Specific modulation of nongenomic androgen signaling in the ovary

White, Stacy; Jamnongjit, Michelle; Gill, Arvind; Lutz, Lindsey B.; Hammes, Stephen R.

doi:10.1016/j.steroids.2005.02.008

Cited by 30 publications

(21 citation statements)

References 55 publications

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“…In contrast to these suggestions, we found that E 2 , DHT, dihydronandrolone, and 19-nortestosterone could not reproduce the effects of estren on differentiation of uncommitted osteoblast precursors even at concentrations 5 orders of magnitude higher. In line with our findings, White and colleagues have found that estren is a weak regulator of AR-mediated transcription but a moderate promoter of Xenopus oocyte maturation, a process that involves nongenotropic actions of androgens (45,62). In contrast, 19-nortestosterone is a highly potent regulator of AR-mediated transcription but a very weak activator of Xenopus oocyte maturation.…”

Section: Vol 27 2007 Osteoblast Differentiation By Er Actions On Kisupporting

confidence: 91%

Induction of Osteoblast Differentiation by Selective Activation of Kinase-Mediated Actions of the Estrogen Receptor

Kousteni

Almeida

Han

et al. 2007

Molecular and Cellular Biology

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Estrogens control gene transcription by cis or trans interactions of the estrogen receptor (ER) with target DNA or via the activation of cytoplasmic kinases. We report that selective activation of kinase-mediated actions of the ER with 4-estren-3␣,17␤-diol (estren) or an estradiol-dendrimer conjugate, each a synthetic compound that stimulates kinase-mediated ER actions 1,000 to 10,000 times more potently than direct DNA interactions, induced osteoblastic differentiation in established cell lines of uncommitted osteoblast precursors and primary cultures of osteoblast progenitors by stimulating Wnt and BMP-2 signaling in a kinase-dependent manner. In sharp contrast, 17␤-estradiol (E 2 ) suppressed BMP-2-induced osteoblast progenitor commitment and differentiation. Consistent with the in vitro findings, estren, but not E 2 , stimulated Wnt/␤-catenin-mediated transcription in T-cell factor-lacZ transgenic mice. Moreover, E 2 stimulated BMP signaling in mice in which ER␣ lacks DNA binding activity and classical estrogen response element-mediated transcription (ER␣ NERKI/؊ ) but not in wild-type controls. This evidence reveals for the first time the existence of a large signalosome in which inputs from the ER, kinases, bone morphogenetic proteins, and Wnt signaling converge to induce differentiation of osteoblast precursors. ER can either induce it or repress it, depending on whether the activating ligand (and presumably the resulting conformation of the receptor protein) precludes or accommodates EREmediated transcription.Steroid hormones, including estrogens and androgens, can induce cellular responses not only through direct activation of gene transcription resulting from cis or trans interactions of their receptors with DNA binding sequences on target gene promoters but also indirectly. The latter responses result from extranuclear actions of the same hormone receptors, causing activation of various cytoplasmic protein kinase cascades, which in turn alter the activities of other transcription factors or coactivators of the receptors themselves (5,6,27,40,43,46,53,67). During the last few years, we and others have identified several synthetic compounds that, unlike estradiol, can selectively activate kinase-initiated routes by which the estrogen receptor (ER) controls gene transcription (28,38,60). By use of these compounds, substantial evidence that kinase-mediated effects on gene transcription are dissociable from direct cis or trans effects on transcription has been obtained (28,38,39,54). Moreover, the use of selective activators of kinases, as well as compounds that dissociate the classical genomic actions of the estrogen receptor from cross talk with other transcription factors (8, 56), has provided extensive proof of the general concept that it is possible to eliminate the uterotropic activity of estrogens while retaining other nonreproductive actions. Together with cell and murine models expressing mutant receptors that cannot enter the nucleus and interact with DNA directly, these tools have become increas...

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Section: Vol 27 2007 Osteoblast Differentiation By Er Actions On Kisupporting

confidence: 91%

Induction of Osteoblast Differentiation by Selective Activation of Kinase-Mediated Actions of the Estrogen Receptor

Kousteni

Almeida

Han

et al. 2007

Molecular and Cellular Biology

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“…So far, progesterone had convincingly been shown to induce oocyte meiotic maturation in X. laevis (Bagowski et al 2001, White et al 2005. Progesterone actions on meiotic resumption in X. laevis are non-genomic and RU486 antagonises the genomic effects of the progesterone receptor (Bayaa et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Epiregulin can effectively mature isolated cumulus–oocyte complexes, but fails as a substitute for the hCG/epidermal growth factor stimulus on cultured follicles

Romero

Smitz²

2009

Reproduction

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REPRODUCTION RESEARCHEpiregulin can effectively mature isolated cumulus-oocyte complexes, but fails as a substitute for the hCG/epidermal growth factor stimulus on cultured follicles Sergio Romero and Johan SmitzFollicle Biology Laboratory (FOBI), Vrije Universiteit Brussel (VUB), UZ Brussel, Laarbeeklaan 101, Brussels 1090, BelgiumCorrespondence should be addressed to S Romero; Email: sromerol@vub.ac.be AbstractEpiregulin mediates LH ovulatory effects in vitro. This study evaluated the use of epiregulin as an alternative to hCG/epidermal growth factor (EGF) stimulus upon cultured ovarian follicles in contrast to isolated cumulus-oocyte complexes (COCs). Pre-antral mouse ovarian follicles were cultured for 12 days and final maturation was induced by administration of 0.65 nM EGF or 100 nM epiregulin without or with 1.2 IU/ml hCG. Results showed that both EGF or epiregulin as sole stimulators are poor inducers of mucification/expansion of cumulus cells and oocyte meiotic reinitiation in follicle-enclosed COCs (25G17 and 22G16% GVBD respectively; versus 97G4 and 90G15% GVBD by control hCG/EGF and hCG/epiregulin respectively; meanGS.D). Furthermore, EGF or epiregulin did not induce follicle luteinisation: progesterone production was marginally increased and oestradiol was incompletely shut down. Supposing that the sub-normal progesterone secretion was a potential cause for incomplete meiosis in this model, effectiveness of progesterone supplementation and addition of a progesterone receptor inhibitor (RU486) were evaluated on meiotic resumption. Progesterone was not found to be a major regulator of meiosis in this mouse model. Epiregulin induced meiosis more effectively in COCs isolated from cultured preovulatory follicles in a secondary culture well. In conclusion, epiregulin has similar effects as EGF upon fully grown follicles. Used as a sole stimulator of periovulatory events in intact cultured follicles, both are poor inducers of follicle luteinisation and oocyte maturation. By contrast, epiregulin is as efficient as hCG/EGF, when used as meiotic stimulator for COCs isolated from the follicular environment (mural granulosa and theca cells; and conditioned medium).

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“…While multiple steroids are equally potent promoters of oocyte maturation in vitro, including progesterone, testosterone, and androstenedione [19][20][21], hCG stimulation of ovaries both in vitro and in vivo demonstrates that the androgens androstenedione and testosterone are produced at 10-fold higher amounts than progesterone [19,20]. Furthermore, inhibition of androgen production downstream of progesterone in the steroidogenic pathway markedly inhibits both hCG-stimulated oocyte maturation and ovulation in live female frogs [22].…”

Section: Meiosis In Frog Oocytesmentioning

confidence: 99%

“…To start, androgens appear to activate extra-nuclear classical androgen receptors (ARs), as pharmacologic blockade of steroid binding to the AR, or reduction of AR expression by RNA interference, results in decreased steroid-triggered Gβγ signaling (Hammes, in press) and subsequent oocyte maturation [18,20,22]. While the detailed mechanisms are still not well-understood, androgenactivated ARs appear to attenuate G protein signaling through protein-protein complexes that may involve the scaffold molecule called the Modulator of Nongenomic Actions of steroid Receptors (MNAR) [23,24].…”

Section: Meiosis In Frog Oocytesmentioning

confidence: 99%

Gβγ signaling reduces intracellular cAMP to promote meiotic progression in mouse oocytes

Gill

Hammes

2007

Steroids

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In nearly every vertebrate species, elevated intracellular cAMP maintains oocytes in prophase I of meiosis. Prior to ovulation, gonadotropins trigger various intra-ovarian processes, including the breakdown of gap junctions, the activation of EGF receptors, and the secretion of steroids. These events in turn decrease intracellular cAMP levels in select oocytes to allow meiotic progression, or maturation, to resume. Studies suggest that cAMP levels are kept elevated in resting oocytes by constitutive G protein signaling, and that the drop in intracellular cAMP that accompanies maturation is due to attenuation of this inhibitory G protein-mediated signaling. Interestingly, one of these G protein regulators of meiotic arrest is the Gα s protein, which stimulates adenylyl cyclase to raise intracellular cAMP in two important animal models of oocyte development: Xenopus leavis frogs and mice. In addition to Gα s , constitutive Gβ γ activity similarly stimulates adenylyl cyclase to raise cAMP and prevent maturation in Xenopus oocytes; however, the role of Gβ γ in regulating meiosis in mouse oocytes has not been examined. Here we show that Gβγ does not contribute to the maintenance of murine oocyte meiotic arrest. In fact, contrary to observations in frog oocytes, Gβγ signaling in mouse oocytes reduces cAMP and promotes oocyte maturation, suggesting that Gβγ might in fact play a positive role in promoting oocyte maturation. These observations emphasize that, while many general concepts and components of meiotic regulation are conserved from frogs to mice, specific differences exist that may lead to important insights regarding ovarian development in vertebrates.

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Specific modulation of nongenomic androgen signaling in the ovary

Cited by 30 publications

References 55 publications

Induction of Osteoblast Differentiation by Selective Activation of Kinase-Mediated Actions of the Estrogen Receptor

Induction of Osteoblast Differentiation by Selective Activation of Kinase-Mediated Actions of the Estrogen Receptor

Epiregulin can effectively mature isolated cumulus–oocyte complexes, but fails as a substitute for the hCG/epidermal growth factor stimulus on cultured follicles

Gβγ signaling reduces intracellular cAMP to promote meiotic progression in mouse oocytes

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