Activation of Mitogen-activated protein kinase (MAPK) by GnRH is cell-context dependent

Dobkin-Bekman, Masha; Naidich, Michal; Pawson, Adam J.; Millar, Robert P.; Seger, Rony; Naor, Zvi

doi:10.1016/j.mce.2006.03.035

Cited by 71 publications

(41 citation statements)

References 50 publications

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“…The GnRH-I receptor binding assays were carried out using pituitary cells and fibroblasts. Therefore, we cannot confirm a complete antagonism in tumor cells because the GnRH signal transduction is cell context dependent (38). However, it cannot be ruled out that GnRH-II antagonists-induced apoptosis is mediated through the GnRH-I receptor.…”

Section: Discussionmentioning

confidence: 88%

GnRH-II Antagonists Induce Apoptosis in Human Endometrial, Ovarian, and Breast Cancer Cells via Activation of Stress-Induced MAPKs p38 and JNK and Proapoptotic Protein Bax

et al. 2009

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Recently, we could show that gonadotropin-releasing hormone (GnRH)-II antagonists induce apoptosis in human endometrial, ovarian, and breast cancer cells in vitro and in vivo. In the present study, we have ascertained receptor binding and effects of GnRH-II antagonists on mitogenic signal transduction and on activation of proapoptotic protein Bax. The GnRH-II antagonists tested showed EC 50 values for GnRH-I receptor binding in the range of 1 to 2 nmol/L. The GnRH-II agonist [D-Lys 6 ]GnRH-II showed an EC 50 value for GnRH-I receptor binding of f1,000 nmol/L. Agonistic activity on GnRH-I receptor function with an EC 50 of 13 nmol/L has been determined for [D-Lys 6 ]GnRH-II. Antagonistic activities with EC 50 values in the range of 1 nmol/L were determined for the GnRH-II antagonists. Treatment of human endometrial, ovarian, and breast cancer cells with GnRH-II antagonists resulted in time-dependent activation of stress-induced mitogen-activated protein kinases p38 and c-Jun NH 2 -terminal kinase. In addition, treatment with GnRH-II antagonists induced time-dependent activation of proapoptotic protein Bax. GnRH-II antagonists are not involved in activation of protein kinase B/Akt or extracellular signal-regulated kinase 1/2. The GnRH-II antagonists tested had similar binding affinities to the GnRH-I receptor comparable with that of GnRH-I antagonist Cetrorelix. Referring to the cyclic AMP response element reporter gene activation assay, the GnRH-II agonist ]GnRH-II has to be classified as an agonist at the GnRH-I receptor, whereas the GnRH-II antagonists tested are clear antagonists at the GnRH-I receptor. GnRH-II antagonists induce apoptotic cell death in human endometrial, ovarian, and breast cancer cells via activation of stressinduced mitogen-activated protein kinases p38 and c-Jun NH 2 -terminal kinase followed by activation of proapoptotic protein Bax. [Cancer Res 2009;69(16):6473-81]

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Section: Discussionmentioning

confidence: 88%

GnRH-II Antagonists Induce Apoptosis in Human Endometrial, Ovarian, and Breast Cancer Cells via Activation of Stress-Induced MAPKs p38 and JNK and Proapoptotic Protein Bax

et al. 2009

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“…2), and as previously shown in the white adipose tissue (Zhang et al 2005), maintains the activation of MAPK by protecting it from the effects of a MAPK-specific phosphatase (Kim et al 2001, Navratil et al 2010. The signal pathways activated by GnRH-R include major members of the MAPK family (Yang et al 2005, Dobkin-Bekman et al 2006. Opn3 has been shown to be involved in light sensation and circadian rhythms, with its implicated function being light reception for light-induced exocytosis in the PC12 cells and primary embryonic telencephalon cells (Henkel et al 2006).…”

Section: Cmentioning

confidence: 85%

Identification of estradiol/ERα-regulated genes in the mouse pituitary

Kim¹,

Gieske²,

Trudgen³

et al. 2011

Journal of Endocrinology

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Estrogen acts to prime the pituitary prior to the GnRHinduced LH surge by undiscovered mechanisms. This study aimed to identify the key components that mediate estrogen action in priming the pituitary. RNA extracted from the pituitaries of metestrous (low estrogen) and proestrus (high estrogen) stage mice, as well as from ovariectomized wildtype and estrogen receptor a (ERa) knockout mice treated with 17b-estradiol (E 2 ) or vehicle, was used for gene expression microarray. Microarray data were then aggregated, built into a functional electronic database, and used for further characterization of E 2 /ERa-regulated genes. These data were used to compile a list of genes representing diverse biological pathways that are regulated by E 2 via an ERa-mediated pathway in the pituitary. This approach substantiates ERa regulation of membrane potential regulators and intracellular vesicle transporters, among others, but not the basic components of secretory machinery. Subsequent characterization of six selected genes (Cacna1a, Cacna1g, Cited1, Abep1, Opn3, and Kcne2) confirmed not only ERa dependency for their pituitary expression but also the significance of their expression in regulating GnRH-induced LH secretion. In conclusion, findings from this study suggest that estrogen primes the pituitary via ERa by equipping pituitary cells with critical cellular components that potentiate LH release on subsequent GnRH stimulations.

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“…50), it has been reported that GnRH signaling may not be exclusively linked to G␣ q/11 -coupled pathway but also may involve other pathways and may be cell context dependent (51). In fact, GnRH-R was also reported to be coupled to G␣ s to stimulate the AC/cAMP/ PKA pathway (38,52).…”

Section: Discussionmentioning

confidence: 99%

Gonadotropin-Inhibitory Hormone Inhibits GnRH-Induced Gonadotropin Subunit Gene Transcriptions by Inhibiting AC/cAMP/PKA-Dependent ERK Pathway in LβT2 Cells

et al. 2012

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A neuropeptide that directly inhibits gonadotropin secretion from the pituitary was discovered in quail and named gonadotropin-inhibitory hormone (GnIH). The presence and functional roles of GnIH orthologs, RF-amide-related peptides (RFRP), that possess a common C-terminal LPXRF-amide (X ϭ L or Q) motif have also been demonstrated in mammals. GnIH orthologs inhibit gonadotropin synthesis and release by acting on pituitary gonadotropes and GnRH neurons in the hypothalamus via its receptor (GnIH receptor). It is becoming increasingly clear that GnIH is an important hypothalamic neuropeptide controlling reproduction, but the detailed signaling pathway mediating the inhibitory effect of GnIH on target cells is still unknown. In the present study, we investigated the pathway of GnIH cell signaling and its possible interaction with GnRH signaling using a mouse gonadotrope cell line, L␤T2. First, we demonstrated the expression of GnIH receptor mRNA in L␤T2 cells by RT-PCR. We then examined the inhibitory effects of mouse GnIH orthologs [mouse RFRP (mRFRP)] on GnRH-induced cell signaling events. We showed that mRFRP effectively inhibited GnRH-induced cAMP signaling by using a cAMP-sensitive reporter system and measuring cAMP levels, indicating that mRFRP function as an inhibitor of adenylate cyclase. We further showed that mRFRP inhibited GnRH-stimulated ERK phosphorylation, and this effect was mediated by the inhibition of the protein kinase A pathway. Finally, we demonstrated that mRFRP inhibited GnRHstimulated gonadotropin subunit gene transcriptions and also LH release. Taken together, the results indicate that mRFRP function as GnIH to inhibit GnRH-induced gonadotropin subunit gene transcriptions by inhibiting adenylate cyclase/cAMP/protein kinase A-dependent ERK activation in L␤T2 cells. (Endocrinology 153: 2332-2343, 2012)

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Activation of Mitogen-activated protein kinase (MAPK) by GnRH is cell-context dependent

Cited by 71 publications

References 50 publications

GnRH-II Antagonists Induce Apoptosis in Human Endometrial, Ovarian, and Breast Cancer Cells via Activation of Stress-Induced MAPKs p38 and JNK and Proapoptotic Protein Bax

GnRH-II Antagonists Induce Apoptosis in Human Endometrial, Ovarian, and Breast Cancer Cells via Activation of Stress-Induced MAPKs p38 and JNK and Proapoptotic Protein Bax

Identification of estradiol/ERα-regulated genes in the mouse pituitary

Gonadotropin-Inhibitory Hormone Inhibits GnRH-Induced Gonadotropin Subunit Gene Transcriptions by Inhibiting AC/cAMP/PKA-Dependent ERK Pathway in LβT2 Cells

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