GnRH as a Cell Proliferation Regulator: Mechanism of Action and Evolutionary Implications (original) (raw)
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Molecular Biology of Gonadotropin-Releasing Hormone (GnRH)-I, GnRH-II, and Their Receptors in Humans
Endocrine Reviews, 2005
In human beings, two forms of GnRH, termed GnRH-I and GnRH-II, encoded by separate genes have been identified. Although these hormones share comparable cDNA and genomic structures, their tissue distribution and regulation of gene expression are significantly dissimilar. The actions of GnRH are mediated by the GnRH receptor, which belongs to a member of the rhodopsin-like G protein-coupled receptor superfamily. However, to date, only one conventional GnRH receptor subtype (type I GnRH receptor) uniquely lacking a carboxyl-terminal tail has been found in the human body. Studies on the transcriptional regulation of the human GnRH receptor gene have indicated that tissue-specific gene expression is mediated by differential promoter usage in various cell types. Functionally, there is growing evidence showing that both GnRH-I and GnRH-II are potentially important autocrine and/or paracrine regulators in some extrapituitary compartments. Recent cloning of a second GnRH receptor subtype (type II GnRH receptor) in nonhuman primates revealed that it is structurally and functionally distinct from the mammalian type I receptor. However, the human type II receptor gene homolog carries a frameshift and a premature stop codon, suggesting that a full-length type II receptor does not exist in humans. (Endocrine Reviews 26: 283-306, 2005) I. Introduction II. GnRH Isoforms in Humans: GnRH-I and GnRH-II A. cDNA and genomic structures B. Tissue distribution in humans C. Regulation of gene expression in humans III. Molecular Characterization of Human Type I GnRH Receptor Gene A. cDNA cloning B. Genomic organization and chromosomal localization C. Untranslated and 5Ј-flanking regions D. Tissue distribution in humans E. Regulation of gene expression in humans F. Pathophysiology of human GnRH receptor mutations IV. Transcriptional Regulation of Human Type I GnRH Receptor Gene A. Cell-specific promoters B. Transcriptional regulation by GnRH-I C. Transcriptional regulation by the cAMP-dependent signal transduction pathway D. Transcriptional regulation by gonadal steroid hormones E. Transcriptional repression V. Signal Transduction Mechanism of the Mammalian Type I GnRH Receptor A. G protein coupling B. MAPKs C. Receptor desensitization and internalization VI. Biological Actions of GnRH-I and GnRH-II in Humans A. Gonadotropin subunit gene transcription and secretion B. Ovarian steroidogenesis C. Cell proliferation D. Apoptosis E. Embryo implantation F. Other extrapituitary actions VII. Type II GnRH Receptor: Existence in Humans? A. Nonhuman primate type II GnRH receptors B. Putative type II GnRH receptor genes in the human genome C. Tissue distribution of human type II GnRH receptor mRNA VIII. Conclusions
Endocrinology, 2003
tumor growth that may, in part, be mediated by direct activation of GnRH receptors (GnRHRs) expressed on tumor cells. However, it is not fully understood how the GnRHR mediates these growth effects. This study aimed to determine how the presence or absence of this receptor in different cell types might affect the ability of GnRH to directly mediate growth effects. We demonstrate that continuous treatment with GnRH or a GnRH agonist (GnRHA) induces an anti-proliferative effect in a gonadotrope-derived cell line (LβT2) and also in HEK293 cells stably expressing either the rat or human GnRHR. The anti-proliferative effect was time-and dose-dependent and was verified using [ 3 H]-thymidine incorporation, light microscopy and analysis of cell number. Inhibition was specifically mediated via the GnRHR as cotreatment of the GnRHR-expressing cell lines with a GnRH antagonist blocked the growth suppressive effect induced by GnRHA treatment. Cell cycle analysis revealed that the GnRHA treated HEK/GnRHR cell lines induced an accumulation of cells in the G2/M phase while a G0/G1 arrest was observed in LβT2 cells. GnRHA treatment also caused a small but significant increase in apoptotic cells. This study provides evidence for a direct role for the GnRHR in mediating anti-proliferative events in two cell systems neither of which were derived from extra-pituitary reproductive tumors. The ability to induce these effects, irrespective of the cell system involved, has implications regarding the use of GnRH analogs for the treatment of endocrine-related disorders and tumors. K, Plonowski A, Varga JL, Halmos G. 2001 Hypothalamic hormones and cancer. Front Neuroendocrinol 22:248-91 3. Schally AV 1999 Luteinizing hormone-releasing hormone analogs: their impact on the control of tumorigenesis. Peptides 20:1247-62 4. Eidne KA, Flanagan CA, Millar RP 1985 Gonadotropin-releasing hormone binding sites in human breast carcinoma. Science 229:989-91 5. Eidne KA, Flanagan CA, Harris NS, Millar RP 1987 Gonadotropinreleasing hormone (GnRH)-binding sites in human breast cancer cell lines and inhibitory effects of GnRH antagonists. J Clin Endocrinol Metab 64:425-32 6. Miller WR, Scott WN, Morris R, Fraser HM, Sharpe RM 1985 Growth of human breast cancer cells inhibited by a luteinizing hormonereleasing hormone agonist. Nature 313:231-3 7. Limonta P, Dondi D, Moretti RM, Maggi R, Motta M 1992 Antiproliferative effects of luteinizing hormone-releasing hormone agonists on the human prostatic cancer cell line LNCaP. J Clin Endocrinol Metab 75:207-12 8. Dondi D, Limonta P, Moretti RM, Marelli MM, Garattini E, Motta M 1994 Antiproliferative effects of luteinizing hormone-releasing hormone (LHRH) agonists on human androgen-independent prostate cancer cell line DU 145: evidence for an autocrine-inhibitory LHRH loop. Cancer
Endocrinology, 2003
hibition of tumor growth that may be mediated in part by direct activation of GnRH receptors (GnRHRs) expressed on tumor cells. However, it is not fully understood how the GnRHR mediates these growth effects. This study aimed to determine how the presence or absence of this receptor in different cell types might affect the ability of GnRH to directly mediate growth effects. We demonstrate that continuous treatment with GnRH or a GnRH agonist (GnRHA) induces an antiproliferative effect in a gonadotrope-derived cell line (LT2) and also in HEK293 cells stably expressing either the rat or human GnRHR. The antiproliferative effect was time and dose dependent and was verified using [ 3 H]thymidine incorporation, light microscopy, and analysis of cell number. Inhibition was specifically mediated via the GnRHR, as co-treatment of the GnRHR-expressing cell lines with a GnRH antagonist blocked the growth-suppressive effect induced by GnRHA treatment. Cell cycle analysis revealed that GnRHA-treated HEK/GnRHR cell lines induced an accumulation of cells in the G 2 /M phase, whereas a G 0 /G 1 arrest was observed in LT2 cells. GnRHA treatment also caused a small, but significant, increase in apoptotic cells. This study provides evidence for a direct role for the GnRHR in mediating antiproliferative events in two cell systems, neither of which was derived from extrapituitary reproductive tumors. The ability to induce these effects, regardless of the cell system involved, has implications regarding the use of GnRH analogs for the treatment of endocrine-related disorders and tumors.
Endocrinology, 2005
Humans possess only one functional GnRH receptor, the type I GnRH receptor (GnRHR-I). A type II GnRH receptor (GnRHR-II) gene homolog exists, but it is disrupted by a frame shift and premature stop codon, suggesting that a conventional receptor is not translated from this gene. However, the gene remains transcriptionally active and displays alternative splicing. We identified a putative translational start site 117 bp downstream of the premature stop codon. Use of this start codon encodes a protein (designated as the GnRHR-IIreliquum) corresponding to the domains from the cytoplasmic end of transmembrane domain-5 to the carboxyl terminus of the putative full-length receptor. Immunocytochemistry revealed that GnRHR-II-reliquum expression appeared to be localized throughout the cytoplasm. Transient cotransfection of GnRHR-I and GnRHR-II-reliquum constructs into COS-7 cells resulted in reduced expression of the GnRHR-I at the cell surface and impaired signaling via the GnRHR-I as revealed by reduction of GnRH-induced inositol phosphate accumulation. This inhibitory effect was specific and dependent on the degree of GnRHR-II-reliquum coexpressed. Immunoblot analysis revealed that the total cell GnRHR-I complement, i.e. both cell-surface and nascent intracellular receptors, was markedly reduced by coexpression of the GnRHR-II-reliquum. Treatments with cell-permeable agents that blocked either de novo protein synthesis (cycloheximide) or proteinase-mediated degradation (leupeptin and phenylmethylsulfonyl fluoride) failed to alter the inhibitory effect of GnRHR-II-reliquum coexpression, suggesting that the inhibitory effect is exerted at the nucleus/endoplasmic reticulum or Golgi apparatus level, possibly by perturbing normal processing of GnRHR-I from these sites. We suggest that the GnRHR-IIreliquum plays a modulatory role in GnRHR-I expression.
Endocrinology, 2004
hibition of tumor growth that may be mediated in part by direct activation of GnRH receptors (GnRHRs) expressed on tumor cells. However, it is not fully understood how the GnRHR mediates these growth effects. This study aimed to determine how the presence or absence of this receptor in different cell types might affect the ability of GnRH to directly mediate growth effects. We demonstrate that continuous treatment with GnRH or a GnRH agonist (GnRHA) induces an antiproliferative effect in a gonadotrope-derived cell line (LT2) and also in HEK293 cells stably expressing either the rat or human GnRHR. The antiproliferative effect was time and dose dependent and was verified using [ 3 H]thymidine incorporation, light microscopy, and analysis of cell number. Inhibition was specifically mediated via the GnRHR, as co-treatment of the GnRHR-expressing cell lines with a GnRH antagonist blocked the growth-suppressive effect induced by GnRHA treatment. Cell cycle analysis revealed that GnRHA-treated HEK/GnRHR cell lines induced an accumulation of cells in the G 2 /M phase, whereas a G 0 /G 1 arrest was observed in LT2 cells. GnRHA treatment also caused a small, but significant, increase in apoptotic cells. This study provides evidence for a direct role for the GnRHR in mediating antiproliferative events in two cell systems, neither of which was derived from extrapituitary reproductive tumors. The ability to induce these effects, regardless of the cell system involved, has implications regarding the use of GnRH analogs for the treatment of endocrine-related disorders and tumors.
Scientific Reports, 2019
Continuous, as opposed to pulsatile, delivery of hypothalamic gonadotropin-releasing hormone (GnRH) leads to a marked decrease in secretion of pituitary gonadotropins LH and FSH and impairment of reproductive function. Here we studied the expression profile of gonadotropin subunit and GnRH receptor genes in rat pituitary in vitro and in vivo to clarify their expression profiles in the absence and continuous presence of GnRH. Culturing of pituitary cells in GnRH-free conditions downregulated Fshb, Cga, and Gnrhr expression, whereas continuous treatment with GnRH agonists upregulated Cga expression progressively and Gnrhr and Fshb expression transiently, accompanied by a prolonged blockade of Fshb but not Gnrhr expression. In contrast, Lhb expression was relatively insensitive to loss of endogenous GnRH and continuous treatment with GnRH, probably reflecting the status of Egr1 and Nr5a1 expression. Similar patterns of responses were observed in vivo after administration of a GnRH agon...
Gonadotropin inhibitory hormone (GnIH) as a regulator of gonadotropes
Molecular and Cellular Endocrinology, 2014
Gonadotropin inhibitory hormone (GnIH) has emerged as a negative regulator of gonadotrope function in a range of species. In rodents, such as rats and mice, GnIH exerts influence upon GnRH cells within the brain. In other species, however, the peptide is secreted into hypophysial portal blood to act on pituitary gonadotropes. In particular, a series of studies in sheep have demonstrated potent actions at the level of the pituitary gland to counteract the function of GnRH in terms of the synthesis and secretion of gonadotropins. This review focuses on the action of GnIH at the level of the gonadotrope.
GnRH and GnRH receptors in the pathophysiology of the human female reproductive system
Human Reproduction Update, 2015
† Introduction † Methods † GnRH and GnRH receptors GnRH GnRH isoforms GnRHRs GnRH analogues † Development of GnRH neurons and related diseases † GnRH neuron function and GnRH secretion Control of GnRH secretion GnRH action on gonadotrope cells Dysregulation of pulsatile GnRH release GnRH pulsatility in the onset of puberty † GnRH and GnRH receptors in female peripheral sexual organs Peripheral versus central GnRHRs The GnRH/GnRHR system in the endometrium The GnRH/GnRHR system in the ovary † Pharmacology of GnRH and GnRH analogues in human female reproduction and diseases GnRH analogues for stimulating or to blocking the reproductive axis GnRH analogues in benign gynaecological diseases GnRH analogues in gynaecological tumours GnRH analogues for fertility preservation in female patients undergoing chemotherapy † Conclusions and future perspectives background: Human reproduction depends on an intact hypothalamic-pituitary-gonadal (HPG) axis. Hypothalamic gonadotrophin-releasing hormone (GnRH) has been recognized, since its identification in 1971, as the central regulator of the production and release of the pituitary gonadotrophins that, in turn, regulate the gonadal functions and the production of sex steroids. The characteristic peculiar development, distribution and episodic activity of GnRH-producing neurons have solicited an interdisciplinary interest on the etiopathogenesis of several reproductive diseases. The more recent identification of a GnRH/GnRH receptor (GnRHR) system in both the human endometrium and ovary has widened the spectrum of action of the peptide and of its analogues beyond its hypothalamic function.