Cross Talk in Hormonally Regulated Gene Transcription through Induction of Estrogen Receptor Ubiquitylation

ABSTRACT Estrogen tightly regulates the levels of circulating gonadotropins, but a direct effect of estrogen receptor alpha (ERα) on the mammalian LHβ gene has remained poorly defined. We demonstrate here that ERα can associate with the LHβ promoter through interactions with Sf-1 and Pitx1 without requiring an estrogen response element (ERE). We show that gonadotropin-releasing hormone (GnRH) promotes ERα ubiquitylation and also degradation while stimulating expression of ubc4. GnRH also increases the association and lengthens the cycling time of ERα on the LHβ promoter. The ERα association and transactivation of the LHβ gene, as well as ERα degradation, are increased following ubc4 overexpression, while the effects of GnRH are abated following ubc4 knockdown. Our results indicate that ERα ubiquitylation and subsequent transactivation of the LHβ gene can be induced by increasing the levels of the E2 enzyme as a result of signaling by an extracellular hormone, thus providing a new form of cross talk in hormonally stimulated regulation of gene expression.

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ESTROGEN RESPONSE ELEMENT DEPENDENT AND INDEPENDENT ESTROGEN RECEPTOR ALPHA SIGNALING PATHWAYS DIFFERENTIALLY REGULATE PITUITARY GONADOTROPIN TRANSCRIPTION AND SECRETION IN THE FEMALE MOUSE

Biology of Reproduction ◽

10.1093/biolreprod/77.s1.185a ◽

2007 ◽

Vol 77 (Suppl_1) ◽

pp. 185-185

Author(s):

Christine Glidewell-Kenney ◽

Lisa Hurley ◽

Liza Pfaff ◽

Jon Levine ◽

Jeffrey Weiss ◽

...

Keyword(s):

Estrogen Receptor ◽

Signaling Pathways ◽

Female Mouse ◽

Estrogen Receptor Alpha ◽

Estrogen Response Element ◽

Response Element ◽

Receptor Alpha ◽

Pituitary Gonadotropin ◽

Estrogen Response

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A Functional Serine 118 Phosphorylation Site in Estrogen Receptor-α Is Required for Down-Regulation of Gene Expression by 17β-Estradiol and 4-Hydroxytamoxifen

Endocrinology ◽

10.1210/en.2007-0148 ◽

2007 ◽

Vol 148 (10) ◽

pp. 4634-4641 ◽

Cited By ~ 38

Author(s):

Jingwei Cheng ◽

Chen Zhang ◽

David J. Shapiro

Keyword(s):

Estrogen Receptor ◽

Regulation Of Gene Expression ◽

Phosphorylation Site ◽

Estrogen Receptor Α ◽

Estrogen Response Element ◽

Down Regulation ◽

Response Element ◽

Estrogen Response ◽

Endogenous Genes ◽

17Β Estradiol

To evaluate the contribution of ERK1/2 phosphorylation of estrogen receptor (ER)-α to activation and repression of endogenous genes, we produced stably transfected lines of HeLa cells with functional ERK1/2 pathways that express similar levels of wild-type human ERα and ERα mutated to inactivate the well-known MAPK site at serine 118 (ERαS118A). We compared effects of the S118A mutation on 17β-estradiol (E2)-mediated transactivation, which is heavily dependent on activation function (AF) 2 of ERα and on 4-hydroxytamoxifen (OHT)-mediated transactivation, which is heavily dependent on AF1, which includes S118. To examine whether S118 was the key ERK/MAPK phosphorylation site in ERα action, we compared the effects of the S118A mutant and the ERK inhibitor U0126 on expression of endogenous genes. In several estrogen response element-containing genes, the S118A mutation strongly reduced induction by E2, and U0126 did not further reduce expression. Expression of another group of estrogen response element-containing genes was largely unaffected by the S118A mutation. The S118A mutation had variable effects on genes induced by ER tethering or binding near specificity protein-1 and activator protein-1 sites. For five mRNAs whose expression is strongly down-regulated by E2 and partially or completely down-regulated by OHT, the S118A mutation reduced or abolished down-regulation by E2 and nearly abolished down-regulation by OHT. In contrast, for Sma and mothers against decapentaplegic-3-related, which is down-regulated by E2 and not OHT, the S118A mutation had little effect. These data suggest that there may be distinct groups of genes down-regulated by ERα and suggest a novel role for ERK phosphorylation at serine 118 in AF1 in regulating expression of the set of genes down-regulated by OHT.

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