Disease relevance of Ghrh

• To investigate the mechanisms involved, we treated male nude mice bearing xenografts of DU-145 human androgen-independent prostate cancer for 8 weeks with potent GH-RH antagonist MZ-5-156 at a dose of 20 microg/animal s.c. twice a day [1].
• We investigated the effect of antagonists of growth hormone-releasing hormone (GHRH) MZ-J-7-138 and JV-1-92 on H460 human non-small cell lung carcinoma (NSCLC) xenografted orthotopically into nude mice [2].
• Synergistic inhibition of growth of lung carcinomas by antagonists of growth hormone-releasing hormone in combination with docetaxel [2].
• Antagonists of growth hormone-releasing hormone and somatostatin analog RC-160 inhibit the growth of the OV-1063 human epithelial ovarian cancer cell line xenografted into nude mice [3].
• Mice with deficits in growth hormone releasing hormone (GHRH) signaling (lit/lit mice) respond to influenza virus challenge with a progressive decrease in sleep and lower survival rates [4].

Psychiatry related information on Ghrh

• GHRH contents and mRNA levels in the hypothalamus correlate with sleep-wake activity during the diurnal cycle and sleep deprivation and recovery sleep [5].
• Within the critical period, the survival of spinal cord neurons was significantly decreased (30-35%) after incubation with 1 nM peptide histidyl-isoleucine amide (PHI-27) or 0.1 nM growth hormone releasing factor (GRF) [6].

High impact information on Ghrh

• The molecular basis for the little (lit) mouse phenotype, characterized by a hypoplastic anterior pituitary gland, is the mutation of a single nucleotide that alters Asp 60 to Gly in the growth hormone releasing factor receptor [7].
• Pit-1-dependent expression of the receptor for growth hormone releasing factor mediates pituitary cell growth [8].
• Here we report the cloning of mouse and rat complementary DNAs encoding a new member of the seven-transmembrane-helix, G-protein-coupled receptor family restricted to the pituitary gland, which mediates increases in intracellular cAMP and cAMP-dependent gene transcription in response to GRF [8].
• Pre-somatotroph proliferation is stimulated by increased intracellular levels of cyclic AMP, normally induced by growth hormone releasing factor (GRF; refs 7-17) [8].
• We conclude that transcriptional activation of CREB is necessary for the normal development of a highly restricted cell type, and that environmental cues, possibly provided by the hypothalamic growth hormone-releasing factor, are necessary for population of the pituitary by somatotrophic cells [9].

Chemical compound and disease context of Ghrh

• In this study, the authors investigated the effects of the GH-RH antagonist JV-1-38 on MNNG/HOS human osteosarcoma and SK-ES-1 human Ewing sarcoma cell lines [10].
• When tumor size exceeded 8% of body weight, GHRH-treated mice showed normal urea, creatinine, and kidney volume, while controls displayed signs of renal insufficiency [11].
• Inhibition of growth and metastases of MDA-MB-435 human estrogen-independent breast cancers by an antagonist of growth hormone-releasing hormone [12].
• The substrate requirements for the catalytic activity of the mouse Cdc25 homolog Guanine nucleotide Release Factor, GRF, were determined using the catalytic domain of GRF expressed in insect cells and E. coli expressed H-Ras mutants [13].

Biological context of Ghrh

• Using ligand competition assays with (125)I-labeled GH-RH antagonist JV-1-42, specific high-affinity binding sites for GH-RH were found on tumor membranes [14].
• This sex difference in sst2A distribution on GHRH neurons may play an important role in the sexually differentiated pattern of GH secretion [15].
• Growth hormone-releasing hormone (GHRH) stimulates the production and release of growth hormone in the pituitary and induces cell proliferation in a variety of peripheral tissues and tumors [16].
• The role of the somatotropic axis in sleep regulation was studied by using the lit/lit mouse with nonfunctional growth hormone (GH)-releasing hormone (GHRH) receptors (GHRH-Rs) and control heterozygous C57BL/6J mice, which have a normal phenotype [17].
• Furthermore, there were no significant differences in cAMP generation in response to GHRH between genotypes [18].

Anatomical context of Ghrh

• The pulsatile pattern of GH secretion exhibits sexual dimorphism that is likely to depend on somatostatin (SRIH) effects on somatoliberin (GHRH) neurons in the hypothalamus [15].
• We also showed localization of the GHRH immunoreactive peptides in Golgi and secretory granules in neuroendocrine cells by an immunofluorescence assay [19].
• On the contrary, testis were positive for SV1 and not for GHRH expression [16].
• These tissues were also positive for GHRH expression, however, tissues such as the endometrium were positive only for GHRH and not for SV1 expression [16].
• Growth hormone (GH)-releasing hormone (GHRH) is a neuropeptide that stimulates secretion of GH from the pituitary gland [20].

Associations of Ghrh with chemical compounds

• Growth hormone-releasing hormone antagonist MZ-5-156 inhibits growth of DU-145 human androgen-independent prostate carcinoma in nude mice and suppresses the levels and mRNA expression of insulin-like growth factor II in tumors [1].
• A loss of dopamine signaling via hypothalamic D2Rs at a critical age causes the reduced release of GHRH from hypophyseotropic neurons leading to inadequate clonal expansion of the somatotrope population [18].
• These data are consistent with the hypothesis that the sleep response to influenza infection is mediated, in part, by an up-regulation of hypothalamic sleep-related transcripts and they also show that a primary deficit in GHRH signaling is associated with enhanced corticosterone secretion and attenuated hypothalamic cytokine response to infection [4].
• Our results suggest that the sex difference of ARC GHRH neurons and PeN SS neurons appears by stimulation with testosterone during the development life [21].
• Characterization and localization of mouse hypothalamic growth hormone-releasing factor and effect of gold thioglucose-induced hypothalamic lesions [22].

Regulatory relationships of Ghrh

• Our work suggests that GH-RH antagonist MZ-5-156 may inhibit the growth of DU-145 human androgen-independent prostate cancers through a reduction in the production and mRNA expression of IGF-II by the tumor tissue [1].
• These changes are believed to be due to a rise in hypothalamic neuropeptide Y (NPY) that inhibits GHRH expression [23].
• The effects of DAT deletion on pituitary function result from elevated DA levels that down-regulate the lactotroph D2 DA receptors and depress hypothalamic growth hormone-releasing hormone content [24].
• Overexpression of Ikaros enhanced GHRH promoter activity and induced endogenous GHRH gene expression [25].
• Nuclear factor of activated T cells (NFAT) is involved in the depolarization-induced activation of growth hormone-releasing hormone gene transcription in vitro [26].

Other interactions of Ghrh

• In several experimental cancers, treatment with antagonists of growth hormone-releasing hormone (GH-RH) produces a reduction in IGF-I and -II, concomitant to inhibition of tumor growth [1].
• 4) The Q10R mutant was significantly more susceptible to furin cleavage at the N-terminal site than the wild-type pro-GHRH [19].
• 3) PC2 was much weaker in cleaving the C-terminal site relative to PC1/3 to generate mature GHRH [19].
• These extrapituitary effects of GHRH are in many cases mediated by a splice variant of GHRH receptor designated SV1 that differs from the pituitary GHRH receptor in a small portion of its amino-terminal region [16].
• The similarity of the pituitary defect in the D2R KO mouse to that of GHRH-deficient models suggests a probable mechanism [18].

Analytical, diagnostic and therapeutic context of Ghrh

• In addition, the levels of GHRH-like immunoreactivity in serum from nude mice bearing H-69 xenografts were higher than in tumor-free mice [27].
• Treatment with GH-RH antagonist JV-1-38 significantly (P < 0.05-0.001) inhibited tumor growth as demonstrated by a 58% decrease in final tumor volume, 54% reduction in tumor weight, and the extension of tumor-doubling time from 8.5 +/- 1.38 to 12 +/- 1.07 days as compared with controls [14].
• Intraperitoneal injection of GHRH (50 microg/kg) failed to promote sleep in the lit/lit mice, whereas it enhanced NREMS in the heterozygous mice [17].
• In order to test this hypothesis, the number of GHRH and SRIH ME-projecting neurons was evaluated in normal and dwarf mice using a combination of retrograde tract-tracing and neuron phenotype identification by immunocytochemistry (ICC) [28].
• Decrease in telomerase activity in U-87MG human glioblastomas after treatment with an antagonist of growth hormone-releasing hormone [29].

References