Follicle-Stimulating Hormone Receptor Expression in the Rat Ovary: Increases during Prepubertal Development and Regulation by the Opposing Actions of Transforming Growth Factors β and α1

Dunkel, Leo; Tilly, Jonathan L.; Shikone, Toshihiko; Nishimori, K.; Hsueh, Aaron J. W.

doi:10.1095/biolreprod50.4.940

Cited by 90 publications

(46 citation statements)

References 51 publications

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“…Results from a previous study indicated that TGFb1 could increase FSH receptor mRNA level and FSH binding activity in granulosa cells (Gitay-Goren et al 1993, Dunkel et al 1994. Also, TGFb1 increased the expression of transcription factor GATA4 in a granulosa tumor cell line KK1 (Anttonen et al 2006), and GATA4 has recently been reported to bind and stimulate FSH receptor promoter activity in mouse granulosa cells (Bennett et al 2012).…”

Section: Fs Hrmentioning

confidence: 94%

Calcineurin and CRTC2 mediate FSH and TGF 1 upregulation of Cyp19a1 and Nr5a in ovary granulosa cells

Lai¹,

Yeh

Fang³

et al. 2014

Journal of Molecular Endocrinology

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Estrogens are essential for female reproduction and overall well-being, and estrogens in the circulation are largely synthesized in ovarian granulosa cells. Using primary cultures of ovarian granulosa cells from gonadotropin-primed immature rats, we have recently discovered that pituitary FSH and ovarian cytokine transforming growth factor beta 1 (TGFb1) induce calcineurin-mediated dephosphorylation-activation of cAMP-response element-binding protein (CREB)-regulated transcription coactivator (CRTC2) to modulate the expression of Star, Cyp11a1, and Hsd3b leading to increased production of progesterone. This study explored the role of calcineurin and CRTC2 in FSH and TGFb1 regulation of Cyp19a1 expression in granulosa cells. Ovarian granulosa cells treated with FSH displayed increased aromatase protein at 24 h post-treatment, which subsided by 48 h, while TGFb1 acting through its type 1 receptor augmented the action of FSH with a greater and longer effects. It is known that the ovary-specific Cyp19a1 PII-promoter contains crucial response elements for CREB and nuclear receptor NR5A subfamily liver receptor homolog 1 (LRH1/NR5A2) and steroidogenic factor 1 (SF1/NR5A1), and that the Nr5a2 promoter also has a potential CREB-binding site. Herein, we demonstrate that FSHCTGFb1 increased LRH1 and SF1 protein levels, and their binding to the Cyp19a1 PII-promoter evidenced, determined by chromatin immunoprecipitation analysis. Moreover, pretreatment with calcineurin auto-inhibitory peptide (CNI) abolished the FSHCTGFb1-upregulated but not FSH-upregulated aromatase activity at 48 h, and the corresponding mRNA changes in Cyp19a1, and Nr5a2 and Nr5a1 at 24 h. In addition, FSH and TGFb1 increased CRTC2 binding to the Cyp19a1 PII-promoter and Nr5a2 promoter at 24 h, with CREB bound constitutively. In summary, the results of this study indicate that calcineurin and CRTC2 have important roles in mediating FSH and TGFb1 collateral Key Words Journal of Molecular EndocrinologyResearch W-A LAI and others Calcineurin and CRTC2 in ovary Cyp19a1 Nr5a expression 53:2 259-270

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Section: Fs Hrmentioning

confidence: 94%

Calcineurin and CRTC2 mediate FSH and TGF 1 upregulation of Cyp19a1 and Nr5a in ovary granulosa cells

Lai¹,

Yeh

Fang³

et al. 2014

Journal of Molecular Endocrinology

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“…through site(s) close to the level of FSH receptor activation other than downstream signal crosstalking, such as an interaction of Smad3-Akt (Conery et al 2004, Remy et al 2004 or Smad3-PKA regulatory subunit (Zhang et al 2004). Early reports have shown that TGFb1 attenuated FSH-induced downregulation of FSH receptors, and increased the expression of FSH receptors in granulosa cells (Gitay-Goren et al 1993, Dunkel et al 1994. In addition, recent progress indicates that the molecular mechanism of receptor endocytosis is pivotal on signal transduction (Miaczynska et al 2004, Le Roy & Wrana 2005.…”

Section: Fsh+tgfβ1mentioning

confidence: 99%

Interplay of PI3K and cAMP/PKA signaling, and rapamycin-hypersensitivity in TGFβ1 enhancement of FSH-stimulated steroidogenesis in rat ovarian granulosa cells

Chen¹,

Hsiao²,

Lee³

et al. 2007

Journal of Endocrinology

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Transforming growth factor (TGF)b1 facilitates FSH-induced differentiation of rat ovarian granulosa cells. The signaling crosstalk between follicle stimulating hormone (FSH) and TGFb receptors remains unclear. This study was to investigate the interplay of cAMP/protein kinase A (PKA) and phosphatidylinositol-3-kinase (PI3K) signaling including mammalian target of rapamycin (mTOR)C1 dependence in FSH-and TGFb1-stimulated steroidogenesis in rat granulosa cells. To achieve this aim, inhibitors of PKA (PKAI), PI3K (wortmannin), and mTORC1 (rapamycin) were employed. PKAI and wortmannin suppressions of the FSH-increased progesterone production were partly attributed to decreased level of 3b-HSD, and their suppression of the FSH plus TGFb1 effect was attributed to the reduction of all the three key players, steroidogenic acute regulatory (StAR) protein, P450scc, and 3b-HSD. Further, FSH activated the PI3K pathway including increased integrin-linked kinase (ILK) activity and phosphorylation of Akt(S473), mTOR(S2481), S6K(T389), and transcription factors particularly FoxO1(S256) and FoxO3a(S253), which were reduced by wortmannin treatment but not by PKAI. Interestingly, PKAI suppression of FSH-induced phosphorylation of cAMP regulatory element-binding protein (CREB(S133)) disappeared in the presence of wortmannin, suggesting that wortmannin may affect intracellular compartmentalization of signaling molecule(s).In addition, TGFb1 had no effect on FSH-activated CREB and PI3K signaling mediators. We further found that rapamycin reduced the TGFb1-enhancing effect of FSH-stimulated steroidogenesis, yet it exhibited no effect on FSH action. Surprisingly, rapamycin displayed a suppressive effect at concentrations that had no effect on mTORC1 activity. Together, this study demonstrates a delicate interplay between cAMP/PKA and PI3K signaling in FSH and TGFb1 regulation of steroidogenesis in rat granulosa cells. Furthermore, we demonstrate for the first time that TGFb1 acts in a rapamycinhypersensitive and mTORC1-independent manner in augmenting FSH-stimulated steroidogenesis in rat granulosa cells.

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“…Apart from activin, other members of the transforming growth factor-(TGF-) family of peptides, notably TGF-, have been shown to locally regulate aspects of ovarian function (Knecht et al 1987, Zhang et al 1988, Dunkel et al 1994, Lanuza et al 1999. TGF-stimulated inhibin production by isolated granulosa cells (Zhang et al 1988, Lanuza et al 1999, with the suggestion that inhibin-B may be stimulated in preference to inhibin-A (Lanuza et al 1999).…”

Section: Introductionmentioning

confidence: 99%

Temporal and hormonal regulation of inhibin protein and subunit mRNA expression by post-natal and immature rat ovaries

Drummond

Dyson

Thean

et al. 2000

Journal of Endocrinology

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The contribution of specific follicle populations to dimeric inhibin production and inhibin subunit mRNA expression by the rat ovary has been investigated in two model systems, granulosa cells isolated from 25-day-old diethylstilboestrol (DES)-treated rats and post-natal rat ovaries, dispersed in culture or whole ovaries, using specific two-site immunoassays and 'real time' PCR. Media from FSH-stimulated granulosa cell cultures fractionated by gel filtration and RP-high performance liquid chromatography revealed two predominant peaks of subunit activity which were attributed to subunit and 31 k dimeric inhibin-A. The corresponding inhibin-B levels were low. FSH stimulation did not alter the ratio of inhibin-A: subunit produced by granulosa cells. All three inhibin subunit mRNAs were expressed by granulosa cells, with eight-fold more subunit mRNA relative to either of the subunits. Administration of DES to immature rats prior to the isolation of granulosa cells from the ovary led to A and B mRNA expression being down-regulated in the absence of any significant change in subunit expression by the granulosa cells. Inhibin-A, -B and -subunit were produced by basal and stimulated cultures of ovarian cells prepared from 4-, 8-and 12-day-old rats, indicating that primary, preantral and antral follicles contribute to total inhibin production. Consistent with these results, follicles within these ovaries expressed all three inhibin subunit mRNAs, with maximal expression observed in the ovaries of 8-day-old rats. The appearance of antral follicles in the ovary at day 12 led to a decline in the mRNA levels of each of the subunits but was most evident for the subunits. There was a profound influence of secondary preantral follicles on dimeric inhibin-A production, with FSH stimulation increasing inhibin-A relative to subunit levels in cultures of ovarian cells prepared from 8-day-old rats. Thus, preantral follicles exposed to FSH contribute significantly to A subunit production by the ovary. In contrast, primary and preantral follicles did not produce inhibin-B in response to FSH stimulation. Transforming growth factor-(TGF-) enhanced, in a time-dependent manner, the production of the inhibin forms by ovarian cells in culture, although inhibin-B production was not responsive until day 8. The simultaneous treatment of ovarian cell cultures with FSH and TGF-elicited the greatest increases in production of all the inhibin forms.In summary, ovaries of 4-, 8-and 12-day-old rats expressed inhibin subunit mRNAs and produced dimeric inhibin-A and -B and free subunit. Preantral follicles (day-8 ovarian cell cultures) were particularly sensitive to stimulation by FSH and TGF-and had a substantial capacity for inhibin production. The production of oestrogen by follicles may be instrumental in regulating inhibin production given that subunit mRNA expression was down-regulated by DES. The mechanisms by which inhibin-A and inhibin-B are individually regulated are likely to be similar during the post-natal period, when folliculoge...

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Follicle-Stimulating Hormone Receptor Expression in the Rat Ovary: Increases during Prepubertal Development and Regulation by the Opposing Actions of Transforming Growth Factors β and α1

Cited by 90 publications

References 51 publications

Calcineurin and CRTC2 mediate FSH and TGF 1 upregulation of Cyp19a1 and Nr5a in ovary granulosa cells

Calcineurin and CRTC2 mediate FSH and TGF 1 upregulation of Cyp19a1 and Nr5a in ovary granulosa cells

Interplay of PI3K and cAMP/PKA signaling, and rapamycin-hypersensitivity in TGFβ1 enhancement of FSH-stimulated steroidogenesis in rat ovarian granulosa cells

Temporal and hormonal regulation of inhibin protein and subunit mRNA expression by post-natal and immature rat ovaries

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