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Hormone Receptor (hormone + receptor)
Kinds of Hormone Receptor Terms modified by Hormone Receptor Selected AbstractsSingle-Nucleotide Polymorphisms in Corticotropin Releasing Hormone Receptor 1 Gene (CRHR1) Are Associated With Quantitative Trait of Event-Related Potential and Alcohol DependenceALCOHOLISM, Issue 6 2010Andrew C. H. Chen Background:, Endophenotypes reflect more proximal effects of genes than diagnostic categories, hence providing a more powerful strategy in searching for genes involved in complex psychiatric disorders. There is strong evidence suggesting the P3 amplitude of the event-related potential (ERP) as an endophenotype for the risk of alcoholism and other disinhibitory disorders. Recent studies demonstrated a crucial role of corticotropin releasing hormone receptor 1 (CRHR1) in the environmental stress response and ethanol self-administration in animal models. The aim of the present study was to test the potential associations between single-nucleotide polymorphisms (SNPs) in the CRHR1 gene and the quantitative trait, P3 amplitude during the processing of visual target signals in an oddball paradigm, as well as alcohol dependence diagnosis. Methods:, We analyzed a sample from the Collaborative Study on the Genetics of Alcoholism (COGA) comprising 1049 Caucasian subjects from 209 families (including 472 alcohol-dependent individuals). Quantitative transmission disequilibrium test (QTDT) and family-based association test (FBAT) were used to test the association, and false discovery rate (FDR) was applied to correct for multiple comparisons. Results:, Significant associations (p < 0.05) were found between the P3 amplitude and alcohol dependence with multiple SNPs in the CRHR1 gene. Conclusions:, Our results suggest that CRHR1 may be involved in modulating the P3 component of the ERP during information processing and in vulnerability to alcoholism. These findings underscore the utility of electrophysiology and the endophenotype approach in the genetic study of psychiatric disorders. [source] Fluorescence resonance energy transfer and anisotropy reveals both hetero- and homo-energy transfer in the pleckstrin homology-domain and the parathyroid hormone-receptorMICROSCOPY RESEARCH AND TECHNIQUE, Issue 1 2009Ralf Steinmeyer Abstract We present a method and an apparatus of polarized fluorescence resonance energy transfer (FRET) and anisotropy imaging microscopy done in parallel for improved interpretation of the photophysical interactions. We demonstrate this apparatus to better determine the protein,protein interactions in the pleckstrin homology domain and the conformational changes in the Parathyroid Hormone Receptor, a G-protein coupled receptor, both fused to the cyan and yellow fluorescent proteins for either inter- or intramolecular FRET. In both cases, the expression levels of proteins and also background autofluorescence played a significant role in the depolarization values measured in association with FRET. The system has the sensitivity and low-noise capability of single-fluorophore detection. Using counting procedures from single-molecule methods, control experiments were performed to determine number densities of green fluorescence protein variants CFP and YFP where homo resonance energy transfer can occur. Depolarization values were also determined for flavins, a common molecule of cellular background autofluorescence. From the anisotropy measurements of donor and acceptor, the latter when directly excited or when excited by energy transfer, we find that our instrumentation and method also characterizes crucial effects from homotransfer, polarization specific photobleaching and background molecules. Microsc. Res. Tech., 2009. © 2008 Wiley-Liss, Inc. [source] Modulation of Ovarian Function in Female Dogs Immunized with Bovine Luteinizing Hormone ReceptorREPRODUCTION IN DOMESTIC ANIMALS, Issue 1 2002BB Saxena Adult female dogs were immunized with 0.5 mg bovine luteinizing hormone receptor (LH-R) encapsulated in a silastic subdermal implant and subsequently with four intramuscular booster injections of 0.1 mg LH-R each. Circulating LH-R antibody was detected in the sera 3 weeks post-implant. The appearance of LH-R antibody was associated with a decline in the serum progesterone concentrations to a range of 0,0.5 ng/ml until day 365 in the immunized dogs in comparison with a range of 5,10 ng in the control animals, suggesting a lack of ovulation and corpus luteum function in immunized dogs. The immunized dogs did not show signs of `standing heat' and failed to ovulate when induced by LH-RH challenge. Serum oestradiol levels, however, remained in the range of 30,40 pg/ml in both the immunized and the control dogs. With the decline in the antibody titres, the hormonal profile and vaginal cytology returned to a fertile state and the dogs exhibited signs of `standing heat', as well as vaginal bleeding. Dogs immunized with LH-R did not show any serious metabolic, local or systemic adverse effects. The hypothalamic,pituitary gonadal axis remained intact as indicated by little difference in pituitary LH levels between control and immunized animals, and by the release of LH by LH-RH challenge. These studies demonstrate that active immunization of female dogs with LH-R could immunomodulate ovarian function to cause a reversible state of infertility. It may be postulated that, due to extensive interspecies homology, a recombinant LH receptor-based immunocontraceptive vaccine may also be effective in other vertebrates. [source] The Story of Hormone Receptor Assays: Why Are We Still Searching?THE BREAST JOURNAL, Issue 4 2001Shahla Masood No abstract is available for this article. [source] Development of the Thyroid Hormone Receptor ,-Subtype Agonist KB-141 : A Strategy for Body Weight Reduction and Lipid Lowering with Minimal Cardiac Side EffectsCARDIOVASCULAR THERAPEUTICS, Issue 2 2005Gary J. Grover ABSTRACT Few treatments for obesity exist and improvements for treatment of hyperlipidemia are still desirable. Thyroid hormone receptors (TRs) regulate body weight, adiposity, and cholesterol levels. However, thyroid hormones can have deleterious effects, particularly cardiac acceleration, that limits the use of hormones in the treatment of obesity. There is evidence that the TR, subtype mediates lowering of blood cholesterol levels and possibly elevation of metabolic rate, whereas TR, appears to control heart rate. In studies, described in this review article, we examined the effects of selective TR, activation on metabolic rate and heart rate in mice, rats and monkeys. T3 had a greater effect on increasing heart rate in wild type (WT) than in TR,-/- mice (ED15 values of 34 and 469 nmol/kg/day, respectively). T3 increased metabolic rate (MVO2) in both WT and TR,-/- mice, but the effect on TR,-/- mice was less pronounced compared to WT mice. Stimulation of MVO2 is mediated by both TR, and TR,, but with different profiles. In cholesterol-fed rats, KB-141, a selective TR, agonist, increased MVO2 with a 10-fold selectivity and lowered cholesterol with a 27-fold selectivity vs. tachycardia. In primates, KB-141 caused significant, cholesterol, Lp(a) and body weight reduction after 1 week of treatment with no effect on heart rate. These data suggest that selective TR, agonists may represent a novel class of drugs for the treatment of obesity, hypercholesterolemia and elevated Lp(a), which may make them useful therapeutics for patients with metabolic syndrome. [source] The Use of Three-Dimensional Shape and Electrostatic Similarity Searching in the Identification of a Melanin-Concentrating Hormone Receptor 1 AntagonistCHEMICAL BIOLOGY & DRUG DESIGN, Issue 2 2006Steven W. Muchmore To aid in the identification of novel melanin-concentrating hormone receptor 1 (MCHr1) antagonists, a unique virtual library of readily synthesized molecules was designed and assembled based on 323 monomer compounds containing reactive moieties in combination with 30 core molecules having diamine functionality. The resulting library of 3 129 870 molecules was searched using three-dimensional shape similarity measures that were complimented with a novel electrostatic distribution similarity-matching algorithm. One of the top scoring hits in this library was synthesized and characterized for MCHr1 antagonism, where it exhibited at least a threefold improvement in binding affinity and cellular potency relative to the parent MCHr1 ligand. This work demonstrates that the use of shape and electrostatic similarity matching in combination with a well-designed virtual library can be used to augment standard medicinal chemistry techniques. [source] Synthesis and Evaluation of Urea-Based Indazoles as Melanin-Concentrating Hormone Receptor 1 Antagonists for the Treatment of Obesity.CHEMINFORM, Issue 40 2005Andrew J. Souers Abstract For Abstract see ChemInform Abstract in Full Text. [source] Lack of association between amplification of her-2 and response to preoperative taxanes in patients with breast carcinomaCANCER, Issue 2 2004Ana M. Gonzalez-Angulo M.D. Abstract BACKGROUND The objective of the current study was to determine whether her-2 amplification was associated with a pathologic response to preoperative chemotherapy with taxanes in patients with early-stage breast carcinoma. METHODS The authors evaluated 71 patients treated for AJCC Stage II and III breast carcinoma with preoperative taxanes whose tissue specimens were still available. Fifty-seven patients (80%) had received paclitaxel and 14 (20%) had received docetaxel (4 cycles of either drug). Amplification of the her-2 gene was determined using fluorescence in situ hybridization. RESULTS The median patient age was 49 years (range, 21,70 years). Forty-eight patients (68%) had Stage II breast carcinoma and 23 (32%) had Stage III disease. her-2 gene amplification was detected in 19 tumor specimens (28%). Hormone receptors (estrogen and/or progesterone) were detected in 11 her-2,positive tumor specimens (58%) and in 31 her-2,negative tumor specimens (85%). Eight pathologic complete responses (pCR; breast and axillary lymph nodes) occurred, 3 (16%) in patients with her-2,positive tumor specimens and five (10%) in patients with her-2,negative tumor specimens (P = 0.68). Twelve patients achieved pCR in the breast, 5 (26%) in patients with her-2,positive tumors and 7 (15%) in patients with her-2,negative tumors (P = 0.3). At a median follow-up of 61 months, none of the patients with a pCR developed recurrent disease, regardless of their her-2 status. The progression-free and overall survival rates were similar in both HER-2,positive and her-2,negative groups (P = 0.45 and P = 0.14, respectively). CONCLUSIONS her-2 gene amplification was not found to be predictive of a pathologic response to preoperative taxanes in patients with early-stage breast carcinoma. Cancer 2004. © 2004 American Cancer Society. [source] How applicable is the general adaptation syndrome to the unicellular Tetrahymena?CELL BIOCHEMISTRY AND FUNCTION, Issue 1 2009György Csaba Abstract Hormone receptors, hormones and signal transduction pathways characteristic of higher vertebrates can be observed also in the unicellular Tetrahymena. Previous work showed that stress conditions (starvation, high temperature, high salt concentration, formaldehyde or alcohol treatment) elevated the intracellular level of four hormones (ACTH, endorphin, serotonin and T3). Here, the effect of other stressors (CuSO4 poisoning, tryptophan hydroxylase inhibitor parachlorphenylalanine (PCPA) treatment) on the same and other hormones (epinephrine, insulin, histamine) was studied, using immunocytochemistry and flow cytometric analysis. It was found, that each effect increased the intracellular hormone contents, but some hormones (histamine, T3) were less reactive. Insulin,which is a life-saving factor for Tetrahymena,itself provoked elevation of hormone amounts in association with a stressor, further increased the level of hormones. It was concluded that the ancestor of Selye's General Adaptation Syndrome (GAS) can be found already at unicellular level, and this possibly has a life saving function. Copyright © 2008 John Wiley & Sons, Ltd. [source] Thyroid hormone receptor , can control action potential duration in mouse ventricular myocytes through the KCNE1 ion channel subunitACTA PHYSIOLOGICA, Issue 2 2010A. Mansén Abstract Aims:, The reduced heart rate and prolonged QTend duration in mice deficient in thyroid hormone receptor (TR) ,1 may involve aberrant expression of the K+ channel ,-subunit KCNQ1 and its regulatory ,-subunit KCNE1. Here we focus on KCNE1 and study whether increased KCNE1 expression can explain changes in cardiac function observed in TR,1-deficient mice. Methods:, TR-deficient, KCNE1-overexpressing and their respective wildtype (wt) mice were used. mRNA and protein expression were assessed with Northern and Western blot respectively. Telemetry was used to record electrocardiogram and temperature in freely moving mice. Patch-clamp was used to measure action potentials (APs) in isolated cardiomyocytes and ion currents in Chinese hamster ovary (CHO) cells. Results:, KCNE1 was four to 10-fold overexpressed in mice deficient in TR,1. Overexpression of KCNE1 with a heart-specific promoter in transgenic mice resulted in a cardiac phenotype similar to that in TR,1-deficient mice, including a lower heart rate and prolonged QTend time. Cardiomyocytes from KCNE1-overexpressing mice displayed increased AP duration. CHO cells transfected with expression plasmids for KCNQ1 and KCNE1 showed an outward rectifying current that was maximal at equimolar plasmids for KCNQ1-KCNE1 and decreased at higher KCNE1 levels. Conclusion:, The bradycardia and prolonged QTend time in hypothyroid states can be explained by altered K+ channel function due to decreased TR,1-dependent repression of KCNE1 expression. [source] Developmental delay and unstable state of the testes in the rdw rat with congenital hypothyroidismDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 4 2004Yasuhiro Sakai From the present study of the rdw rat, it is clear that the thyroid hormone is essential for the development and maintenance of the testes. In previous studies, the thyroid hormone has few serious effects on the testes except during the neonatal stage when the thyroid hormone receptor is mainly present. However, there is little knowledge concerning the prolonged effect of thyroid hormone deficiency throughout the rat's life span. In the present study, a morphological analysis was performed on the testes of rdw rats with congenital hypothyroidism. The rdw testes required a longer time to develop into the normal adult structure. Moreover, the developed, normal structure began to degenerate after full maturation. Specific characteristics of the rdw testes include: (i) a prolonged proliferation of Sertoli cells during postnatal development; (ii) a developmental delay in the appearance of spermatocytes and spermatid; (iii) direct contact with each other for both spermatocytes and spermatids, without Sertoli cell cytoplasm completely intervening between adjacent germ cells; (iv) subsequent apoptosis of germ cells after maturation; (v) reduction in the height of the seminiferous epithelium; and (vi) lower testosterone levels in the rdw rats, especially during old age. Thus, we conclude that the thyroid hormone plays an important role in developing and maintaining normal function of testes. [source] Transient expression of thyroid hormone nuclear receptor TR,2 sets S opsin patterning during cone photoreceptor genesisDEVELOPMENTAL DYNAMICS, Issue 5 2007M.L. Applebury Abstract Cone photoreceptors in the murine retina are patterned by dorsal repression and ventral activation of S opsin. TR,2, the nuclear thyroid hormone receptor , isoform 2, regulates dorsal repression. To determine the molecular mechanism by which TR,2 acts, we compared the spatiotemporal expression of TR,2 and S opsin from embryonic day (E) 13 through adulthood in C57BL/6 retinae. TR,2 and S opsin are expressed in cone photoreceptors only. Both are transcribed by E13, and their levels increase with cone genesis. TR,2 is expressed uniformly, but transiently, across the retina. mRNA levels are maximal by E17 at completion of cone genesis and again minimal before P5. S opsin is also transcribed by E13, but only in ventral cones. Repression in dorsal cones is established by E17, consistent with the occurrence of patterning during cone cell genesis. The uniform expression of TR,2 suggests that repression of S opsin requires other dorsal-specific factors in addition to TR,2. The mechanism by which TR,2 functions was probed in transgenic animals with TR,2 ablated, TR,2 that is DNA binding defective, and TR,2 that is ligand binding defective. These studies show that TR,2 is necessary for dorsal repression, but not ventral activation of S opsin. TR,2 must bind DNA and the ligand T3 (thyroid hormone) to repress S opsin. Once repression is established, T3 no longer regulates dorsal S opsin repression in adult animals. The transient, embryonic action of TR,2 is consistent with a role (direct and/or indirect) in chromatin remodeling that leads to permanent gene silencing in terminally differentiated, dorsal cone photoreceptors. Developmental Dynamics 236:1203,1212, 2007. © 2007 Wiley-Liss, Inc. [source] Genistein prevents thyroid hormone-dependent tail regression of Rana catesbeiana tadpoles by targetting protein kinase C and thyroid hormone receptor ,DEVELOPMENTAL DYNAMICS, Issue 3 2007L. Ji Abstract Thyroid hormone (TH)-regulated gene expression is mainly mediated by TH binding to nuclear thyroid hormone receptors (TRs). Despite extensive studies in mammalian cell lines that show that phosphorylation signaling pathways are important in TH action, little is known about their roles on TH signaling in vivo during development. Anuran metamorphosis is a postembryonic process that is absolutely dependent upon TH and tadpole tail resorption can be precociously induced by exogenous administration of 3,5,3,-triiodothyronine (T3). We demonstrate that genistein (a major isoflavone in soy products and tyrosine kinase inhibitor) and the PKC inhibitor (H7) prevent T3 -induced regression of the Rana catesbeiana tadpole tail. T3 -induced protein kinase C tyrosine phosphorylation and kinase activity are inhibited by genistein while T3 -induced up-regulation of TR, mRNA, but not TR, mRNA, is significantly attenuated, most likely through inhibition of T3 -dependent phosphorylation of the TR, protein. This phosphorylation may be modulated through PKC. These data demonstrate that T3 signaling in the context of normal cells in vivo includes phosphorylation as an important factor in establishing T3 -dependent tail regression during development. Developmental Dynamics 236:777,790, 2007. © 2007 Wiley-Liss, Inc. [source] Dual mechanisms governing muscle cell death in tadpole tail during amphibian metamorphosisDEVELOPMENTAL DYNAMICS, Issue 2 2003Keisuke Nakajima Abstract The tadpole tail, which is twice as long as the body, is induced to resorb completely by thyroid hormone within several days during the anuran metamorphosis. To investigate the underlying mechanism, we undertook two approaches. First, we examined the effect of dominant-negative thyroid hormone receptor (DNTR) on muscle cell death in vitro. The overexpression of DNTR suppressed the death of a tail-derived myoblastic cell line induced by thyroid hormone. Second, tadpole tails were injected with a reporter gene and the DNTR expression construct, and the reporter gene expression in muscle cells was followed during the spontaneous metamorphosis. DNTR overexpression inhibited a decrease of the reporter gene expression that began at stage 57 in the control tadpoles but only delayed massive muscle cell death at stage 63 when tails shrink very rapidly. Some remained even a few weeks after the metamorphosis, although most DNTR-overexpressing cells died by the end of the metamorphosis. These results led us to propose that thyroid hormone induces the suicide of muscle cells (the cell-autonomous death) in the tail between stage 57 and 62 and that both the murder and suicide mechanisms execute muscle cell death in stage 62,64 to remove muscle promptly and completely. Developmental Dynamics 227:246,255, 2003. © 2003 Wiley-Liss, Inc. [source] Effect of di(n -butyl) phthalate on testicular oxidative damage and antioxidant enzymes in hyperthyroid ratsENVIRONMENTAL TOXICOLOGY, Issue 3 2007Ena Lee Abstract This study compared the effects of di(n-butyl) phthalate (DBP) on the oxidative damage and antioxidant enzymes activity in testes of hyperthyroid rats. Hyperthyroidism was induced in pubertal male rats by intraperitoneal injection of triiodothyronine (T3, 10 ,g/kg body weight) for 30 days. An oral dose of DBP (750 mg/kg) was administered simultaneously to normal or hyperthyroid (T3) rats over a 30-day period. No changes in body weight were observed in the hyperthyroid groups (T3, T3 + DBP) compared with controls. There were significantly higher serum T3 levels observed in the hyperthyroid rats than in the control, but the serum thyroid stimulating hormone levels were markedly lower in the hyperthyroid rats. DBP significantly decreased the weight of the testes in the normal (DBP) and hyperthyroid (T3 + DBP) groups. The serum testosterone concentrations were significantly lower in only DBP group. DBP significantly increased the 8-hydroxy-2-deoxyguanosine (8-OHdG) level in the testes, whereas the DBP-induced 8-OHdG levels were slightly higher in T3 + DBP group. Superoxide dismutase and glutathione peroxidase activities were significantly higher in the testes of the DBP or T3 + DBP groups. Catalase (CAT) activity was significantly higher in the DBP treatment group, but the T3 + DBP group showed slightly lower DBP-induced CAT activity. The testicular expression of thyroid hormone receptor ,-1 (TR,-1) was significantly higher in the DBP groups, and androgen receptor (AR) expression was not detected in the DBP treatment group. In addition, DBP significantly increased the peroxisome proliferator-activated receptor-r (PPAR-r) levels in the testis. These results suggest that hyperthyroidism can cause a change in the expression level of PPAR-r in testes, and may increase the levels of oxidative damage induced by the metabolic activation of DBP. © 2007 Wiley Periodicals, Inc. Environ Toxicol 22: 245,255, 2007. [source] Time-Dependent transcriptional profiles of genes of the hypothalamic-pituitary-gonadal axis in medaka (Oryzias latipes) exposed to fadrozole and 17,-trenboloneENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 12 2008Xiaowei Zhang Abstract Both the anabolic androgen 17,-trenbolone (TRB) and the aromatase inhibitor fadrozole (FAD) can cause decreased plasma concentrations of estrogen (E2) and reduce fecundity of fish. However, the underlying mechanisms and the molecular pathways involved are largely unknown. The present study was designed to assess time-dependent effects of FAD and TRB on the transcriptional responses of the hypothalamic-pituitary-gonadal (HPG) axis of Japanese medaka (Oryzias latipes). Fourteen-week-old Japanese medaka were exposed to 50 ,g FAD/L or 2 ,g TRB/L in a 7-d static renewal test, and the expression profiles of 36 HPG axis genes were measured by means of a medaka HPG real-time reverse-transcription polymerase chain reaction array after 8 h, 32 h, or 7 d of exposure. Exposure to TRB or FAD caused lesser fecundity of Japanese medaka and down-regulated transcription of vitellogenin and choriogenin (CHG) gene expression in the liver of females. Exposure to FAD for 8 h resulted in an 8-fold and 71-fold down-regulation of expression of estrogen receptor , and choriogenin L (CHG L), respectively, in female liver. 17,-Trenbolone caused similar down-regulation of these genes, but the effects were not observed until 32 h of exposure. These results support the hypothesis that FAD reduces plasma E2 more quickly by inhibiting aromatase enzyme activity than does TRB, which inhibits the production of the E2 precursor testosterone. Exposure to FAD and TRB resulted in rapid (after 8 h) down-regulation of luteinizing hormone receptor and low-density-lipoprotein receptor in the testis to compensate for excessive androgen levels. Overall, the molecular responses observed in the present study differentiate the mechanisms of the reduced fecundity by TRB and FAD. [source] GENETIC STUDY: H2 haplotype at chromosome 17q21.31 protects against childhood sexual abuse-associated risk for alcohol consumption and dependenceADDICTION BIOLOGY, Issue 1 2010Elliot C. Nelson ABSTRACT Animal research supports a central role for corticotropin-releasing factor (CRF) in actions of ethanol on brain function. An examination of alcohol consumption in adolescents reported a significant genotype × environment (G × E) interaction involving rs1876831, a corticotropin-releasing hormone receptor 1 (CRHR1) polymorphism, and negative events. CRHR1 and at least four other genes are located at 17q21.31 in an extremely large block of high linkage disequilibrium resulting from a local chromosomal inversion; the minor allele of rs1876831 is contained within the H2 haplotype. Here, we examine whether G × E interactions involving this haplotype and childhood sexual abuse (CSA) are associated with risk for alcohol consumption and dependence in Australian participants (n = 1128 respondents from 476 families) of the Nicotine Addiction Genetics project. Telephone interviews provided data on DSM-IV alcohol dependence diagnosis and CSA and enabled calculation of lifetime alcohol consumption factor score (ACFS) from four indices of alcohol consumption. Individuals reporting a history of CSA had significantly higher ACFS and increased risk for alcohol dependence. A significant G × E interaction was found for ACFS involving the H2 haplotype and CSA (P < 0.017). A similar G × E interaction was associated with protective effects against alcohol dependence risk (odds ratio 0.42; 95% confidence interval 0.20,0.89). For each outcome, no significant CSA-associated risk was observed in H2 haplotype carriers. These findings support conducting further investigation of the H2 haplotype to determine the gene(s) responsible. Our results also suggest that severe early trauma may prove to be an important clinical covariate in the treatment of alcohol dependence. [source] Growth hormone excess and the development of growth hormone receptor antagonistsEXPERIMENTAL PHYSIOLOGY, Issue 11 2008C. E. Higham In 1990, a single amino acid substitution in the growth hormone (GH) gene at position 119 was found to transform the consequent protein from an agonist to an antagonist at the growth hormone receptor (GHR). Further amino acid substitutions plus prolongation of the half-life of the protein by pegylation resulted in the first clinically effective GHR antagonist, pegvisomant. Following extensive clinical trials, this medication has emerged as the most efficacious therapy for treatment-resistant acromegaly. Subsequent advances in our understanding of GH,GHR interactions and downstream GH signalling pathways suggest that pegvisomant binds to preformed GHR dimers and prevents rotational changes within the receptor,GH complex necessary for intracellular signalling to occur. This article reviews the discovery of pegvisomant, from initial experimental data to successful licensing of the drug for treatment-resistant acromegaly, and discusses its other potential therapeutic uses in diseases with abnormalities in the GH,IGF-I axis. [source] Thyroid hormone induces the expression of 4-1BB and activation of caspases in a thyroid hormone receptor-dependent mannerFEBS JOURNAL, Issue 14 2003Toshiko Yamada-Okabe Thyroid hormone has various effects on cell proliferation, growth and apoptosis. To gain more insight into the molecular dynamics caused by thyroid hormone, gene expression in HeLaTR cells that constitutively overexpressed the thyroid hormone receptor (TR) was analyzed. Gene expression profiling of the HeLaTR cells with an oligonucleotide microarray yielded 229 genes whose expression was significantly altered by T3. Among these genes, the expression of 4-1BB, which is known to initiate a signal cascade activating NF-,B, was significantly up-regulated by T3. Although treatment of the HeLaTR cells with T3 did not induce expression of NF-,B reporter luciferase, even in the presence of the 4-1BB-Ligand, it increased the caspase activities. An increase in the caspase activities was also observed in the HeLaTR cells transfected with 4-1BB cDNA, and the 4-1BB-Ligand further increased the caspase activities of the HeLaTR cells overexpressing the 4-1BB. Furthermore, up-regulation of 4-1BB and an increase in caspase activities also occurred in the rat FRTL cells that expressed only authentic TR. These results demonstrate that the expression of 4-1BB serves as the mediator of signals from T3 to activate caspases. [source] Sodium pump and steroid hormone receptorFEBS JOURNAL, Issue 10 2002Na+/K+ -ATPase No abstract is available for this article. [source] Hormonal regulation of multiple promoters of the rat mitochondrial glycerol-3-phosphate dehydrogenase geneFEBS JOURNAL, Issue 14 2001Identification of a complex hormone-response element in the ubiquitous promoter B Rat mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) is regulated by multiple promoters in a tissue-specific manner. Here, we demonstrate that thyroid hormone (3,5,3,-tri-iodo- l -thyronine) and steroid hormone but not the peroxisome proliferator clofibrate and retinoic acid stimulate the activation of the ubiquitous promoter B in a receptor-dependent manner, whereas the more tissue-restricted promoters A and C are not inducible by these hormones. Thyroid hormone action is mediated by a direct repeat +4 (DR+4) hormone-response element as identified by deletion and mutation analyses of promoter B in transient transfection analyses. The DR+4 element was able to bind to an in vitro translated thyroid hormone receptor in band-shift and supershift experiments. The hormone-response element comaps with a recognition site for the transcription factor Sp1, suggesting complex regulation of this sequence element. Mutation of this Sp1-recognition site reduces the basal promoter B activity dramatically in HepG2 and HEK293 cells in transient transfection and abolishes the binding of Sp1 in band-shift experiments. As demonstrated by Western-blot experiments, administration of tri-iodothyronine to euthyroid rats increases hepatic mGPDH protein concentrations in vivo. As it has recently been reported that human mGPDH promoter B is not regulated by tri-iodothyronine, this is the first example of a differentially tri-iodothyronine-regulated orthologous gene promoter in man and rat. [source] Analysis of growth hormone receptor polymorphism in Japanese semisuper centenariansGERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 2 2006Yuchen Du Background: Recent studies have demonstrated a significant association between mutations in genes involved in the GHR/IGF1 signaling pathway and extension of the lifespan of model organisms. Exon 3 insertion or deletion is one common polymorphism in the growth hormone receptor (GHR) of humans. The exon 3 deletion allele is reported to have stronger signaling in the GH/GHR pathway, which may correlate to short lifespan. Methods: We investigated the common polymorphic variation in 119 Japanese semisuper centenarians (SSC; older than 105) compared with 104 healthy younger controls via the polymorphism-based polymerase chain reaction method. Results: The frequency of exon 3 deletion variation of GHR in SSC was found to be higher than controls, although this was not significant statistically. Also, the single nucleotide polymorphism genotype frequency and allele frequency exhibited no differences between SSC and controls. Conclusions: These results show that SSC in Japan do not tend to have the allele of GHR, which has a lower signaling capacity. [source] Immunophenotypic features of MELF pattern invasion in endometrial adenocarcinoma: evidence for epithelial,mesenchymal transitionHISTOPATHOLOGY, Issue 1 2009Colin J R Stewart Aims:, Endometrial endometrioid adenocarcinomas (EEC) may show a distinctive morphological alteration characterized by the presence of microcystic, elongated and fragmented (,MELF') glands. These changes share features of epithelial,mesenchymal transition (EMT) in carcinomas arising at other sites. The aim was to compare the immunophenotypic profile of MELF-type epithelium with conventional glandular areas of EEC. Methods and results:, Twenty-one EEC were stained immunohistochemically for cytokeratin (CK) AE1/AE3, CK7, vimentin, oestrogen receptor, progesterone receptor and E-cadherin. Conventional tumour glands usually showed preserved membranous E-cadherin immunoreactivity with peripheral accentuation of vimentin and hormone receptor expression. MELF-type invasion was characterized by strong CK7 expression, sometimes in contrast to adjacent unstained tumour glands. MELF areas were usually negative for hormone receptors and showed reduced E-cadherin expression. Conclusions:, The expression of hormone receptors and intermediate filaments shows specific distribution patterns within EEC. MELF pattern invasion shows an altered immunophenotype compared with conventional glandular tumour areas. These findings suggest that MELF-type invasion represents a specific tumour alteration, and the reduction in hormone receptor and E-cadherin expression would be consistent with EMT. Immunohistochemical studies of EEC should consider micro anatomical variations in immunoreactivity, since these may be relevant to tumour invasion and progression. [source] Triple negative tumours: a critical reviewHISTOPATHOLOGY, Issue 1 2008J S Reis-Filho Breast cancer is a heterogeneous disease that encompasses several distinct entities with remarkably different biological characteristics and clinical behaviour. Currently, breast cancer patients are managed according to algorithms based on a constellation of clinical and histopathological parameters in conjunction with assessment of hormone receptor (oestrogen and progesterone receptor) status and HER2 overexpression/gene amplification. Although effective tailored therapies have been developed for patients with hormone receptor-positive or HER2+ disease, chemotherapy is the only modality of systemic therapy for patients with breast cancers lacking the expression of these markers (triple-negative cancers). Recent microarray expression profiling analyses have demonstrated that breast cancers can be systematically characterized into biologically and clinically meaningful groups. These studies have led to the re-discovery of basal-like breast cancers, which preferentially show a triple-negative phenotype. Both triple-negative and basal-like cancers preferentially affect young and African-American women, are of high histological grade and have more aggressive clinical behaviour. Furthermore, a significant overlap between the biological and clinical characteristics of sporadic triple-negative and basal-like cancers and breast carcinomas arising in BRCA1 mutation carriers has been repeatedly demonstrated. In this review, we critically address the characteristics of basal-like and triple-negative cancers, their similarities and differences, their response to chemotherapy as well as strategies for the development of novel therapeutic targets for these aggressive types of breast cancer. In addition, the possible mechanisms are discussed leading to BRCA1 pathway dysfunction in sporadic triple-negative and basal-like cancers and animal models for these tumour types. [source] Molecular cloning and immunolocalization of a diuretic hormone receptor in rice brown planthopper (Nilaparvata lugens)INSECT MOLECULAR BIOLOGY, Issue 5 2004D. R. G. Price Abstract RNA extracted from guts of rice brown planthopper, Nilaparvata lugens, was used to clone cDNA predicted to encode a diuretic hormone receptor (DHR). The DHR, a member of the calcitonin/secretin/corticotropin-releasing factor family of G-protein-coupled receptors, contains seven transmembrane domains and a large N-terminal extracellular domain potentially involved in hormone binding. The N-terminal domain was expressed as a recombinant protein, purified and used to raise antibodies. Anti-DHR IgG bound specifically to Malpighian tubules in immunolocalization experiments using dissected guts, and to a putative DHR polypeptide from N. lugens gut on Western blots. Anti-DHR IgG delivered orally to insects was not detected in the haemolymph, and showed no binding to gut or tubules, confirming that DHR N-terminal hormone-binding domain is not exposed to the gut lumen. [source] Steroid hormone receptors and coregulators in endocrine-resistant and estrogen-independent breast cancer cellsINTERNATIONAL JOURNAL OF CANCER, Issue 4 2006Nanna Sarvilinna Abstract Resistance to hormonal therapy is often a problem in the treatment of breast cancer patients. It has been suggested that resistance could be explained by altered nuclear hormone receptor or coregulator levels or inappropriately increased agonist activity of selective estrogen receptor modulator (SERM). To test these hypotheses, we have established novel MCF-7 cell line-derived in vitro models of anti-estrogen- and progestin-resistant and estrogen-independent breast cancer by long-term culture in the presence of toremifene and medroxyprogesterone acetate (MPA) and in the absence of estradiol, respectively. Using cell growth and multiprobe ribonuclease protection assays, the expression of 5 nuclear hormone receptors and 9 coregulators as well as the alterations in the cell proliferation and target gene transcription in response to hormonal treatments were studied. Progesterone receptor (PR) expression was decreased and silencing mediator for retinoid acid and thyroid hormone receptors (SMRT) and amplified in breast cancer-1 (AIB1) expression increased in anti-estrogen-resistant cells. Estrogen caused PR and ER, upregulation in all cell lines, but we did not observe increased agonist activity of anti-estrogen measured by regulation of these estrogen target genes. Basal ER, levels and estrogenic growth response were decreased and p300/CBP-associated factor (pCAF) and AIB1 upregulated by estrogen in progestin-resistant cells, but coregulator levels were unchanged. Estrogen-independent cells were still estrogen-responsive and PR, nuclear receptor corepressor (N-CoR) and SMRT expression was increased whereas steroid receptor coactivator-1 (SRC-1a) and CBP-related protein p300 (p300) expression decreased. Their growth was inhibited by toremifene, but estradiol was able to abrogate this effect, which might have interesting clinical implications concerning the use of postmenopausal hormone replacement therapy. © 2005 Wiley-Liss, Inc. [source] Akt is frequently activated in HER2/neu-positive breast cancers and associated with poor prognosis among hormone-treated patientsINTERNATIONAL JOURNAL OF CANCER, Issue 2 2006Eriko Tokunaga Abstract Akt/PKB is a serine/threonine kinase that plays an important role in survival when cells are exposed to different apoptotic stimuli. Aberrant activation of Akt/PKB in breast carcinoma is associated with poor prognosis and resistance to endocrine therapy and chemotherapy. The Akt signaling pathway currently attracts considerable attention as a new target for effective therapeutic strategies. We therefore investigated the relationship between activation of Akt and clinicopathologic variables including hormone receptor and HER2/neu status. Breast cancer tissues obtained from 252 patients were utilized for this study. We evaluated Akt activation by immunohistochemical assessment of the expression of phosphorylated Akt (pAkt) at Ser-473. Eighty-four cases (33.3%) were diagnosed as positive for pAkt expression. pAkt was significantly associated with HER2/neu overexpression (p < 0.0001). There was an inverse correlation between pAkt and PR expression (p = 0.0321); however, there was no association between pAkt and ER expression. Survival analysis showed that pAkt positivity was associated with poor disease-free survival in cases with postoperative hormone therapy; however, there was no association in cases without hormone therapy. Our results indicate that Akt activation induced poor prognosis in patients who received adjuvant hormone therapy. This finding suggests that inhibition of the Akt signaling pathway may increase the efficacy of hormone therapy and improve the prognosis of patients who receive adjuvant hormone therapy. © 2005 Wiley-Liss, Inc. [source] Simultaneous triple organ specific autoantibody profiling in adult patients with type 1 diabetes mellitus and their first-degree relatives,INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 3 2009S. Dagdelen Summary Aims:, We aimed to document prevalence and clinical presentations of seropositivities for glutamate decarboxylase (GAD)-antibody, celiac's disease (CD) and autoimmune thyroiditis (AIT) in adult patients with type 1 diabetes mellitus (T1DM), and their first-degree relatives. Methods:, Sixty-five patients with T1DM, 124 first-degree relatives and 65 healthy controls were screened for GAD-antibody, anti-thyroid peroxidase (ATPO), anti-thyroid stimulating hormone receptor (TSHR), anti-tissue transglutaminase and anti-gliadin antibodies in a matched case,control study. Results:, Prevalence of more than one seropositivity for CD-associated antibodies in T1DM-group is 6.0 times increased, compared with controls (p < 0.05). ATPO seropositivity is 5.3 times increased in T1DM group (p < 0.05), but TSHR antibody is comparable with controls (p > 0.05). Seropositivities for T1DM, AIT and CD are 4.3, 1.9 and 2.4 times more prevalent among first-degree relatives respectively, compared with controls (p < 0.05). Pathologically confirmed cases with CD among first-degree relatives were all identified at screening. In contrast, all of pathologically confirmed cases with CD in T1DM group, were either previously diagnosed or symptomatic at time of screening. In the group of patients with T1DM, 31% of seropositive cases for anti-ATPO were clinically latent for AIT, and 74% of ATPO (+) cases were identified at current screening study. Sixty-four per cent of ATPO (+) first-degree relatives were clinically latent for AIT, and 54% were identified at screening. Conclusion:, Type 1 diabetes mellitus, CD and AIT represent a significant overlap in an adult population with already-diagnosed T1DM and their first-degree relatives. With regard to clinical presentations, CD was less likely to be clinically silent than AIT among patients with T1DM. [source] Effects of vegetable feed ingredients on bone health in Atlantic salmonJOURNAL OF APPLIED ICHTHYOLOGY, Issue 2 2010P. G. Fjelldal Summary The aim of the present study was to examine if dietary inclusion of vegetable lipids (VL) and proteins (VP) influenced markers of bone health in Atlantic salmon. Triplicate groups were fed one of four different diets; 100% fish protein (FP) and fish lipids (FL) (FPFL), 80% VP and 35% VL (80VP35VL), 40% VP and 70% VL (40VP70VL), or 80% VP and 70% VL (80VP70VL) for 12 months on-growth in sea water. Fish were analyzed for vertebral bone mineralization (mineral content, as % of bone dry weight), vertebral deformities (radiology), vertebral bone mRNA expression of factors involved in mineralization (bone gla protein, bgp) and growth regulation (igf-I and growth hormone receptor), as well as plasma vitamin D metabolites. The fish grew from 0.35 to 4 kg during the experimental period. At the end of the experiment, significantly lower prevalence of fish with one or more deformed vertebrae was observed in the 80VP70VL group (11%) compared to the other groups (33,43%). There was a significant higher relative expression of igf -I mRNA in vertebral bone of fish fed the 80VP70VL diet compared to control fish (FPFL), while the other genes studied were unaffected. Elevated plasma 25-hydroxyvitamin D3 recorded in the marine feed group is discussed as a predictor for later development of bone deformities. In conclusion, the present study shows that high inclusion levels of vegetable lipids and proteins may have a positive effect on bone health in Atlantic salmon postsmolts. [source] Quantitative analysis of agonist-dependent parathyroid hormone receptor trafficking in whole cells using a functional green fluorescent protein conjugateJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2001Bruce R. Conway Many G-protein coupled receptors (GPCRs) undergo ligand-dependent internalization upon activation. The parathyroid hormone (PTH) receptor undergoes endocytosis following prolonged exposure to ligand although the ultimate fate of the receptor following internalization is largely unknown. To investigate compartmentalization of the PTH receptor, we have established a stable cell line expressing a PTH receptor,green fluorescent protein (PTHR,GFP) conjugate and an algorithm to quantify PTH receptor internalization. HEK 293 cells expressing the PTHR,GFP were compared with cells expressing the wild-type PTH receptor in whole-cell binding and functional assays. 125I-PTH binding studies revealed similar Bmax and kD values in cells expressing either the PTHR,GFP or the wild-type PTH receptor. PTH-induced cAMP accumulation was similar in both cell lines suggesting that addition of the GFP to the cytoplasmic tail of the PTH receptor does not alter the ligand binding or G-protein coupling properties of the receptor. Using confocal fluorescence microscopy, we demonstrated that PTH treatment of cells expressing the PTHR,GFP conjugate produced a time-dependent redistribution of the receptor to the endosomal compartment which was blocked by pretreatment with PTH antagonist peptides. Treatment with hypertonic sucrose prevented PTH-induced receptor internalization, suggesting that the PTH receptor internalizes via a clathrin-dependent mechanism. Moreover, co-localization with internalized transferrin showed that PTHR,GFP trafficking utilized the endocytic recycling compartment. Experiments using cycloheximide to inhibit protein synthesis demonstrated that recycling of the PTHR,GFP back to the plasma membrane was complete within 1,2 h of ligand removal and was partially blocked by pretreatment with cytochalasin D, but not nocodazole. We also demonstrated that the PTH receptor, upon recycling to the plasma membrane, is capable of undergoing a second round of internalization, a finding consistent with a role for receptor recycling in functional resensitization. © 2001 Wiley-Liss, Inc. [source] | |||||||||||||||||||||||||||||||||||||