a developmental strategy adopted by insects to survive in challenging environments such as the low temperatures of a winter. This unique process is regulated by diapause hormone (DH), which is a neuropeptide hormone that induces egg diapause in Bombyx mori and is involved in terminating pupal diapause in heliothis moths. An G protein-coupled receptor from the silkworm, B. mori, has been identified as a specific cell surface receptor for DH. However, the detailed information on the DH-DHR system and its mechanism(s) involved in the induction of embryonic diapause remains unknown. Here, we combined functional assays with various specific inhibitors to elucidate the DHR-mediated signaling pathways. Upon activation by DH, B. mori DHR is coupled to the Gq protein, leading to a significant increase of intracellular Ca(2+) and cAMP response element-driven luciferase activity in an UBO-QIC, a specific Gq inhibitor, sensitive manner. B. mori DHR elicited ERK1/2 phosphorylation in a dose- and time-dependent manner in response to DH. This effect was almost completely inhibited by co-incubation with UBO-QIC and was also significantly suppressed by PLC inhibitor U73122, PKC inhibitors Gö6983 and the Ca(2+) chelator EGTA. Moreover, DHR-induced activation of ERK1/2 was significantly attenuated by treatment with the Gβγ specific inhibitors gallein and M119K and the PI3K specific inhibitor Wortmannin, but not by the Src specific inhibitor PP2. Our data also demonstrates that the EGFR-transactivation pathway is not involved in the DHR-mediated ERK1/2 phosphorylation. Future efforts are needed to clarify the role of the ERK1/2 signaling pathway in the DH-mediated induction of B. mori embryonic diapause. Copyright © 2016 Elsevier Ltd. All rights reserved.

Resistance to thyroid hormone due to defective thyroid receptor alpha.

Science.gov (United States)

Moran, Carla; Chatterjee, Krishna

2015-08-01

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, skeletal dysplasia (macrocephaly, epiphyseal dysgenesis), growth retardation, constipation, dyspraxia and intellectual deficit. Biochemical abnormalities include low/low-normal T4 and high/high-normal T3 concentrations, a subnormal T4/T3 ratio, variably reduced reverse T3, raised muscle creatine kinase and mild anaemia. The disorder is mediated by heterozygous, loss-of-function, mutations involving either TRα1 alone or both TRα1 and α2, with no discernible phenotype attributable to defective α2. Whole exome sequencing and diagnostic biomarkers may enable greater ascertainment of RTHα, which is important as thyroxine therapy reverses some metabolic abnormalities and improves growth, constipation, dyspraxia and wellbeing. The genetic and phenotypic heterogeneity of RTHα and its optimal management remain to be elucidated. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

The little women of Loja--growth hormone-receptor deficiency in an inbred population of southern Ecuador.

Science.gov (United States)

Rosenbloom, A L; Guevara Aguirre, J; Rosenfeld, R G; Fielder, P J

1990-11-15

Laron-type dwarfism, which is characterized by the clinical appearance of isolated growth hormone deficiency with elevated serum levels of growth hormone and decreased serum levels of insulin-like growth factor I (IGF-I), has been described in approximately 50 patients. This condition is caused by a deficiency of the cellular receptor for growth hormone, and it is transmitted as an autosomal recessive trait, as indicated by an equal sex distribution and a high rate of consanguinity in affected families. We studied 20 patients (19 females and 1 male, 2 to 49 years of age), from an inbred Spanish population in southern Ecuador, who had the clinical features of Laron-type dwarfism. Seventeen patients were members of two large pedigrees. Among the 13 affected sibships, there were 19 affected and 24 unaffected female siblings and 1 affected and 21 unaffected male siblings. The patients' heights ranged from 10.0 to 6.7 SD below the normal mean height for age in the United States. In addition to the previously described features, 15 patients had limited elbow extensibility, all had blue scleras, affected adults had relatively short extremities, and all four affected women over 30 years of age had hip degeneration. Basal serum concentrations of growth hormone were elevated in all affected children (30 to 160 micrograms per liter) and normal to moderately elevated in the adults. The serum level of growth hormone-binding protein ranged from 1 to 30 percent of normal; IGF-I concentrations were low--less than or equal to 7 micrograms per liter in the children and less than or equal to 66 micrograms per liter in the adults (normal for Ecuadorean women, 98 to 238). Serum levels of IGF-II and growth hormone-dependent IGF-binding protein-3 were also low. We describe an inbred population with a high incidence of growth hormone-receptor deficiency resulting in a clinical picture resembling Laron-type dwarfism but differing principally in showing a marked predominance of affected

A growth hormone receptor SNP promotes lung cancer by impairment of SOCS2-mediated degradation

DEFF Research Database (Denmark)

Chhabra, Y.; Wong, H. Y.; Nikolajsen, Louise Fletcher

2018-01-01

Both humans and mice lacking functional growth hormone (GH) receptors are known to be resistant to cancer. Further, autocrine GH has been reported to act as a cancer promoter. Here we present the first example of a variant of the GH receptor (GHR) associated with cancer promotion, in this case lu......-mesenchymal transition and metastases (TWIST1, SNAI2, EGFR, MYC and CCND1) at 2 h after a GH pulse. This is consistent with prolonged GH signalling acting to promote cancer progression in lung cancer.Oncogene advance online publication, 2 October 2017; doi:10.1038/onc.2017.352....

Review of hormonal treatment of breast cancer | Abdulkareem ...

African Journals Online (AJOL)

This critical review focuses on the role of steroid hormones and their receptors in the development and treatment of breast cancer, with special reference to estrogen receptors, as well as mechanisms of receptor.ligand interactions, response or resistance to hormonal therapy against breast cancer, in conjunction with other ...

Lipids Derived from Virulent Francisella tularensis Broadly Inhibit Pulmonary Inflammation via Toll-Like Receptor 2 and Peroxisome Proliferator-Activated Receptor α

Science.gov (United States)

Crane, Deborah D.; Ireland, Robin; Alinger, Joshua B.; Small, Pamela

2013-01-01

Francisella tularensis is a Gram-negative facultative intracellular pathogen that causes an acute lethal respiratory disease in humans. The heightened virulence of the pathogen is linked to its unique ability to inhibit Toll-like receptor (TLR)-mediated inflammatory responses. The bacterial component and mechanism of this inhibition are unknown. Here we show that lipids isolated from virulent but not attenuated strains of F. tularensis are not detected by host cells, inhibit production of proinflammatory cytokines by primary macrophages in response to known TLR ligands, and suppress neutrophil recruitment in vivo. We further show that lipid-mediated inhibition of inflammation is dependent on TLR2, MyD88, and the nuclear hormone and fatty acid receptor peroxisome proliferator-activated receptor α (PPARα). Pathogen lipid-mediated interference with inflammatory responses through the engagement of TLR2 and PPARα represents a novel manipulation of host signaling pathways consistent with the ability of highly virulent F. tularensis to efficiently evade host immune responses. PMID:23925884

Relationship between the functional exon 3 deleted growth hormone receptor polymorphism and symptomatic osteoarthritis in women

NARCIS (Netherlands)

Claessen, K. M. J. A.; Kloppenburg, M.; Kroon, H. M.; Bijsterbosch, J.; Pereira, A. M.; Romijn, J. A.; van der Straaten, T.; Nelissen, R. G. H. H.; Hofman, A.; Uitterlinden, A. G.; Duijnisveld, B. J.; Lakenberg, N.; Beekman, M.; van Meurs, J. B.; Slagboom, P. E.; Biermasz, N. R.; Meulenbelt, I.

2014-01-01

Background Several studies suggest a role of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in the pathophysiology of primary osteoarthritis (OA). A common polymorphism of the GH receptor (exon 3 deletion, d3-GHR) is associated with increased GH/IGF-1 activity. Objective To study

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...... and prostate cancer.......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 related...... PRL receptor (PRLR) ligand. This structure allows one to draw up an exhaustive inventory of the residues involved at the PRL.PRLR site 2 interface, consistent with all previously reported site-directed mutagenesis data. We propose, with this description, an interaction model involving three structural...

Removal of reproductive suppression reveals latent sex differences in brain steroid hormone receptors in naked mole-rats, Heterocephalus glaber.

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Swift-Gallant, Ashlyn; Mo, Kaiguo; Peragine, Deane E; Monks, D Ashley; Holmes, Melissa M

2015-01-01

Naked mole-rats are eusocial mammals, living in large colonies with a single breeding female and 1-3 breeding males. Breeders are socially dominant, and only the breeders exhibit traditional sex differences in circulating gonadal steroid hormones and reproductive behaviors. Non-reproductive subordinates also fail to show sex differences in overall body size, external genital morphology, and non-reproductive behaviors. However, subordinates can transition to breeding status if removed from their colony and housed with an opposite-sex conspecific, suggesting the presence of latent sex differences. Here, we assessed the expression of steroid hormone receptor and aromatase messenger RNA (mRNA) in the brains of males and females as they transitioned in social and reproductive status. We compared in-colony subordinates to opposite-sex subordinate pairs that were removed from their colony for either 1 day, 1 week, 1 month, or until they became breeders (i.e., produced a litter). Diencephalic tissue was collected and mRNA of androgen receptor (Ar), estrogen receptor alpha (Esr1), progesterone receptor (Pgr), and aromatase (Cyp19a1) was measured using qPCR. Testosterone, 17β-estradiol, and progesterone from serum were also measured. As early as 1 week post-removal, males exhibited increased diencephalic Ar mRNA and circulating testosterone, whereas females had increased Cyp19a1 mRNA in the diencephalon. At 1 month post-removal, females exhibited increased 17β-estradiol and progesterone. The largest changes in steroid hormone receptors were observed in breeders. Breeding females had a threefold increase in Cyp19a1 and fivefold increases in Esr1 and Pgr, whereas breeding males had reduced Pgr and increased Ar. These data demonstrate that sex differences in circulating gonadal steroids and hypothalamic gene expression emerge weeks to months after subordinate animals are removed from reproductive suppression in their home colony.

Levels of central oxytocin and glucocorticoid receptor and serum adrenocorticotropic hormone and corticosterone in mandarin voles with different levels of sociability.

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Qiao, Xufeng; Yan, Yating; Tai, Fadao; Wu, Ruiyong; Hao, Ping; Fang, Qianqian; Zhang, Shuwei

2014-11-01

Sociability is the prerequisite to social living. Oxytocin and the hypothalamo-pituitary-adrenocortical axis mediate various social behaviors across different social contexts in different rodents. We hypothesized that they also mediate levels of non-reproductive social behavior. Here we explored naturally occurring variation in sociability through a social preference test and compared central oxytocin, glucocorticoid receptors, serum adrenocorticotropic hormone and corticosterone in mandarin voles with different levels of sociability. We found that low-social voles showed higher levels of anxiety-like behavior in open field tests, and had more serum adrenocorticotropic hormone and corticosterone than high-social voles. High-social individuals had more glucocorticoid receptor positive neurons in the hippocampus and more oxytocin positive neurons in the paraventricular nuclei and supraoptic nuclei of the hypothalamus than low-social individuals. Within the same level of sociability, females had more oxytocin positive neurons in the paraventricular nuclei and supraoptic nuclei of the hypothalamus than males. These results indicate that naturally occurring social preferences are associated with higher levels of central oxytocin and hippocampus glucocorticoid receptor and lower levels of anxiety and serum adrenocorticotropic hormone and corticosterone. Copyright © 2014 Elsevier B.V. All rights reserved.

Characterization of Leptin Intracellular Trafficking

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E Walum

2009-12-01

Full Text Available Leptin is produced by adipose tissue, and its concentration in plasma is related to the amount of fat in the body. The leptin receptor (OBR is a member of the class I cytokine receptor family and several different isoforms, produced by alternative mRNA splicing are found in many tissues, including the hypothalamus. The two predominant isoforms includes a long form (OBRl with an intracellular domain of 303 amino acids and a shorter form (OBRs with an intracellular domain of 34 amino acids. Since OBRl is mainly expressed in the hypotalamus, it has been suggested to be the main signalling form. The peripheral production of leptin by adipocyte tissue and its effects as a signal of satiety in the central nervous system imply that leptin gains access to regions of the brain regulating in energy balance by crossing the blood-brain barrier. In an attempt to characterize the intracellular transport of leptin, we have followed binding internalization and degradation of leptin in HEK293 cells. We have also monitored the intracellular transport pathway of fluorescent conjugated leptin in HEK293 cells. Phenylarsine oxide, a general inhibitor of endocytosis, as well as incubation at mild hypertonic conditions, prevented the uptake of leptin, confirming a receptor-mediated internalization process. When internalized, 125I-leptin was rapidly accumulated inside the cells and reached a maximum after 10 min. After 70 minutes about 40-50% of total counts in each time point were found in the medium as TCA-soluble material. Leptin sorting, at the level of early endosomes, did not seem to involve recycling endosomes, since FITC-leptin was sorted from Cy3- transferrin containing compartments at 37°C. At 45 minutes of continuos internalization, FITC-leptin appeared mainly accumulated in late endocytic structures colocalizing with internalized rhodamine coupled epidermial growth factor (EGF and the lysosomal marker protein lamp-1. The transport of leptin was also shown

Fanconi Anemia a Is a Nucleocytoplasmic Shuttling Molecule Required for Gonadotropin-Releasing Hormone (GnRH) Transduction of the GnRH Receptor

OpenAIRE

Larder, Rachel; Karali, Dimitra; Nelson, Nancy; Brown, Pamela

2006-01-01

GnRH binds its cognate G protein-coupled GnRH receptor (GnRHR) located on pituitary gonadotropes and drives expression of gonadotropin hormones. There are two gonadotropin hormones, comprised of a common α- and hormone-specific β-subunit, which are required for gonadal function. Recently we identified that Fanconi anemia a (Fanca), a DNA damage repair gene, is differentially expressed within the LβT2 gonadotrope cell line in response to stimulation with GnRH. FANCA is mutated in more than 60%...

Role of the ERC motif in the proximal part of the second intracellular loop and the C-terminal domain of the human prostaglandin F2alpha receptor (hFP-R) in G-protein coupling control.

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Pathe-Neuschäfer-Rube, Andrea; Neuschäfer-Rube, Frank; Püschel, Gerhard P

2005-05-15

The human FP-R (F2alpha prostaglandin receptor) is a Gq-coupled heptahelical ectoreceptor, which is of significant medical interest, since it is a potential target for the treatment of glaucoma and preterm labour. On agonist exposure, it mediates an increase in intracellular inositol phosphate formation. Little is known about the structures that govern the agonist-dependent receptor activation. In other prostanoid receptors, the C-terminal domain has been inferred in the control of agonist-dependent receptor activation. A DRY motif at the beginning of the second intracellular loop is highly conserved throughout the G-protein-coupled receptor family and appears to be crucial for controlling agonist-dependent receptor activation. It is replaced by an ERC motif in the FP-R and no evidence for the relevance of this motif in ligand-dependent activation of prostanoid receptors has been provided so far. The aim of the present study was to elucidate the potential role of the C-terminal domain and the ERC motif in agonist-controlled intracellular signalling in FP-R mutants generated by site-directed mutagenesis. It was found that substitution of the acidic Glu(132) in the ERC motif by a threonine residue led to full constitutive activation, whereas truncation of the receptor's C-terminal domain led to partial constitutive activation of all three intracellular signal pathways that had previously been shown to be activated by the FP-R, i.e. inositol trisphosphate formation, focal adhesion kinase activation and T-cell factor signalling. Inositol trisphosphate formation and focal adhesion kinase phosphorylation were further enhanced by ligand binding in cells expressing the truncation mutant but not the E132T (Glu132-->Thr) mutant. Thus C-terminal truncation appeared to result in a receptor with partial constitutive activation, whereas substitution of Glu132 by threonine apparently resulted in a receptor with full constitutive activity.

Liver X receptor β controls thyroid hormone feedback in the brain and regulates browning of subcutaneous white adipose tissue.

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Miao, Yifei; Wu, Wanfu; Dai, Yubing; Maneix, Laure; Huang, Bo; Warner, Margaret; Gustafsson, Jan-Åke

2015-11-10

The recent discovery of browning of white adipose tissue (WAT) has raised great research interest because of its significant potential in counteracting obesity and type 2 diabetes. Browning is the result of the induction in WAT of a newly discovered type of adipocyte, the beige cell. When mice are exposed to cold or several kinds of hormones or treatments with chemicals, specific depots of WAT undergo a browning process, characterized by highly activated mitochondria and increased heat production and energy expenditure. However, the mechanisms underlying browning are still poorly understood. Liver X receptors (LXRs) are one class of nuclear receptors, which play a vital role in regulating cholesterol, triglyceride, and glucose metabolism. Following our previous finding that LXRs serve as repressors of uncoupling protein-1 (UCP1) in classic brown adipose tissue in female mice, we found that LXRs, especially LXRβ, also repress the browning process of subcutaneous adipose tissue (SAT) in male rodents fed a normal diet. Depletion of LXRs activated thyroid-stimulating hormone (TSH)-releasing hormone (TRH)-positive neurons in the paraventricular nucleus area of the hypothalamus and thus stimulated secretion of TSH from the pituitary. Consequently, production of thyroid hormones in the thyroid gland and circulating thyroid hormone level were increased. Moreover, the activity of thyroid signaling in SAT was markedly increased. Together, our findings have uncovered the basis of increased energy expenditure in male LXR knockout mice and provided support for targeting LXRs in treatment of obesity.

Comparative Functional Alanine Positional Scanning of the α-Melanocyte Stimulating Hormone and NDP-Melanocyte Stimulating Hormone Demonstrates Differential Structure-Activity Relationships at the Mouse Melanocortin Receptors.

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Todorovic, Aleksandar; Ericson, Mark D; Palusak, Ryan D; Sorensen, Nicholas B; Wood, Michael S; Xiang, Zhimin; Haskell-Luevano, Carrie

2016-07-20

The melanocortin system has been implicated in the regulation of various physiological functions including melanogenesis, steroidogenesis, energy homeostasis, and feeding behavior. Five melanocortin receptors have been identified to date and belong to the family of G protein-coupled receptors (GPCR). Post-translational modification of the proopiomelanocortin (POMC) prohormone leads to the biosynthesis of the endogenous melanocortin agonists, including α-melanocyte stimulating hormone (α-MSH), β-MSH, γ-MSH, and adrenocorticotropic hormone (ACTH). All the melanocortin agonists derived from the POMC prohormone contain a His-Phe-Arg-Trp tetrapeptide sequence that has been implicated in eliciting the pharmacological responses at the melanocortin receptors. Herein, an alanine (Ala) positional scan is reported for the endogenous α-MSH ligand and the synthetic, more potent, NDP-MSH peptide (Ac-Ser(1)-Tyr(2)-Ser(3)-Nle(4)-Glu(5)-His(6)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-Lys(11)-Pro(12)-Val(13)-NH2) at the cloned mouse melanocortin receptors to test the assumption that the structure-activity relationships of one ligand would apply to the other. Several residues outside of the postulated pharmacophore altered potency at the melanocortin receptors, most notably the 1560-, 37-, and 15-fold potency loss when the Glu(5) position of α-MSH was substituted with Ala at the mMC1R, mMC3R, and mMC4R, respectively. Importantly, the altered potencies due to Ala substitutions in α-MSH did not necessarily correlate with equivalent Ala substitutions in NDP-MSH, indicating that structural modifications and corresponding biological activities in one of these melanocortin ligands may not be predictive for the other agonist.

Growth hormone secretagogues protect mouse cardiomyocytes from in vitro ischemia/reperfusion injury through regulation of intracellular calcium.

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Yi Ma

Full Text Available BACKGROUND: Ischemic heart disease is a leading cause of mortality. To study this disease, ischemia/reperfusion (I/R models are widely used to mimic the process of transient blockage and subsequent recovery of cardiac coronary blood supply. We aimed to determine whether the presence of the growth hormone secretagogues, ghrelin and hexarelin, would protect/improve the function of heart from I/R injury and to examine the underlying mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: Isolated hearts from adult male mice underwent 20 min global ischemia and 30 min reperfusion using a Langendorff apparatus. Ghrelin (10 nM or hexarelin (1 nM was introduced into the perfusion system either 10 min before or after ischemia, termed pre- and post-treatments. In freshly isolated cardiomyocytes from these hearts, single cell shortening, intracellular calcium ([Ca(2+](i transients and caffeine-releasable sarcoplasmic reticulum (SR Ca(2+ were measured. In addition, RT-PCR and Western blots were used to examine the expression level of GHS receptor type 1a (GHS-R1a, and phosphorylated phospholamban (p-PLB, respectively. Ghrelin and hexarelin pre- or post-treatments prevented the significant reduction in the cell shortening, [Ca(2+](i transient amplitude and caffeine-releasable SR Ca(2+ content after I/R through recovery of p-PLB. GHS-R1a antagonists, [D-Lys3]-GHRP-6 (200 nM and BIM28163 (100 nM, completely blocked the effects of GHS on both cell shortening and [Ca(2+](i transients. CONCLUSION/SIGNIFICANCE: Through activation of GHS-R1a, ghrelin and hexarelin produced a positive inotropic effect on ischemic cardiomyocytes and protected them from I/R injury probably by protecting or recovering p-PLB (and therefore SR Ca(2+ content to allow the maintenance or recovery of normal cardiac contractility. These observations provide supporting evidence for the potential therapeutic application of ghrelin and hexarelin in patients with cardiac I/R injury.

Receptor-mediated endocytosis of polypeptide hormones is a regulated process: inhibition of [125I]iodoinsulin internalization in hypoinsulinemic diabetes of rat and man

International Nuclear Information System (INIS)

Carpentier, J.L.; Robert, A.; Grunberger, G.; van Obberghen, E.; Freychet, P.; Orci, L.; Gorden, P.

1986-01-01

Much data suggest that receptor-mediated endocytosis is regulated in states of hormone excess. Thus, in hyperinsulinemic states there is an accelerated loss of cell surface insulin receptors. In the present experiments we addressed this question in hypoinsulinemic states, in which insulin binding to cell surface receptors is generally increased. In hepatocytes obtained from hypoinsulinemic streptozotocin-induced diabetic rats, [ 125 I]iodoglucagon internalization was increased, while at the same time [ 125 I]iodoinsulin internalization was decreased. The defect in [ 125 I]iodoinsulin internalization was corrected by insulin treatment of the animal. In peripheral blood monocytes from patients with type I insulinopenic diabetes, internalization of [ 125 I]iodoinsulin was impaired; this defect was not present in insulin-treated patients. These data in the hypoinsulinemic rat and human diabetes suggest that receptor-mediated endocytosis is regulated in states of insulin deficiency as well as insulin excess. Delayed or reduced internalization of the insulin-receptor complex could amplify the muted signal caused by deficient hormone secretion

The carboxy-terminal tail or the intracellular loop 3 is required for β-arrestin-dependent internalization of a mammalian type II GnRH receptor.

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Madziva, Michael T; Mkhize, Nonhlanhla N; Flanagan, Colleen A; Katz, Arieh A

2015-08-15

The type II GnRH receptor (GnRH-R2) in contrast to mammalian type I GnRH receptor (GnRH-R1) has a cytosolic carboxy-terminal tail. We investigated the role of β-arrestin 1 in GnRH-R2-mediated signalling and mapped the regions in GnRH-R2 required for recruitment of β-arrestin, employing internalization assays. We show that GnRH-R2 activation of ERK is dependent on β-arrestin and protein kinase C. Appending the tail of GnRH-R2 to GnRH-R1 enabled GRK- and β-arrestin-dependent internalization of the chimaeric receptor. Surprisingly, carboxy-terminally truncated GnRH-R2 retained β-arrestin and GRK-dependent internalization, suggesting that β-arrestin interacts with additional elements of GnRH-R2. Mutating serine and threonine or basic residues of intracellular loop 3 did not abolish β-arrestin 1-dependent internalization but a receptor lacking these basic residues and the carboxy-terminus showed no β-arrestin 1-dependent internalization. Our results suggest that basic residues at the amino-terminal end of intracellular loop 3 or the carboxy-terminal tail are required for β-arrestin dependent internalization. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Nuclear hormone receptor expression in mouse kidney and renal cell lines.

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Daisuke Ogawa

Full Text Available Nuclear hormone receptors (NHRs are transcription factors that regulate carbohydrate and lipid metabolism, immune responses, and inflammation. Although several NHRs, including peroxisome proliferator-activated receptor-γ (PPARγ and PPARα, demonstrate a renoprotective effect in the context of diabetic nephropathy (DN, the expression and role of other NHRs in the kidney are still unrecognized. To investigate potential roles of NHRs in the biology of the kidney, we used quantitative real-time polymerase chain reaction to profile the expression of all 49 members of the mouse NHR superfamily in mouse kidney tissue (C57BL/6 and db/m, and cell lines of mesangial (MES13, podocyte (MPC, proximal tubular epithelial (mProx24 and collecting duct (mIMCD3 origins in both normal and high-glucose conditions. In C57BL/6 mouse kidney cells, hepatocyte nuclear factor 4α, chicken ovalbumin upstream promoter transcription factor II (COUP-TFII and COUP-TFIII were highly expressed. During hyperglycemia, the expression of the NHR 4A subgroup including neuron-derived clone 77 (Nur77, nuclear receptor-related factor 1, and neuron-derived orphan receptor 1 significantly increased in diabetic C57BL/6 and db/db mice. In renal cell lines, PPARδ was highly expressed in mesangial and proximal tubular epithelial cells, while COUP-TFs were highly expressed in podocytes, proximal tubular epithelial cells, and collecting duct cells. High-glucose conditions increased the expression of Nur77 in mesangial and collecting duct cells, and liver x receptor α in podocytes. These data demonstrate NHR expression in mouse kidney cells and cultured renal cell lines and suggest potential therapeutic targets in the kidney for the treatment of DN.

In vivo experimental stroke and in vitro organ culture induce similar changes in vasoconstrictor receptors and intracellular calcium handling in rat cerebral arteries

DEFF Research Database (Denmark)

Povlsen, Gro Klitgaard; Waldsee, Roya; Ahnstedt, Hilda

2012-01-01

Cerebral arteries subjected to different types of experimental stroke upregulate their expression of certain G-protein-coupled vasoconstrictor receptors, a phenomenon that worsens the ischemic brain damage. Upregulation of contractile endothelin B (ET(B)) and 5-hydroxytryptamine 1B (5-HT(1B......)) receptors has been demonstrated after subarachnoid hemorrhage and global ischemic stroke, but the situation is less clear after focal ischemic stroke. Changes in smooth muscle calcium handling have been implicated in different vascular diseases but have not hitherto been investigated in cerebral arteries...... and extracellular sources, whereas 5-HT(1B) receptor-mediated contraction was solely dependent on extracellular calcium. Organ culture and stroke increased basal intracellular calcium levels in MCA smooth muscle cells and decreased the expression of inositol triphosphate receptor and transient receptor potential...

Chromosomal localization of the gonadotropin-releasing hormone receptor gene to human chromosome 4q13. 1-q21. 1 and mouse chromosome 5

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Kaiser, U.B.; Dushkin, H.; Beier, D.R.; Chin, W.W. (Harvard Medical School, Boston, MA (United States)); Altherr, M.R. (Los Alamos National Lab., NM (United States))

1994-04-01

The gonadotropin-releasing hormone receptor (GRHR) is a G-protein-coupled receptor on the cell surface of pituitary gonadotropes, where it serves to transduce signals from the extracellular ligand, the hypothalamic factor gonadotropin-releasing hormone, and to modulate the synthesis and secretion of luteinizing hormone and follicle-stimulating hormone. The authors have localized the GRHR gene to the q13.1-q21.1 region of the human chromosome 4 using mapping panels of human/rodent somatic cell hybrids containing different human chromosomes or different regions of human chromosome 4. Furthermore, using linkage analysis of single-strand conformational polymorphisms, the murine GRHR gene was localized to mouse chromosome 5, linked to the endogenous retroviral marker Pmv-11. This is consistent with the evolutionary conservation of homology between these two regions, as has been previously suggested from comparative mapping of several other loci. The localization of the GRHR gene may be useful in the study of disorders of reproduction. 22 refs., 2 figs.

Intracellular Catalytic Domain of Symbiosis Receptor Kinase Hyperactivates Spontaneous Nodulation in Absence of Rhizobia1[W

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Saha, Sudip; Dutta, Ayan; Bhattacharya, Avisek; DasGupta, Maitrayee

2014-01-01

Symbiosis Receptor Kinase (SYMRK), a member of the Nod factor signaling pathway, is indispensible for both nodule organogenesis and intracellular colonization of symbionts in rhizobia-legume symbiosis. Here, we show that the intracellular kinase domain of a SYMRK (SYMRK-kd) but not its inactive or full-length version leads to hyperactivation of the nodule organogenic program in Medicago truncatula TR25 (symrk knockout mutant) in the absence of rhizobia. Spontaneous nodulation in TR25/SYMRK-kd was 6-fold higher than rhizobia-induced nodulation in TR25/SYMRK roots. The merged clusters of spontaneous nodules indicated that TR25 roots in the presence of SYMRK-kd have overcome the control over both nodule numbers and their spatial position. In the presence of rhizobia, SYMRK-kd could rescue the epidermal infection processes in TR25, but colonization of symbionts in the nodule interior was significantly compromised. In summary, ligand-independent deregulated activation of SYMRK hyperactivates nodule organogenesis in the absence of rhizobia, but its ectodomain is required for proper symbiont colonization. PMID:25304318

A Thapsigargin-Resistant Intracellular Calcium Sequestering Compartment in Rat Brain

Science.gov (United States)

2000-03-31

have a major impact on neuronal intracellular signaling. Most of the ER in neurons and glia appears to accumulate calcium by energy driven ion pumps...secretion of exocrine, endocrine, and neurocrine products, regulation of glycogenolysis and gluconeogenesis , intracellular transport, secretion of fluids...the RyRs [140]. Furthermore, the intracellular expression of these receptor-channels in neuronal ER is also reciprocal with RyRs located primarily in

GAR22: A novel target gene of thyroid hormone receptor causes growth inhibition in human erythroid cells

Czech Academy of Sciences Publication Activity Database

Gamper, I.; Koh, K.-R.; Ruau, D.; Ullrich, K.; Bartůňková, Jana; Piroth, D.; Hacker, C.; Bartůněk, Petr; Zenke, M.

2009-01-01

Roč. 37, č. 5 (2009), s. 539-548 ISSN 0301-472X R&D Projects: GA MŠk(CZ) LC06077 Institutional research plan: CEZ:AV0Z50520514 Keywords : Thyroid hormone receptor * GAR22 * erythropoiesis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.106, year: 2009

Growth hormone-specific induction of the nuclear localization of porcine growth hormone receptor in porcine hepatocytes.

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Lan, H N; Hong, P; Li, R N; Shan, A S; Zheng, X

2017-10-01

The phenomenon of nuclear translocation of growth hormone receptor (GHR) in human, rat, and fish has been reported. To date, this phenomenon has not been described in a domestic animal (such as pig). In addition, the molecular mechanisms of GHR nuclear translocation have not been thoroughly elucidated. To this end, porcine hepatocytes were isolated and used as a cell model. We observed that porcine growth hormone (pGH) can induce porcine GHR's nuclear localization in porcine hepatocytes. Subsequently, the dynamics of pGH-induced pGHR's nuclear localization were analyzed and demonstrated that pGHR's nuclear localization occurs in a time-dependent manner. Next, we explored the mechanism of pGHR nuclear localization using different pGHR ligands, and we demonstrated that pGHR's nuclear translocation is GH(s)-dependent. We also observed that pGHR translocates into cell nuclei in a pGH dimerization-dependent fashion, whereas further experiments indicated that IMPα/β is involved in the nuclear translocation of the pGH-pGHR dimer. The pGH-pGHR dimer may form a pGH-GHR-JAK2 multiple complex in cell nuclei, which would suggest that similar to its function in the cell membrane, the nuclear-localized pGH-pGHR dimer might still have the ability to signal. Copyright © 2017 Elsevier Inc. All rights reserved.

Highly potent metallopeptide analogues of luteinizing hormone-releasing hormone

International Nuclear Information System (INIS)

Bajusz, S.; Janaky, T.; Csernus, V.J.; Bokser, L.; Fekete, M.; Srkalovic, G.; Redding, T.W.; Schally, A.V.

1989-01-01

Metal complexes related to the cytotoxic complexes cisplatin [cis-diamminedichloroplatinum(II)] and transbis(salicylaldoximato)copper(II) were incorporated into suitably modified luteinizing hormone-releasing hormone (LH-RH) analogues containing D-lysine at position 6. Some of the metallopeptides thus obtained proved to be highly active LH-RH agonists or antagonists. Most metallopeptide analogues of LH-RH showed high affinities for the membrane receptors of rat pituitary and human breast cancer cells. Some of these metallopeptides had cytotoxic activity against human breast cancer and prostate cancer and prostate cancer cell lines in vitro. Such cytostatic metallopeptides could be envisioned as targeted chemotherapeutic agents in cancers that contain receptors for LH-RH-like peptides

Estrogen receptor of primary breast cancers: evidence for intracellular proteolysis

International Nuclear Information System (INIS)

Maaroufi, Younes; Lacroix, Marc; Lespagnard, Laurence; Journé, Fabrice; Larsimont, Denis; Leclercq, Guy

2000-01-01

Iodinated oestradiol-labeled oestrogen receptor (ER) isoforms devoid of amino-terminal ABC domains represent about two-thirds of the whole receptor population detected in cytosol samples from human breast cancers. This high frequency could not be ascribed to the expression of truncated mRNAs, or to the proteolysis of the native ER peptide at the time of homogenization or assay, suggesting an intracellular proteolysis. Free amino-terminal and ligand-binding domains maintained together within oligomeric structure(s); increase of ionic strength separated them. The amino-terminal region was consistently detected in the cell nucleus by specific immunohistochemistry leading to the concept of a potential intranuclear association between ER cleavage products and/or other regulatory proteins. We previously reported that about two-thirds of [ 125 I]oestradiol-labelled cytosolic ERs from breast cancer samples eluted as low-molecular-weight isoforms (≤ 37 kDa, size-exclusion fast pressure liquid chromatography [FPLC]). These isoforms failed to adsorb strongly to hydroxylapatite at high ionic strength, a property that was ascribed to receptors devoid of amino-terminal ABC domains. In view of recent data concerning intracellular proteolysis of several transcriptional regulators, the possibility of such behaviour for ER was assessed. The clinical significance of ER measurement in breast cancer cytosols is well established; approximately 50% of ER-positive cases respond to endocrine therapy. Whether such a poor correlation is related to a high proportion of cleaved ER is a question of prime importance. Failure of routine ER assays to discriminate between full-length and cleaved receptors led us to develop an oestradiol-binding assay based on hydroxylapatite adsorption. The aims of the present study were to demonstrate that hydroxylapatite adsorption assay easily identifies cleaved cytosolic ER forms and to assess the origin of such ER forms. Breast cancer cytosols classified as

[Differences in dynamics of insulin and insulin-like growth I (IGF-I) receptors internalization in isolated rat hepatocytes].

Science.gov (United States)

Kolychev, A P; Ternovskaya, E E; Arsenieva, A V; Shapkina, E V

2013-01-01

Insulin and IGF-I are two related peptides performing in the mammalian body functionally different roles of the metabolic and growth hormones, respectively. Internalization of the insulin-receptor complex (IRC) is the most important chain of mechanism of the action of hormone. To elucidate differences in the main stages of internalization of the two related hormones, the internalization dynamics of 125I-insulin and 125I-IGF-I was traced in isolated rat hepatocytes at 37 and 12 degrees C. There were established marked differences in the process of internalization of labeled hormones, which is stimulated by insulin and IGF-I. At 37 degrees C the insulin-stimulated internalization, unlike the process initiated by IGF-I, did not reach the maximal level for 1 h of incubation. However, essential differences in the internalization course of these two related peptide were obvious at the temperature of 12 degrees C. The internalization level of insulin receptors at 12 degrees C decreased by one third in spite of a significant increase of the insulin receptor binding on the hepatocytes plasma membrane. At 12 degrees C a slight decrease of the proportion of intracellular 125I-IGF-I correlated with a decrease in the 125I-IGF-I binding to receptors on the cell membrane. Internalization of IGF-I receptors was not affected by low temperature, as neither its level, nor the rate changed at 12 degrees C. The paradoxical decrease of the insulin-stimulated internalization at low temperature seems to represent a peculiar "inhibition mechanism" of immersion of IRC into the cell, which leads to accumulation of the complexes on the cell surface and possibly to a readjustment of the insulin biological activity. The resistance of internalization of the IGF-I receptor to cold seems to be related to the more ancient origin of this mechanism in the poikilothermal vertebrates.

Evaluation of Therapy Management and Patient Compliance in Postmenopausal Patients with Hormone Receptor-positive Breast Cancer Receiving Letrozole Treatment: The EvaluateTM Study

Science.gov (United States)

Fasching, P. A.; Fehm, T.; Kellner, S.; de Waal, J.; Rezai, M.; Baier, B.; Baake, G.; Kolberg, H.-C.; Guggenberger, M.; Warm, M.; Harbeck, N.; Würstlein, R.; Deuker, J.-U.; Dall, P.; Richter, B.; Wachsmann, G.; Brucker, C.; Siebers, J. W.; Fersis, N.; Kuhn, T.; Wolf, C.; Vollert, H.-W.; Breitbach, G.-P.; Janni, W.; Landthaler, R.; Kohls, A.; Rezek, D.; Noesslet, T.; Fischer, G.; Henschen, S.; Praetz, T.; Heyl, V.; Kühn, T.; Krauß, T.; Thomssen, C.; Kümmel, S.; Hohn, A.; Tesch, H.; Mundhenke, C.; Hein, A.; Rauh, C.; Bayer, C. M.; Jacob, A.; Schmidt, K.; Belleville, E.; Hadji, P.; Wallwiener, D.; Grischke, E.-M.; Beckmann, M. W.; Brucker, S. Y.

2014-01-01

Introduction: The EvaluateTM study (Evaluation of therapy management and patient compliance in postmenopausal hormone receptor-positive breast cancer patients receiving letrozole treatment) is a prospective, non-interventional study for the assessment of therapy management and compliance in the routine care of postmenopausal women with invasive hormone receptor-positive breast cancer receiving letrozole. The parameters for inclusion in the study are presented and discussed here. Material and Methods: Between January 2008 and December 2009 a total of 5045 patients in 310 study centers were recruited to the EvaluateTM study. Inclusion criteria were hormone receptor-positive breast cancer and adjuvant treatment or metastasis. 373 patients were excluded from the analysis for various reasons. Results: A total of 4420 patients receiving adjuvant treatment and 252 patients with metastasis receiving palliative treatment were included in the study. For 4181 patients receiving adjuvant treatment, treatment with the aromatase inhibitor letrozole commenced immediately after surgery (upfront). Two hundred patients had initially received tamoxifen and started aromatase inhibitor treatment with letrozole at 1–5 years after diagnosis (switch), und 39 patients only commenced letrozole treatment 5–10 years after diagnosis (extended endocrine therapy). Patient and tumor characteristics were within expected ranges, as were comorbidities and concurrent medication. Conclusion: The data from the EvaluateTM study will offer a good overview of therapy management in the routine care of postmenopausal women with hormone receptor-positive breast cancer. Planned analyses will look at therapy compliance and patient satisfaction with how information is conveyed and the contents of the conveyed information. PMID:25568468

Effect of long-term treatment with steroid hormones or tamoxifen on the progesterone receptor and androgen receptor in the endometrium of ovariectomized cynomolgus macaques

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Cline J Mark

2003-02-01

Full Text Available Abstract The progesterone receptor (PR and androgen receptor (AR belong to the nuclear receptor superfamily. Two isoforms of PR (A and B have been identified with different functions. The expression of AR, each isoform of PR and their involvement in long-term effects on the endometrium after hormonal replacement therapy (HRT or tamoxifen (TAM treatment is not known. The aims of this study were to determine PR(A+B, PRB and AR distribution by immunohistochemistry in the macaque (Macaca fascicularis endometrium. Ovariectomized (OVX animals were orally treated continuously for 35 months with either conjugated equine estrogens (CEE; medroxyprogesterone acetate (MPA; the combination of CEE/MPA; or TAM. Treatment with CEE/MPA tended to down-regulate PR in the superficial glands, but increased it in the stroma. TAM treatment increased both the PR and PRB levels in the stroma. Overall, less than 20% of the cells were positive for the PRB isoform and less variation was observed after steroid treatment. AR was found in the stroma, mainly distributed in the basal layer of the endometrium in the OVX and steroid treated groups, but was absent in the TAM treated group. No AR was found in the glandular epithelium. The present data show that long-term hormone treatment affects the PR level, and also the ratio between PRA and PRB in the endometrium.

Thyroid hormone signaling in the hypothalamus

NARCIS (Netherlands)

Alkemade, Anneke; Visser, Theo J.; Fliers, Eric

2008-01-01

PURPOSE OF REVIEW: Proper thyroid hormone signaling is essential for brain development and adult brain function. Signaling can be disrupted at many levels due to altered thyroid hormone secretion, conversion or thyroid hormone receptor binding. RECENT FINDINGS: Mutated genes involved in thyroid

Diminished hepatic growth hormone receptor binding in sex-linked dwarf broiler and leghorn chickens.

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Leung, F C; Styles, W J; Rosenblum, C I; Lilburn, M S; Marsh, J A

1987-02-01

Hepatic growth hormone (GH) receptor binding was compared in normal and sex-linked dwarfs (SLD) from both Hubbard and Cornell strain chickens. At 6, 8, and 20 weeks of age, hepatic GH receptor binding in the Hubbard SLD chickens was significantly lower than that of normal fast-growing birds. At 20 weeks of age, only 2 of 22 SLD chickens in the Hubbard broiler strain showed positive binding at a high enough level to allow for Scatchard analysis. The affinity constants and binding capacities of these two SLD chickens were numerically (but not significantly) lower than those of the normal fast-growing birds. We further examined hepatic GH receptor binding in two closely related White Leghorn strains of chickens that have been maintained as closed breeding populations for many years. We observed no detectable hepatic GH binding in the Cornell SLD chickens (N = 20), as compared to the normal-growing control strain (K strain). In both SLD strains, pretreatment with 4 M MgCl2 did not enhance GH binding, suggesting that there was no endogenous GH binding to the receptor. Based on these data, we suggest that the lack, or greatly reduced number, of GH receptors may be a major contributing factor to the dwarfism observed in these strains.

Hormone Therapy for Breast Cancer

Science.gov (United States)

... Common Cancer Types Recurrent Cancer Common Cancer Types Bladder Cancer Breast Cancer Colorectal Cancer Kidney (Renal Cell) Cancer ... sensitive breast cancer cells contain proteins called hormone receptors that become activated when hormones bind to them. ...

From bench to bedside: What do we know about hormone receptor-positive and human epidermal growth factor receptor 2-positive breast cancer?

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Wu, Victoria Shang; Kanaya, Noriko; Lo, Chiao; Mortimer, Joanne; Chen, Shiuan

2015-09-01

Breast cancer is a heterogeneous disease. Thanks to extensive efforts from research scientists and clinicians, treatment for breast cancer has advanced into the era of targeted medicine. With the use of several well-established biomarkers, such as hormone receptors (HRs) (i.e., estrogen receptor [ER] and progesterone receptor [PgR]) and human epidermal growth factor receptor-2 (HER2), breast cancer patients can be categorized into multiple subgroups with specific targeted treatment strategies. Although therapeutic strategies for HR-positive (HR+) HER2-negative (HER2-) breast cancer and HR-negative (HR-) HER2-positive (HER2+) breast cancer are well-defined, HR+ HER2+ breast cancer is still an overlooked subgroup without tailored therapeutic options. In this review, we have summarized the molecular characteristics, etiology, preclinical tools and therapeutic options for HR+ HER2+ breast cancer. We hope to raise the attention of both the research and the medical community on HR+ HER2+ breast cancer, and to advance patient care for this subtype of disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

Ovarian hormones modify anxiety behavior and glucocorticoid receptors after chronic social isolation stress.

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Ramos-Ortolaza, Dinah L; Doreste-Mendez, Raura J; Alvarado-Torres, John K; Torres-Reveron, Annelyn

2017-06-15

Chronic social isolation could lead to a disruption in the Hypothalamic-Pituitary-Adrenal (HPA) axis, resulting in anxiety and depressive-like behaviors but cycling estrogens could modify these behaviors. The aim of this study was to determine if changes in ovarian hormones during the normal cycle could interact with social isolation to alter anxiety and depressive-like behaviors. In parallel, we examined the expression of glucocorticoid receptor (GR) and synaptic vesicle protein synaptophysin in the hippocampus and hypothalamus of Sprague Dawley normal cycling female rats. We assigned rats to either isolated or paired housing for 8 weeks. To assess anxiety and depressive-like behaviors, we used the open field test and forced swim test, respectively. Female rats were tested at either diestrus, estrus, or proestrus stage of the estrous cycle. After behaviors, rats were perfused and brains collected. Brain sections containing hippocampus and hypothalamus were analyzed using immunohistochemistry for synaptophysin and glucocorticoid receptor (GR) levels. We found an increase in depressive-like behaviors for isolated animals compared to paired housed rats, regardless of the estrous cycle stage. Interestingly, we found a decrease in anxiety behaviors in females in the estrus stage accompanied by a decrease in GR expression in hippocampal DG and CA3. However, no changes in synaptophysin were observed in any of the areas of studied. Our results support the beneficial effects of circulating ovarian hormones in anxiety, possibly by decreasing GR expression. Copyright © 2017 Elsevier B.V. All rights reserved.

Mathematical modeling of gonadotropin-releasing hormone signaling.

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Pratap, Amitesh; Garner, Kathryn L; Voliotis, Margaritis; Tsaneva-Atanasova, Krasimira; McArdle, Craig A

2017-07-05

Gonadotropin-releasing hormone (GnRH) acts via G-protein coupled receptors on pituitary gonadotropes to control reproduction. These are G q -coupled receptors that mediate acute effects of GnRH on the exocytotic secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), as well as the chronic regulation of their synthesis. GnRH is secreted in short pulses and GnRH effects on its target cells are dependent upon the dynamics of these pulses. Here we overview GnRH receptors and their signaling network, placing emphasis on pulsatile signaling, and how mechanistic mathematical models and an information theoretic approach have helped further this field. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Association of Exon 10A and 10B inactivating mutation of follicle stimulating hormone receptor gene (FSHR) and Polycystic Ovarian Syndrome in Vellore cohort

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Sekar, Nishu; Kulkarni, Rucha; Ozalkar, Sharvari; Prabhu, Yogamaya D.; Renu, Kaviyarasi; Ramgir, Shalaka S.; Abilash, V. G.

2017-11-01

Polycystic ovarian syndrome is the most common heterogenous endocrine disorder in women. Follicle stimulating hormone receptor is associated with normal development as well as maturation of follicles and triggers estrogen production in granulosa cells of the ovary. Inactivating mutation in FSHR gene correlated with reduction of ovarian function in women is due to damage to receptor function. This study aims to investigate whether inactivating mutations, in follicle stimulating hormone receptor gene is related to polycystic ovarian morphology in women with PCOS. Genomic DNA isolated from 15 subjects from Sandhya Hospital, Vellore (10 patients with PCOS and 5 healthy controls) was taken for this study. Patient data included a clinical report, hormonal levels, and ovarian morphological details. DNA isolation was followed by DNA amplification by polymerase chain reaction using Exon 10 A and Exon 10 B primers. The PCR-RFLP analysis was performed using Dde1 restriction enzyme. Here we discuss inactivating mutation found in Exon 10 of FSHR gene in patients with PCOS.The absence of inactivating mutation was observed through PCR-RFLP study on Exon 10A and Exon 10B.

A Bacterial Receptor PcrK Senses the Plant Hormone Cytokinin to Promote Adaptation to Oxidative Stress

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Fang-Fang Wang

2017-12-01

Full Text Available Summary: Recognition of the host plant is a prerequisite for infection by pathogenic bacteria. However, how bacterial cells sense plant-derived stimuli, especially chemicals that function in regulating plant development, remains completely unknown. Here, we have identified a membrane-bound histidine kinase of the phytopathogenic bacterium Xanthomonas campestris, PcrK, as a bacterial receptor that specifically detects the plant cytokinin 2-isopentenyladenine (2iP. 2iP binds to the extracytoplasmic region of PcrK to decrease its autokinase activity. Through a four-step phosphorelay, 2iP stimulation decreased the phosphorylation level of PcrR, the cognate response regulator of PcrK, to activate the phosphodiesterase activity of PcrR in degrading the second messenger 3′,5′-cyclic diguanylic acid. 2iP perception by the PcrK-PcrR remarkably improves bacterial tolerance to oxidative stress by regulating the transcription of 56 genes, including the virulence-associated TonB-dependent receptor gene ctrA. Our results reveal an evolutionarily conserved, inter-kingdom signaling by which phytopathogenic bacteria intercept a plant hormone signal to promote adaptation to oxidative stress. : How pathogenic bacteria use receptors to recognize the signals of the host plant is unknown. Wang et al. have identified a bacterial receptor histidine kinase that specifically senses the plant hormone cytokinin. Through a four-step phosphorelay, cytokinin perception triggers degradation of a second messenger, c-di-GMP, to activate the bacterial response to oxidative stress. Keywords: histidine kinase, ligand, cytokinin, autokinase activity, phosphorelay, response regulator, two-component signal transduction system, Xanthomonas campestris pv. campestris, virulence, oxidative stress

Nuclear translocation and retention of growth hormone

DEFF Research Database (Denmark)

Mertani, Hichem C; Raccurt, Mireille; Abbate, Aude

2003-01-01

We have previously demonstrated that GH is subject to rapid receptor-dependent nuclear translocation. Here, we examine the importance of ligand activation of the GH-receptor (GHR)-associated Janus kinase (JAK) 2 and receptor dimerization for hormone internalization and nuclear translocation by use...... of cells stably transfected with cDNA for the GHR. Staurosporine and herbimycin A treatment of cells did not affect the ability of GH to internalize but resulted in increased nuclear accumulation of hormone. Similarly, receptor mutations, which prevent the association and activation of JAK2, did not affect...... the ability of the hormone to internalize or translocate to the nucleus but resulted in increased nuclear accumulation of GH. These results were observed both by nuclear isolation and confocal laser scanning microscopy. Staurosporine treatment of cells in which human GH (hGH) was targeted to the cytoplasm...

Cell-autonomous intracellular androgen receptor signaling drives the growth of human prostate cancer initiating cells.

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Vander Griend, Donald J; D'Antonio, Jason; Gurel, Bora; Antony, Lizamma; Demarzo, Angelo M; Isaacs, John T

2010-01-01

The lethality of prostate cancer is due to the continuous growth of cancer initiating cells (CICs) which are often stimulated by androgen receptor (AR) signaling. However, the underlying molecular mechanism(s) for such AR-mediated growth stimulation are not fully understood. Such mechanisms may involve cancer cell-dependent induction of tumor stromal cells to produce paracrine growth factors or could involve cancer cell autonomous autocrine and/or intracellular AR signaling pathways. We utilized clinical samples, animal models and a series of AR-positive human prostate cancer cell lines to evaluate AR-mediated growth stimulation of prostate CICs. The present studies document that stromal AR expression is not required for prostate cancer growth, since tumor stroma surrounding AR-positive human prostate cancer metastases (N = 127) are characteristically AR-negative. This lack of a requirement for AR expression in tumor stromal cells is also documented by the fact that human AR-positive prostate cancer cells grow equally well when xenografted in wild-type versus AR-null nude mice. AR-dependent growth stimulation was documented to involve secretion, extracellular binding, and signaling by autocrine growth factors. Orthotopic xenograft animal studies documented that the cellautonomous autocrine growth factors which stimulate prostate CIC growth are not the andromedins secreted by normal prostate stromal cells. Such cell autonomous and extracellular autocrine signaling is necessary but not sufficient for the optimal growth of prostate CICs based upon the response to anti-androgen plus/or minus preconditioned media. AR-induced growth stimulation of human prostate CICs requires AR-dependent intracellular pathways. The identification of such AR-dependent intracellular pathways offers new leads for the development of effective therapies for prostate cancer. (c) 2009 Wiley-Liss, Inc.

Luteinizing hormone receptors in human ovarian follicles and corpora lutea during the menstrual cycle

International Nuclear Information System (INIS)

Yamoto, M.; Nakano, R.; Iwasaki, M.; Ikoma, H.; Furukawa, K.

1986-01-01

The binding of 125 I-labeled human luteinizing hormone (hLH) to the 2000-g fraction of human ovarian follicles and corpora lutea during the entire menstrual cycle was examined. Specific high affinity, low capacity receptors for hLH were demonstrated in the 2000-g fraction of both follicles and corpora lutea. Specific binding of 125 I-labeled hLH to follicular tissue increased from the early follicular phase to the ovulatory phase. Specific binding of 125 I-labeled hLH to luteal tissue increased from the early luteal phase to the midluteal phase and decreased towards the late luteal phase. The results of the present study indicate that the increase and decrease in receptors for hLH during the menstrual cycle might play an important role in the regulation of the ovarian cycle

Involvement of Human Estrogen Related Receptor Alpha 1 (hERR Alpha 1) in Breast Cancer and Hormonally Insensitive Disease

Science.gov (United States)

2001-08-01

Identification of a new class of steroid hormone receptors. Nature, 331: 91-94, 1988. 4. Vanacker , J. M ., Pettersson, K., Gustafsson, J. A., and...Lippman, M . E., Thompson, E. B., Simon, R., Barlock, A., Green, L., Huff, K. K., Do, H. M ., Aitken, S. C., and Warren, R. Estrogen receptor status: an...important variable in predicting response to endocrine therapy in metastatic breast cancer. Eur J Cancer, 16: 323-331, 1980. 2. Clark, G. M . and

Elabela-apelin receptor signaling pathway is functional in mammalian systems.

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Wang, Zhi; Yu, Daozhan; Wang, Mengqiao; Wang, Qilong; Kouznetsova, Jennifer; Yang, Rongze; Qian, Kun; Wu, Wenjun; Shuldiner, Alan; Sztalryd, Carole; Zou, Minghui; Zheng, Wei; Gong, Da-Wei

2015-02-02

Elabela (ELA) or Toddler is a recently discovered hormone which is required for normal development of heart and vasculature through activation of apelin receptor (APJ), a G protein-coupled receptor (GPCR), in zebrafish. The present study explores whether the ELA-APJ signaling pathway is functional in the mammalian system. Using reverse-transcription PCR, we found that ELA is restrictedly expressed in human pluripotent stem cells and adult kidney whereas APJ is more widely expressed. We next studied ELA-APJ signaling pathway in reconstituted mammalian cell systems. Addition of ELA to HEK293 cells over-expressing GFP-AJP fusion protein resulted in rapid internalization of the fusion receptor. In Chinese hamster ovarian (CHO) cells over-expressing human APJ, ELA suppresses cAMP production with EC50 of 11.1 nM, stimulates ERK1/2 phosphorylation with EC50 of 14.3 nM and weakly induces intracellular calcium mobilization. Finally, we tested ELA biological function in human umbilical vascular endothelial cells and showed that ELA induces angiogenesis and relaxes mouse aortic blood vessel in a dose-dependent manner through a mechanism different from apelin. Collectively, we demonstrate that the ELA-AJP signaling pathways are functional in mammalian systems, indicating that ELA likely serves as a hormone regulating the circulation system in adulthood as well as in embryonic development.

TBLR1 regulates the expression of nuclear hormone receptor co-repressors

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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

Immunodetection of Thyroid Hormone Receptor (Alpha1/Alpha2) in the Rat Uterus and Oviduct

International Nuclear Information System (INIS)

Öner, Jale; Öner, Hakan

2007-01-01

The aim of this study was to investigate the immunolocalization and the existence of thyroid hormone receptors (THR) (alpha1/alpha2) in rat uterus and oviduct. For this purpose 6 female Wistar albino rats found in estrous period were used. Tissue samples fixed in 10% neutral formalin were examined immunohistochemically. Sections were incubated with primary mouse-monoclonal THR (alpha1/alpha2) antibody. In uterus, THR (alpha1/alpha2) immunoreacted strongly with uterine luminal epithelium, endometrial gland epithelium and endometrial stromal cells and, moderately with myometrial smooth muscle. In oviduct, they were observed moderately in the epithelium of the tube and the smooth muscle cells of the muscular layer. In conclusion, the presence of THR in uterus and oviduct suggests that these organs are an active site of thyroid hormones

Chloroquine allows the secretion of internalized 125I-epidermal growth factor from fibroblasts

International Nuclear Information System (INIS)

Wakshull, E.; Cooper, J.L.; Wharton, W.

1985-01-01

Incubation of cells with labelled hormone in the presence of the lysosomotropic agent chloroquine produces an enhanced intracellular accumulation of hormone and receptor. Using a pulse-chase paradigm in which cell surface receptors were labelled with 125 I-EGF at 4 degrees C, it was found that when 100 microM chloroquine was present in the 37 degrees C chase medium intact hormone was accumulated in the medium. Without chloroquine, low molecular weight (mw) degradation products were found in the medium. The processes of receptor-mediated endocytosis and subcellular distribution of 125 I-EGF-receptor complexes were unchanged by chloroquine. The source of the intact hormone accumulating in the medium was therefore an intracellular compartment(s). The 125 I-EGF released from the cells could rebind to surface receptors and be re-internalized; rebinding was inhibited by unlabelled EGF or Concanavalin A in the incubation medium. The concentration of unlabelled EGF required to inhibit rebinding was more than three orders of magnitude greater than the amount of 125 I-EGF whose rebinding was inhibited. Thus, the 125 I-EGF released from intracellular sites was rebound preferentially over exogenous EGF. The possible pathways for secretion of intact 125 I-EGF and mechanisms of its preferential rebinding are discussed

Evaluation of Intracellular Signaling Downstream Chimeric Antigen Receptors.

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Hannah Karlsson

Full Text Available CD19-targeting CAR T cells have shown potency in clinical trials targeting B cell leukemia. Although mainly second generation (2G CARs carrying CD28 or 4-1BB have been investigated in patients, preclinical studies suggest that third generation (3G CARs with both CD28 and 4-1BB have enhanced capacity. However, little is known about the intracellular signaling pathways downstream of CARs. In the present work, we have analyzed the signaling capacity post antigen stimulation in both 2G and 3G CARs. 3G CAR T cells expanded better than 2G CAR T cells upon repeated stimulation with IL-2 and autologous B cells. An antigen-driven accumulation of CAR+ cells was evident post antigen stimulation. The cytotoxicity of both 2G and 3G CAR T cells was maintained by repeated stimulation. The phosphorylation status of intracellular signaling proteins post antigen stimulation showed that 3G CAR T cells had a higher activation status than 2G. Several proteins involved in signaling downstream the TCR were activated, as were proteins involved in the cell cycle, cell adhesion and exocytosis. In conclusion, 3G CAR T cells had a higher degree of intracellular signaling activity than 2G CARs which may explain the increased proliferative capacity seen in 3G CAR T cells. The study also indicates that there may be other signaling pathways to consider when designing or evaluating new generations of CARs.

Receptor-mediated endocytosis and intracellular trafficking of insulin and low-density lipoprotein by retinal vascular endothelial cells.

Science.gov (United States)

Stitt, A W; Anderson, H R; Gardiner, T A; Bailie, J R; Archer, D B

1994-08-01

The authors investigated the receptor-mediated endocytosis (RME) and intracellular trafficking of insulin and low-density lipoprotein (LDL) in cultured retinal vascular endothelial cells (RVECs). Low-density lipoprotein and insulin were conjugated to 10 nm colloidal gold, and these ligands were added to cultured bovine RVECs for 20 minutes at 4 degrees C. The cultures were then warmed to 37 degrees C and fixed after incubation times between 30 seconds and 1 hour. Control cells were incubated with unconjugated gold colloid at times and concentrations similar to those of the ligands. Additional control cells were exposed to several concentrations of anti-insulin receptor antibody or a saturating solution of unconjugated insulin before incubation with gold insulin. Using transmission electron microscopy, insulin gold and LDL gold were both observed at various stages of RME. Insulin-gold particles were first seen to bind to the apical plasma membrane (PM) before clustering in clathrin-coated pits and internalization in coated vesicles. Gold was later visualized in uncoated cytoplasmic vesicles, corresponding to early endosomes and multivesicular bodies (MVBs) or late endosomes. In several instances, localized regions of the limiting membrane of the MVBs appeared coated, a feature of endosomal membranes not previously described. After RME at the apical PM and passage through the endosomal system, the greater part of both insulin- and LDL-gold conjugates was seen to accumulate in large lysosome-like compartments. However, a small but significant proportion of the internalized ligands was transcytosed and released as discrete membrane-associated quanta at the basal cell surface. The uptake of LDL gold was greatly increased in highly vacuolated, late-passage RVECs. In controls, anti-insulin receptor antibody and excess unconjugated insulin caused up to 89% inhibition in gold-insulin binding and internalization. These results illustrate the internalization and intracellular

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

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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.

[Common physicochemical characteristics of endogenous hormones-- liberins and statins].

Science.gov (United States)

Zamiatnin, A A; Voronina, O L

1998-01-01

The common chemical features of oligopeptide releasing-hormones and release inhibiting hormones were investigated with the aid of computer methods. 339 regulatory molecules of such type have been extracted out of data from computer bank EROP-Moscow. They contain from 2 to 47 amino acid residues and their sequences include short sites, which play apparently a decisive role in realization of interactions with the receptors. The analysis of chemical radicals shows that all liberins and statins contain positively charged group and cyclic radical of some amino acids or hydrophobic group. Results of this study indicate that the most chemical radicals of hormones are open for the interaction with potential receptors of target-cells. The mechanism of hormone ligand and receptors binding and conceivable role of amino acid and neurotransmitter radicals in hormonal properties of liberins and statins is discussed.

Growth Hormone Resistance—Special Focus on Inflammatory Bowel Disease

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Christoffer Soendergaard

2017-05-01

Full Text Available Growth hormone (GH plays major anabolic and catabolic roles in the body and is important for regulating several aspects of growth. During an inflammatory process, cells may develop a state of GH resistance during which their response to GH stimulation is limited. In this review, we will emphasize specific mechanisms governing the formation of GH resistance in the active phase of inflammatory bowel disease. The specific molecular effects mediated through individual inflammatory mediators and processes will be highlighted to provide an overview of the transcriptional, translational and post-translational inflammation-mediated impacts on the GH receptor (GHR along with the impacts on GH-induced intracellular signaling. We also will review GH’s effects on mucosal healing and immune cells in the context of experimental colitis, human inflammatory bowel disease and in patients with short bowel syndrome.

CHARACTERIZATION OF THE RECEPTOR FOR GONADOTROPIN-RELEASING HORMONE IN THE PITUITARY OF THE AFRICAN CATFISH, CLARIAS-GARIEPINUS

NARCIS (Netherlands)

de Leeuw, R.; Conn, P. M.; van't Veer, C.; Goos, H. J.; van Oordt, P. G.

1988-01-01

Receptors for gonadotropin-releasing hormone (GnRH) were characterized using a radioligand prepared from a superactive analog of salmon GnRH (sGnRH), D-Arg(6)-Pro(9)-sGnRH-NEt (sGnRHa). Binding of(125)I-sGnRHa to catfish pituitary membrane fractions reached equilibrium after 2 h incubation at 4°C.

The chicken c-erbA alpha-product induces expression of thyroid hormone-responsive genes in 3,5,3'-triiodothyronine receptor-deficient rat hepatoma cells

DEFF Research Database (Denmark)

Muñoz, A; Höppner, W; Sap, J

1990-01-01

To determine the capacity of the chicken c-erbA (cTR-alpha) gene product in regulating expression of known thyroid hormone-responsive genes, both the cTR-alpha and the viral v-erbA genes were expressed in FAO cells, a rat hepatoma cell line defective for functional thyroid hormone receptors. Upon...

The immune-endocrine loop during aging: role of growth hormone and insulin-like growth factor-I.

Science.gov (United States)

Burgess, W; Liu, Q; Zhou, J; Tang, Q; Ozawa, A; VanHoy, R; Arkins, S; Dantzer, R; Kelley, K W

1999-01-01

Why a primary lymphoid organ such as the thymus involutes during aging remains a fundamental question in immunology. Aging is associated with a decrease in plasma growth hormone (somatotropin) and IGF-I, and this somatopause of aging suggests a connection between the neuroendocrine and immune systems. Several investigators have demonstrated that treatment with either growth hormone or IGF-I restores architecture of the involuted thymus gland by reversing the loss of immature cortical thymocytes and preventing the decline in thymulin synthesis that occurs in old or GH-deficient animals and humans. The proliferation, differentiation and functions of other components of the immune system, including T and B cells, macrophages and neutrophils, also demonstrate age-associated decrements that can be restored by IGF-I. Knowledge of the mechanism by which cytokines and hormones influence hematopoietic cells is critical to improving the health of aged individuals. Our laboratory has recently demonstrated that IGF-I prevents apoptosis in promyeloid cells, which subsequently permits these cells to differentiate into neutrophils. We also demonstrated that IL-4 acts much like IGF-I to promote survival of promyeloid cells and to activate the enzyme phosphatidylinositol 3'-kinase (PI 3-kinase). However, the receptors for IGF-I and IL-4 are completely different, with the intracellular beta chains of the IGF receptor possessing intrinsic tyrosine kinase activity and the alpha and gammac subunit of the heterodimeric IL-4 receptor utilizing the Janus kinase family of nonreceptor protein kinases to tyrosine phosphorylate downstream targets. Both receptors share many of the components of the PI 3-kinase signal transduction pathway, converging at the level of insulin receptor substrate-1 or insulin receptor subtrate-2 (formally known as 4PS, or IL-4 Phosphorylated Substrate). Our investigations with IGF-I and IL-4 suggest that PI 3-kinase inhibits apoptosis by maintaining high levels of

Colocalization of corticotropin-releasing hormone and oestrogen receptor-alpha in the paraventricular nucleus of the hypothalamus in mood disorders

NARCIS (Netherlands)

Bao, Ai-Min; Hestiantoro, Andon; van Someren, Eus J. W.; Swaab, Dick F.; Zhou, Jiang-Ning

2005-01-01

Oestrogens may modulate the activity of the hypothalamic-pituitary-adrenal (HPA) axis. The present study was to investigate whether the activity of the HPA axis in mood disorders might be directly modulated by oestrogens via oestrogen receptors (ORs) in the corticotropin-releasing hormone (CRH)

Methylation of the thyroid stimulating hormone receptor: diagnostic marker of malignity in thyroid cancer

International Nuclear Information System (INIS)

Marrero Rodriguez, Maria Teresa

2007-01-01

The methylation state of the gene promoter for the receptor of the thyroid stimulating hormone (TSH) in the diagnosis of thyroid tumors of epithelial origin was analyzed. The study was conducted in thyroid tissue obtained from paraffin blocks of different thyroid pathologies (papillary, follicular and undifferentiated carcinoma and follicular adenomas). The work was done by using the DNA modification technique with sodium bisulfite, and polymerase chain reaction was applied to analyze the gene methylation state. Methylation of the promoter for the gene of the TSH receptor was found in the papillary carcinomas (33 of 40; 82.5 %), in 10 undifferentiated carcinomas (100 %), and in 10 of the 15 follicular carcinomas analyzed (66.6 %). No methylation was observed in the 8 follicular adenomas under study. The methylation of the gene for the TSH receptor was proposed as a new diagnostic marker of malignity and as a basis for using demethylating agents together with radioiodine therapy in patients with thyroid cancer of epithelial origin that do not respond to therapy. (Author)

The Endocannabinoid System and Sex Steroid Hormone-Dependent Cancers

Directory of Open Access Journals (Sweden)

Thangesweran Ayakannu

2013-01-01

Full Text Available The “endocannabinoid system (ECS” comprises the endocannabinoids, the enzymes that regulate their synthesis and degradation, the prototypical cannabinoid receptors (CB1 and CB2, some noncannabinoid receptors, and an, as yet, uncharacterised transport system. Recent evidence suggests that both cannabinoid receptors are present in sex steroid hormone-dependent cancer tissues and potentially play an important role in those malignancies. Sex steroid hormones regulate the endocannabinoid system and the endocannabinoids prevent tumour development through putative protective mechanisms that prevent cell growth and migration, suggesting an important role for endocannabinoids in the regulation of sex hormone-dependent tumours and metastasis. Here, the role of the endocannabinoid system in sex steroid hormone-dependent cancers is described and the potential for novel therapies assessed.

Thyroid hormone increases fibroblast growth factor receptor expression and disrupts cell mechanics in the developing organ of corti

Science.gov (United States)

2013-01-01

Background 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. Results 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. Conclusions 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. PMID:23394545

microRNA-379 couples glucocorticoid hormones to dysfunctional lipid homeostasis

Science.gov (United States)

de Guia, Roldan M; Rose, Adam J; Sommerfeld, Anke; Seibert, Oksana; Strzoda, Daniela; Zota, Annika; Feuchter, Yvonne; Krones-Herzig, Anja; Sijmonsma, Tjeerd; Kirilov, Milen; Sticht, Carsten; Gretz, Norbert; Dallinga-Thie, Geesje; Diederichs, Sven; Klöting, Nora; Blüher, Matthias; Berriel Diaz, Mauricio; Herzig, Stephan

2015-01-01

In mammals, glucocorticoids (GCs) and their intracellular receptor, the glucocorticoid receptor (GR), represent critical checkpoints in the endocrine control of energy homeostasis. Indeed, aberrant GC action is linked to severe metabolic stress conditions as seen in Cushing's syndrome, GC therapy and certain components of the Metabolic Syndrome, including obesity and insulin resistance. Here, we identify the hepatic induction of the mammalian conserved microRNA (miR)-379/410 genomic cluster as a key component of GC/GR-driven metabolic dysfunction. Particularly, miR-379 was up-regulated in mouse models of hyperglucocorticoidemia and obesity as well as human liver in a GC/GR-dependent manner. Hepatocyte-specific silencing of miR-379 substantially reduced circulating very-low-density lipoprotein (VLDL)-associated triglyceride (TG) levels in healthy mice and normalized aberrant lipid profiles in metabolically challenged animals, mediated through miR-379 effects on key receptors in hepatic TG re-uptake. As hepatic miR-379 levels were also correlated with GC and TG levels in human obese patients, the identification of a GC/GR-controlled miRNA cluster not only defines a novel layer of hormone-dependent metabolic control but also paves the way to alternative miRNA-based therapeutic approaches in metabolic dysfunction. PMID:25510864

Secretion of biologically active glycoforms of bovine follicle stimulating hormone in plants

NARCIS (Netherlands)

Dirnberger, D.; Steinkellner, H.; Abdennebi, L.; Remy, J.J.; Wiel, van de D.

2001-01-01

We chose the follicle stimulating hormone (FSH), a pituitary heterodimeric glycoprotein hormone, as a model to assess the ability of the plant cell to express a recombinant protein that requires extensive N-glycosylation for subunit folding and assembly, intracellular trafficking, signal

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 incuba...

Luteinizing hormone receptors in human ovarian follicles and corpora lutea during the menstrual cycle

Energy Technology Data Exchange (ETDEWEB)

Yamoto, M.; Nakano, R.; Iwasaki, M.; Ikoma, H.; Furukawa, K.

1986-08-01

The binding of /sup 125/I-labeled human luteinizing hormone (hLH) to the 2000-g fraction of human ovarian follicles and corpora lutea during the entire menstrual cycle was examined. Specific high affinity, low capacity receptors for hLH were demonstrated in the 2000-g fraction of both follicles and corpora lutea. Specific binding of /sup 125/I-labeled hLH to follicular tissue increased from the early follicular phase to the ovulatory phase. Specific binding of /sup 125/I-labeled hLH to luteal tissue increased from the early luteal phase to the midluteal phase and decreased towards the late luteal phase. The results of the present study indicate that the increase and decrease in receptors for hLH during the menstrual cycle might play an important role in the regulation of the ovarian cycle.

Anti-Muellerian hormone, inhibin A, gonadotropins, and gonadotropin receptors in bull calves after partial scrotal resection, orchidectomy, and Burdizzo castration.

Science.gov (United States)

Scarlet, Dragos; Aurich, Christine; Ille, Natascha; Walter, Ingrid; Weber, Corinna; Pieler, Dagmar; Peinhopf, Walter; Wohlsein, Peter; Aurich, Jörg

2017-01-01

Eight-week-old calves were either castrated by partial scrotal resection (SR) without removing the testes (n = 10), Burdizzo (BZ) clamp (n = 10), orchidectomy (OR; n = 10), or were left gonad intact as controls (CO; n = 10). Concentrations of anti-Muellerian hormone (AMH), inhibin A, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in plasma were determined from 16 to 48 weeks of age. At 18 months, testes of SR, BZ, and CO bulls were obtained and the immunolocalization of LH and FSH receptors and AMH analyzed. Concentration of AMH in plasma of CO and SR bulls decreased with increasing age (P < 0.001). A similar AMH profile in CO and SR indicates that SR did not induce a true cryptorchid state. In groups OR and BZ, AMH was undetectable. Plasma inhibin concentration was higher in groups CO and SR than BZ and OR (P < 0.001). Plasma LH and FSH concentrations decreased over time (P < 0.001) and were higher in groups BZ and OR than SR and CO (P < 0.001). In the testes, immunolabeling for AMH existed in Sertoli cells of CO and SR but not BZ bulls. FSH receptors were localized in Sertoli cells, Leydig cells, spermatocytes, and the epididymis of CO and SR animals, whereas LH receptors were restricted to Leydig cells. In BZ animals, FSH and LH receptors and AMH were absent, indicating complete testicular degeneration. In conclusion, AMH is a more reliable marker for the presence of testicular tissue in bulls than inhibin. Scrotal resection did not induce a true inguinal cryptorchid state but affected testicular responsiveness to gonadotropic stimulation. Copyright © 2016 Elsevier Inc. All rights reserved.

Hypertonic saline enhances host response to bacterial challenge by augmenting receptor-independent neutrophil intracellular superoxide formation.

LENUS (Irish Health Repository)

Shields, Conor J

2012-02-03

OBJECTIVE: This study sought to determine whether hypertonic saline (HTS) infusion modulates the host response to bacterial challenge. METHODS: Sepsis was induced in 30 Balb-C mice by intraperitoneal injection of Escherichia coli (5 x 107 organisms per animal). In 10 mice, resuscitation was performed at 0 and 24 hours with a 4 mL\\/kg bolus of HTS (7.5% NaCl), 10 animals received 4 mL\\/kg of normal saline (0.9% NaCl), and the remaining animals received 30 mL\\/kg of normal saline. Samples of blood, spleen, and lung were cultured at 8 and 36 hours. Polymorphonucleocytes were incubated in isotonic or hypertonic medium before culture with E. coli. Phagocytosis was assessed by flow cytometry, whereas intracellular bacterial killing was measured after inhibition of phagocytosis with cytochalasin B. Intracellular formation of free radicals was assessed by the molecular probe CM-H(2)DCFDA. Mitogen-activated protein (MAP) kinase p38 and ERK-1 phosphorylation, and nuclear factor kappa B (NFkappaB) activation were determined. Data are represented as means (SEM), and an analysis of variance test was performed to gauge statistical significance. RESULTS: Significantly reduced bacterial culture was observed in the animals resuscitated with HTS when compared with their NS counterparts, in blood (51.8 +\\/- 4.3 vs. 82.0 +\\/- 3.3 and 78.4 +\\/- 4.8, P = 0.005), lung (40.0 +\\/- 4.1 vs. 93.2 +\\/- 2.1 and 80.9 +\\/- 4.7, P = 0.002), and spleen (56.4 +\\/- 3.8 vs. 85.4 +\\/- 4.2 and 90.1 +\\/- 5.9, P = 0.05). Intracellular killing of bacteria increased markedly (P = 0.026) and superoxide generation was enhanced upon exposure to HTS (775.78 +\\/- 23.6 vs. 696.57 +\\/- 42.2, P = 0.017) despite inhibition of MAP kinase and NFkappaB activation. CONCLUSIONS: HTS significantly enhances intracellular killing of bacteria while attenuating receptor-mediated activation of proinflammatory cascades.

Regulation of the Type III InsP3 Receptor by InsP3 and ATP

OpenAIRE

Hagar, Robert E.; Ehrlich, Barbara E.

2000-01-01

Many hormones and neurotransmitters raise intracellular calcium (Ca(2+)) by generating InsP(3) and activating the inositol 1,4, 5-trisphosphate receptor (InsP(3)R). Multiple isoforms with distinct InsP(3) binding properties () have been identified (). The type III InsP(3)R lacks Ca(2+)-dependent inhibition, a property that makes it ideal for signal initiation (). Regulation of the type III InsP(3)R by InsP(3) and ATP was explored in detail using planar lipid bilayers. In comparison to the typ...

Sex-specific hormone receptors in urothelial carcinomas of the human urinary bladder: a comparative analysis of clinicopathological features and survival outcomes according to receptor expression.

Science.gov (United States)

Tuygun, Can; Kankaya, Duygu; Imamoglu, Abdurrahim; Sertcelik, Ayse; Zengin, Kursad; Oktay, Murat; Sertcelik, Nurettin

2011-01-01

To investigate the expression of sex-specific hormone receptors in normal bladder urothelium and urothelial carcinomas (UCs) of the bladder, and to analyze clinicopathological features and survival outcomes according to receptor expression. We evaluated the clinical data and tumor specimens of 139 patients with bladder cancer (BC). In addition, 72 samples of normal urothelium were included. Immunohistochemistry was performed using streptavidin-biotin peroxidase method, a monoclonal androgen receptor (AR), and an estrogen receptor-β (ERβ) antibody on paraffin-embedded tissue sections. Expression levels of each receptor were assessed by evaluating 500 tumor cells for each case and the percentage of positively-stained nuclei was recorded. None of the 58 male control cases showed any AR and ERβ expression. Five (35, 71%) of the 14 female control cases expressed ERβ. Of the 139 patients with UCs, 71 (51, 07%) expressed AR (62 male vs. 9 female; P = 0.413) and 44 (31, 65%) (39 male vs. 5 female; P = 0.402) showed ERβ expression (P receptors alone cannot be responsible for gender differences in BC rates because they were expressed in similar rates in both sexes. Copyright © 2011 Elsevier Inc. All rights reserved.

Mechanisms of action of nonpeptide hormones on resveratrol-induced antiproliferation of cancer cells.

Science.gov (United States)

Lin, Hung-Yun; Hsieh, Meng-Ti; Cheng, Guei-Yun; Lai, Hsuan-Yu; Chin, Yu-Tang; Shih, Ya-Jung; Nana, André Wendindondé; Lin, Shin-Ying; Yang, Yu-Chen S H; Tang, Heng-Yuan; Chiang, I-Jen; Wang, Kuan

2017-09-01

Nonpeptide hormones, such as thyroid hormone, dihydrotestosterone, and estrogen, have been shown to stimulate cancer proliferation via different mechanisms. Aside from their cytosolic or membrane-bound receptors, there are receptors on integrin α v β 3 for nonpeptide hormones. Interaction between hormones and integrin α v β 3 can induce signal transduction and eventually stimulate cancer cell proliferation. Resveratrol induces inducible COX-2-dependent antiproliferation via integrin α v β 3 . Resveratrol and hormone-induced signals are both transduced by activated extracellular-regulated kinases 1 and 2 (ERK1/2); however, hormones promote cell proliferation, while resveratrol induces antiproliferation in cancer cells. Hormones inhibit resveratrol-stimulated phosphorylation of p53 on Ser15, resveratrol-induced nuclear COX-2 accumulation, and formation of p53-COX-2 nuclear complexes. Subsequently, hormones impair resveratrol-induced COX-2-/p53-dependent gene expression. The inhibitory effects of hormones on resveratrol action can be blocked by different antagonists of specific nonpeptide hormone receptors but not integrin α v β 3 blockers. Results suggest that nonpeptide hormones inhibit resveratrol-induced antiproliferation in cancer cells downstream of the interaction between ligand and receptor and ERK1/2 activation to interfere with nuclear COX-2 accumulation. Thus, the surface receptor sites for resveratrol and nonpeptide hormones are distinct and can induce discrete ERK1/2-dependent downstream antiproliferation biological activities. It also indicates the complex pathways by which antiproliferation is induced by resveratrol in various physiological hormonal environments. . © 2017 New York Academy of Sciences.

Amenorrhea secondary to a vismodegib-induced blockade of follicle-stimulating hormone-receptor activation.

Science.gov (United States)

Strasswimmer, John; Latimer, Benjamin; Ory, Steven

2014-08-01

To report a novel mechanism suggestive of early ovarian failure secondary to the anti-tumor hedgehog-pathway inhibitor vismodegib. Case report and literature review. Academic and private dermatology and fertility practices. A 34-year-old nulliparous woman with locally advanced basal cell carcinomas who became amenorrheic while receiving oral therapy with vismodegib. Physical examination and endocrine evaluation. Elevated follicle-stimulating hormone (FSH) and low estrogen in the setting of a normal anti-Müllerian hormone. FSH was elevated; estrogen was low. Preantral follicles were detected and anti-Müllerian hormone activity was normal. Menses resumed 5 weeks after cessation of therapy. Vismodegib, a first-in-class inhibitor of the hedgehog signaling pathway is indicated for advanced basal cell carcinoma and is associated with amenorrhea. The mechanism is unknown; it has some features of ovarian failure but preserves ovarian potential through blockading of FSH-receptor-dependent signal transduction. This effect appears to be rapidly reversible upon cessation of therapy. Vismodegib and related compounds may have potential for a role in intervention for gynecologic and endocrine disorders and in therapy for other issues involving FSH-dependent function. Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

A Macrocyclic Agouti-Related Protein/[Nle4, DPhe7]α-Melanocyte Stimulating Hormone Chimeric Scaffold Produces Sub-nanomolar Melanocortin Receptor Ligands

OpenAIRE

Ericson, Mark D.; Freeman, Katie T.; Schnell, Sathya M.; Haskell-Luevano, Carrie

2017-01-01

The melanocortin system consists of five receptor subtypes, endogenous agonists, and naturally occurring antagonists. These receptors and ligands have been implicated in numerous biological pathways including processes linked to obesity and food intake. Herein, a truncation structure-activity relationship study of chimeric agouti-related protein (AGRP)/[Nle4, DPhe7]α-Melanocyte Stimulating Hormone (NDP-MSH) ligands is reported. The tetrapeptide His-DPhe-Arg-Trp or tripeptide DPhe-Arg-Trp repl...

Thyroid hormone and retinoid X receptor function and expression during sea lamprey (Petromyzon marinus) metamorphosis.

Science.gov (United States)

Manzon, Lori A; Youson, John H; Holzer, Guillaume; Staiano, Leopoldo; Laudet, Vincent; Manzon, Richard G

2014-08-01

Sea lampreys (Petromyzon marinus) are members of the ancient class Agnatha and undergo a metamorphosis that transforms blind, sedentary, filter-feeding larvae into free-swimming, parasitic juveniles. Thyroid hormones (THs) appear to be important for lamprey metamorphosis, however, serum TH concentrations are elevated in the larval phase, decline rapidly during early metamorphosis and remain low until metamorphosis is complete; these TH fluctuations are contrary to those of other metamorphosing vertebrates. Moreover, thyroid hormone synthesis inhibitors (goitrogens) induce precocious metamorphosis and exogenous TH treatments disrupt natural metamorphosis in P. marinus. Given that THs exert their effects by binding to TH nuclear receptors (TRs) that often act as heterodimers with retinoid X receptors (RXRs), we cloned and characterized these receptors from P. marinus and examined their expression during metamorphosis. Two TRs (PmTR1 and PmTR2) and three RXRs (PmRXRs) were isolated from P. marinus cDNA. Phylogenetic analyses group the PmTRs together on a branch prior to the gnathostome TRα/β split. The three RXRs also group together, but our data indicated that these transcripts are most likely either allelic variants of the same gene locus, or the products of a lamprey-specific duplication event. Importantly, these P. marinus receptors more closely resemble vertebrate as opposed to invertebrate chordate receptors. Functional analysis revealed that PmTR1 and PmTR2 can activate transcription of TH-responsive genes when treated with nanomolar concentrations of TH and they have distinct pharmacological profiles reminiscent of vertebrate TRβ and TRα, respectively. Also similar to other metamorphosing vertebrates, expression patterns of the PmTRs during lamprey metamorphosis suggest that PmTR1 has a dynamic, tissue-specific expression pattern that correlates with tissue morphogenesis and biochemical changes and PmTR2 has a more uniform expression pattern. This TR

Lateral septum growth hormone secretagogue receptor affects food intake and motivation for sucrose reinforcement.

Science.gov (United States)

Terrill, Sarah J; Wall, Kaylee D; Medina, Nelson D; Maske, Calyn B; Williams, Diana L

2018-03-28

The hormone ghrelin promotes eating and is widely considered to be a hunger signal. Ghrelin receptors, growth hormone secretagogue receptors (GHSRs), are found in a number of specific regions throughout the brain, including the lateral septum (LS), an area not traditionally associated with the control of feeding. Here we investigated whether GHSRs in the LS play a role in the control of food intake. We examined the feeding effects of ghrelin and the GHSR antagonists ([D-Lys3]-GHRP-6 and JMV 2959), at doses subthreshold for effect when delivered to the lateral ventricle. Intra-LS ghrelin significantly increased chow intake during the mid-light phase, suggesting that pharmacologic activation of LS GHSRs promotes feeding. Conversely, GHSR antagonist delivered to the LS shortly before dark onset significantly reduced chow intake. These data support the hypothesis that exogenous and endogenous stimulation of GHSRs in the LS influence feeding. Ghrelin is known to affect motivation for food, and the dorsal subdivision of LS (dLS) has been shown to play a role in motivation. Thus, we investigated the role of dLS GHSRs in motivation for food reward by examining operant responding for sucrose on a progressive ratio (PR) schedule. Intra-dLS ghrelin increased PR responding for sucrose, while blockade of LS GHSRs did not affect responding in either a fed or fasted state. Together these findings for the first time substantiate the LS as a site of action for ghrelin signaling in the control of food intake.

Influence of music on steroid hormones and the relationship between receptor polymorphisms and musical ability: a pilot study.

Science.gov (United States)

Fukui, Hajime; Toyoshima, Kumiko

2013-01-01

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 (AR) 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.

Disruption of growth hormone receptor gene causes diminished pancreatic islet size and increased insulin sensitivity in mice.

Science.gov (United States)

Liu, Jun-Li; Coschigano, Karen T; Robertson, Katie; Lipsett, Mark; Guo, Yubin; Kopchick, John J; Kumar, Ujendra; Liu, Ye Lauren

2004-09-01

Growth hormone, acting through its receptor (GHR), plays an important role in carbohydrate metabolism and in promoting postnatal growth. GHR gene-deficient (GHR(-/-)) mice exhibit severe growth retardation and proportionate dwarfism. To assess the physiological relevance of growth hormone actions, GHR(-/-) mice were used to investigate their phenotype in glucose metabolism and pancreatic islet function. Adult GHR(-/-) mice exhibited significant reductions in the levels of blood glucose and insulin, as well as insulin mRNA accumulation. Immunohistochemical analysis of pancreatic sections revealed normal distribution of the islets despite a significantly smaller size. The average size of the islets found in GHR(-/-) mice was only one-third of that in wild-type littermates. Total beta-cell mass was reduced 4.5-fold in GHR(-/-) mice, significantly more than their body size reduction. This reduction in pancreatic islet mass appears to be related to decreases in proliferation and cell growth. GHR(-/-) mice were different from the human Laron syndrome in serum insulin level, insulin responsiveness, and obesity. We conclude that growth hormone signaling is essential for maintaining pancreatic islet size, stimulating islet hormone production, and maintaining normal insulin sensitivity and glucose homeostasis.

Growth inhibition of tumor cells in vitro by using monoclonal antibodies against gonadotropin-releasing hormone receptor.

Science.gov (United States)

Lee, Gregory; Ge, Bixia

2010-07-01

As the continuation of a previous study, synthetic peptides corresponding to the extracellular domains of human gonadotropin-releasing hormone (GnRH) receptor were used to generate additional monoclonal antibodies which were further characterized biochemically and immunologically. Among those identified to recognize GnRH receptor, monoclonal antibodies designated as GHR-103, GHR-106 and GHR-114 were found to exhibit high affinity (Kd L37), when cancer cells were incubated with GnRH or GHR-106. The widespread expressions of GnRH receptor in almost all of the studied human cancer cell lines were also demonstrated by RT-PCR and Western blot assay, as well as indirect immunofluorescence assay with either of these monoclonal antibodies as the primary antibody. In view of the longer half life of antibodies as compared to that of GnRH or its analogs, anti-GnRH receptor monoclonal antibodies in humanized forms could function as GnRH analogs and serve as an ideal candidate of anti-cancer drugs for therapeutic treatments of various cancers in humans as well as for fertility regulations.

NUTRIGENOMICS ANALYZE OF EXPRESSION OF EXTRACELLULAR LEPTIN RECEPTOR BY THE FOLLOWING ESSENTIAL OIL MONITORING AT THE AVIAN MODELS

Directory of Open Access Journals (Sweden)

Pavol Bajzík

2011-04-01

Full Text Available Leptin gene was identified in 1994 by positional cloning. His mutation is considered extreme obesity surface phenotype and infertility in ob/ob mice. Most of the research, which followed the discovery of this hormone, focused on the role of leptin in regulating body weight,  in order to clarify the pathophysiology of obesity. Many research results show that leptin is not only important in regulating food intake and energy balance, but also performs functions such as metabolic and neuroendocrine hormone. Using herbs and essential oils depends on their antimicrobial activity. Most plants have favorable multifunctional properties, which are the specific content of bioactive components. Some authors characterize fytogénne substance such as natural substancese plant origin, which leave no residues in animal products and is not necessary to keep the trade period before slaughter animals. Analyses suggest that the structural function of the receptor exists as a dimer constructively in the plasma membrane. Each receptor dimer pair is reversibly bound to one molecule of leptin. When bound, signaling pathways are responsible for beginning the activation receptor associated Janus kinase 2 (JAK2 and tyrosine phosphorylation of two key residues in the intracellular part of receptor.doi:10.5219/128 

Nature and regulation of the receptors for insulin-like growth factors

International Nuclear Information System (INIS)

Rechler, M.M.; Nissley, S.P.

1985-01-01

Two subtypes of IGF receptors have been identified. Type I IGF receptors have a Mr greater than 300,000 and are composed of disulfide-linked 130,000-dalton (alpha) and approximately 90,000-dalton (beta) subunits. Type I receptors preferentially bind IGF-I but also bind IGF-II and, more weakly, insulin. Type II IGF receptors consist of a 250,000-dalton protein that contains internal disulfide bonds but is not linked to other membrane components. Type II receptors bind IGF-II with higher affinity than IGF-I. They do not interact with even very high concentrations of insulin. Type I IGF receptors and insulin receptors are homologous structures. Type II IGF receptors do not appear to be homologous to type I receptors. Type II receptors do not appear to be downregulated. Insulin acutely upregulates type II IGF receptors in intact rat adipose cells by effecting a redistribution of receptors cycling between a large intracellular pool and the plasma membrane. Insulin and the IGFs elicit the same biological responses, either by cross-reacting with one of the receptors for the heterologous ligand or by concurrent activation of convergent effector pathways by binding to the homologous receptor. Which mechanism is utilized appears to depend more on the tissue than on the biological response. Insulin desensitizes rat hepatoma cells to the actions of insulin and IGFs, mediated by both insulin and IGF receptors, by mechanisms distal to hormone binding and possibly common to IGF and insulin effector pathways

Action of luteinizing hormone-releasing hormone in rat ovarian cells: Hormone production and signal transduction

Energy Technology Data Exchange (ETDEWEB)

Wang, Jian.

1989-01-01

The present study was conducted to investigate the hypothesis that the breakdown of membrane phosphoinositides may participate in the actions of luteinizing hormone-releasing hormone (LHRH) on hormone production in rat granulosa cells. In cells prelabeled with ({sup 3}H)inositol or ({sup 3}H)arachidonic acid (AA), treatment with LHRH increased the formation of radiolabeled inositol 1,4,5-trisphosphate (IP{sub 3}) and diacylglycerol (DG), and the release of radiolabeled AA. Since IP{sub 3} induces intracellular Ca{sup 2+} mobilization, changes in the cytosolic free calcium ion concentrations ((Ca{sup 2+})i) induced by LHRH were studied in individual cells using fura-2 microspectrofluorimetry. Alterations in (Ca{sup 2+})i induced by LHRH were rapid and transient, and could be completely blocked by a LHRH antagonist. Sustained perifusion of LHRH resulted in a desensitization of the (Ca{sup 2+})i response to LHRH. LHRH treatment accelerated (Ca{sup 2+})i depletion in the cells perifused with Ca{sup 2+} free medium, indicating the involvement of intracellular Ca{sup 2+} pool(s) in (Ca{sup 2+})i changes. The actions of LHRH on the regulation of progesterone (P{sub 4}) and prostaglandin E{sub 2} (PGE{sub 2}) production were also examined. LHRH increased basal P{sub 4} production and attenuated FSH induced P{sub 4} production. Both basal and FSH stimulated PGE{sub 2} formation were increased by LHRH. Since LHRH also increased the formation of DG that stimulates the activity of protein kinase C, an activator of protein kinase C (12-0-tetradecanolyphorbol-13-acetate: TPA) was used with the Ca{sup 2+} ionophore A23187 and melittin (an activator of phospholipase A{sub 2}) to examine the roles of protein kinase C, Ca{sup 2+} and free AA, respectively, in LHRH action.

Candesartan decreases the sympatho-adrenal and hormonal response to isolation stress

Directory of Open Access Journals (Sweden)

Ines Armando

2001-03-01

Full Text Available A change from group housing to isolation in unfamiliar metabolic cages represents, for rodents, a significant emotional stress. We studied the effect of candesartan, a peripheral and central angiotensin II AT1-receptor antagonist, on the hormonal and sympathetic response to acute isolation. We pretreated rats with 1 mg/kg/day candesartan for 13 days via subcutaneously implanted osmotic minipumps, followed by 24-hour isolation in individual metabolic cages. We measured brain, pituitary and adrenal angiotensin II (Ang II receptor binding by quantitative autoradiography and adrenal hormones and catecholamines by RIA and HPLC. Isolation increased adrenal catecholamines, aldosterone and corticosterone, AT1-receptor binding in the zona glomerulosa and AT2-receptor binding in the adrenal medulla. Candesartan pretreatment decreased adrenal catecholamines, aldosterone and corticosterone, AT1-receptor binding in adrenal zona glomerulosa and medulla, pituitary gland and the hypothalamic paraventricular nucleus, and AT2-receptor binding in adrenal medulla, but increased AT2-receptor binding in zona glomerulosa. We conclude that peripheral and central AT1-receptor blockade with candesartan decreases the sympatho-adrenal and hormonal response to acute stress. Our results indicate that Ang II is an important stress hormone and suggest that blockade of the physiologically active AT 1-receptors could influence stress-related disorders.

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...... patients, correlated positively with both plasma oestradiol and testosterone (n = 31). Glycerol concentration during clamp (a marker of lipolysis) correlated inversely with expression of alpha2A-adrenergic-receptor, ratio of subcutaneous to total abdominal fat mass, and limb fat, respectively. Expression...

Vitamin-caused faulty perinatal hormonal imprinting and its consequences in adult age.

Science.gov (United States)

Csaba, G

2017-09-01

Lipid-soluble vitamins (vitamins A, D, E, and K) are actually hormones (exohormones), as they can be directly bound by hormone receptors or are in connection with molecules, which influence hormone receptors. Vitamin D is a transition between endo- and exohormones and the possibility of similar situation in case of other lipid-soluble hormones is discussed. The perinatal exposition with these "vitamins" can cause faulty perinatal hormonal imprinting with similar consequences as the faulty imprinting by the synthetic endohormones, members of the same hormone family or industrial, communal, or medical endocrine disruptors. The faulty imprinting leads to late (lifelong) consequences with altered hormone binding by receptors, altered sexuality, brain function, immunity, bone development, and fractures, etc. In addition, as hormonal imprinting is an epigenetic process, the effect of a single exposure by fat-soluble vitamins is inherited to the progeny generations. As vitamins are handled differently from hormones; however, perinatal treatments take place frequently and sometimes it is forced, the negative late effect of faulty perinatal vitamin-caused hormonal imprinting must be considered.

Intracellular cholesterol level regulates sensitivity of glioblastoma cells against temozolomide-induced cell death by modulation of caspase-8 activation via death receptor 5-accumulation and activation in the plasma membrane lipid raft.

Science.gov (United States)

Yamamoto, Yutaro; Tomiyama, Arata; Sasaki, Nobuyoshi; Yamaguchi, Hideki; Shirakihara, Takuya; Nakashima, Katsuhiko; Kumagai, Kosuke; Takeuchi, Satoru; Toyooka, Terushige; Otani, Naoki; Wada, Kojiro; Narita, Yoshitaka; Ichimura, Koichi; Sakai, Ryuichi; Namba, Hiroki; Mori, Kentaro

2018-01-01

Development of resistance against temozolomide (TMZ) in glioblastoma (GBM) after continuous treatment with TMZ is one of the critical problems in clinical GBM therapy. Intracellular cholesterol regulates cancer cell biology, but whether intracellular cholesterol is involved in TMZ resistance of GBM cells remains unclear. The involvement of intracellular cholesterol in acquired resistance against TMZ in GBM cells was investigated. Intracellular cholesterol levels were measured in human U251 MG cells with acquired TMZ resistance (U251-R cells) and TMZ-sensitive control U251 MG cells (U251-Con cells), and found that the intracellular cholesterol level was significantly lower in U251-R cells than in U251-Con cells. In addition, treatment by intracellular cholesterol remover, methyl-beta cyclodextrin (MβCD), or intracellular cholesterol inducer, soluble cholesterol (Chol), regulated TMZ-induced U251-Con cell death in line with changes in intracellular cholesterol level. Involvement of death receptor 5 (DR5), a death receptor localized in the plasma membrane, was evaluated. TMZ without or with MβCD and/or Chol caused accumulation of DR5 into the plasma membrane lipid raft and formed a complex with caspase-8, an extrinsic caspase cascade inducer, reflected in the induction of cell death. In addition, treatment with caspase-8 inhibitor or knockdown of DR5 dramatically suppressed U251-Con cell death induced by combination treatment with TMZ, MβCD, and Chol. Combined treatment of Chol with TMZ reversed the TMZ resistance of U251-R cells and another GBM cell model with acquired TMZ resistance, whereas clinical antihypercholesterolemia agents at physiological concentrations suppressed TMZ-induced cell death of U251-Con cells. These findings suggest that intracellular cholesterol level affects TMZ treatment of GBM mediated via a DR5-caspase-8 mechanism. Copyright © 2017 Elsevier Inc. All rights reserved.

The gene encoding the melanin-concentrating hormone receptor 1 is associated with schizophrenia in a Danish case-control sample

DEFF Research Database (Denmark)

Demontis, Ditte; Nyegaard, Mette; Christensen, Jane H

2012-01-01

OBJECTIVE: The MCHR1 gene encoding the melanin-concentrating hormone receptor 1 is located on chromosome 22q13.2 and has previously been associated with schizophrenia in a study of cases and controls from the Faroe Islands and Scotland. Herein we report an association between variations in the MCHR...

Gastrointestinal hormone research - with a Scandinavian annotation

DEFF Research Database (Denmark)

Rehfeld, Jens F

2015-01-01

Gastrointestinal hormones are peptides released from neuroendocrine cells in the digestive tract. More than 30 hormone genes are currently known to be expressed in the gut, which makes it the largest hormone-producing organ in the body. Modern biology makes it feasible to conceive the hormones...... as a blood-borne hormone, a neurotransmitter, a local growth factor or a fertility factor. The targets of gastrointestinal hormones are specific G-protein-coupled receptors that are expressed in the cell membranes also outside the digestive tract. Thus, gut hormones not only regulate digestive functions...

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

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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.

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

Science.gov (United States)

Van Gilst, Marc R; Hadjivassiliou, Haralambos; Jolly, Amber; Yamamoto, Keith R

2005-02-01

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.

Neuroprotective Actions of Ghrelin and Growth Hormone Secretagogues

Science.gov (United States)

Frago, Laura M.; Baquedano, Eva; Argente, Jesús; Chowen, Julie A.

2011-01-01

The brain incorporates and coordinates information based on the hormonal environment, receiving information from peripheral tissues through the circulation. Although it was initially thought that hormones only acted on the hypothalamus to perform endocrine functions, it is now known that they in fact exert diverse actions on many different brain regions including the hypothalamus. Ghrelin is a gastric hormone that stimulates growth hormone secretion and food intake to regulate energy homeostasis and body weight by binding to its receptor, growth hormone secretagogues–GH secretagogue-receptor, which is most highly expressed in the pituitary and hypothalamus. In addition, ghrelin has effects on learning and memory, reward and motivation, anxiety, and depression, and could be a potential therapeutic agent in neurodegenerative disorders where excitotoxic neuronal cell death and inflammatory processes are involved. PMID:21994488

Extended and structurally supported insights into extracellular hormone binding, signal transduction and organization of the thyrotropin receptor.

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Gerd Krause

Full Text Available The hormone thyrotropin (TSH and its receptor (TSHR are crucial for the growth and function of the thyroid gland. The TSHR is evolutionary linked with the receptors of follitropin (FSHR and lutropin/choriogonadotropin (LHR and their sequences and structures are similar. The extracellular region of TSHR contains more than 350 amino acids and binds hormone and antibodies. Several important questions related to functions and mechanisms of TSHR are still not comprehensively understood. One major reason for these open questions is the lack of any structural information about the extracellular segment of TSHR that connects the N-terminal leucine-rich repeat domain (LRRD with the transmembrane helix (TMH 1, the hinge region. It has been shown experimentally that this segment is important for fine tuning of signaling and ligand interactions. A new crystal structure containing most of the extracellular hFSHR region in complex with hFSH has recently been published. Now, we have applied these new structural insights to the homologous TSHR and have generated a structural model of the TSHR LRRD/hinge-region/TSH complex. This structural model is combined and evaluated with experimental data including hormone binding (bTSH, hTSH, thyrostimulin, super-agonistic effects, antibody interactions and signaling regulation. These studies and consideration of significant and non-significant amino acids have led to a new description of mechanisms at the TSHR, including ligand-induced displacements of specific hinge region fragments. This event triggers conformational changes at a convergent center of the LRRD and the hinge region, activating an "intramolecular agonistic unit" close to the transmembrane domain.

Extended and structurally supported insights into extracellular hormone binding, signal transduction and organization of the thyrotropin receptor.

Science.gov (United States)

Krause, Gerd; Kreuchwig, Annika; Kleinau, Gunnar

2012-01-01

The hormone thyrotropin (TSH) and its receptor (TSHR) are crucial for the growth and function of the thyroid gland. The TSHR is evolutionary linked with the receptors of follitropin (FSHR) and lutropin/choriogonadotropin (LHR) and their sequences and structures are similar. The extracellular region of TSHR contains more than 350 amino acids and binds hormone and antibodies. Several important questions related to functions and mechanisms of TSHR are still not comprehensively understood. One major reason for these open questions is the lack of any structural information about the extracellular segment of TSHR that connects the N-terminal leucine-rich repeat domain (LRRD) with the transmembrane helix (TMH) 1, the hinge region. It has been shown experimentally that this segment is important for fine tuning of signaling and ligand interactions. A new crystal structure containing most of the extracellular hFSHR region in complex with hFSH has recently been published. Now, we have applied these new structural insights to the homologous TSHR and have generated a structural model of the TSHR LRRD/hinge-region/TSH complex. This structural model is combined and evaluated with experimental data including hormone binding (bTSH, hTSH, thyrostimulin), super-agonistic effects, antibody interactions and signaling regulation. These studies and consideration of significant and non-significant amino acids have led to a new description of mechanisms at the TSHR, including ligand-induced displacements of specific hinge region fragments. This event triggers conformational changes at a convergent center of the LRRD and the hinge region, activating an "intramolecular agonistic unit" close to the transmembrane domain.

Not all elevated hormones are toxic: A case of thyroid hormone resistance

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Rajeev Philip

2016-01-01

Full Text Available Resistance to thyroid hormone syndrome (RTH is a rare disorder and is usually inherited as dominantly negative autosomal trait. RTH is caused by mutations in the thyroid hormone receptor beta. Patients with RTH usually do not have signs and symptoms of thyrotoxicosis, but the thyroid function test shows an elevated T3 and T4, which get misinterpreted as hyperthyroidism, resulting in unnecessary treatment.

Investigational hormone receptor agonists as ongoing female contraception: a focus on selective progesterone receptor modulators in early clinical development.

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Nelson, Anita L

2015-01-01

As efforts are made to continue to increase the safety of contraceptive methods, those without estrogen have attracted new attention. Progestin-only options are available in many delivery systems, but most cause disturbed bleeding patterns. For gynecologic patients, selective progesterone receptor modulators (SPRMs) have been approved for medical abortion, for ovulation suppression in emergency contraception, and for the treatment of heavy menstrual bleeding due to leiomyoma. This article discusses the role of SPRMs in controlling fertility on an ongoing basis with particular emphasis on mifepristone and ulipristal acetate (UPA), since none of the other compounds has progressed out of early Phase I - II testing. It also discusses important information about the mechanisms of action and safety of these two SPRMs. Of all the investigational hormone agonist/antagonists, SPRMs have demonstrated the greatest potential as ongoing female contraceptives. They have the ability to suppress ovulation after initiation of the luteinizing hormone (LH) surge without affecting ovarian production of estrogen or inducing any significant metabolic changes. SPRMs may well be able to provide longer term contraception as oral agents, vaginal rings, and perhaps even intrauterine devices. UPA has the greatest promise. Current research needs to be expanded.

Hsp70 cochaperones HspBP1 and BAG-1M differentially regulate steroid hormone receptor function.

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Regina T Knapp

Full Text Available Hsp70 binding protein 1 (HspBP1 and Bcl2-associated athanogene 1 (BAG-1, the functional orthologous nucleotide exchange factors of the heat shock protein 70 kilodalton (Hsc70/Hsp70 chaperones, catalyze the release of ADP from Hsp70 while inducing different conformational changes of the ATPase domain of Hsp70. An appropriate exchange rate of ADP/ATP is crucial for chaperone-dependent protein folding processes. Among Hsp70 client proteins are steroid receptors such as the glucocorticoid receptor (GR, the mineralocorticoid receptor (MR, and the androgen receptor (AR. BAG-1 diversely affects steroid receptor activity, while to date the influence of HspBP1 on steroid receptor function is mostly unknown. Here, we compared the influence of HspBP1 and BAG-1M on Hsp70-mediated steroid receptor folding complexes and steroid receptor activity. Coimmunoprecipitation studies indicated preferential binding of Hsp40 and the steroid receptors to BAG-1M as compared to HspBP1. Furthermore, Hsp70 binding to the ligand-binding domain of GR was reduced in the presence of HspBP1 but not in the presence of BAG-1M as shown by pull-down assays. Reporter gene experiments revealed an inhibitory effect on GR, MR, and AR at a wide range of HspBP1 protein levels and at hormone concentrations at or approaching saturation. BAG-1M exhibited a transition from stimulatory effects at low BAG-1M levels to inhibitory effects at higher BAG-1M levels. Overall, BAG-1M and HspBP1 had differential impacts on the dynamic composition of steroid receptor folding complexes and on receptor function with important implications for steroid receptor physiology.

Multiple estrogen receptor subtypes influence ingestive behavior in female rodents.

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Santollo, Jessica; Daniels, Derek

2015-12-01

Postmenopausal women are at an increased risk of obesity and cardiovascular-related diseases. This is attributable, at least in part, to loss of the ovarian hormone estradiol, which inhibits food and fluid intake in humans and laboratory animal models. Although the hypophagic and anti-dipsogenic effects of estradiol have been well documented for decades, the precise mechanisms underlying these effects are not fully understood. An obvious step toward addressing this open question is identifying which estrogen receptor subtypes are involved and what intracellular processes are involved. This question, however, is complicated not only by the variety of estrogen receptor subtypes that exist, but also because many subtypes have multiple locations of action (i.e. in the nucleus or in the plasma membrane). This review will highlight our current understanding of the roles that specific estrogen receptor subtypes play in mediating estradiol's anorexigenic and anti-dipsogenic effects along with highlighting the many open questions that remain. This review will also describe recent work being performed by our laboratory aimed at answering these open questions. Copyright © 2015 Elsevier Inc. All rights reserved.

Binding properties of beetal recombinant caprine growth hormone to ...

African Journals Online (AJOL)

SAM

2014-07-23

Jul 23, 2014 ... The aim of the study was to illustrate the radio-receptor assay of beetal recombinant caprine growth hormone (rcGH) ... interaction with microsomal membrane that shall be beneficial to study hormone receptor interactions of other Bovidae .... adding 1 ml of ice cold assay buffer, followed by 1 ml of 25% (w/v).

The Role of Thyroid Hormone Signaling in the Prevention of Digestive System Cancers

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Rosalia C. M. Simmen

2013-08-01

Full Text Available Thyroid hormones play a critical role in the growth and development of the alimentary tract in vertebrates. Their effects are mediated by nuclear receptors as well as the cell surface receptor integrin αVβ3. Systemic thyroid hormone levels are controlled via activation and deactivation by iodothyronine deiodinases in the liver and other tissues. Given that thyroid hormone signaling has been characterized as a major effector of digestive system growth and homeostasis, numerous investigations have examined its role in the occurrence and progression of cancers in various tissues of this organ system. The present review summarizes current findings regarding the effects of thyroid hormone signaling on cancers of the esophagus, stomach, liver, pancreas, and colon. Particular attention is given to the roles of different thyroid hormone receptor isoforms, the novel integrin αVβ3 receptor, and thyroid hormone-related nutrients as possible protective agents and therapeutic targets. Future investigations geared towards a better understanding of thyroid hormone signaling in digestive system cancers may provide preventive or therapeutic strategies to diminish risk, improve outcome and avert recurrence in afflicted individuals.

Components of the CCR4-NOT complex function as nuclear hormone receptor coactivators via association with the NRC-interacting Factor NIF-1.

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Garapaty, Shivani; Mahajan, Muktar A; Samuels, Herbert H

2008-03-14

CCR4-NOT is an evolutionarily conserved, multicomponent complex known to be involved in transcription as well as mRNA degradation. Various subunits (e.g. CNOT1 and CNOT7/CAF1) have been reported to be involved in influencing nuclear hormone receptor activities. Here, we show that CCR4/CNOT6 and RCD1/CNOT9, members of the CCR4-NOT complex, potentiate nuclear receptor activity. RCD1 interacts in vivo and in vitro with NIF-1 (NRC-interacting factor), a previously characterized nuclear receptor cotransducer that activates nuclear receptors via its interaction with NRC. As with NIF-1, RCD1 and CCR4 do not directly associate with nuclear receptors; however, they enhance ligand-dependent transcriptional activation by nuclear hormone receptors. CCR4 mediates its effect through the ligand binding domain of nuclear receptors and small interference RNA-mediated silencing of endogenous CCR4 results in a marked decrease in nuclear receptor activation. Furthermore, knockdown of CCR4 results in an attenuated stimulation of RARalpha target genes (e.g. Sox9 and HoxA1) as shown by quantitative PCR assays. The silencing of endogenous NIF-1 also resulted in a comparable decrease in the RAR-mediated induction of both Sox9 and HoxA1. Furthermore, CCR4 associates in vivo with NIF-1. In addition, the CCR4-enhanced transcriptional activation by nuclear receptors is dependent on NIF-1. The small interference RNA-mediated knockdown of NIF-1 blocks the ligand-dependent potentiating effect of CCR4. Our results suggest that CCR4 plays a role in the regulation of certain endogenous RARalpha target genes and that RCD1 and CCR4 might mediate their function through their interaction with NIF-1.

Association between lifetime exposure to passive smoking and risk of breast cancer subtypes defined by hormone receptor status among non-smoking Caucasian women.

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Loreta Strumylaite

Full Text Available Tobacco smoking is inconsistently associated with breast cancer. Although some studies suggest that breast cancer risk is related to passive smoking, little is known about the association with breast cancer by tumor hormone receptor status. We aimed to explore the association between lifetime passive smoking and risk of breast cancer subtypes defined by estrogen receptor and progesterone receptor status among non-smoking Caucasian women. A hospital-based case-control study was performed in 585 cases and 1170 controls aged 28-90 years. Information on lifetime passive smoking and other factors was collected via a self-administered questionnaire. Logistic regression was used for analyses restricted to the 449 cases and 930 controls who had never smoked actively. All statistical tests were two-sided. Adjusted odds ratio of breast cancer was 1.01 (95% confidence interval (CI: 0.72-1.41 in women who experienced exposure to passive smoking at work, 1.88 (95% CI: 1.38-2.55 in women who had exposure at home, and 2.80 (95% CI: 1.84-4.25 in women who were exposed at home and at work, all compared with never exposed regularly. Increased risk was associated with longer exposure: women exposed ≤ 20 years and > 20 years had 1.27 (95% CI: 0.97-1.66 and 2.64 (95% CI: 1.87-3.74 times higher risk of breast cancer compared with never exposed (Ptrend 0.05. There was evidence of interaction between passive smoking intensity and menopausal status in both overall group (P = 0.02 and hormone receptor-positive breast cancer group (P < 0.05. In Caucasian women, lifetime exposure to passive smoking is associated with the risk of breast cancer independent of tumor hormone receptor status with the strongest association in postmenopausal women.

Changes in gonadotropin-releasing hormone and gonadotropin-releasing hormone receptor gene expression after an increase in carbon monoxide concentration in the cavernous sinus of male wild boar and pig crossbread.

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Romerowicz-Misielak, M; Tabecka-Lonczynska, A; Koziol, K; Gilun, P; Stefanczyk-Krzymowska, S; Och, W; Koziorowski, M

2016-06-01

Previous studies indicate that there are at least a few regulatory systems involved in photoperiodic synchronisation of reproductive activity, which starts with the retina and ends at the gonadotropin-releasing hormone (GnRH) pulse generator. Recently we have shown indicated that the amount of carbon monoxide (CO) released from the eye into the ophthalmic venous blood depends on the intensity of sunlight. The aim of this study was to test whether changes in the concentration of carbon monoxide in the ophthalmic venous blood may modulate reproductive activity, as measured by changes in GnRH and GnRH receptor gene expression. The animal model used was mature male swine crossbred from wild boars and domestic sows (n = 48). We conducted in vivo experiments to determine the effect of increased CO concentrations in the cavernous sinus of the mammalian perihypophyseal vascular complex on gene expression of GnRH and GnRH receptors as well as serum luteinizing hormone (LH) levels. The experiments were performed during long photoperiod days near the summer solstice (second half of June) and short photoperiod days near the winter solstice (second half of December). These crossbred swine demonstrated a seasonally-dependent marked variation in GnRH and GnRH receptor gene expression and systemic LH levels in response to changes in CO concentration in ophthalmic venous blood. These results seem to confirm the hypothesis of humoral phototransduction as a mechanism for some of bright light's effects in animal chronobiology and the effect of CO on GnRH and GnRH receptor gene expression.

Regulation of ghrelin secretion and action.

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Camiña, Jesus P; Carreira, Marcos C; Micic, Dragan; Pombo, Manuel; Kelestimur, Fahrettin; Dieguez, Carlos; Casanueva, Felipe F

2003-10-01

The pulsatile release of growth hormone (GH) from anterior pituitary gland is regulated by the interplay of at least two hypothalamic hormones, GH-releasing hormone (GHRH) and somatostatin, via their engagement with specific cell surface receptors on the anterior pituitary somatotroph. Furthermore, release of GH in vivo may also be controlled by a third type of receptor, the growth hormone secretagogue receptor, a G-protein-coupled receptor, called GHS receptor type 1a (GHSR1a), which was identified in the pituitary and the hypothalamus in humans using a nonpeptidyl growth hormone secretagogue (MK-0677). Ghrelin, the endogenous ligand for the GHS-R1a, is a 28-amino-acid peptide isolated from human stomach that is modified by a straight chain octanoyl group covalently linked to Ser3, which is essential for its endocrine activity. This hormone, predominantly expressed and secreted by the stomach, has a dual action on GH secretion and food intake, showing interdependency between these actions. The finding that fasting and food intake, respectively, increase and decrease the secretion of ghrelin suggests that this hormone may be the bridge connecting somatic growth and body composition with energy metabolism, and appears to play a role in the alteration of energy homeostasis and body weight in pathophysiological states such as hypothyroidism and hyperthyroidism. Despite this, little is known about the intracellular signaling through which ghrelin exerts its regulatory actions. Activation of intracellular calcium mobilization is one of the earliest known cellular signals elicited by ghrelin. In HEK- 293 cells expressing the GHS-R1a, ghrelin induces a biphasic cytosolic calcium elevation characterized by a spike phase of the response, which reflects Ins(1,4,5)P3- dependent calcium mobilization of intracellular stores, and a sustained phase of the response, which is due to calcium influx across the plasma membrane triggered by aperture of capacitative calcium channels

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

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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.

Effects of corticotropin-releasing hormone and its antagonist on the gene expression of gonadotrophin-releasing hormone (GnRH) and GnRH receptor in the hypothalamus and anterior pituitary gland of follicular phase ewes.

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Ciechanowska, Magdalena; Łapot, Magdalena; Malewski, Tadeusz; Mateusiak, Krystyna; Misztal, Tomasz; Przekop, Franciszek

2011-01-01

There is no information in the literature regarding the effect of corticotropin-releasing hormone (CRH) on genes encoding gonadotrophin-releasing hormone (GnRH) and the GnRH receptor (GnRHR) in the hypothalamus or on GnRHR gene expression in the pituitary gland in vivo. Thus, the aim of the present study was to investigate, in follicular phase ewes, the effects of prolonged, intermittent infusion of small doses of CRH or its antagonist (α-helical CRH 9-41; CRH-A) into the third cerebral ventricle on GnRH mRNA and GnRHR mRNA levels in the hypothalamo-pituitary unit and on LH secretion. Stimulation or inhibition of CRH receptors significantly decreased or increased GnRH gene expression in the hypothalamus, respectively, and led to different responses in GnRHR gene expression in discrete hypothalamic areas. For example, CRH increased GnRHR gene expression in the preoptic area, but decreased it in the hypothalamus/stalk median eminence and in the anterior pituitary gland. In addition, CRH decreased LH secretion. Blockade of CRH receptors had the opposite effect on GnRHR gene expression. The results suggest that activation of CRH receptors in the hypothalamus of follicular phase ewes can modulate the biosynthesis and release of GnRH through complex changes in the expression of GnRH and GnRHR genes in the hypothalamo-anterior pituitary unit. © CSIRO 2011 Open Access

Chronic alcohol feeding potentiates hormone-induced calcium signalling in hepatocytes.

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Bartlett, Paula J; Antony, Anil Noronha; Agarwal, Amit; Hilly, Mauricette; Prince, Victoria L; Combettes, Laurent; Hoek, Jan B; Gaspers, Lawrence D

2017-05-15

Chronic alcohol consumption causes a spectrum of liver diseases, but the pathogenic mechanisms driving the onset and progression of disease are not clearly defined. We show that chronic alcohol feeding sensitizes rat hepatocytes to Ca 2+ -mobilizing hormones resulting in a leftward shift in the concentration-response relationship and the transition from oscillatory to more sustained and prolonged Ca 2+ increases. Our data demonstrate that alcohol-dependent adaptation in the Ca 2+ signalling pathway occurs at the level of hormone-induced inositol 1,4,5 trisphosphate (IP 3 ) production and does not involve changes in the sensitivity of the IP 3 receptor or size of internal Ca 2+ stores. We suggest that prolonged and aberrant hormone-evoked Ca 2+ increases may stimulate the production of mitochondrial reactive oxygen species and contribute to alcohol-induced hepatocyte injury. ABSTRACT: 'Adaptive' responses of the liver to chronic alcohol consumption may underlie the development of cell and tissue injury. Alcohol administration can perturb multiple signalling pathways including phosphoinositide-dependent cytosolic calcium ([Ca 2+ ] i ) increases, which can adversely affect mitochondrial Ca 2+ levels, reactive oxygen species production and energy metabolism. Our data indicate that chronic alcohol feeding induces a leftward shift in the dose-response for Ca 2+ -mobilizing hormones resulting in more sustained and prolonged [Ca 2+ ] i increases in both cultured hepatocytes and hepatocytes within the intact perfused liver. Ca 2+ increases were initiated at lower hormone concentrations, and intercellular calcium wave propagation rates were faster in alcoholics compared to controls. Acute alcohol treatment (25 mm) completely inhibited hormone-induced calcium increases in control livers, but not after chronic alcohol-feeding, suggesting desensitization to the inhibitory actions of ethanol. Hormone-induced inositol 1,4,5 trisphosphate (IP 3 ) accumulation and phospholipase C

Evidence for gating roles of protein kinase A and protein kinase C in estradiol-induced luteinizing hormone receptor (lhcgr) expression in zebrafish ovarian follicle cells.

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Liu, Ka-Cheuk; Ge, Wei

2013-01-01

Estradiol (E2) stimulates luteinizing hormone receptor (lhcgr) expression in zebrafish follicle cells via nuclear estrogen receptors (nERs) that are likely expressed on the membrane, and lhcgr responds to E2 in a biphasic manner during 24-h treatment. These observations raise an interesting question on the signaling mechanism underlying E2 regulation, in particular the biphasic response of lhcgr expression. In the present study, we demonstrated that E2 regulation of lhcgr was significantly influenced by the activity of cAMP-PKA pathway. Activation of cAMP-PKA pathway by forskolin or db-cAMP suppressed E2-stimulated lhcgr expression in short-term (3 h) but enhanced its effect in long-term (24 h), suggesting differential roles of PKA at these two phases of lhcgr response. PKA inhibitor H89 showed reversed effects. In contrast, PKC pathway had consistent permissive effect on E2-induced lhcgr expression as evidenced by strong inhibition of E2 effect by PKC inhibitors GF109203X and Ro-31-8220 at both 3 and 24 h. One of the mechanisms by which PKA and PKC gated E2 effect might be through regulating nERs, particularly esr2a. Despite the strong influence of PKA and PKC, our data did not suggest direct mediating roles for these two pathways in E2 stimulation of lhcgr expression; yet they likely play critical gating roles in E2 signal transduction. As a follow-up study to our previous report on E2 regulation of gonadotropin receptors in the zebrafish ovary, the present study provides further evidence for the involvement of classical intracellular signal transduction pathways in E2 stimulation of lhcgr expression in the follicle cells.

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

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...

Molecular and functional characterization of a novel gonadotropin-releasing-hormone receptor isolated from the common octopus (Octopus vulgaris)

Science.gov (United States)

Kanda, Atsuhiro; Takahashi, Toshio; Satake, Honoo; Minakata, Hiroyuki

2005-01-01

GnRH (gonadotropin-releasing hormone) plays a pivotal role in the regulation of reproduction in vertebrates through interaction with a specific receptor. Previously, we isolated a GnRH homo-logue, oct-GnRH, from the common octopus (Octopus vulgaris). In the present study, we have identified a GnRH receptor (oct-GnRHR) specific for oct-GnRH from Octopus brain. Oct-GnRHR includes domains and motifs typical of vertebrate GnRH receptors. The intron-inserted positions are conserved between oct-GnRHR and the chordate GnRHR genes. The oct-GnRHR expressed in Xenopus (South African clawed frog) oocytes was responsive to oct-GnRH, but not to any other HPLC fractions of the Octopus brain extract. These results show that oct-GnRHR is an authentic receptor for oct-GnRH. Southern blotting of reverse-transcription PCR products revealed that the oct-GnRHR mRNA was widely distributed in the central and peripheral nervous systems and in several peripheral tissues. In situ hybridiz-ation showed that oct-GnRHR mRNA was expressed in some regions involved in autonomic functions, feeding, memory and movement. Oct-GnRH was shown to induce steroidogenesis of testosterone, progesterone and 17β-oestradiol in Octopus ovary and testis, where oct-GnRHR was abundantly expressed. These results suggest that oct-GnRH, like its vertebrate counterparts, acts as a multifunctional neurotransmitter, neuromodulator and hormone-like factor, both in Octopus central nervous system and peripheral tissues, and that both structure and functions of the GnRH family are, at least partially, evolutionarily conserved between octopuses and chordates. PMID:16367741

Molecular and functional characterization of a novel gonadotropin-releasing-hormone receptor isolated from the common octopus (Octopus vulgaris).

Science.gov (United States)

Kanda, Atsuhiro; Takahashi, Toshio; Satake, Honoo; Minakata, Hiroyuki

2006-04-01

GnRH (gonadotropin-releasing hormone) plays a pivotal role in the regulation of reproduction in vertebrates through interaction with a specific receptor. Previously, we isolated a GnRH homologue, oct-GnRH, from the common octopus (Octopus vulgaris). In the present study, we have identified a GnRH receptor (oct-GnRHR) specific for oct-GnRH from Octopus brain. Oct-GnRHR includes domains and motifs typical of vertebrate GnRH receptors. The intron-inserted positions are conserved between oct-GnRHR and the chordate GnRHR genes. The oct-GnRHR expressed in Xenopus (South African clawed frog) oocytes was responsive to oct-GnRH, but not to any other HPLC fractions of the Octopus brain extract. These results show that oct-GnRHR is an authentic receptor for oct-GnRH. Southern blotting of reverse-transcription PCR products revealed that the oct-GnRHR mRNA was widely distributed in the central and peripheral nervous systems and in several peripheral tissues. In situ hybridization showed that oct-GnRHR mRNA was expressed in some regions involved in autonomic functions, feeding, memory and movement. Oct-GnRH was shown to induce steroidogenesis of testosterone, progesterone and 17beta-oestradiol in Octopus ovary and testis, where oct-GnRHR was abundantly expressed. These results suggest that oct-GnRH, like its vertebrate counterparts, acts as a multifunctional neurotransmitter, neuromodulator and hormone-like factor, both in Octopus central nervous system and peripheral tissues, and that both structure and functions of the GnRH family are, at least partially, evolutionarily conserved between octopuses and chordates.

Thyroid-Stimulating Hormone Receptor Antibodies in Pregnancy: Clinical Relevance

Science.gov (United States)

Bucci, Ines; Giuliani, Cesidio; Napolitano, Giorgio

2017-01-01

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 fetal

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

Progress of measurement of hormones

International Nuclear Information System (INIS)

Ohsawa, Nakaaki

1977-01-01

Description was made as to an outline of the theory of radioreceptor assay (RRA) in which hormone receptor was used as specific binding protein, as same as the theory of RIA, and as to its practical use. Meaning of RRA for measurement of hormones in consideration of the site of immunological and biological activation and meaning of difference in measurement values between this method and in RIA in the same materials, were mentioned, and effectiveness of use of this method together with RIA was described. Detection of receptor site, analysis of binding specificity, and numerical calculation were mentioned as receptor analysis by this method. As practical use of these functions, arrangement mechanism of receptor, and analysis of abnormality were mentioned. Especially, analysis of testicular feminization syndrome, insulinresistenter diabetes, hyperthyroidism, and myasthenia gravis, and relationship between these diseases and autoimmune diseases were described, and clinical meaning of this method in internal medicine and surgery was mentioned. (Kanao, N.)

In Situ Hybridization Method Reveals (Pro)renin Receptor Expressing Cells in the Pituitary Gland of Rats: Correlation with Anterior Pituitary Hormones.

Science.gov (United States)

Takahashi, Kazuhiro; Yatabe, Megumi; Fujiwara, Ken; Hirose, Takuo; Totsune, Kazuhito; Yashiro, Takashi

2013-02-28

Expression of (pro)renin receptor ((P)RR), a specific receptor for renin and prorenin, was studied in rat pituitary gland. In situ hybridization showed that cells expressing (P)RR mRNA were widely distributed in the anterior lobe and intermediate lobe of the pituitary gland. Double-staining using in situ hybridization for (P)RR mRNA and immunohistochemistry for the pituitary hormones showed that (P)RR mRNA was expressed in most of the GH cells and ACTH cells in the anterior lobe. (P)RR mRNA was also expressed in a few prolactin cells and TSH cells, but not in LH cells. The present study has shown for the first time the distribution of (P)RR mRNA expressing cells in the rat pituitary gland. These findings suggest that (P)RR plays physiological roles in the pituitary gland, such as the modulation of the pituitary hormone secretion.

In Situ Hybridization Method Reveals (Pro)renin Receptor Expressing Cells in the Pituitary Gland of Rats: Correlation with Anterior Pituitary Hormones

International Nuclear Information System (INIS)

Takahashi, Kazuhiro; Yatabe, Megumi; Fujiwara, Ken; Hirose, Takuo; Totsune, Kazuhito; Yashiro, Takashi

2013-01-01

Expression of (pro)renin receptor ((P)RR), a specific receptor for renin and prorenin, was studied in rat pituitary gland. In situ hybridization showed that cells expressing (P)RR mRNA were widely distributed in the anterior lobe and intermediate lobe of the pituitary gland. Double-staining using in situ hybridization for (P)RR mRNA and immunohistochemistry for the pituitary hormones showed that (P)RR mRNA was expressed in most of the GH cells and ACTH cells in the anterior lobe. (P)RR mRNA was also expressed in a few prolactin cells and TSH cells, but not in LH cells. The present study has shown for the first time the distribution of (P)RR mRNA expressing cells in the rat pituitary gland. These findings suggest that (P)RR plays physiological roles in the pituitary gland, such as the modulation of the pituitary hormone secretion

A radioligand immunoassay for 1,25-dihydroxyvitamin D3 receptors using monoclonal antibody: detection of a phenotypic receptor variant in vitamin D-dependency rickets (type II) which does not bind hormone

International Nuclear Information System (INIS)

Pike, J.W.; Dokoh, Shigeharu; Liberman, U.A.; Eil, C.; Haussler, M.R.; Marx, S.J.

1984-01-01

Vitamin D-dependency rickets, type II (VDDRII), is a well recognized heritable disorder characterized by peripheral target organ resistance to 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), the hormonally active form of the vitamin. Recently, cultured skin fibroblasts obtained from a number of patients with VDDRII have been utilized to characterize the underlying molecular defects associated with this malady. Recently monoclonal antibodies to the vitamin D receptor have been generated, and a radioligand immunoassay (RLIA) for the detection of this molecule has been developed which is independent of its hormone-binding capacity. This report describes the application of the immunoassay in the detection of receptor-like molecules in fibroblasts derived from patients with VDDRII. The results indicate that the molecule is generally present in all patients, and provides a mechanism for individual responsiveness to pharmacologic treatment with vitamin D 3 metabolites. 8 refs.; 3 figs.; 1 table

Thyroid Hormone Receptor β (TRβ) and Liver X Receptor (LXR) Regulate Carbohydrate-response Element-binding Protein (ChREBP) Expression in a Tissue-selective Manner*

Science.gov (United States)

Gauthier, Karine; Billon, Cyrielle; Bissler, Marie; Beylot, Michel; Lobaccaro, Jean-Marc; Vanacker, Jean-Marc; Samarut, Jacques

2010-01-01

Thyroid hormone (TR) and liver X (LXR) receptors are transcription factors involved in lipogenesis. Both receptors recognize the same consensus DNA-response element in vitro. It was previously shown that their signaling pathways interact in the control of cholesterol elimination in the liver. In the present study, carbohydrate-response element-binding protein (ChREBP), a major transcription factor controlling the activation of glucose-induced lipogenesis in liver, is characterized as a direct target of thyroid hormones (TH) in liver and white adipose tissue (WAT), the two main lipogenic tissues in mice. Using genetic and molecular approaches, ChREBP is shown to be specifically regulated by TRβ but not by TRα in vivo, even in WAT where both TR isoforms are expressed. However, this isotype specificity is not found in vitro. This TRβ specific regulation correlates with the loss of TH-induced lipogenesis in TRβ−/− mice. Fasting/refeeding experiments show that TRβ is not required for the activation of ChREBP expression particularly marked in WAT following refeeding. However, TH can stimulate ChREBP expression in WAT even under fasting conditions, suggesting completely independent pathways. Because ChREBP has been described as an LXR target, the interaction of LXR and TRβ in ChREBP regulation was assayed both in vitro and in vivo. Each receptor recognizes a different response element on the ChREBP promoter, located only 8 bp apart. There is a cross-talk between LXR and TRβ signaling on the ChREBP promoter in liver but not in WAT where LXR does not regulate ChREBP expression. The molecular basis for this cross-talk has been determined in in vitro systems. PMID:20615868

Steroidogenesis and early response gene expression in MA-10 Leydig tumor cells following heterologous receptor down-regulation and cellular desensitization

Directory of Open Access Journals (Sweden)

Tsuey-Ming Chen

2016-03-01

Full Text Available The Leydig tumor cell line, MA-10, expresses the luteinizing hormone receptor, a G protein-coupled receptor that, when activated with luteinizing hormone or chorionic gonadotropin (CG, stimulates cAMP production and subsequent steroidogenesis, notably progesterone. These cells also respond to epidermal growth factor (EGF and phorbol esters with increased steroid biosynthesis. In order to probe the intracellular pathways along with heterologous receptor down-regulation and cellular desensitization, cells were preincubated with EGF or phorbol esters and then challenged with CG, EGF, dibutryl-cyclic AMP, and a phorbol ester. Relative receptor numbers, steroid biosynthesis, and expression of the early response genes, JUNB and c-FOS, were measured. It was found that in all cases but one receptor down-regulation and decreased progesterone production were closely coupled under the conditions used; the exception involved preincubation of the cells with EGF followed by addition of CG where the CG-mediated stimulation of steroidogenesis was considerably lower than the level of receptor down-regulation. In a number of instances JUNB and c-FOS expression paralleled the decreases in receptor number and progesterone production, while in some cases these early response genes were affected little if at all by the changes in receptor number. This finding may indicate that even low levels of activated signaling kinases, e.g. protein kinase A, protein kinase C, or receptor tyrosine kinase, may suffice to yield good expression of JUNB and c-FOS, or it may suggest alternative pathways for regulating expression of these two early response genes.

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

between the groups in terms of changes in serum free fatty acids, glycerol, (V) over dotO(2), or relative fat oxidation. Conclusion: GH might be an important determinant of exercise capacity during prolonged exercise, but GHR antagonist did not alter fat metabolism during exercise. (J Clin Endocrinol......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...... 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...

Role of α7 nicotinic receptor in the immune system and intracellular signaling pathways.

Science.gov (United States)

Zdanowski, Robert; Krzyżowska, Małgorzata; Ujazdowska, Dominika; Lewicka, Aneta; Lewicki, Sławomir

2015-01-01

Acetylcholine has been well known as one of the most exemplary neurotransmitters. In humans, this versatile molecule and its synthesizing enzyme, choline acetyltransferase, have been found in various non-neural tissues such as the epithelium, endothelium, mesothelium muscle, blood cells and immune cells. The non-neuronal acetylcholine is accompanied by the expression of acetylcholinesterase and nicotinic/muscarinic acetylcholine receptors. Increasing evidence of the non-neuronal acetylcholine system found throughout the last few years has indicated this neurotransmitter as one of the major cellular signaling molecules (associated e.g. with kinases and transcription factors activity). This system is responsible for maintenance and optimization of the cellular function, such as proliferation, differentiation, adhesion, migration, intercellular contact and apoptosis. Additionally, it controls proper activity of immune cells and affects differentiation, antigen presentation or cytokine production (both pro- and anti-inflammatory). The present article reviews recent findings about the non-neuronal cholinergic system in the field of immune system and intracellular signaling pathways.

Tritium-labelled steroids, their preparation and application for the determination and location of steroid tissular hormone receptors

International Nuclear Information System (INIS)

Jouquey, Alain; Raynaud, J.P.

1977-01-01

A product is prepared by the action of tritiated methanol on 11β-hydroxy-estra-4,9-dien-3,17-dione, the action of an aromatisation agent on the (11β)-11-methoxy- 3 H 3 -estra-4,9-dien-3,17-dione formed and the action of an ethynylation agent on the resulting (11β)-3-hydroxy-11-methoxy- 3 H 3 -estra-1,3,5(10)-trien-17-one giving (11β, 17α)-11-methoxy- 3 H 3 -19-norpregna-1,3,5(10)-trien-20-yne-3,17 diol, the free hydroxyl function or functions of this product may be etherified or esterified as the case may be. The tritiated methanol acts in the presence of perchloric acid. The aromatisation agent is palladium hydroxide and the operation is carried out in methanol. The ethynylation agent is acetylene and the reaction takes place in the presence of sodium t-amylate in toluene. This product allows the study and determination of the estrogen specific receptor present in the tissue cells of target organs for the action of estrogens: uterus, vagina, hypophysis, hypothalamus and tumours, of the breast and prostate for example, in both animals and man. Not being fixed by the plasma proteins binding such hormones as testosterone and estradiol in women the product is an ideal indicator of the tissular estrogen receptor with which it forms a complex of strong affinity and great stability, especially since it interacts with the tissular receptors of no other steroid hormone groups (glucocorticoids, androgen or progestogen mineralocorticosteroids) [fr

alpha-difluoromethylornithine modifies gonadotropin-releasing hormone release and follicle-stimulating hormone secretion in the immature female rat.

Science.gov (United States)

Thyssen, S M; Becú-Villalobos, D; Lacau-Mengido, I M; Libertun, C

1997-06-01

Polyamines play an essential role in tissue growth and differentiation, in body weight increment, in brain organization, and in the molecular mechanisms of hormonal action, intracellular signaling, and cell-to-cell communication. In a previous study, inhibition of their synthesis by alpha-difluoromethylornithine (DFMO), a specific and irreversible inhibitor of ornithine decarboxylase, during development in female rats, was followed by prolonged high follicle-stimulating hormone (FSH) serum level and a delayed puberty onset. Those changes were relatively independent of body mass and did not impair posterior fertility. The present work studies the mechanisms and site of action of polyamine participation in FSH secretion during development. DFMO was injected in female rats between Days 1 and 9 on alternate days. At 10 days of age, hypothalami from control and DFMO rats were perifused in vitro, and basal and potassium-induced gonadotropin-releasing hormone (GnRH) release were measured. The response to membrane depolarization was altered in DFMO hypothalami. Increased GnRH release in response to a low K+ concentration was evidenced. Adenohypophyses of the same treated prepubertal rats were perifused in vitro and the response to GnRH pulses was checked. In DFMO-treated rats, higher FSH release was observed, with no changes in LH or PRL secretion. Finally, pituitary GnRH receptor number in adenohypophyseal membranes from treated and control groups was quantified. A significant reduction in specific binding was evident in hypophyses from DFMO-treated rats when compared with binding in the control group. In summary, DFMO treatment in a critical developmental period in the female rat impacts the immature GnRH neuronal network and immature gonadotropes. A delay in maturation is evidenced by a higher sensitivity to secretagogs in both pituitary glands and hypothalamic explants. These events could explain the prolonged high FSH serum levels and delayed puberty onset seen in

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.

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...

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

2016-08-01

-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. 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.

Adjuvant Trastuzumab in HER2-Positive Early Breast Cancer by Age and Hormone Receptor Status: A Cost-Utility Analysis.

Directory of Open Access Journals (Sweden)

William Leung

2016-08-01

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.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.

Application of photoshop-based image analysis to quantification of hormone receptor expression in breast cancer.

Science.gov (United States)

Lehr, H A; Mankoff, D A; Corwin, D; Santeusanio, G; Gown, A M

1997-11-01

The benefit of quantifying estrogen receptor (ER) and progesterone receptor (PR) expression in breast cancer is well established. However, in routine breast cancer diagnosis, receptor expression is often quantified in arbitrary scores with high inter- and intraobserver variability. In this study we tested the validity of an image analysis system employing inexpensive, commercially available computer software on a personal computer. In a series of 28 invasive ductal breast cancers, immunohistochemical determinations of ER and PR were performed, along with biochemical analyses on fresh tumor homogenates, by the dextran-coated charcoal technique (DCC) and by enzyme immunoassay (EIA). From each immunohistochemical slide, three representative tumor fields (x20 objective) were captured and digitized with a Macintosh personal computer. Using the tools of Photoshop software, optical density plots of tumor cell nuclei were generated and, after background subtraction, were used as an index of immunostaining intensity. This immunostaining index showed a strong semilogarithmic correlation with biochemical receptor assessments of ER (DCC, r = 0.70, p < 0.001; EIA, r = 0.76, p < 0.001) and even better of PR (DCC, r = 0.86; p < 0.01; EIA, r = 0.80, p < 0.001). A strong linear correlation of ER and PR quantification was also seen between DCC and EIA techniques (ER, r = 0.62, p < 0.001; PR, r = 0.92, p < 0.001). This study demonstrates that a simple, inexpensive, commercially available software program can be accurately applied to the quantification of immunohistochemical hormone receptor studies.

Beyond the HPA-axis: The role of the gonadal steroid hormone receptors in modulating stress-related responses in an animal model of PTSD.

Science.gov (United States)

Fenchel, Daphna; Levkovitz, Yechiel; Vainer, Ella; Kaplan, Zeev; Zohar, Joseph; Cohen, Hagit

2015-06-01

The hypothalamic-pituitary-adrenal (HPA) axis, which plays a major role in the response to stress, and the hypothalamic-pituitary-gonadal (HPG) axis are closely linked with the ability to inhibit the other. Testosterone, a product of the HPG, has many beneficial effects beyond its functions as a sex hormone including anti-anxiety properties. In this study we examined the effect of stress exposure on gonadal hormones, and their efficacy in modulating anxiety-like response in an animal model of PTSD. Male rats were exposed to predator scent stress, followed by analysis of brain expression of androgen receptor (AR) receptor and estrogen receptor α (ERα). The behavioral effects of immediate treatment with testosterone, testosterone receptor antagonist (flutamide) or vehicle were evaluated using the elevated plus-maze, acoustic startle response and trauma-cue response. Levels of circulating corticosterone and testosterone were also measured after treatment. The behavioral effects of delayed testosterone treatment were explored in the same manner. We report that animals whose behavior was extremely disrupted (EBR) selectively displayed significant down-regulation of AR and ERα in the hippocampus. Immediate treatment with flutamide or delayed treatment with testosterone significantly increased prevalence rates of minimal behavioral response (MBR) and decreased prevalence of EBR with favorable behavioral results. Testosterone levels were higher in control un-exposed animals, while corticosterone was higher in control exposed animals. This study suggests that gonadal steroid hormones are involved in the neurobiological response to predator scent stress and thus warrant further study as a potential therapeutic avenue for the treatment of anxiety-related disorders. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Towards the emerging crosstalk: ERBB family and steroid hormones.

Science.gov (United States)

D'Uva, Gabriele; Lauriola, Mattia

2016-02-01

Growth factors acting through receptor tyrosine kinases (RTKs) of ERBB family, along with steroid hormones (SH) acting through nuclear receptors (NRs), are critical signalling mediators of cellular processes. Deregulations of ERBB and steroid hormone receptors are responsible for several diseases, including cancer, thus demonstrating the central role played by both systems. This review will summarize and shed light on an emerging crosstalk between these two important receptor families. How this mutual crosstalk is attained, such as through extensive genomic and non-genomic interactions, will be addressed. In light of recent studies, we will describe how steroid hormones are able to fine-tune ERBB feedback loops, thus impacting on cellular output and providing a new key for understanding the complexity of biological processes in physiological or pathological conditions. In our understanding, the interactions between steroid hormones and RTKs deserve further attention. A system biology approach and advanced technologies for the analysis of RTK-SH crosstalk could lead to major advancements in molecular medicine, providing the basis for new routes of pharmacological intervention in several diseases, including cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

The role of TREM-2 in internalization and intracellular survival of Brucella abortus in murine macrophages.

Science.gov (United States)

Wei, Pan; Lu, Qiang; Cui, Guimei; Guan, Zhenhong; Yang, Li; Sun, Changjiang; Sun, Wanchun; Peng, Qisheng

2015-02-15

Triggering receptor expressed on myeloid cells-2 (TREM-2) is a cell surface receptor primarily expressed on macrophages and dendritic cells. TREM-2 functions as a phagocytic receptor for bacteria as well as an inhibitor of Toll like receptors (TLR) induced inflammatory cytokines. However, the role of TREM-2 in Brucella intracellular growth remains unknown. To investigate whether TREM-2 is involved in Brucella intracellular survival, we chose bone marrow derived macrophages (BMDMs), in which TREM-2 is stably expressed, as cell model. Colony formation Units (CFUs) assay suggests that TREM-2 is involved in the internalization of Brucella abortus (B. abortus) by macrophages, while silencing of TREM-2 decreases intracellular survival of B. abortus. To further study the underlying mechanisms of TREM-2-mediated bacterial intracellular survival, we examined the activation of B. abortus-infected macrophages through determining the kinetics of activation of the three MAPKs, including ERK, JNK and p38, and measuring TNFα production in response to lipopolysaccharide (LPS) of Brucella (BrLPS) or B. abortus stimulation. Our data show that TREM-2 deficiency promotes activation of Brucella-infected macrophages. Moreover, our data also demonstrate that macrophage activation promotes killing of Brucella by enhancing nitric oxygen (NO), but not reactive oxygen species (ROS) production, macrophage apoptosis or cellular death. Taken together, these findings provide a novel interpretation of Brucella intracellular growth through inhibition of NO production produced by TREM-2-mediated activated macrophages. Copyright © 2014 Elsevier B.V. All rights reserved.

Follicle-stimulating hormone receptor-mediated uptake of 45Ca2+ by proteoliposomes and cultured rat sertoli cells: Evidence for involvement of voltage-activated and voltage-independent calcium channels

International Nuclear Information System (INIS)

Grasso, P.; Reichert, L.E. Jr.

1989-01-01

We have previously reported incorporation into liposomes of Triton X-100-solubilized FSH receptor-G-protein complexes derived from purified bovine calf testis membranes. In the present study we have used this model system to show that FSH induces flux of 45Ca2+ into such proteoliposomes in a hormone-specific concentration-dependent manner. FSH, inactivated by boiling, had no stimulatory effect on 45Ca2+ flux, nor did isolated alpha- or beta-subunits of FSH. Addition of GTP (or its analogs 5'-guanylylimidodiphosphate and guanosine-5'-O-[3-thiotriphosphate]) or sodium fluoride (in the presence or absence of GTP or its analogs) failed to induce 45Ca2+ flux into proteoliposomes, suggesting that the uptake of 45Ca2+ was receptor, and not G-protein, related. Voltage-independent (ruthenium red and gadolinium chloride) and voltage-activated (methyoxyverapamil and nifedipine) calcium channel-blocking agents reduced FSH-stimulated 45Ca2+ flux into proteoliposomes to control levels. FSH also induced uptake of 45Ca2+ by cultured rat Sertoli cells. Ruthenium red and gadolinium chloride had no effect on basal levels of 45Ca2+ uptake or estradiol secretion by cultured rat Sertoli cells, nor did methoxyverapamil or nifedipine. All four calcium channel blockers, however, were able to reduce FSH-induced 45Ca2+ uptake to basal levels and FSH-stimulated conversion of androstenedione to estradiol by up to 50%, indicating an involvement of Ca2+ in FSH-stimulated steroidogenesis. Our results suggest that the well documented changes in intracellular calcium levels consequent to FSH binding may be due, at least in part, to an influx of calcium through FSH receptor-regulated calcium channels

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. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Multifunctional Receptor Stabilin-1 in Homeostasis and Disease

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Julia Kzhyshkowska

2010-01-01

Full Text Available The multifunctional scavenger receptor stabilin-1 (STAB1, FEEL-1, CLEVER-1, KIAA0246 is expressed on tissue macrophages and sinusoidal endothelial cells in healthy organisms, and its expression on both macrophages and different subtypes of endothelial cells is induced during chronic inflammation and tumor progression. Stabilin-1 is a type-1 transmembrane receptor that mediates endocytic and phagocytic clearance of “unwanted-self” components, intracellular sorting of the endogenously synthesized chitinase-like protein SI-CLP, and transcytosis of the growth hormone family member placental lactogen. The central sorting station for stabilin-1 trafficking seems to be the trans-Golgi network (TGN. Transport of stabilin-1 in the TGN requires interaction with GGA adaptors that bind to the classical DDSLL motif and a novel acidic cluster in its cytoplasmic tail. Degradation of stabilin-1 seems to depend on the interaction with sorting nexin 17. However, the mechanisms keeping stabilin-1 on the cell surface remain to be identified. This issue deserves specific attention due to the growing amount of data indicating that function of stabilin-1 in cell adhesion events is essential for inflammation and metastasis. Taking into consideration the complexity of stabilin-1—mediated processes, investigation of stabilin-1 functions in the animal models, as well as mathematic modeling of intracellular trafficking and extracellular contact, would enable prediction of stabilin-1 behavior in complex biological systems and would open perspectives for therapeutic targeting of stabilin-1 pathways in chronic inflammation and carcinogenesis.

A regulator of G Protein signaling, RGS3, inhibits gonadotropin-releasing hormone (GnRH-stimulated luteinizing hormone (LH secretion

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Musgrove Lois C

2001-11-01

Full Text Available Abstract Background Luteinizing hormone secreted by the anterior pituitary gland regulates gonadal function. Luteinizing hormone secretion is regulated both by alterations in gonadotrope responsiveness to hypothalamic gonadotropin releasing hormone and by alterations in gonadotropin releasing hormone secretion. The mechanisms that determine gonadotrope responsiveness are unknown but may involve regulators of G protein signaling (RGSs. These proteins act by antagonizing or abbreviating interaction of Gα proteins with effectors such as phospholipase Cβ. Previously, we reported that gonadotropin releasing hormone-stimulated second messenger inositol trisphosphate production was inhibited when RGS3 and gonadotropin releasing hormone receptor cDNAs were co-transfected into the COS cell line. Here, we present evidence for RGS3 inhibition of gonadotropin releasing hormone-induced luteinizing hormone secretion from cultured rat pituitary cells. Results A truncated version of RGS3 (RGS3T = RGS3 314–519 inhibited gonadotropin releasing hormone-stimulated inositol trisphosphate production more potently than did RSG3 in gonadotropin releasing hormone receptor-bearing COS cells. An RSG3/glutathione-S-transferase fusion protein bound more 35S-Gqα than any other member of the G protein family tested. Adenoviral-mediated RGS3 gene transfer in pituitary gonadotropes inhibited gonadotropin releasing hormone-stimulated luteinizing hormone secretion in a dose-related fashion. Adeno-RGS3 also inhibited gonadotropin releasing hormone stimulated 3H-inositol phosphate accumulation, consistent with a molecular site of action at the Gqα protein. Conclusions RGS3 inhibits gonadotropin releasing hormone-stimulated second messenger production (inositol trisphosphate as well as luteinizing hormone secretion from rat pituitary gonadotropes apparently by binding and suppressing the transduction properties of Gqα protein function. A version of RGS3 that is amino

Fatty Acid Signaling: The New Function of Intracellular Lipases

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Zuzana Papackova

2015-02-01

Full Text Available Until recently, intracellular triacylglycerols (TAG stored in the form of cytoplasmic lipid droplets have been considered to be only passive “energy conserves”. Nevertheless, degradation of TAG gives rise to a pleiotropic spectrum of bioactive intermediates, which may function as potent co-factors of transcription factors or enzymes and contribute to the regulation of numerous cellular processes. From this point of view, the process of lipolysis not only provides energy-rich equivalents but also acquires a new regulatory function. In this review, we will concentrate on the role that fatty acids liberated from intracellular TAG stores play as signaling molecules. The first part provides an overview of the transcription factors, which are regulated by fatty acids derived from intracellular stores. The second part is devoted to the role of fatty acid signaling in different organs/tissues. The specific contribution of free fatty acids released by particular lipases, hormone-sensitive lipase, adipose triacylglycerol lipase and lysosomal lipase will also be discussed.

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

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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

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

International Nuclear Information System (INIS)

Mann, Monica; Cortez, Valerie; Vadlamudi, Ratna K.

2011-01-01

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

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.

Intracellular Delivery of Nanobodies for Imaging of Target Proteins in Live Cells.

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Röder, Ruth; Helma, Jonas; Preiß, Tobias; Rädler, Joachim O; Leonhardt, Heinrich; Wagner, Ernst

2017-01-01

Cytosolic delivery of nanobodies for molecular target binding and fluorescent labeling in living cells. Fluorescently labeled nanobodies were formulated with sixteen different sequence-defined oligoaminoamides. The delivery of formulated anti-GFP nanobodies into different target protein-containing HeLa cell lines was investigated by flow cytometry and fluorescence microscopy. Nanoparticle formation was analyzed by fluorescence correlation spectroscopy. The initial oligomer screen identified two cationizable four-arm structured oligomers (734, 735) which mediate intracellular nanobody delivery in a receptor-independent (734) or folate receptor facilitated (735) process. The presence of disulfide-forming cysteines in the oligomers was found critical for the formation of stable protein nanoparticles of around 20 nm diameter. Delivery of labeled GFP nanobodies or lamin nanobodies to their cellular targets was demonstrated by fluorescence microscopy including time lapse studies. Two sequence-defined oligoaminoamides with or without folate for receptor targeting were identified as effective carriers for intracellular nanobody delivery, as exemplified by GFP or lamin binding in living cells. Due to the conserved nanobody core structure, the methods should be applicable for a broad range of nanobodies directed to different intracellular targets.

IGF-1 and insulin as growth hormones.

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Laron, Zvi

2004-01-01

IGF-1 generated in the liver is the anabolic effector and linear growth promoting hormone of the pituitary growth hormone (GH). This is evidenced by dwarfism in states of congenital IGF-1 deficiency, Igf1 gene mutation/deletions or knockouts, and in Laron syndrome (LS), due to GH receptor gene mutations/deletions or IGF-1 receptor blocking. In a positive way, daily IGF-1 administration to stunted patients with LS or hGH gene deletion accelerates linear growth velocity. IGF-1 acts on the proliferative cells of the epiphyseal cartilage. IGF-1 also induces organ and tissue growth; its absence causing organomicria. Insulin shares a common ancestry with IGF-1 and with 45% amino acid homology, as well as very close relationships in the structure of its receptors and post-receptor cascade, also acts as a growth hormone. It has protein anabolic activity and stimulates IGF-1 synthesis. Pancreas agenesis causes short babies, and obese children with hyperinsulinism, with or without pituitary GH, have an accelerated growth rate and skeletal maturation; so do babies with macrosomia. Whether the insulin growth effect is direct, or mediated by IGF-1 or leptin is controversial.

Using paleogenomics to study the evolution of gene families: origin and duplication history of the relaxin family hormones and their receptors.

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Sergey Yegorov

Full Text Available Recent progress in the analysis of whole genome sequencing data has resulted in the emergence of paleogenomics, a field devoted to the reconstruction of ancestral genomes. Ancestral karyotype reconstructions have been used primarily to illustrate the dynamic nature of genome evolution. In this paper, we demonstrate how they can also be used to study individual gene families by examining the evolutionary history of relaxin hormones (RLN/INSL and relaxin family peptide receptors (RXFP. Relaxin family hormones are members of the insulin superfamily, and are implicated in the regulation of a variety of primarily reproductive and neuroendocrine processes. Their receptors are G-protein coupled receptors (GPCR's and include members of two distinct evolutionary groups, an unusual characteristic. Although several studies have tried to elucidate the origins of the relaxin peptide family, the evolutionary origin of their receptors and the mechanisms driving the diversification of the RLN/INSL-RXFP signaling systems in non-placental vertebrates has remained elusive. Here we show that the numerous vertebrate RLN/INSL and RXFP genes are products of an ancestral receptor-ligand system that originally consisted of three genes, two of which apparently trace their origins to invertebrates. Subsequently, diversification of the system was driven primarily by whole genome duplications (WGD, 2R and 3R followed by almost complete retention of the ligand duplicates in most vertebrates but massive loss of receptor genes in tetrapods. Interestingly, the majority of 3R duplicates retained in teleosts are potentially involved in neuroendocrine regulation. Furthermore, we infer that the ancestral AncRxfp3/4 receptor may have been syntenically linked to the AncRln-like ligand in the pre-2R genome, and show that syntenic linkages among ligands and receptors have changed dynamically in different lineages. This study ultimately shows the broad utility, with some caveats, of