Molecular Biology of Gonadotropin-Releasing Hormone (GnRH)-I, GnRH-II, and Their Receptors in Humans

Cheng, Chi Keung; Leung, Peter C.K.

doi:10.1210/er.2003-0039

Cited by 268 publications

(255 citation statements)

References 338 publications

(227 reference statements)

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“…Indeed, GNRH1 expression has been described in a number of other tissues, including prostate, retina, and developing teeth (25,30,31), but the fact that patient 1 exhibits no obvious phenotypes aside from IHH argues against a critical function for GNRH1 in these tissues. GnRH is also expressed in the testes (32), and at face value patient 1's subnormal response to hCG stimulation might suggest a direct role for GnRH in the testes.…”

Section: Discussionmentioning

confidence: 99%

GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism

Chan

Guillebon

Lang‐Muritano

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

181

138

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Idiopathic hypogonadotropic hypogonadism (IHH) is a condition characterized by failure to undergo puberty in the setting of low sex steroids and low gonadotropins. IHH is due to abnormal secretion or action of the master reproductive hormone gonadotropin-releasing hormone (GnRH). Several genes have been found to be mutated in patients with IHH, yet to date no mutations have been identified in the most obvious candidate gene, GNRH1 itself, which encodes the preprohormone that is ultimately processed to produce GnRH. We screened DNA from 310 patients with normosmic IHH (nIHH) and 192 healthy control subjects for sequence changes in GNRH1. In 1 patient with severe congenital nIHH (with micropenis, bilateral cryptorchidism, and absent puberty), a homozygous frameshift mutation that is predicted to disrupt the 3 C-terminal amino acids of the GnRH decapeptide and to produce a premature stop codon was identified. Heterozygous variants not seen in controls were identified in 4 patients with nIHH: 1 nonsynonymous missense mutation in the eighth amino acid of the GnRH decapeptide, 1 nonsense mutation that causes premature termination within the GnRH-associated peptide (GAP), which lies C-terminal to the GnRH decapeptide within the GnRH precursor, and 2 sequence variants that cause nonsynonymous amino-acid substitutions in the signal peptide and in GnRH-associated peptide. Our results establish mutations in GNRH1 as a genetic cause of nIHH.GnRH ͉ luteinizing hormone-releasing hormone ͉ LHRH

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Section: Discussionmentioning

confidence: 99%

GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism

Chan

Guillebon

Lang‐Muritano

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

181

138

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“…It is known that the GnRH precursor must be cleaved to become active (Cheng and Leung, 2005), and the lack of response with GnRH receptor inhibition in Figure 7 Cytoplasmic localization of p120 ctn is important for GnRH-mediated cell migration and invasion. (a) Schematic representation of the IL2R/E-cadherin membrane proximal chimera (IL2R/Ecad MP).…”

Section: Discussionmentioning

confidence: 99%

Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer

2010

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Gonadotropin-releasing hormone (GnRH) receptor expression is often elevated in ovarian cancer, but its potential role in ovarian cancer metastasis has just begun to be revealed. Cadherin switching is a crucial step during tumorigenesis, particularly in metastasis. Here, we showed that GnRH is an inducer of E-to P-cadherin switching, which is reminiscent of that seen during ovarian tumor progression. Overexpression of P-cadherin significantly enhanced, whereas knockdown of P-cadherin reduced migration and invasion regardless of E-cadherin expression, suggesting that inappropriate expression of P-cadherin contributes to the invasive phenotype. These effects of P-cadherin were mediated by activation of the Rho GTPases, Rac1, and Cdc42, through accumulation of p120 catenin (p120 ctn ) in the cytoplasm. The use of p120 ctn small interfering RNA or chimeric cadherin construct to inhibit p120 ctn expression and cytoplasmic localization, respectively, resulted in significant inhibition of cell migration and invasion, with a concomitant reduction in Rac1 and Cdc42 activation, confirming that the effect was p120 ctn specific. Similarly, the migratory/invasive phenotype could be reversed by expression of dominant-negative Rac1 and Cdc42. These results identify for the first time cadherin switching and p120 ctn signaling as important targets of GnRH function and as novel mediators of invasiveness and tumor progression in ovarian cancer.

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“…The presence of GnRH receptors in breast cancer tissue [31] and the demonstration of antiproliferative actions of GnRH analogs in breast cancer cell lines [32,47,96] supported this interpretation. Antiproliferative effects of GnRH analogs and the expression of GnRH receptors have now been demonstrated in a number of cell lines of reproductive tract tumors, including prostate, uterine and ovarian cancers, and also in nonreproductive tract tumors [21,43,47,70,73,79]. In contrast to GnRH actions at the gonadotrope, which are mediated through the G αq protein, these antiproliferative and apoptotic effects on tumor cells are thought to be mediated via the G αi protein [42,54,81], focal adhesion complexes involving c-Src, and the JNK and P38 stress-activated kinases [42,54,70,73,81].…”

Section: Direct Inhibition Of Proliferation and Stimulation Of Apoptomentioning

confidence: 99%

“…These include various regions of the central and peripheral nervous system, in most reproductive tissues, in many non-reproductive tissues, in immune cells and also in many cancer cells [21,48].…”

Section: Introductionmentioning

confidence: 99%

Diversity of actions of GnRHs mediated by ligand-induced selective signaling

Millar

Pawson

Morgan

et al. 2008

Frontiers in Neuroendocrinology

122

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Geoffrey Wingfield Harris' demonstration of hypothalamic hormones regulating pituitary function led to their structural identification and therapeutic utilization in a wide spectrum of diseases. Amongst these, Gonadotropin Releasing Hormone (GnRH) and its analogs are widely employed in modulating gonadotropin and sex steroid secretion to treat infertility, precocious puberty and many hormone-dependent diseases including endometriosis, uterine fibroids and prostatic cancer. While these effects are all mediated via modulation of the pituitary gonadotrope GnRH receptor and the G q signaling pathway, it has become increasingly apparent that GnRH regulates many extrapituitary cells in the nervous system and periphery. This review focuses on two such examples, namely GnRH analog effects on reproductive behaviors and GnRH analog effects on the inhibition of cancer cell growth. For both effects the relative activities of a range of GnRH analogs is distinctly different from their effects on the pituitary gonadotrope and different signaling pathways are utilized. As there is only a single functional GnRH receptor type in man we have proposed that the GnRH receptor can assume different conformations which have different selectivity for GnRH analogs and intracellular signaling proteins complexes. This ligand-induced selective-signaling recruits certain pathways while by-passing others and has implications in developing more selective GnRH analogs for highly specific therapeutic intervention.

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Molecular Biology of Gonadotropin-Releasing Hormone (GnRH)-I, GnRH-II, and Their Receptors in Humans

Cited by 268 publications

References 338 publications

GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism

GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism

Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer

Diversity of actions of GnRHs mediated by ligand-induced selective signaling

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