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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth hormone is believed to activate the growth hormone receptor (GHR) by dimerizing two identical receptor subunits, leading to activation of JAK2 kinase associated with the cytoplasmic domain. However, we have reported previously that dimerization alone is insufficient to activate full-length GHR. By comparing the crystal structure of the liganded and unliganded human GHR extracellular domain, we show here that there is no substantial change in its conformation on ligand binding. However, the receptor can be activated by rotation without ligand by inserting a defined number of alanine residues within the transmembrane domain. Fluorescence resonance energy transfer (FRET), bioluminescence resonance energy transfer (BRET) and coimmunoprecipitation studies suggest that receptor subunits undergo specific transmembrane interactions independent of hormone binding. We propose an activation mechanism involving a relative rotation of subunits within a dimeric receptor as a result of asymmetric placement of the receptor-binding sites on the ligand.
Nat Struct Mol Biol 2005 Sep
PMID:Model for growth hormone receptor activation based on subunit rotation within a receptor dimer. 1611 38

Growth hormone and prolactin are important growth factors for pancreatic beta-cells. The effects exerted by these hormones on proliferation and on insulin synthesis and secretion in beta-cells are largely mediated through the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway. Suppressors of cytokine signaling (SOCS) proteins are specific inhibitors of the JAK/STAT pathway acting through a negative-feedback loop. To investigate in vivo effects of SOCS-3 in growth hormone (GH)/prolactin signaling in beta-cells we generated transgenic mice with beta-cell-specific overexpression of SOCS-3. The relative beta-cell proliferation and volume in the mice were measured by morphometry. Beta-cell volume of transgenic female mice was reduced by over 30% compared with beta-cell volume in wild-type female mice. Stimulation of transgenic islets in vitro with GH showed a reduced tyrosine phosphorylation of STAT-5 when compared with wild-type islets. Transduction of primary islet cultures with adenoviruses expressing various SOCS proteins followed by stimulation with GH or glucagon-like peptide-1 (GLP-1) revealed that SOCS-3 inhibited GH- but not GLP-1-mediated islet cell proliferation, indicating that the decreased beta-cell volume observed in female transgenic mice could be caused by an inhibition of GH-induced beta-cell proliferation by SOCS-3. In spite of the reduced beta-cell volume the transgenic female mice exhibited enhanced glucose tolerance compared with wild-type littermates following an oral glucose-tolerance test. Together these data suggest that SOCS-3 modulates cytokine signaling in pancreatic beta-cells and therefore potentially could be a candidate target for development of new treatment strategies for diabetes.
J Mol Endocrinol 2005 Oct
PMID:Regulation of pancreatic beta-cell mass and proliferation by SOCS-3. 1621 5

The human GH family consists of five genes, including the placental chorionic somatomammotropins (CS), within a single locus on chromosome 17. Based on nuclease sensitivity, the entire GH/CS locus is accessible in pituitary chromatin, yet only GH-N is expressed. Previously, we reported a P sequence element (263P) capable of repressing placental CS-A promoter activity in transfected pituitary (GC) cells, and our data indicated a possible role for nuclear factor-1 (NF-1) and regulatory factor X1 in this repression. In this study we show the formation of two independent pituitary complexes in vitro: a repressor complex containing NF-1 and a nonfunctional complex containing regulatory factor X1. In vitro repressor function is stabilized by the presence of P sequence element C (PSE-C), downstream of the previously characterized PSE-A and PSE-B. Repressor function is also dependent on an intact Pit-1 binding site in the CS-A promoter. EMSAs with PSE-C reveal binding of the hepatocyte nuclear factor-3/forkhead (HNF-3/fkh) family of transcription factors in rat pituitary GC cells. This observation is extended to human pituitary tissue, where HNF-3alpha's association with P sequences is confirmed by chromatin immunoprecipitation. Furthermore, protein-protein interactions between HNF-3alpha and NF-1 family members are demonstrated. These results identify HNF-3alpha as an additional member of the pituitary P sequence regulatory complex, implicating it in tissue-specific expression of the human GH/CS family.
Mol Endocrinol 2006 Mar
PMID:Hepatocyte nuclear factor-3alpha binding at P sequences of the human growth hormone locus is associated with pituitary repressor function. 1623 59

Growth hormone (GH) is known to play a key role in the regulation of body growth and metabolism. Similar to mammals, GH secretion in fish is under the control of hypothalamic factors. Besides, signals generated within the pituitary and/or from peripheral tissues/organs can also exert a feedback control on GH release by effects acting on both the hypothalamus and/or anterior pituitary. Among these feedback signals, the functional role of IGF is well conserved from fish to mammals. In contrast, the effects of steroids and thyroid hormones are more variable and appear to be species-specific. Recently, a novel intrapituitary feedback loop regulating GH release and GH gene expression has been identified in fish. This feedback loop has three functional components: (i) LH induction of GH release from somatotrophs, (ii) amplification of GH secretion by GH autoregulation in somatotrophs, and (iii) GH feedback inhibition of LH release from neighboring gonadotrophs. In this article, the mechanisms for feedback control of GH synthesis and secretion are reviewed and functional implications of this local feedback loop are discussed. This intrapituitary feedback loop may represent a new facet of pituitary research with potential applications in aquaculture and clinical studies.
Comp Biochem Physiol A Mol Integr Physiol 2006 Jul
PMID:Feedback regulation of growth hormone synthesis and secretion in fish and the emerging concept of intrapituitary feedback loop. 1640 25

Growth hormone (GH) mRNA and protein have recently been localized in the neural retina of embryonic chicks, in which exogenous GH promotes cell survival. GH is also expressed in the rat CNS, in which it has neuroprotective roles, although its presence in the rat neural retina is unknown and is the focus of the present study. GH immunoreactivity, to a 22-kDa protein, was present in extracts of fetal (embryonic day [ED]17) eyes and in extracts from the neural retinas of newborn pups, comparable to GH immunoreactivity in pituitary extracts. The GH immunoreactivity in the neural retina was widespread but was most intense in large rounded cells in the retinal ganglion cell (RGC) layer and in the optic fiber layer derived from the axons of the RGCs. A 693-bp cDNA was also generated by the RT-PCR of RNA extracted from the eyes of ED17 rats and from the neural retinas and eyes of newborn rats, when amplified in the presence of oligonucleotide primers for the rat GH cDNA. Expression of the GH gene in the neural retina was also shown by specific in situ hybridization of an antisense GH riboprobe to cells in the neural retina, particularly those in the RGC layers of fetal and adult rat eyes. These results demonstrate GH expression in the neural retinas of fetal, newborn, and adult rats, in which retinal GH might have neuroprotective roles.
J Mol Neurosci 2006
PMID:Retinal growth hormone in perinatal and adult rats. 1669 Oct 13

Growth hormone-deficient (GHD) patients show a decreased number of adipocytes, which is normalized by GH replacement, indicating an adipogenic effect of GH. However, the precise mechanisms underlying this effect remain to be clarified. In this study, we investigated the adipogenic effect of GH. GH stimulated MDI (3-isobutyl-1-methylxanthine, dexamethasone, and insulin)-induced adipogenesis of 3T3-L1 cells with early induction of peroxisome proliferator-activated receptors (PPAR)gamma2 expression. This adipogenic effect of GH was suppressed by overexpression of Stat5A mutant (Stat5A-Y694F), a transcriptional suppressor for the GH-Stat5A/5B signaling pathway, with the reduction of PPARgamma2 expression. Next, we investigated the relationship between Stat5A/5B and CCAAT/enhancer binding protein (C/EBP)beta/delta orPPARgamma in 3T3-L1 cells. Stat5A/5B stimulated C/EBPbeta- and C/EBPdelta-induced adipogenesis with enhancement of PPARgamma2 expression. In addition, Stat5A/5B enhanced the transcriptional activity of C/EBPbeta/delta in the PPARgamma gene promoter. Furthermore, Stat5A/5B stimulated PPARgamma-induced adipogenesis and enhanced the transcriptional activity of PPARgamma. These results suggest that the GH-Stat5A/5B signaling pathway stimulates adipogenesis in cooperation with C/EBPbeta/delta and PPARgamma. To completely understand the effect of GH, cDNA microarray analysis was performed to screen genes affected by GH during MDI-induced adipogenesis. Among 4277 genes, 18 and 19 genes were up- and down-regulated respectively. cDNA microarray analysis also indicated the up-regulation of PPARgamma and the modulation of expression of genes coding for growth factors or growth factor receptors, suggesting that GH stimulates adipogenesis in association with the modulation of cell growth. Thus, the GH-Stat5A/B signaling pathway stimulates adipogenesis through two distinct steps. In addition, cDNA microarray data provide us the further insights underlying the adipogenic effect of GH.
J Mol Endocrinol 2007 Feb
PMID:Growth hormone stimulates adipogenesis of 3T3-L1 cells through activation of the Stat5A/5B-PPARgamma pathway. 1724 67

Growth hormone (GH) has many important physiological roles in the control of growth, metabolism and reproduction, which is mediated by growth hormone receptor (GHR). In this study, two cDNAs encoding GHR were isolated from the liver of Nile tilapia (Oreochromis niloticus). The two cDNAs, one consisting of 1908 bp and the other of 1728 bp, encoding for putative 635- and 575-amino acid GHR (designated ntGHR1 and ntGHR2, respectively), shared 34.4% identity in nucleotide sequence and 29.6% in deduced amino acid sequence. Northern blot analysis indicated a single 6.0-kb transcript of ntGHR1 and a single 4.0-kb transcript of ntGHR2 in the liver. Real-time RT-PCR analysis showed that both ntGHR1 and ntGHR2 mRNAs were presented in all tissues tested and expressed extremely highly in the liver. In most tissues, ntGHR2 expressed significantly higher than ntGHR1. Analysis of the ntGHRs expression profiles in the gonad during reproductive cycle indicated that the mRNA levels of ntGHRs in ovary were significantly higher at sexual matured stage while those in testis were significantly higher at sexual recrudescent stage, suggesting that GH/IGF-I axis might be involved in reproduction under a regulatory mechanism of GHR gene expression.
Comp Biochem Physiol B Biochem Mol Biol 2007 Jun
PMID:Two growth hormone receptors in Nile tilapia (Oreochromis niloticus): molecular characterization, tissue distribution and expression profiles in the gonad during the reproductive cycle. 1734 48

Growth hormone overexpression increases growth and consequently increases the metabolic rate in fishes. Therefore, the objective of this study was to evaluate the effects of growth hormone overexpression in zebrafish Danio rerio in terms of growth, oxygen consumption, reactive oxygen species production, lipid hydroperoxide content, antioxidant enzyme activity and glutamate-cysteine ligase catalytic subunit gene expression. The employed models were wild type and transgenic (hemizygous and homozygous) zebrafish expressing the Odonthestes argentinensis growth hormone gene directed by the Cyprinus carpio beta-actin promoter. Higher growth parameters were observed in the hemizygous group. The homozygous group possessed higher oxygen consumption and reactive oxygen species production. Growth hormone transgenesis causes a decrease in glutamate-cysteine ligase catalytic subunit expression, an enzyme responsible for glutathione synthesis. Although the lipid hydroperoxide content was similar between groups, we demonstrate that growth hormone overexpression has the potential to generate oxidative stress in fishes.
Comp Biochem Physiol B Biochem Mol Biol 2008 Jan
PMID:Metabolic rate and reactive oxygen species production in different genotypes of GH-transgenic zebrafish. 1793 20

Steroid receptor coactivator 3 (SRC-3/AIB1/ACTR/NCoA-3) is a transcriptional coactivator for nuclear receptors including vitamin D receptor (VDR). Growth hormone (GH) regulates insulin-like growth factor I (IGF-I) expression, and IGF-I forms complexes with acid-labile subunit (ALS) and IGF-binding protein 3 (IGFBP-3) to maintain its circulating concentration and endocrine function. This study demonstrated that the circulating IGF-I was significantly reduced in SRC-3(-/-) mice with the C57BL/6J background. However, SRC-3 deficiency affected neither GH nor ALS expression. The low IGF-I level in SRC-3(-/-) mice was not due to the failure of IGF-I mRNA and protein synthesis but was a consequence of rapid degradation. The rapid IGF-I degradation was associated with drastically reduced IGFBP-3 levels. Because IGF-I and IGFBP-3 stabilize each other, SRC-3(-/-) mice were crossbred with the liver-specific transthyretin (TTR)-IGF-I transgenic mice to assess the relationship between reduced IGF-I and IGFBP-3. In SRC-3(-/-)/TTR-IGF-I mice, the IGF-I level was significantly increased over that in SRC-3(-/-) mice, but the IGFBP-3 level failed to increase proportionally, indicating that the low IGFBP-3 level is a responsible factor that limits the IGF-I level in SRC-3(-/-) mice. Furthermore, IGFBP-3 mRNA was reduced in SRC-3(-/-) mice. The IGFBP-3 promoter activity induced by vitamin D, through VDR, was diminished in SRC-3(-/-) cells, suggesting an important role of SRC-3 in VDR-mediated transactivation of the IGFBP-3 gene. In agreement with the role of SRC-3 in VDR function, the expression of several VDR target genes was also reduced in SRC-3(-/-) mice. Therefore, SRC-3 maintains IGF-I in the circulation through enhancing VDR-regulated IGFBP-3 expression.
Mol Cell Biol 2008 Apr
PMID:Steroid receptor coactivator 3 maintains circulating insulin-like growth factor I (IGF-I) by controlling IGF-binding protein 3 expression. 1821 51

Growth hormone (GH), insulin-like growth factor I (IGF-I), progesterone (P4) and 17beta-estradiol (17-E2) concentrations have been studied in 84 mammary tumours (44 dysplasias and benign tumours and 40 malignant neoplasias) from 33 female dogs. Thirteen normal mammary glands from 80 healthy female dogs were also analysed as controls. GH concentrations were determined in mammary homogenates by radio-immunoassay. IGF-I, P4 and 17-E2 tissue levels were determined by enzyme-immunoassay (EIA) techniques. The potential correlations between GH/IGF-I concentrations and P4 and 17-E2 mammary tissue levels were investigated. Tissue GH (p<0.01) and IGF-I concentrations (p<0.01) were significantly higher in malignant tumours than in benign neoplasms. Likewise, malignant tumours were the mammary lesions that displayed the highest P4 and 17-E2 tissue levels. Strong correlations between GH/IGF-I (n=84; r=0.436; p<0.001), P4/GH (n=84; r=0.562; p<0.001) and 17-E2/IGF-I (n=84; r=0.638; p<0.001) were observed in tumoral tissue homogenates. Our study provides evidence that P4 might increase autocrine GH production which might directly stimulate local or systemic IGF-I secretion. Additionally, the IGF-I effect might be influenced by local levels of 17-E2. These results suggest that all these hormones and factors might act as local growth factors stimulating the development and/or maintenance of canine mammary tumours in an autocrine/paracrine manner.
J Steroid Biochem Mol Biol 2008 May
PMID:Crosstalk between GH/IGF-I axis and steroid hormones (progesterone, 17beta-estradiol) in canine mammary tumours. 1836 92


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