Disease relevance of Ghr

• Seven of eight Tag/Ghr(+/+) mice harbored prostatic intraepithelial neoplasia lesions of various grades [1].
• To investigate the effect of a newly developed GH receptor (GHR) antagonist (G120K-PEG) on renal/glomerular hypertrophy and urinary albumin excretion (UAE), streptozotocin-induced diabetic and nondiabetic mice were injected with G120K-PEG every 2nd day for 28 days [2].
• The present study suggests that specific GHR blockade may present a new concept in the treatment of diabetic kidney disease [2].
• GHR antagonism had a blunting effect on renal/glomerular hypertrophy and albuminuria in diabetic NOD mice [3].
• Although reduced in size, the histological features of GHR(-/-) mouse pituitaries were suggestive of somatotrope hyperplasia [4].

High impact information on Ghr

• Growth hormone receptor (GHR) forms a complex with a tyrosine kinase, suggesting involvement of a ligand-activated tyrosine kinase in intracellular signaling by growth hormone (GH) [5].
• SOCS2 was found to bind 2 phosphorylated tyrosines on the GH receptor, and mutational analysis of these amino acids showed that both were essential for SOCS2 function [6].
• Reduced bone growth in GHR(-/-) mice, due to a premature reduction in chondrocyte proliferation and cortical bone growth, was detected after 2 weeks of age [7].
• IGF-I treatment almost completely rescued all effects of the GHR(-/-) on both bone growth and remodeling, supporting a direct effect of IGF-I on both osteoblasts and chondrocytes [7].
• Down-regulation of GHR expression was associated with reduced nuclear abundance and DNA binding of the GHR gene-promoter transactivator, Sp3 [8].

Chemical compound and disease context of Ghr

• GHR(-/-) mice exhibited 50% reduction in the ratio of islet cell mass to body weight and increased insulin sensitivity but impaired glucose tolerance [9].
• To establish that these mammary cancers were estrogen-independent, 12-week-old TAg/Ghr(+/+) mice, which lack visible hyperplasia, were either ovariectomized (ovx) or sham operated (sham) [10].

Biological context of Ghr

• In 10-month-old animals, GH-induced phosphorylation of the GHR complex was maximal 10 min after the addition of hormone, whereas GH-induced MAP kinase activity was maximal at 15 min [11].
• In this study, the effects of aging on GHR signal transduction were assessed in hepatic tissue to determine whether alterations in the response to GH contribute to the decline in IGF-I [11].
• The major effect on reproductive function seen in GHR/GHBP knockout (KO) compared with wild-type animals is a dramatic decrease in litter size; this defect is due to a reduction of the ovulation rate [12].
• Expression of the hGHRH transgene in 2-month-old GHR intact (GHR(+)) mice resulted in the doubling of pituitary weight that was largely attributed to an increase in the number of GH-immunopositive cells [4].
• GH resistance due to downregulation of GHR expression may be attributed primarily to the obstructive cholestasis; therapies that specifically increase GHR expression may restore GH signaling in this setting [13].

Anatomical context of Ghr

• These experiments demonstrated that the GHR in the epithelium is not required for functional mammary development [14].
• Plasma IGF-I is regulated by GH released from the pituitary gland, and although data demonstrate a decline in GH secretion with age, GH receptor (GHR) density in liver tissue has been reported to increase [11].
• Growth hormone receptor gene deficiency causes delayed insulin responsiveness in skeletal muscles without affecting compensatory islet cell overgrowth in obese mice [15].
• To assess the relevance of the GH and PRLRs in the mammary gland development, GHR and PRLR null epithelia were transplanted into cleared fat pads of wild-type mice [16].
• Developmental aspects of adipose tissue in GH receptor and prolactin receptor gene disrupted mice: site-specific effects upon proliferation, differentiation and hormone sensitivity [17].

Associations of Ghr with chemical compounds

• Female diabetic (nonketotic) NOD mice treated with a polyethylene glycol-treated GHR antagonist (2 mg/kg, every other day) (DA group) or saline (D group) and their nonhyperglycemic age-matched littermates (control animals) were euthanized 3 wk after the onset of diabetes [3].
• Materials and Methods: Dihydrotestosterone (DHT) or testosterone (T) were administered to orchidectomized (ORX) male GH receptor gene knockout (GHRKO) and corresponding wildtype (WT) mice during late puberty (6-10 weeks of age) [18].
• Disruption of the GHR gene altered neither prostate androgen receptor expression nor serum testosterone titers [1].
• TNFalpha down-regulated GHR abundance and prevented GH-induced tyrosine phosphorylation of STAT5 in rat hepatocytes in culture [8].
• Compared with GHR(-/-) alone, IGF-I overexpression on a GHR(-/-) background caused no change in the diminished blood glucose and serum insulin levels, pancreatic insulin contents, and insulin tolerance but improved glucose tolerance and insulin secretion [9].

Physical interactions of Ghr

• GHR expression was reduced in BDL mice; in liver, this was associated with reduced Sp3 binding to a GHR gene promoter cis element [13].
• Liver GH receptor (GHR) and GH binding protein (GHBP) mRNA levels, as well as liver membrane GH binding assays were deeply decreased in the 30d DM group in comparison to controls [19].
• Ames dwarf mice that do not express growth hormone (GH) or prolactin (PRL) genes were used to study the effects of GH deficiency on the presence and the characteristics of GH-binding protein (GHBP) in serum [20].

Enzymatic interactions of Ghr

• Like JAK2, HMW JAK2 is tyrosine phosphorylated in response to GH treatment of cells and is coimmunoprecipitated with anti-GHR serum [21].

Regulatory relationships of Ghr

• Neither female GH-antagonist dwarf mice nor GH-receptor knockout mice had any granular cells expressing EGF in any gland [22].

Other interactions of Ghr

• Kidney IGF-I and GHR mRNA levels were decreased in both the D and DA groups [3].
• Results showed that the levels of messenger RNA for both GH-R and PRL-R were elevated in transgenic mice expressing high levels of serum oGH [23].
• Aryl hydrocarbon receptor-mediated suppression of GH receptor and Janus kinase 2 expression in mice [24].
• In contrast, only one of the eight Tag/Ghr(-/-) mice exhibited atypia (P < 0.01, Fischer's exact test) [1].
• Prior studies suggest cross-talk between the GH receptor and EGFR signaling systems [25].

Analytical, diagnostic and therapeutic context of Ghr

• Total cellular RNA was isolated from livers of transgenic and nontransgenic mice and analyzed on Northern blots using probes specific for GH-R and PRL-R [23].
• To create a mammalian model for this disease, we generated mice bearing a disrupted GHR/binding protein (GHR/BP) gene through a homologous gene targeting approach [26].
• Immunohistochemistry and in situ hybridization analyses revealed a marked reduction in the expression of the IGF-I receptor, as well as in the GH receptor [27].
• Subcutaneous injections of ATL 227446 reduced GH receptor mRNA levels, GH binding activity and serum IGF-I levels in mice after seven days of dosing [28].
• The present study investigated the diurnal variation in GH receptor (GHR) mRNA in liver and skeletal muscle of 3-month-old GH-deficient and -sufficient mice using quantitative real-time RT-PCR. lit/lit (GH deficient) or lit/+ (GH sufficient) mice were fed ad libitum and lights were on between 0600 and 2000 [29].

References