Estrogen Regulation of Neurokinin B Gene Expression in the Mouse Arcuate Nucleus Is Mediated by Estrogen Receptor α

Abstract Neurokinin B (NKB) gene expression is elevated in the infundibular (arcuate) nucleus of the hypothalamus in postmenopausal women. Estrogen replacement decreases both the number of NKB mRNA-expressing neurons and the level of expression within individual cells. Similarly, NKB gene expression is elevated in ovariectomized rats and reduced after estrogen treatment. The actions of estrogen in the brain can be mediated via either estrogen receptor α (ERα) or estrogen receptor β (ERβ). In the rodent arcuate nucleus (ARC), more ERα- than ERβ-containing cells are present, suggesting that ERα might be directly responsible for estrogen regulation of NKB gene expression. However, an indirect effect via ERβ could not be ruled out. Here we used ERα knockout and ERβ knockout mice to identify the type of ER responsible for mediating estrogen action on NKB gene expression in the ARC. Using in situ hybridization histochemistry, we have found that estrogen treatment significantly reduced NKB gene expression in the ARC of ovariectomized ERβ knockout mice, but had no effect on NKB mRNA levels in ERα knockout mice. These data indicate that ERα mediates the increase in NKB gene expression associated with ovariectomy in rodents and might also be responsible for the increase in NKB in postmenopausal women.

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Estrogen Receptor α Inhibits IL-1β Induction of Gene Expression in the Mouse Liver

Endocrinology ◽

10.1210/endo.143.7.8919 ◽

2002 ◽

Vol 143 (7) ◽

pp. 2559-2570 ◽

Cited By ~ 34

Author(s):

Mark J. Evans ◽

Kehdih Lai ◽

Lucinda J. Shaw ◽

Douglas C. Harnish ◽

Christopher C. Chadwick

Keyword(s):

Gene Expression ◽

Estrogen Receptor ◽

Knockout Mice ◽

Ethinyl Estradiol ◽

Binding Protein ◽

Gene Induction ◽

Estrogen Receptor Α ◽

Ovariectomized Mice ◽

Prostaglandin D Synthase ◽

Short Heterodimer Partner

Abstract Estrogens have been suggested to modulate several inflammatory processes. Here, we show that IL-1β treatment induced the expression of approximately 75 genes in the liver of ovariectomized mice. 17α-Ethinyl estradiol (EE) pretreatment reduced the IL-1β induction of approximately one third of these genes. Estrogen receptor α (ERα) was required for this inhibitory activity, because EE inhibition of IL-1β-stimulated gene expression occurred in ERβ knockout mice, but not in ERα knockout mice. EE treatment induced expression of 40 genes, including the transcriptional repressor short heterodimer partner and prostaglandin D synthase, known modulators of nuclear factor-κB signaling. However, the ER agonists genistein and raloxifene both inhibited IL-1β gene induction without stimulating the expression of prostaglandin D synthase, short heterodimer partner, or other ER-inducible genes, indicating that induction of gene expression was not required for ER inhibition of IL-1β signaling. Finally, the ability of EE to repress IL-1β gene induction varied among tissues. For example, EE inhibited IL-1β induction of lipopolysaccharide-induced c-x-c chemokine (LIX) in the liver, but not in the spleen or lung. The degree of EE repression did not correlate with ER expression. cAMP response element binding protein-binding protein (CBP)/p300 levels also varied between tissues. Together, these results are consistent with a model of in vivo ER interference with IL-1β signaling through a coactivator-based mechanism.

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Neurokinin B Gene Expression Is Increased in the Arcuate Nucleus of Ovariectomized Rats

Neuroendocrinology ◽

10.1159/000126768 ◽

1994 ◽

Vol 60 (4) ◽

pp. 337-345 ◽

Cited By ~ 77

Author(s):

Naomi E. Rance ◽

Tami R. Bruce

Keyword(s):

Gene Expression ◽

Arcuate Nucleus ◽

Ovariectomized Rats ◽

Neurokinin B

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Inhibition of Oxytocin Receptor and Estrogen Receptor-α Expression, But Not Relaxin Receptors (LGR7), in the Myometrium of Late Pregnant Relaxin Gene Knockout Mice

Endocrinology ◽

10.1210/en.2003-0548 ◽

2003 ◽

Vol 144 (10) ◽

pp. 4272-4275 ◽

Cited By ~ 24

Author(s):

Andrew L. Siebel ◽

Helen M. Gehring ◽

Irna Grace T. Reytomas ◽

Laura J. Parry

Keyword(s):

Gene Expression ◽

Estrogen Receptor ◽

Knockout Mice ◽

Gene Knockout ◽

Estrogen Receptor Α ◽

Oxytocin Receptor ◽

Receptor Expression ◽

Late Gestation ◽

Mrna Levels ◽

Gene Knockout Mice

This study used relaxin (RLX) gene knockout mice (Rlx−/−) to investigate the effects of RLX on myometrial oxytocin receptor (OTR) and estrogen receptor (ER)-α gene expression in late gestation. We also characterized the temporal expression of the RLX receptor (LGR7) and demonstrated gene transcripts in the myometrium of Rlx+/+ and Rlx−/− mice. There was a significant (P < 0.05) decrease in myometrial LGR7 gene expression on d 17.5 and 18.5 post coitum (pc) compared with earlier stages of gestation, but no differences between Rlx+/+ and Rlx−/− mice. Myometrial OTR mRNA levels increased at the end of gestation in Rlx+/+ but not Rlx−/− mice. ERα gene expression was up-regulated on d 14.5 pc in Rlx+/+ mice, with mRNA levels remaining high throughout late gestation. In contrast, ERα mRNA levels were significantly lower in Rlx−/− mice on d 14.5 and 18.5 pc. These data show that the increases in myometrial OTR and ERα expression in late pregnant Rlx+/+ mice were attenuated in Rlx−/− mice. The effects of RLX on OTRs are probably mediated via activation of ERα. Finally, RLX receptor expression in the myometrium of Rlx−/− mice did not differ from wild-type mice, implying that RLX does not influence expression of its receptor.

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ERα-dependent stimulation of LCN2 in uterine epithelium during mouse early pregnancy

Reproduction ◽

10.1530/rep-19-0616 ◽

2020 ◽

Vol 159 (4) ◽

pp. 493-501

Author(s):

Y-F Liu ◽

M-Y Li ◽

Y-P Yan ◽

W Wei ◽

B Li ◽

...

Keyword(s):

Escherichia Coli ◽

Estrogen Receptor ◽

Bacterial Infection ◽

Early Pregnancy ◽

Estrogen Receptor Α ◽

Bacterial Activity ◽

Uterine Epithelium ◽

Estrogen Treatment ◽

Lipocalin 2 ◽

Estrogen Regulation

Maintenance of a suitable uterine milieu is important for embryo development and subsequent implantation during early pregnancy. High estrogen level in proestrous and estrous stages is essential for uterine anti-bacterial activity during preimplantation period. Lipocalin-2 is an essential molecule which prevents bacterial infection by sequestering iron. In this study, the highest expression of lipocalin-2 is observed in the endometrial epithelium on day 1 of normal pregnancy and pseudopregnancy, which exhibit a similar hormone scenario. By injecting the agonists for estrogen receptor α and estrogen receptor β in ovariectomized mice, we found estrogen receptor α is the dominant member for estrogen regulation on lipocalin-2 expression. Estrogen treatment in estrogen receptor α-knockout mice further confirmed the role of estrogen receptor α. Using published data from whole-genome estrogen receptor α binding site assay, significant estrogen receptor α recruitment peaks are found at the downstream of lipocalin-2 gene after estrogen treatment. Furthermore, to study the anti-bacterial activity of lipocalin-2 in uterus, Escherichia coli is injected to mimic bacterial infection. Our results showed an obvious induction of lipocalin-2 in Escherichia coli-treated group. Taken together, this study indicates estrogen regulation of lipocalin-2 in uterine epithelium is mediated by estrogen receptor α, and lipocalin-2 may have anti-bacterial activity during early pregnancy.

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Inflammatory response of coronary artery disease postmenopausal women is associated with the IVS1-397T > C estrogen receptor α polymorphism

Clinical Immunology ◽

10.1016/j.clim.2008.09.017 ◽

2009 ◽

Vol 130 (3) ◽

pp. 355-364 ◽

Cited By ~ 8

Author(s):

Jolanta Myśliwska ◽

Aleksandra Rutkowska ◽

Łukasz Hak ◽

Janusz Siebert ◽

Krzysztof Szyndler ◽

...

Keyword(s):

Coronary Artery Disease ◽

Estrogen Receptor ◽

Coronary Artery ◽

Inflammatory Response ◽

Postmenopausal Women ◽

Estrogen Receptor Α ◽

Artery Disease

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Loading-related regulation of gene expression in bone in the contexts of estrogen deficiency, lack of estrogen receptor α and disuse

Bone ◽

10.1016/j.bone.2009.10.021 ◽

2010 ◽

Vol 46 (3) ◽

pp. 628-642 ◽

Cited By ~ 65

Author(s):

Gul Zaman ◽

Leanne K. Saxon ◽

Andrew Sunters ◽

Helen Hilton ◽

Peter Underhill ◽

...

Keyword(s):

Gene Expression ◽

Estrogen Receptor ◽

Regulation Of Gene Expression ◽

Estrogen Receptor Α ◽

Estrogen Deficiency

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Relationship Between Plasma Estradiol Levels and Estrogen-Responsive Gene Expression in Estrogen Receptor–Positive Breast Cancer in Postmenopausal Women

Journal of Clinical Oncology ◽

10.1200/jco.2009.23.9616 ◽

2010 ◽

Vol 28 (7) ◽

pp. 1161-1167 ◽

Cited By ~ 75

Author(s):

Anita K. Dunbier ◽

Helen Anderson ◽

Zara Ghazoui ◽

Elizabeth J. Folkerd ◽

Roger A'Hern ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Estrogen Receptor ◽

Postmenopausal Women ◽

Multivariable Analysis ◽

Independent Set ◽

Breast Cancers ◽

Plasma Estradiol ◽

Er Positive ◽

Positive Breast Cancer

Purpose To determine whether plasma estradiol (E2) levels are related to gene expression in estrogen receptor (ER)–positive breast cancers in postmenopausal women. Materials and Methods Genome-wide RNA profiles were obtained from pretreatment core-cut tumor biopsies from 104 postmenopausal patients with primary ER-positive breast cancer treated with neoadjuvant anastrozole. Pretreatment plasma E2 levels were determined by highly sensitive radioimmunoassay. Genes were identified for which expression was correlated with pretreatment plasma E2 levels. Validation was performed in an independent set of 73 ER-positive breast cancers. Results The expression of many known estrogen-responsive genes and gene sets was highly significantly associated with plasma E2 levels (eg, TFF1/pS2, GREB1, PDZK1 and PGR; P < .005). Plasma E2 explained 27% of the average expression of these four average estrogen-responsive genes (ie, AvERG; r = 0.51; P < .0001), and a standardized mean of plasma E2 levels and ER transcript levels explained 37% (r, 0.61). These observations were validated in an independent set of 73 ER-positive tumors. Exploratory analysis suggested that addition of the nuclear coregulators in a multivariable analysis with ER and E2 levels might additionally improve the relationship with the AvERG. Plasma E2 and the standardized mean of E2 and ER were both significantly correlated with 2-week Ki67, a surrogate marker of clinical outcome (r = −0.179; P = .05; and r = −0.389; P = .0005, respectively). Conclusion Plasma E2 levels are significantly associated with gene expression of ER-positive breast cancers and should be considered in future genomic studies of ER-positive breast cancer. The AvERG is a new experimental tool for the study of putative estrogenic stimuli of breast cancer.

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