Disease relevance of Ghr

• The UMR 106 cell line is a rat clonal osteosarcoma cell line with osteoblast-like phenotypic properties, one is the endogenous expression of GH receptor (GHR) [1].
• However, the abundance of GHR protein was not different in liver from Control, Sepsis, or Sepsis + TNFbp rats [2].
• The suppression of GHR and IGF-I immunoreactivity in steroid-treated animals infers the mechanism whereby bone resorption and deposition, necessary for orthodontic tooth movement, may be inhibited by prednisolone [3].
• The present data suggest that muscle atrophy is associated with a muscle fiber type-specific GHR mRNA up-regulation mechanism that helps protect atrophying fibers in EDL but might be part of an attempt to repair in SOL [4].
• To develop such a cell line, we used rat C6 glioma cells which, as determined by RNase protection assay, express the IGF-I gene but not the GH receptor gene [5].

High impact information on Ghr

• These results suggest that the mechanism for production of the rat serum GH-binding protein is by alternative splicing of the gene for the rat GH receptor [6].
• The protein coding region of this cDNA was identical in sequence to the extracellular domain of the rat liver GH receptor up to three amino acids before the putative transmembrane domain [6].
• Hepatic GH receptor (GHR) mRNA levels were significantly decreased in CRF, but GHR protein abundance and GH binding to microsomal and plasma membranes was unaltered [7].
• Meanwhile, the hormone induced a significant up-regulation of the GHR transcript in hippocampus of adult young rats but not in elderly adult rats [8].
• Recent studies have demonstrated that the activated GH receptor can stimulate Stat1, a cytoplasmic transcription factor that becomes tyrosine phosphorylated and translocates to the nucleus, where it can interact with specific DNA sequences to modulate gene expression [9].

Chemical compound and disease context of Ghr

• Flutamide administration decreased body weight gain, serum IGF-I levels, hepatic IGF-I mRNA, and GH receptor mRNA content [10].
• In summary, continuous insulin treatment in rat H4 hepatoma cells reduces GH binding, immunoreactive GHR, GH-induced phosphorylation of JAK2, and GH-induced tyrosine phosphorylation of STAT5B [11].
• 17 beta-estradiol stimulated 125I-GH binding and GH receptor (GHR) mRNA levels in rat osteosarcoma cells [12].
• We conclude that (1) thyroid hormone affects the transcription of the GHR/GHBP gene; (2) there is a distinct sexual dimorphism in the effect of hypothyroidism on the expression of the GHR/GHBP gene, and (3) this effect is reversible following amelioration of the hypothyroid state [13].

Biological context of Ghr

• In order to elucidate potential sites of direct GH action on the kidney, we used in situ hybridization to localize GH receptor (GHR) gene expression during the course of development and in the adult rat [14].
• The susceptibility of proliferative cells to GHR and IGF-IR down regulation during the period of greatest apoptosis supports a role for the GH-IGF axis in both proliferation and apoptosis during growth plate development [15].
• Orthodontic tooth movement appeared to up-regulate GHR and IGF-IR immunoreactivity, but this up-regulation was reduced following prednisolone treatment [3].
• GHR and IGF-IR cell counts were elevated following appliance-treatment [3].
• GH treatment induced a rapid (within 5 min) internalization of GH.GHR complexes, which coincided with the onset of GHR tyrosine phosphorylation and the appearance in the cytosol of distinct granular structures containing internalized GH [16].

Anatomical context of Ghr

• The GHR mRNA was present in follicular wall tissue and not in the oocyte, while positive immunostaining for GHR was observed in all cells of the pre-antral follicles [17].
• Here, we used the GH-responsive rat liver cell line CWSV-1 to investigate the role of CIS and the proteasome in GH-induced GHR internalization [16].
• When various mutated GHR cDNAs were transfected stably into Chinese hamster ovary cells or transiently into monkey kidney (COS-7) cells, internalization of the GHR was found to be dependent upon a domain located between amino acids 318 and 380 [18].
• Treatment of Hx rats with thyroid hormones (T3 + T4), via subcutaneously (sc) implanted osmotic minipumps, induced little growth and induced a small layer of GHR-positive and GHBP-positive early maturing chondrocytes [19].
• The dual effector theory suggests that GH would act primarily on the "stem cells." However, staining with a GH receptor (GHR) antibody is found in all layers of the growth plate in rabbits and humans [19].

Associations of Ghr with chemical compounds

• This study examined the effect of prednisolone on GHR and IGF-IR expression in dental tissues following orthodontic tooth movement [3].
• These results demonstrate that phenylalanine 346 is essential for GHR internalization and down-regulation but not for transcriptional signaling, suggesting that ligand-mediated endocytosis is not a prerequisite for GH-induced gene transcription [18].
• In contrast, the ability to stimulate transcription of the serine protease inhibitor 2.1 promoter by the GHR was not affected by the phenylalanine 346 to alanine mutation [18].
• The internalization of GH and GHR was inhibited by CIS-R107K, a dominant-negative SH2 domain mutant of CIS, and by the proteasome inhibitors MG132 and epoxomicin, which prolong GHR signaling to STAT5b [16].
• In contrast, dexamethasone treatment of normal rats inhibited their growth and reduced GHR and GHBP staining in the growth plate [19].

Physical interactions of Ghr

• SOCS2 binds to the GH receptor and inhibits GH signaling, including attenuation of STAT5 activation [20].
• Immunohistochemistry was used to study the ontogeny of GH receptor/binding protein (GHR/BP) and IGF-I from the 13-day-old embryo (E13) to the E19 rat fetus in the developing incisor and molar [21].
• Digestion of covalently linked [125I]human (h) GH-receptor complexes with neuraminidase or endoglycosidase F reduced the mass of the principal hormone receptor complex from about 130 kilodaltons (kDa) to 120 and 110 kDa, respectively, suggesting that about 20% of the mass of the GH receptor of rat adipocytes consists of N-linked sialocarbohydrates [22].

Regulatory relationships of Ghr

• CONCLUSION: The mechanism of growth hormone insensitivity induced by endotoxin was associated with down-regulated GHR mRNA expression at receptor level and up-regulated SOCS-3 mRNA expression at post-receptor level [23].
• The finding of endotoxin inhibition of in vivo STAT5 tyrosine phosphorylation in response to a supramaximal dose of GH in the absence of a change in GH receptor abundance or total GH-stimulated JAK2 tyrosine phosphorylation provides the first demonstration of acquired postreceptor GH resistance [24].
• Growth hormone (GH) stimulates protein synthesis in cells transfected with GH receptor complementary DNA [25].
• These data suggest that the regulatory mechanism controlling Sm-C/IGF-I production and growth might be different from those that regulate GH receptor concentrations, with GH pulses being crucial for the maximal stimulation of Sm-C/IGF and growth, but continuous exposure to GH being required for up-regulation of liver GH receptors [26].
• In the male rat, few GHRH-containing neurons in the arcuate nucleus (ARC) appear to express the GH receptor messenger RNA (mRNA); however, some unidentified neurons near GHRH neurons do [27].

Other interactions of Ghr

• GHR expression in the MTAL, which is the site of renal IGF-I synthesis, supports the view that GH has a direct effect on renal IGF-I synthesis [14].
• IL-1 beta markedly decreased the GHR and GHBP mRNA levels (respectively, -68% and -60%, P < 0.05) [28].
• Neither TNF-alpha nor IL-6 affected the GHR/GHBP gene expression [28].
• The only point of convergence for GHR and IGF-I receptor mRNAs was in the MTAL, where IGF-I mRNA was localized [14].
• Presently, we investigate the mechanism of CIS inhibition and CIS's role in down-regulating GHR-JAK2 signaling to STAT5b in cells exposed to GH continuously [29].

Analytical, diagnostic and therapeutic context of Ghr

• Hypophysectomy resulted in a decrease and GH treatment resulted in an increase in renal GHR mRNA levels [14].
• Cell-surface GHR localization and internalization were monitored in GH-stimulated cells by confocal immunofluorescence microscopy using an antibody directed against the GHR extracellular domain [16].
• Expression of GHR mRNA and GHBP mRNA in the growth plate was confirmed by reverse-transcription polymerase chain reaction (RT-PCR) [19].
• In control rats, the RT-PCR mRNAs levels of GHR were greater (+34%) in EDL compared with SOL [4].
• Since GH regulates cellular cytoskeleton with potential implications in GH signaling, we investigated the effects of actin cytoskeleton disruption on the kinetics of GH-activated GHR/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) signaling pathway [30].

References