Disease relevance of GH1

• Thus, our study concludes a possible protective influence of distinct polymorphisms in genes involved in GH1 release on breast cancer risk [1].
• The complementary DNA for hPRL was cloned, expressed in Escherichia coli, and mutated to introduce sequentially those substitutions from hGH that were predicted by alanine-scanning mutagenesis and other studies to be most critical for binding to the hGH receptor from human liver [2].
• A positive scan in patients with GH- and TSH-secreting pituitary tumors is predictive of a good suppressive effect of octreotide on hormone release by these tumors [3].
• When dopamine (0.01-0.1 microM) or bromocriptine (0.01-0.1 microM) was added to the culture media, a significant inhibition of GH and PRL secretion from adenoma cells from acromegalic patients was observed [4].
• Here, we examined the effects of GH using in vitro and in vivo assays of human immunodeficiency virus (HIV)-induced neuronal injury [5].

Psychiatry related information on GH1

• Growth hormone and prolactin response to apomorphine in schizophrenia and the major affective disorders. Relation to duration of illness and depressive symptoms [6].
• Growth hormone responses to growth hormone releasing factor in primary degenerative dementia [7].
• In order to study the response of plasma prolactin (PRL) to acute psychological stress and to compare it with that of growth hormone (GH), the mirror drawing test (MDT) was performed in 20 normal controls (11 male, 9 female) and 22 neurotic patients (12 male, 10 female) [8].
• We showed recently that ghrelin promotes slow-wave sleep and the nocturnal release of GH, cortisol and prolactin in humans [9].
• Nocturnal ghrelin, ACTH, GH and cortisol secretion after sleep deprivation in humans [9].

High impact information on GH1

• Growth hormone binds the growth hormone receptor to activate multiple signaling pathways [10][11].
• Taking into account all these activities, ghrelin plays important roles for maintaining GH release and energy homeostasis in vertebrates [12].
• BACKGROUND: Growth hormone treatment stimulates growth in short children with chronic renal failure [13].
• Effect of growth hormone treatment on the adult height of children with chronic renal failure. German Study Group for Growth Hormone Treatment in Chronic Renal Failure [13].
• Growth hormone in the treatment of dilated cardiomyopathy [14].
• Growth hormone improved cardiac output, particularly during exercise (from 7.4+/-0.7 to 9.7+/-0.9 liters per minute, P=0.003), and enhanced ventricular work, despite reductions in myocardial oxygen consumption (from 56+/-6 to 39+/-5 ml per minute, P=0.005) and energy production (from 1014+/-100 to 701+/-80 J per minute, P=0.002) [15].

Chemical compound and disease context of GH1

• To investigate the mechanism involved, we studied the effects of estrogen on GH signaling through Janus kinase (JAK)2 and the signal transducers and activators of transcription (STATs) in HEK293 cells stably expressing the GH receptor (293GHR), HuH7 (hepatoma) and T-47D (breast cancer) cells [16].
• We have demonstrated that a 500-basepair fragment of the human GH (hGH) gene 5' flanking region can confer cAMP inducibility upon the chloramphenicol acetyltransferase transcription unit in transient transfections of rat pituitary tumor cells treated with forskolin, an activator of adenyl cyclase [17].
• Arginine infusion induced a sharp rise of GH in patients with molar pregnancy and in nonpregnant subjects, but the response in normal pregnancy was blunted [18].
• Failure of serotonin inhibitor to effect nocturnal GH and prolactin secretion in patients with Duchenne muscular dystrophy [19].
• Hybridization experiments were performed between dot-blotted mRNA originating either from placenta or from one pituitary hGH secreting adenoma and synthetic polynucleotide probes corresponding to specific portions of the hGH-V or hGH-N gene sequences [20].

Biological context of GH1

• Of the plasmids containing two CSEs, -173 PRL was always activated to a greater extent than -145 GH, with this relative activation being stronger in GC and GH1 cells than in 235-1 and GH4C1 cells [21].
• However, we have identified a missense mutation (G705C) in the GH1 gene of a Serbian patient [22].
• By binding to their respective receptors, they control cell proliferation, differentiation and apoptosis in a GH1/IGF-1-dependent manner [1].
• This review focuses primarily on the GH1 mutational spectrum and its unusual features, discusses potential mechanisms of mutagenesis and pathogenesis, and examines the correlation between mutant genotype and clinical phenotype [23].
• GH1 -75A homozygotes had 3.4 more percent density than subjects with at least one G allele (P = 0.04) and also had 32% higher serum growth hormone levels (P = 0.02).CONCLUSION: We have found associations between mammographic density and two SNPs in the pituitary growth hormone gene, one of them also associated with serum growth hormone levels [24].

Anatomical context of GH1

• Our results suggest that GH directly initiates proliferation in mammalian chondrocytes [25].
• Recently, we reported that local administration of human GH (hGH) into the proximal cartilage growth plate of the tibia of hypophysectomized rats stimulated longitudinal bone growth on the side injected with the hormone [25].
• Recombinant human growth hormone (HuGH) and human prolactin (HuPRL), but not GH of bovine or porcine origin, prime human neutrophils for enhanced superoxide anion (O2-) secretion [26].
• However, at high concentrations (approximately 70 microM) hGH inhibits proliferation of both these cell lines [27].
• In human IM-9 lymphocytes, which endogenously express GHRs, and in Chinese hamster ovary cells heterologously expressing wild-type or cytoplasmic domain internal deletion mutant rabbit GHRs, brief exposure to GH inhibited PMA-induced GHR proteolysis (receptor loss and remnant accumulation) by 60-93% [28].

Associations of GH1 with chemical compounds

• However, novel analogues from both groups were 30-40% more potent than octreotide and lanreotide in suppressing GH (P < 0.05) [29].
• The pattern of change in serum hPRL in the human fetus contrasts sharply with that of serum hGH, luteinizing hormone, or follicle-stimulating hormone [30].
• The minimum effective concentration of dopamine required for a significant inhibition of PRL secretion (0.01 microM) was lower than that for GH release (0.1 microM) [4].
• We found a heterozygous single-base substitution (A-->G) in exon 4 of the GH-1 gene of a girl with short stature, clinically suspected to indicate the presence of bioinactive GH and resulting in the substitution of glycine for aspartic acid at codon 112 [31].
• Growth hormone responses to tryptophan were significantly decreased in patients who lost less than 10 lb [32].

Physical interactions of GH1

• Comparisons with the hGH-hGHR complex reveal how hGH can bind to the two distinctly different receptor binding surfaces [33].
• We present here the crystal structure of the 1:1 complex of hGH bound to the extracellular domain of the hPRLR [33].
• This hPRL variant binds one-sixth as strongly as wild-type hGH, but shares only 26 percent overall sequence identity with hGH [2].
• Experiments with hGH deletion constructs reveal that binding sites for transcription factor AP-2 and the pituitary-specific factor GHF-1 are not required for forskolin stimulation, but that GHF-1 may potentiate the effect [17].
• The regulation of pituitary GH gene expression depends on binding of transcriptional activation proteins to cis-active DNA sequences preceding the GH-1 gene [34].

Enzymatic interactions of GH1

• Injection of 400 microgram TRH as a bolus induced in 7 out of 10 patients a clear-cut GH rise (larger than or equal 10 ng/ml) occurring 15-120 min after the injection, and no effect on GH levels in controls [35].
• The disulfide-linked form of the hGHR accounted for a substantial fraction of the receptors that became tyrosine phosphorylated early into hGH treatment [36].

Regulatory relationships of GH1

• An SSTR5-specific analog also exclusively inhibited GH in acromegalic tumor cells [37].
• This variant GH is possibly expressed from the human GH-V gene or a mutant allele [38].
• Both hGH and bGH stimulated tyrosine phosphorylation of a 95-kDa protein in cells transfected with WT GHR, but bGH was less effective in cells expressing mutant GHR [39].
• E(2) suppressed GH-induced JAK2 phosphorylation, an effect attenuated by actinomycin D, suggesting a requirement for gene expression [16].
• Therefore, GH probably exerts its effects as a human macrophage-activating factor through either GH or PRL receptors, without requiring production of IGF-I [40].

Other interactions of GH1

• PRL and GH are hormones with a wide spectrum of actions [41].
• Clinical introduction of octreotide, a long-acting somatostatin analog, has opened a new era in the medical therapy of patients with growth hormone (GH)- and thyroid-stimulating hormone (TSH)-secreting pituitary tumors [3].
• There was no significant effect of exogenous hGH on elemental balances or on plasma SmC [42].
• These results indicate that the D112G mutation in the GH-1 gene causes production of bioinactive GH, which prevents dimerization of GHR and is therefore responsible for the patient's short stature [31].
• Two nonclassical cAMP-response element motifs (CGTCA) are located at nucleotides -187/-183 (distal cAMP-response element; dCRE) and -99/-95 (proximal cAMP-response element; pCRE) of the human GH promoter and are required for cAMP responsiveness, along with the pituitary-specific transcription factor Pit-1 (official nomenclature, POU1F1) [43].

Analytical, diagnostic and therapeutic context of GH1

• A strategy of iterative site-directed mutagenesis and binding analysis was used to incorporate the receptor-binding determinants from human growth hormone (hGH) into the nonbinding homolog, human prolactin (hPRL) [2].
• We confirmed the presence of mutant GH in the serum using isoelectric focusing analysis [31].
• Growth hormone (GH) deficiency, diagnosed by radioimmunoassay (RIA) measurements of GH in blood after provocation or in continuous 24 h samples of venous blood, is usually associated with growth failure [38].
• In the absence of added Zn2+, G120R shows weak but full agonist activity in the bioassay, and this can be blocked by co-incubation with recombinant hGH-binding protein [44].
• Using cell culture model systems, we now explore the effects of GH treatment on inducible GHR proteolysis and GHBP shedding [28].

References