208. Absence of GH-R exon 3 in marsupials and monotremes argues for a eutherian specific origin and fetal specific purpose of this domain

2008 ◽  
Vol 20 (9) ◽  
pp. 8
Author(s):  
B. R. Menzies ◽  
G. Shaw ◽  
T. P. Fletcher ◽  
A. J. Pask ◽  
M. B. Renfree
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Receptor ◽  
Critical Role ◽  
Protein Sequences ◽  
Tammar Wallaby ◽  
Evolutionary Divergence ◽  
R Gene ◽  
Orthologous Region ◽  
Gh Receptor ◽  
Evolutionary Origins

Growth hormone receptor (GH-R) plays a critical role in the control of growth and metabolism in all vertebrates. GH-R consists of 9 coding exons (2–10) in all eutherian mammals, while the chicken only has 8 coding exons, and does not have an orthologous region to eutherian exon 3. To further understand the evolutionary origins of exon 3 of the GH-R we have cloned the full-length GH-R sequence in a marsupial, the tammar wallaby to determine whether exon 3 was present or absent in marsupial liver cDNA. There was no evidence for the presence of an exon 3 containing mRNA in sequence of tammar pouch young and adult livers. We next examined the genomes of the platypus (a monotreme mammal) and the grey short-tailed opossum (another marsupial). Like the tammar, the GH-R gene of neither species contained an exon 3. GH receptor can obviously function in the absence of this exon, raising speculation about the function of this domain, if any, in eutherians. A comparison of exon 3 protein sequences within 16 species of eutherian mammals showed that there was ~75% homology in the domain despite only 3 residues being identical (Leu12, Gln13 and Pro17). Interestingly, we detected greater evolutionary divergence in exon 3 sequences from species that have variants of GH or prolactin (PRL) in their placentas. These data show that exon 3 was inserted into the GH-R after the divergence of marsupial and eutherian lineages at least 130 million years ago.

The interrelationship between and the regulation of hepatic growth hormone receptors and circulating GH binding protein in the pig

1992 ◽  
Vol 126 (2) ◽  
pp. 155-161 ◽  
Author(s):  
Geoffrey R Ambler ◽  
Bernhard H Breier ◽  
Andrzej Surus ◽  
Hugh T Blair ◽  
Stuart N McCutcheon ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Receptor ◽  
Hormone Receptors ◽  
Binding Capacity ◽  
Binding Protein ◽  
Somatic Growth ◽  
Gh Receptor ◽  
Age Related ◽  
Igf I ◽  
Serum Gh

We evaluated the interrelationship between, and regulation of, the hepatic growth hormone receptor and serum GH binding protein (GH BP) in pigs treated with recombinant porcine growth hormone (rpGH). Infant and pubertal male pigs (N = 5 per group) received either rpGH 0.15 mg/kg daily or diluent intramuscularly for 12 days. Somatic growth, serum IGF-I and GH BP and [125I]bovine GH (bGH) binding to MgCl2-treated hepatic membrane homogenates were examined. Marked age-related increases were seen in serum GH BP (p<0.001) and [125I]bGH binding to hepatic membranes (p<0.001). GH BP was increased in rpGH treated animals (p = 0.03), from 13.8±1.2 (mean±1 x sem) (controls) to 17.8±2.0% in infants, and from 35.2±2.6 (controls) to 41.8±3.4% in pubertal animals. [125I]bGH binding to hepatic membranes was also increased by rpGH treatment (p<0.05), from 7.0±1.6 (controls) to 15.4±3.6% in infants and from 53.7±7.1 (controls) to 65.1±11.8% in pubertal animals. No significant interaction between age and treatment was seen. Overall, serum GH BP correlated significantly with [125I]bGH membrane capacity (r=0.82, p<0.001), with a correlation of r= 0.83 in the infant animals but no significant correlation in the pubertal animals considered alone (r=0.13). Serum IGF-I correlated significantly with serum GH BP (r=0.93, p<0.001) and [125]bGH membrane binding capacity (r = 0.91, p< 0.001). These observations suggest that serum GH BP levels reflect major changes of hepatic GH receptor status. In addition, the present study demonstrates that the hepatic GH receptor can be induced by GH in the infant pig, despite a developmentally low GH receptor population at this age, suggesting potential efficacy of GH at earlier ages than generally considered.

Mechanism of signaling by growth hormone receptor

1996 ◽  
Vol 76 (4) ◽  
pp. 1089-1107 ◽  
Author(s):  
L. S. Argetsinger ◽  
C. Carter-Su
Keyword(s):  
Growth Hormone ◽  
Protein Kinase ◽  
Growth Hormone Receptor ◽  
Second Messengers ◽  
Current Model ◽  
Mitogen Activated Protein Kinase ◽  
Gh Receptor ◽  
Insulin Receptor Substrates ◽  
Mitogen Activated Protein ◽  
Control Body

Growth hormone (GH) has long been known to stimulate linear growth and regulate metabolism. The cellular mechanism by which GH elicits these effects has only recently begun to be understood. This review provides an overview of a current model of GH signaling. Briefly, binding of GH to GH receptor induces receptor dimerization and activation of the tyrosine kinase JAK2. Tyrosyl phosphorylation of GH receptor and JAK2 recruits and activates signaling molecules such as Stat transcription factors, SHC, and insulin receptor substrates 1 and 2 that lead to the release of second messengers such as diacylglycerol, calcium, and nitric oxide and the activation of enzymes such as mitogen-activated protein kinase, protein kinase C, phospholipase A2, and phosphatidylinositol 3'-kinase. These pathways regulate cellular function including gene transcription, metabolite transport, and enzymatic activity that result in the ability of GH to control body growth and metabolism.

scholarly journals Dose-response effects of a new growth hormone receptor antagonist (B2036-PEG) on circulating, hepatic and renal expression of the growth hormone/insulin-like growth factor system in adult mice

2000 ◽  
Vol 167 (2) ◽  
pp. 295-303 ◽  
Author(s):  
JW van Neck ◽  
NF Dits ◽  
V Cingel ◽  
IA Hoppenbrouwers ◽  
SL Drop ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Receptor Antagonist ◽  
Growth Hormone Receptor ◽  
Binding Protein ◽  
Mrna Levels ◽  
Insulin Like Growth Factor ◽  
Gh Receptor ◽  
Igf I ◽  
Igfbp 3

The effects of growth hormone (GH) in regulating the expression of the hepatic and renal GH and insulin-like growth factor (IGF) system were studied by administering a novel GH receptor antagonist (GHRA) (B2036-PEG) at different doses (0, 1.25, 2.5, 5 and 10 mg/kg/day) to mice for 7 days. No differences were observed in the groups with respect to body weight, food consumption or blood glucose. However, a dose-dependent decrease was observed in circulating IGF-I levels and in hepatic and renal IGF-I levels at the highest doses. In contrast, in the 5 and 10 mg/kg/day GHRA groups, circulating and hepatic transcriptional IGF binding protein-3 (IGFBP-3) levels were not modified, likely resulting in a significantly decreased IGF-I/IGFBP-3 ratio. Hepatic GH receptor (GHR) and GH binding protein (GHBP) mRNA levels increased significantly in all GHRA dosage groups. Endogenous circulatory GH levels increased significantly in the 2.5 and 5 mg/kg/day GHRA groups. Remarkably, increased circulating IGFBP-4 and hepatic IGFBP-4 mRNA levels were observed in all GHRA administration groups. Renal GHR and GHBP mRNA levels were not modified by GHRA administration at the highest doses. Also, renal IGFBP-3 mRNA levels remained unchanged in most GHRA administration groups, whereas IGFBP-1, -4 and -5 mRNA levels were significantly increased in the 5 and 10 mg/kg/day GHRA administration groups. In conclusion, the effects of a specific GHR blockade on circulating, hepatic and renal GH/IGF axis reported here, may prove useful in the future clinical use of GHRAs.

Growth Hormone Receptor Antagonist Therapy in Acromegalic Patients Resistant to Somatostatin Analogs*

2000 ◽  
Vol 85 (8) ◽  
pp. 2958-2961 ◽  
Author(s):  
Vivien S. Herman-Bonert ◽  
Kenneth Zib ◽  
John A. Scarlett ◽  
Shlomo Melmed
Keyword(s):  
Growth Hormone ◽  
Receptor Antagonist ◽  
Growth Hormone Receptor ◽  
Hormone Secretion ◽  
Somatostatin Analogs ◽  
Growth Hormone Secretion ◽  
Primary Therapy ◽  
Gh Receptor ◽  
Gh Receptor Antagonist ◽  
Octreotide Therapy

Transsphenoidal surgical resection is the primary therapy for acromegaly caused by GH secreting pituitary adenomas. Medical therapy for patients not controlled by surgery includes primarily somatostatin analogs and secondarily dopamine agonists, both of which inhibit pituitary growth hormone secretion. A novel GH receptor antagonist (pegvisomant) binds to hepatic GH receptors and inhibits peripheral insulin-like growth factor-1 generation. Six patients resistant to maximal doses of octreotide therapy received pegvisomant—three received placebo or pegvisomant 30 mg or 80 mg weekly for 6 weeks and three received placebo and pegvisomant 10–20 mg/d for 12 weeks. Thereafter, all patients received daily pegvisomant injections of doses determined by titrating IGF-1 levels. Serum total IGF-1 levels were normalized in all six acromegalic patients previously shown to be resistant to somatostatin analogs via a novel mechanism of peripheral GH receptor antagonism. The GH receptor antagonist is a useful treatment for patients harboring GH-secreting tumors who are resistant to octreotide.

scholarly journals The Effect of ZJXG Decoction on The Serum Level of Growth Hormone and The Expression of GH Receptor in Callus

2019 ◽  
Vol 12 ◽  
pp. 2320-2330
Author(s):  
Zhen Zhou ◽  
Guanxi Wang ◽  
Zhaogang Liu ◽  
Yunliang Guo
Keyword(s):  
Growth Hormone ◽  
Serum Level ◽  
Growth Hormone Receptor ◽  
Femur Fracture ◽  
Healing Process ◽  
Enzyme Linked Immunosorbent Assay ◽  
Middle Point ◽  
X Ray ◽  
Gh Receptor ◽  
Hematoxylin Eosin

The aim of experiment was to investigate the effects of Zhuangjin XuGu decoction (ZJXG decoction) on growth hormone (GH) serum and GH receptor (GHR) expression in callus. The femur fracture animal models were generated in 72 Wistar rats by cutting femur transversely at the middle point. The rats models were administered orally ZJXG decoction for 28 days. Anatomy, X-ray and hematoxylin- eosin (HE) staining were used to observe the healing process in rats. The expression of growth hormone receptor (GHR) in fibroblasts and osteoblasts in callus was evaluated by immunohistochemical assay (IHC). The serum level of GH was passed by enzyme linked immunosorbent assay (ELISA). Anatomy, X-ray and H-E staining indicated that the fibrous callus at the fracture-end increased and the fibrous granular tissue changed gradually to fibrous, cartilaginous and osseous callus. IHC and ELISA showed that after 28 days of ZJXG Decoction treatment, that GH in the fibroblasts and osteoblasts of callus and their serum level increased significantly. These results suggested that ZJXG decoction could enhance the fracture healing by enhancing GH activity and promoting the expression of GHR in the fibroblasts and osteoblasts of callus in rats.

GROWTH HORMONE RECEPTOR GENE: NOVEL EXPRESSION IN PITUITARY TISSUE

1991 ◽  
Vol 128 (3) ◽  
pp. R9-R11 ◽  
Author(s):  
R.A. Fraser ◽  
K. Siminoski ◽  
S. Harvey
Keyword(s):  
Growth Hormone ◽  
Plasma Membranes ◽  
Growth Hormone Receptor ◽  
Radioligand Binding ◽  
Receptor Gene ◽  
Northern Analysis ◽  
Binding Studies ◽  
Human Pituitary ◽  
Gh Receptor ◽  
Pituitary Tissue

ABSTRACT Specific hybridization of polyadenylated RNA, extracted from rat, rabbit and human pituitary glands with a 638 bp rabbit GH receptor (rGHR) cRNA was demonstrated by Northern analysis. In-situ hybridization of tissue sections with the probe demonstrated the localization of rGHR mRNA throughout the rat pituitary gland and its presence in the anterior lobe of the rabbit pituitary. Growth hormone binding sites on pituitary membranes were not, however, demonstrated by radioligand binding studies. Thus, although the GH receptor gene is expressed in pituitary tissue, functional GH receptors may not be inserted into pituitary plasma membranes.

Expression of GH receptor mRNA in regenerating skeletal muscle of normal and hypophysectomized rats. An in situ hybridization study

1991 ◽  
Vol 125 (6) ◽  
pp. 595-602 ◽  
Author(s):  
Eva Jennische ◽  
Göran L. Andersson
Keyword(s):  
Skeletal Muscle ◽  
Growth Hormone ◽  
In Situ Hybridization ◽  
Growth Hormone Receptor ◽  
Receptor Expression ◽  
Muscle Fibres ◽  
Receptor Mrna ◽  
Gh Receptor ◽  
Hypophysectomized Rats

Abstract. Expression of growth hormone receptor mRNA was investigated by in situ hybridization in skeletal muscle from normal and hypophysectomized rats during the first seven days of regeneration after ischemic injury. A digoxigenin-labelled RNA probe directed against the extracellular part of the rat GH receptor was used. In both normal and hypophysectomized rats distinct expression of GH receptor mRNA could be demonstrated in the regenerating muscle cells at the myoblast/myotube stage. The GH receptor expression appeared to decline with increasing maturation of the regenerated muscle fibres. In hypophysectomized rats, the regeneration process and the expression of GH receptor mRNA was delayed compared with that in normal animals. It is concluded that growth hormone may affect also the early phase of muscle regeneration in normal animals. To what extent lack of growth hormone contributes to the delayed regeneration observed in the hypophysectomized rats remains to be elucidated.

scholarly journals Association of the Growth Hormone Receptor d3-Variant and Catch-up Growth of Preterm Infants with Birth Weight of Less Than 1500 Grams

2007 ◽  
Vol 92 (11) ◽  
pp. 4489-4493 ◽  
Author(s):  
Felix Schreiner ◽  
Sonja Stutte ◽  
Peter Bartmann ◽  
Bettina Gohlke ◽  
Joachim Woelfle
Keyword(s):  
Growth Hormone ◽  
Birth Weight ◽  
Low Birth Weight ◽  
Preterm Infants ◽  
Growth Pattern ◽  
Growth Hormone Receptor ◽  
Very Low Birth Weight ◽  
Postnatal Growth ◽  
Gh Receptor ◽  
Catch Up

Abstract Background: Preterm infants with very low birth weight frequently exhibit impaired longitudinal growth during the first years of life. Recently, the d3-isoform (genomic deletion of exon 3) of the GH receptor (GHR) has been linked to an increased responsiveness to GH. Objective: Our objective was to test whether the GHRd3 isoform is associated with postnatal catch-up growth in very low birth weight preterm infants. Design and Patients: We compared the postnatal growth pattern of 77 otherwise healthy preterm infants (mean gestational age, 28.5 wk; range, 23–35 wk) with a birth weight below 1500 g (mean birth weight, 941 g) to their GHR exon 3 genotype, which was analyzed by multiplex PCR. On examination, mean age of the children was 6.0 yr (range, 4.2–8.0 yr). Results: Children homozygous or heterozygous for the GHRd3 allele showed a significantly higher rate of postnatal catch-up, compared with those homozygous for the full-length allele. Conclusions: Our results define the GHR exon 3 genotype as a predictor for the postnatal growth pattern of very low birth weight preterm infants. Those who carry at least one GHRd3 allele are more likely to catch-up.

Developmental changes and differential regulation by testosterone and estradiol of growth hormone receptor expression in the rabbit

1996 ◽  
Vol 135 (5) ◽  
pp. 583-590 ◽  
Author(s):  
Yu M Yu ◽  
Horacio M Domené ◽  
Jorge Sztein ◽  
Debra R Counts ◽  
Fernando Cassorla
Keyword(s):  
Growth Hormone ◽  
Hormone Receptor ◽  
Growth Hormone Receptor ◽  
Treated Group ◽  
Differential Regulation ◽  
Receptor Expression ◽  
Developmental Changes ◽  
Mrna Levels ◽  
R Gene ◽  
Hormone Receptor Expression

Yu YM, Domené HM, Sztein J, Counts DR, Cassorla F. Developmental changes and differential regulation by testosterone and estradiol of growth hormone receptor expression in the rabbit. Eur J Endocrinol 1996;135:583–90. ISSN 0804–4643 To investigate the effects of testosterone and estradiol (E2) on growth hormone receptor (GH-R) gene expression, we measured GH-R mRNA levels in relation to the changes of sex steroid concentrations in the normal male rabbits aged 1–12 months and after administration of testosterone or E2 to castrated male rabbits. In the normal animals, E2 levels were below the detection limit in all age groups, and testosterone levels were below the detection limit at 1 month, increased at 2 months and reached the plateau of the adult levels after 4 months. Liver GH-R mRNA levels were low at 1 month, reached a peak at 2 months and then decreased slightly thereafter. In the castrated animals, liver and growth plate GH-R mRNA levels were increased in the testosterone-treated group (162.0 ± 12.0%, p < 0.025; 128.4 ± 7.6%; p < 0.025) and reduced in the E2-treated group (29.6 ± 6.2%, p < 0.005; 53.6 ± 11.3%, p < 0.025). Sex steroid administration did not result in any significant change in GH-R mRNA levels in striated muscle, kidney and heart. Serum GH concentrations were increased in E2 (15.3 ± 7.7 μg/l vs 4.8 ± 2.2 μg/l, p < 0.025) but the increase was not significant in testosterone-treated animals (8.4 ± 7.7 μg/l vs 4.8 ± 2.2 μg/l). Both testosterone and E2 treatment resulted in a reduction of mean serum growth hormone-binding protein (GHBP) levels compared to control animals (1077 ± 422 pmol/l, p < 0.01; 1137 ± 443 pmol/l, p < 0.01; 2308 ± 565 pmol/l). We conclude that in addition to their stimulatory effect on GH secretion, testosterone and E2 have opposite effects on GH-R gene expression in liver and growth plate in the rabbit. The modulation of GH-R expression by sex steroids may be important for growth during sexual maturation in mammals. Yu M Yu, MD, 11600 Bootjack Court, Gaithersburg, MD 20878, USA

The ubiquitin-proteasome pathway regulates lysosomal degradation of the growth hormone receptor and its ligand

2001 ◽  
Vol 29 (4) ◽  
pp. 488-493 ◽  
Author(s):  
P. van Kerkhof ◽  
G. J. Strous
Keyword(s):  
Growth Hormone ◽  
Proteasome Inhibitor ◽  
Growth Hormone Receptor ◽  
Proteasome Inhibitors ◽  
Plasma Membrane Protein ◽  
Lysosomal Degradation ◽  
Ubiquitin Proteasome Pathway ◽  
Gh Receptor ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

The growth hormone (GH) receptor (GHR) is a mammalian plasma membrane protein whose internalization is mediated by the ubiquitin-proteasome pathway. GH internalization and degradation are inhibited when cells are treated with proteasome inhibitors. Here we show that a GHR truncated at residue 369 can enter the cells in the presence of a proteasome inhibitor, but that the subsequent lysosomal degradation of GH is blocked. Lysosomal inhibitors prolong the half-life of both receptor and ligand. Experiments with antibodies against different receptor tail sections show that degradation of the GHR cytosolic domain precedes degradation of the extracellular GH-binding domain. A possible role for the ubiquitin-proteasome pathway in the degradation of the receptor and ligand is discussed.

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