Prolactin Inhibits Annexin 5 Expression and Apoptosis in the Corpus Luteum of Pseudopregnant Rats: Involvement of Local Gonadotropin-Releasing Hormone

Kawaminami, Mitsumori; Shibata, Yutaka; Yaji, Akiko; Kurusu, Shiro; Hashimoto, Itaru

doi:10.1210/en.2003-0118

Cited by 31 publications

(40 citation statements)

References 38 publications

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“…This protection was eliminated when prostate cancer cells overexpressed an I B superrepressor, suggesting that activation of NF B is required in the androgen survival signaling. Similarly in the corpus luteum of pregnancy we may assume that PRL, which is a survival factor according to recent evidence presented from our as well as another laboratory (Goyeneche et al 2003b, Kawaminami et al 2003, may elicit its effect by activating NF B.…”

Section: Discussionsupporting

confidence: 52%

Involvement of nuclear factor kappa B in the regulation of rat luteal function: potential roles as survival factor and inhibitor of 20alpha-hydroxysteroid dehydrogenase

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Goyeneche

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et al. 2004

Journal of Molecular Endocrinology

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Nuclear factor kappa B (NF B) is an important intracellular conveyor of extracellular signals and modulates a number of gene responses. Due to the potential significance of NF B in regulating ovarian gene expression, we examined in the rat: (i) whether NF B is activated and developmentally regulated in the corpus luteum (CL) throughout pregnancy; (ii) the proteins forming the NF B complex in luteal cells; and (iii) the role of this transcription factor in luteal function. Western analysis and immunohistochemistry revealed that p65 and p50 were highly expressed throughout pregnancy and were located in both the nucleus and cytoplasm of luteal cells. In addition, because NF B is maintained in the cytoplasm bound to I B, whose phosphorylation allows NF B translocation to the nucleus, we studied the developmental expression of phosphorylated and nonphosphorylated forms of I B . Western analysis revealed that I B was present and phosphorylated throughout pregnancy in the CL whereas by protein/DNA array and electromobility shift assays we found that luteal nuclear extracts bind to an NF B consensus sequence, and that the binding activity decreased along pregnancy. The specific binding was supershifted only by an anti-p65 antibody and not by antibodies against p50, p52, cRel, or RelB. Using day 4 postpartum ovaries, we found higher NF B binding activity in the newly formed CL than in old CL of pregnancy. Furthermore, NF B DNA binding activity was enhanced by prolactin in luteinized granulosa cells. In our first functional study, blockade of NF B/p65 binding to DNA with the sesquiterpene lactone helenalin in luteinized granulosa cells correlated with induction of cell death in a dose-dependent manner. In a second functional study, overexpression of NF B/p65 in luteal cells resulted in inhibition of 20 -hydroxysteroid dehydrogenase (20 HSD) promoter activity as well as endogenous 20 HSD mRNA expression. In summary, we have shown that: (i) NF B is expressed within the CL, primary luteinized granulosa cells, and a rat luteal cell line; (ii) NF B activation within the CL is developmentally regulated in pregnancy, depends on the age of the gland, and can be upregulated by prolactin; (iii) inhibition of NF B/p65 binding to an NF B DNA consensus sequence correlates with induction of cell death in ovarian luteinized granulosa cells; and (iv) overexpression of NF B in luteal cells inhibits 20 HSD gene expression. The results further support a role for NF B as a survival factor in the CL.

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Section: Discussionsupporting

confidence: 52%

Involvement of nuclear factor kappa B in the regulation of rat luteal function: potential roles as survival factor and inhibitor of 20alpha-hydroxysteroid dehydrogenase

Telleria

Goyeneche

Stocco³

et al. 2004

Journal of Molecular Endocrinology

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“…We previously reported that annexin 5 is synthesized by the gonadotropes, and that GnRH stimulates its expression [10][11][12][13]. Annexin 5 was shown to stimulate gonadotropin release leading us to propose that annexin 5 is a signal transduction factor downstream of the GnRH receptor [13,28]. The results obtained in the present study regarding the effect of annexin 5 on prolactin indicate a different mechanism of action from that seen in the gonadotropes, suggesting that annexin 5 has multiple functions in the anterior pituitary gland.…”

Section: Discussioncontrasting

confidence: 45%

Annexin 5 Inhibits Thyrotropin Releasing Hormone (TRH) Stimulated Prolactin Release in the Primary Culture of Rat Anterior Pituitary Cells

et al. 2004

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Abstract. Annexin 5, a novel calcium-phospholipid binding protein, is thought to be involved in hormone secretion by the anterior pituitary gland. Gonadotropin releasing hormone stimulates annexin 5 synthesis, which, in turn, enhances gonadotoropin secretion. On the other hand, annexin 5 was shown to inhibit prolactin release in vitro. To understand the nature of the opposing effects of annexin 5 on these two major pituitary hormones, the present study examines the inhibitory effect of annexin 5 on prolactin release in relation to thyrotropin stimulating hormone (TRH) using primary cultures of anterior pituitary cells of adult female rats. While recombinant rat annexin 5 was found to have little effect on basal prolactin release, it significantly inhibited TRH-stimulated prolactin release. Addition of specific anti-annexin 5 serum to the culture increased basal prolactin release in a concentration dependent manner, and no further increase in prolactin release was observed following application of TRH in the presence of anti-annexin 5. The enhanced basal prolactin release induced by anti-annexin 5 was reversed by the simultaneous administration of indomethacin, an inhibitor of cyclooxygenase. These results demonstrate that endogenous pituitary annexin 5 exerts an inhibitory effect on prolactin release and suggest that this is attained by suppression of eicosanoid synthesis in vitro.

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“…On the other hand, GnRH may exert chronic effect in peripheral tissues since GnRH and its receptor are expressed in a wide variety of extra-pituitary tissues [32][33][34]. In fact, we recently showed that the expression of annexin A5 in the corpus luteum and also Leydig cells is stimulated by local GnRH [35,36]. Surprisingly, we found that the expression of annexin A5 mRNA was not down-regulated by continuous stimulation of GnRHa.…”

Section: Discussionmentioning

confidence: 59%

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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Prolactin Inhibits Annexin 5 Expression and Apoptosis in the Corpus Luteum of Pseudopregnant Rats: Involvement of Local Gonadotropin-Releasing Hormone

Cited by 31 publications

References 38 publications

Involvement of nuclear factor kappa B in the regulation of rat luteal function: potential roles as survival factor and inhibitor of 20alpha-hydroxysteroid dehydrogenase

Involvement of nuclear factor kappa B in the regulation of rat luteal function: potential roles as survival factor and inhibitor of 20alpha-hydroxysteroid dehydrogenase

Annexin 5 Inhibits Thyrotropin Releasing Hormone (TRH) Stimulated Prolactin Release in the Primary Culture of Rat Anterior Pituitary Cells

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

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