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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 (ERalpha) on the mammalian LHbeta gene has remained poorly defined. We demonstrate here that ERalpha can associate with the LHbeta promoter through interactions with Sf-1 and Pitx1 without requiring an estrogen response element (ERE). We show that gonadotropin-releasing hormone (GnRH) promotes ERalpha ubiquitylation and also degradation while stimulating expression of ubc4. GnRH also increases the association and lengthens the cycling time of ERalpha on the LHbeta promoter. The ERalpha association and transactivation of the LHbeta gene, as well as ERalpha degradation, are increased following ubc4 overexpression, while the effects of GnRH are abated following ubc4 knockdown. Our results indicate that ERalpha ubiquitylation and subsequent transactivation of the LHbeta 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.

SUBMITTER: Luo M

PROVIDER: S-EPMC1190261 | biostudies-literature | 2005 Aug

REPOSITORIES: biostudies-literature

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Cross talk in hormonally regulated gene transcription through induction of estrogen receptor ubiquitylation.

Luo Min M Koh Mingshi M Feng Jiajun J Wu Qiang Q Melamed Philippa P

Molecular and cellular biology 20050801 16

Estrogen tightly regulates the levels of circulating gonadotropins, but a direct effect of estrogen receptor alpha (ERalpha) on the mammalian LHbeta gene has remained poorly defined. We demonstrate here that ERalpha can associate with the LHbeta promoter through interactions with Sf-1 and Pitx1 without requiring an estrogen response element (ERE). We show that gonadotropin-releasing hormone (GnRH) promotes ERalpha ubiquitylation and also degradation while stimulating expression of ubc4. GnRH als ...[more]

PMID: 16055746

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Project description:Cross-talk between the aryl hydrocarbon receptor (AHR) and the estrogen receptor (ER) plays a major role in signaling processes in female reproductive organs.We investigated the influence of the AHR ligand 3-methylcholanthrene (3-MC) on ER-mediated signaling in mammary gland tissue of ovariectomized (ovx) rats.After 14 days of hormonal decline, ovx rats were treated for 3 days with 4 ?g/kg 17?-estradiol (E2), 15 mg/kg 8-prenylnaringenin (8-PN), 15 mg/kg 3-MC, or a combination of these compounds (E2 + 3-MC, 8-PN + 3-MC). Whole-mount preparations of the mammary gland were used to count terminal end buds (TEBs). Protein expression studies (immunohistochemistry, immunofluorescence), a cDNA microarray, pathway analyses, and quantitative real-time polymerase chain reaction (qPCR) were performed to evaluate the interaction between AHR- and ER-mediated signaling pathways.E2 treatment increased the number of TEBs and the levels of Ki-67 protein and progesterone receptor (PR); this treatment also changed the expression of 325 genes by more than 1.5-fold. Although 3-MC treatment alone had marginal impact on gene or protein expression, when rats were co-treated with 3-MC and E2, 3-MC strongly inhibited E2-induced TEB development, protein synthesis, and the expression of nearly half of E2-induced genes. This inhibitory effect of 3-MC was partially mirrored when 8-PN was used as an ER ligand. The anti-estrogenicity of ligand-activated AHR was at least partly due to decreased protein levels of ER? in ductal epithelial cells.Our data show transcriptome-wide anti-estrogenic properties of ligand-activated AHR on ER-mediated processes in the mammary gland, thereby contributing an explanation for the chemopreventive and endocrine-disrupting potential of AHR ligands.Helle J, Bader MI, Keiler AM, Zierau O, Vollmer G, Chittur SV, Tenniswood M, Kretzschmar G. 2016. Cross-talk in the female rat mammary gland: influence of aryl hydrocarbon receptor on estrogen receptor signaling. Environ Health Perspect 124:601-610;?http://dx.doi.org/10.1289/ehp.1509680.

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Cross talk in hormonally regulated gene transcription through induction of estrogen receptor ubiquitylation.

Publications

Cross talk in hormonally regulated gene transcription through induction of estrogen receptor ubiquitylation.

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