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Estrogen receptors alpha and beta differentially regulate the transcriptional activity of the Urocortin gene.

ABSTRACT: Urocortin (Ucn), a highly conserved metazoan gene, is related to stress and feeding, behaviors with significant gender differences. We investigated whether estrogens regulate the expression of the Ucn gene using transient transfection in PC12 cells with the human Ucn (hUcn) promoter coupled to luciferase and either alpha or beta estrogen receptors (ERalpha or ERbeta, respectively). The results demonstrate that estradiol (E2) increases the activity of the hUcn promoter via ERalpha, and decreases hUcn promoter activity through ERbeta. Deletions of the hUcn promoter show that the increase in promoter activity mediated by E2-ERalpha depends on a promoter region containing a half-estrogen response element and an Sp1 site, and the decrease mediated by E2-ERbeta depends on a proximal promoter region containing a cAMP response element. Ucn and ERs coexist in neurons of rat hypothalamic nuclei, giving anatomical support for a direct effect of estrogen receptors on the Ucn gene. By in situ hybridization, we observed that cycling female rats have a higher number of cells expressing Ucn mRNA than males in the paraventricular nucleus of the hypothalamus (PVN) and the septum. Both of these brain nuclei are related to stress behaviors and express moderate levels of Ucn. Furthermore, Ucn mRNA was significantly decreased in the PVN and increased in the septum 30 d after ovariectomy. Acute E2 administration to ovariectomized rats significantly increased Ucn mRNA expression in the PVN and septum. In conclusion, our in vitro and in vivo evidence suggests that estrogens exert a direct and differential transcriptional regulation of the Ucn gene.

SUBMITTER: Haeger P

PROVIDER: S-EPMC6674158 | biostudies-literature | 2006 May

REPOSITORIES: biostudies-literature

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Estrogen receptors alpha and beta differentially regulate the transcriptional activity of the Urocortin gene.

Haeger Paola P Andrés María Estela ME Forray María Inés MI Daza Claudia C Araneda Silvia S Gysling Katia K

The Journal of neuroscience : the official journal of the Society for Neuroscience 20060501 18

Urocortin (Ucn), a highly conserved metazoan gene, is related to stress and feeding, behaviors with significant gender differences. We investigated whether estrogens regulate the expression of the Ucn gene using transient transfection in PC12 cells with the human Ucn (hUcn) promoter coupled to luciferase and either alpha or beta estrogen receptors (ERalpha or ERbeta, respectively). The results demonstrate that estradiol (E2) increases the activity of the hUcn promoter via ERalpha, and decreases ...[more]

PMID: 16672665

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Project description:BACKGROUND:Orphan nuclear receptors ERRα, ERRβ and ERRγ that belong to NR3B or type IV nuclear receptor family are well studied for their role in breast cancer pathophysiology. Their homology with the canonical estrogen receptor dictates their possible contributing role in mammary gland development and disease. Although function and regulation of ERRα, ERRγ and less about ERRβ is reported, role of histone methylation in their altered expression in cancer cells is not studied. Transcriptional activity of nuclear receptors depends on co-regulatory proteins. The present study for the first time gives an insight into regulation of estrogen-related receptors by histone methylation specifically through methyltransferase EZH2 in breast cancer. METHODS:Expression of ERRα, ERRβ, ERRγ and EZH2 was assessed by immunohistochemistry in four identical tissue array slides that were prepared as per the protocol. The array slides were stained with ERRα, ERRβ, ERRγ and EZH2 simultaneously. Array data was correlated with expression in MERAV expression dataset. Pearson correlation coeficient r was calculated from the partial matrix expression values available at MERAV database to study the strength of association between EZH2 and three orphan nuclear receptors under study. By western blot and real time PCR, their correlated expression was studied in breast cancer cell lines MCF-7, MDA-MB-231, T47D and MDA-MB-453 including normal breast epithelial MCF-10A cells at both protein and RNA level. Regulation of ERRα, ERRβ, ERRγ by EZH2 was further investigated upon overexpression and silencing of EZH2. The interaction between ERRs and EZH2 was validated in vivo by CHIP-qPCR. RESULTS:We found a negative correlation between estrogen-related receptors and Enhancer of Zeste Homolog 2, a global repressor gene. Immunohistochemistry in primary breast tumors of different grades showed a correlated expression of estrogen-related receptors and EZH2. Their correlated expression was further validated using online MERAV expression dataset where a negative correlation of variable strengths was observed in breast cancer. Ectopic expression of EZH2 in low EZH2-expressing normal breast epithelial cells abrogated their expression and at the same time, its silencing enhanced the expression of estrogen-related receptors in cancerous cells. Global occupancy of EZH2 on ERRα and ERRβ was observed in-vivo. CONCLUSION:Our findings identify EZH2 as a relevant coregulator for estrogen-related receptors in breast carcinoma.

Dataset Information

Estrogen receptors alpha and beta differentially regulate the transcriptional activity of the Urocortin gene.

Publications

Estrogen receptors alpha and beta differentially regulate the transcriptional activity of the Urocortin gene.

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