Activation of MAPK Cascades by GnRH: ERK and Jun N-Terminal Kinase Are Involved in Basal and GnRH-Stimulated Activity of the Glycoprotein Hormone LHβ-Subunit Promoter

Harris, Dagan; Bonfil, David; Chuderland, Dana; Kraus, Sarah; Seger, Rony; Naor, Zvi

doi:10.1210/endo.143.3.8675

Cited by 99 publications

(25 citation statements)

References 29 publications

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“…This mechanism of enhancing Egr-1 transcription and protein level is in keeping with previous reports that insulin regulates Egr-1 transcription (Harada et al, 1995;Mohn et al, 1990;Stumpo and Blackshear, 1991;Alexander-Bridges et al, 1992;Jhun et al, 1995;Sasaoka et al, 1993;Sartipy and Loskutoff, 2003;Keeton et al, 2003). Furthermore, others have shown that GnRH utilizes mitogen-activated protein kinase (MAPK) pathways to regulate expression of gonadotropin genes (Naor et al, 2000;Harris et al, 2002). Regulation of the equine LHβ (eLHβ) promoter by GnRH is mediated partly via a protein kinase C/MAPK pathway (Call and Wolfe, 1999).…”

Section: Resultssupporting

confidence: 87%

Insulin augments GnRH-stimulated LHβ gene expression by Egr-1

Buggs¹,

Weinberg²,

Kim³

et al. 2006

Molecular and Cellular Endocrinology

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Previous studies have shown that insulin augments GnRH-stimulated LH synthesis and release from primary gonadotrophs. In this study, regulation of LHβ gene expression by GnRH and insulin was examined in LβT2 cells. Endogenous LHβ mRNA is stimulated 2.4-fold by insulin alone, 2.6-fold by GnRH alone, and 4.7-fold by insulin together with GnRH. This effect of insulin, like GnRH, mapped to sequences −140 to +1 in the mouse LHβ gene. Insulin together with GnRH stimulates activity of an LHβ-reporter gene 7.1-fold; whereas, GnRH alone or insulin alone stimulates the reporter activity 2.8-and 3.1-fold, respectively. Blocking the binding of Egr-1 to sequences −51 to −42 in the LHβ gene inhibits effects of insulin and GnRH. Insulin together with GnRH increases Egr-1 mRNA levels and total Egr-1 binding to LHβ DNA. These findings indicate that insulin may impact regulation of the reproductive axis at the level of the pituitary.

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Section: Resultssupporting

confidence: 87%

Insulin augments GnRH-stimulated LHβ gene expression by Egr-1

Buggs¹,

Weinberg²,

Kim³

et al. 2006

Molecular and Cellular Endocrinology

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“…A membrane phospholipid, phosphatidyl inositol (4,5)-bis phosphate, is converted to inositol 3 phosphate and diacylglycerol. The former stimulates the release of calcium ion and the latter stimulates protein kinase C. Beside these signal pathways, it has been demonstrated that Gs, Gi and MAPK are also involved in the signal transduction of GnRH receptor [20][21][22][23][24]. It is thus of interest to determine how annexin A5 synthesis is controlled by GnRH in the gonadotrope.…”

mentioning

confidence: 99%

Gonadotropin Releasing Hormone (GnRH) Enhances Annexin A5 mRNA Expression through Mitogen Activated Protein Kinase (MAPK) in L.BETA.T2 Pituitary Gonadotrope Cells

et al. 2008

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Abstract. The mechanism by which GnRH stimulates annexin A5 expression was examined with LβT2 gonadotrope cells. Continuous stimulation with GnRH analog (GnRHa, Des-Gly10 [Pro9]-GnRH ethylamide) transiently elevated LHβ mRNA expression while maintaining annexin A5 mRNA at high levels for 24 h. GnRH antagonist blocked the effect of GnRHa on annexin A5. While 12-O-tetradecanoyl-phorbol-13 acetate, a protein kinase C activator, increased the expression of annexin A5 mRNA, bisindolylmaleimide, an inhibitor of protein kinase C, suppressed GnRHa-stimulated expression of annexin A5 and LHβ mRNA. GnRHa stimulation of LHβ mRNA was inhibited to a greater extent than annexin A5 by a calcium chelator BAPTA/AM. Although a calcium ionophore ionomycin stimulated the expression of both genes, only LHβ was down-regulated. The MAPK kinase inhibitor PD98059 inhibited GnRHa induction of annexin A5 but not LHβ mRNA. EGF stimulated the expression of annexin A5 mRNA but caused only a transient effect on LHβ mRNA expression. These results indicate that GnRH stimulation of signaling pathway for annexin A5 mRNA expression is distinct from that of LHβ mRNA and dependent more on MAPK. GnRH is a hypothalamic neuropeptide that regulates pituitary gonadotropin secretion. GnRH neuron secretes GnRH in a pulsatile fashon at the median eminence of the hypothalamus. Portal blood also shows pulsatile fluctuations of GnRH [1]. The frequency of the GnRH pulses seems to influence the different effects on cell function of the gonadotropes [2][3][4]. Recently, we demonstrated that GnRH stimulates the expression of annexin A5 mRNA in gonadotropes [5][6][7][8]. Because ovariectomy enhanced annexin A5 expression in the gonadotropes and estradiol inhibited it, the expression of pituitary annexin A5 was thought to be physiologically regulated by hypothalamic GnRH [6]. We also demonstrated that annexin A5 participates in GnRH control of gonadotropin secretion. Annexin A5 itself stimulates both LH and FSH release, while an annexin A5 antisense oligonucleotide reduces GnRH stimulation of LH [7]. These findings suggest that intracellular annexin A5 is requisite for GnRH stimulation of gonadotropin secretion.In mammals, the annexin family consists of a group of at least 12 Ca 2+ -dependent phospholipid binding proteins [9,10]. Annexin A1 was first identified as a mediator of the anti-inflammatory activity of glucocorticoids [11]. The identification of other annexins followed, including annexin A5 that was discovered as a protein that inhibits phospholipase A 2 and suppresses blood coagulation [12,13]. These activities are thought to be due to its ability to bind phospholipids, although it is not clear whether these activities are relevant to physiological function. However, as we showed in the gonadotropes, annexin A5 may be at least necessary for an intracellular signaling in some cell types [14][15][16].

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“…In human, the GnRH secretion may be regulated by estrogen and leptin [38]. It has been reported that MAP kinase contributes to the GnRH-induced LHb promoter activation in LbT2 cells [25,26]. In this study, we placed the luciferase reporter gene downstream of the rat FS promoter and found that the single and chronic treatment of LbT2 cells can activate the FS promoter.…”

Section: Discussionmentioning

confidence: 86%

“…It has been reported that GnRH induced the transient activation of the MAP kinase pathway in LbT2 cells [25,26]. Therefore, we examined whether or not the activation of the MAP kinase pathway was necessary for the GnRH-induced activation of the FS promoter.…”

Section: Involvement Of Map Kinase In Fs Promoter Activationmentioning

confidence: 97%

“…LbT2 cells have proven useful for studies on the molecular mechanisms involved in the GnRH-induced synthesis of FSH. We and other laboratories have reported that GnRH induced the transient activation of the mitogen-activated protein (MAP) kinase pathway in the cells [25,26]. However, it is still not clear at present why the activation by GnRH of the MAP kinase pathway is transient.…”

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confidence: 99%

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Activation of Follistatin Promoter by GnRH in LβT2 Gonadotroph Cells

et al. 2006

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Abstract. Follistatin (FS) is produced and secreted from gonadotroph cells in pituitary gland as well as granulosa cells in the ovary. In the present study, we found that the FS promoter is activated by GnRH in the gonadotroph cell line, LbT2. Therefore, we examined the signal transduction pathways involved in the mechanism. The activation of the FS promoter by GnRH was inhibited by calphostin C, a protein kinase C inhibitor, and U0126, a MAP kinase kinase (MEK) inhibitor. Phosphorylation by protein kinase C of myristoylated alanine-rich C kinase substrate (MARCKS) in LbT2 cells was observed after 3-min treatment with GnRH and declined after 30 min. The subsequent activation of MAP kinase was also transient, and down-regulation of protein kinase C completely inhibited the MAP kinase activation by GnRH, suggesting that the transient activation of protein kinase C led to the transient activation of MAP kinase. Although phorbol 12-myristate 13-acetate treatment increased phosphorylation of MARCKS and activated MAP kinase, it did not activate the FS promoter. Genistein, a tyrosine kinase inhibitor, completely inhibited the GnRH-induced activation of the FS promoter, while no inhibition of the MAP kinase pathway was observed. These results suggest that the activations of both the protein kinase C and tyrosine kinase pathways are necessary for the activation of the FS promoter in gonadotroph cells. FOLLISTATIN (FS) was first identified from ovarian follicular fluid on the basis of its ability to suppress the secretion of follicle-stimulating hormone (FSH) from pituitary gonadotrophs [1][2][3][4]. FS is a monomeric glycoprotein structurally unrelated to inhibin [3]. FS binds to activin with high affinity [5] and inhibits the activity of activin to stimulate FSH secretion [6][7][8]. In ovary, the granulosa cells are responsible for producing and secreting FS in most species [9][10][11][12]. FS expression in granulosa cells is increased through both cyclic AMP and protein kinase C pathways [13][14][15][16][17]. In cultured rat granulosa cells, FSH and gonadotropin-releasing hormone (GnRH) increased FS protein production through the cyclic AMP and protein kinase C pathways, respectively. The expression of FS is not limited to the ovary, and FS is secreted within the pituitary gland, where it exerts autocrine/paracrine effect [18]. It has been reported that FS expression in gonadotrophs is regulated by GnRH at the steady state mRNA levels [18,19]. GnRH is a hypothalamic peptide and serves as a critical regulator for the synthesis and secretion of FSH [20,21]. FSH is composed of two noncovalently linked subunits, a and b. It is well known that the synthesis of the b-subunit (FSHb) is the rate-limiting step in the production of FSH [20]. Slow-frequency GnRH pulses increase FSHb mRNA through activation of the

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Activation of MAPK Cascades by GnRH: ERK and Jun N-Terminal Kinase Are Involved in Basal and GnRH-Stimulated Activity of the Glycoprotein Hormone LHβ-Subunit Promoter

Cited by 99 publications

References 29 publications

Insulin augments GnRH-stimulated LHβ gene expression by Egr-1

Insulin augments GnRH-stimulated LHβ gene expression by Egr-1

Gonadotropin Releasing Hormone (GnRH) Enhances Annexin A5 mRNA Expression through Mitogen Activated Protein Kinase (MAPK) in L.BETA.T2 Pituitary Gonadotrope Cells

Activation of Follistatin Promoter by GnRH in LβT2 Gonadotroph Cells

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Activation of MAPK Cascades by GnRH: ERK and Jun N-Terminal Kinase Are Involved in Basal and GnRH-Stimulated Activity of the Glycoprotein Hormone LHβ-Subunit Promoter

Cited by 99 publications

References 29 publications

Insulin augments GnRH-stimulated LHβ gene expression by Egr-1

Insulin augments GnRH-stimulated LHβ gene expression by Egr-1

Gonadotropin Releasing Hormone (GnRH) Enhances Annexin A5 mRNA Expression through Mitogen Activated Protein Kinase (MAPK) in L.BETA.T2 Pituitary Gonadotrope Cells

Activation of Follistatin Promoter by GnRH in L&beta;T2 Gonadotroph Cells

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Activation of Follistatin Promoter by GnRH in LβT2 Gonadotroph Cells