Phosphorylation of Tyrosine 537 on the Human Estrogen Receptor Is Required for Binding to an Estrogen Response Element

Aromatase (estrogen synthetase; EC 1.14.14.1) catalyzes the demethylation of androgens' carbon 19, producing phenolic 18-carbon estrogens. Aromatase is most widely known for its roles in reproduction and reproductive system diseases, and as a target for inhibitor therapy in estrogen-sensitive diseases including cancer, endometriosis, and leiomyoma (141, 143). However, all tissues contain estrogen receptor-expressing cells, the majority of genes have a complete or partial estrogen response element that regulates their expression (61), and there are plentiful nonreceptor effects of estrogens (79); therefore, the effect of aromatase through the provision of estrogen is almost universal in terms of health and disease. This review will provide a brief but comprehensive overview of the enzyme, its role in steroidogenesis, the problems that arise with its functional mutations and mishaps, the roles in human physiology of aromatase and its product estrogens, its current clinical roles, and the effects of aromatase inhibitors. While much of the story is that of the consequences of the formation of its product estrogens, we also will address alternative enzymatic roles of aromatase as a demethylase or nonenzymatic actions of this versatile molecule. Although this short review is meant to be thorough, it is by no means exhaustive; rather, it is meant to reflect the cutting-edge, exciting properties and possibilities of this ancient enzyme and its products.

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The High Mobility Group Protein 1 Enhances Binding of the Estrogen Receptor DNA Binding Domain to the Estrogen Response Element

Molecular Endocrinology ◽

10.1210/mend.12.5.0111 ◽

1998 ◽

Vol 12 (5) ◽

pp. 664-674 ◽

Cited By ~ 23

Author(s):

Lorene E. Romine ◽

Jennifer R. Wood ◽

LuAnne A. Lamia ◽

Paul Prendergast ◽

Dean P. Edwards ◽

...

Keyword(s):

Estrogen Receptor ◽

Dna Binding ◽

High Mobility ◽

High Mobility Group ◽

Estrogen Response Element ◽

Dna Binding Domain ◽

High Mobility Group Protein ◽

Response Element ◽

Estrogen Response ◽

Group Protein

Abstract We have examined the ability of the high-mobility group protein 1 (HMG1) to alter binding of the estrogen receptor DNA-binding domain (DBD) to the estrogen response element (ERE). HMG1 dramatically enhanced binding of purified, bacterially expressed DBD to the consensus vitellogenin A2 ERE in a dose-dependent manner. The ability of HMG1 to stabilize the DBD-ERE complex resulted in part from a decrease in the dissociation rate of the DBD from the ERE. Antibody supershift experiments demonstrated that HMG1 was also capable of forming a ternary complex with the ERE-bound DBD in the presence of HMG1-specific antibody. HMG1 did not substantially affect DBD-ERE contacts as assessed by methylation interference assays, nor did it alter the ability of the DBD to induce distortion in ERE-containing DNA fragments. Because HMG1 dramatically enhanced estrogen receptor DBD binding to the ERE, and the DBD is the most highly conserved region among the nuclear receptor superfamily members, HMG1 may function to enhance binding of other nuclear receptors to their respective response elements and act in concert with coactivator proteins to regulate expression of hormone-responsive genes.

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Regulation of HOXA10 expression by phytoestrogens

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00167.2006 ◽

2007 ◽

Vol 292 (2) ◽

pp. E435-E442 ◽

Cited By ~ 5

Author(s):

G. Eda Akbas ◽

Xiaolan Fei ◽

Hugh S. Taylor

Keyword(s):

Estrogen Receptor ◽

Estrogen Receptor Α ◽

In Utero ◽

Estrogen Response Element ◽

Mouse Uterus ◽

Response Element ◽

Estrogen Response ◽

Uterine Anomalies ◽

Mrna And Protein Expression ◽

Adult Exposure

HOXA10 is necessary for normal development of the Müllerian duct, and continued adult expression in the uterus is necessary for female fertility. HOXA10 expression is altered by diethylstilbestrol, leading to uterine anomalies. Other endocrine disruptors may potentially lead to reproductive anomalies or dysfunction by altering HOXA10 expression. Here we investigated the effect of isoflavones on HOXA10 expression after in utero or adult exposure in the mouse. Genistein, but not diadzein, regulated HOXA10 mRNA and protein expression in the adult mouse uterus. In contrast, in utero genistein or diadzein exposure had no lasting effect on HOXA10 expression in the exposed offspring. Reporter gene expression driven by the HOXA10 estrogen response element was increased in a dose-responsive manner by genistein, but not daidzein. Neither estrogen receptor-α nor estrogen receptor-β binding to the HOXA10 estrogen response element was affected by genistein or daidzein. In utero exposure to isoflavones is unlikely to result in HOXA10-mediated developmental anomalies. Adult genistein exposure alters uterine HOXA10 expression, a potential mechanism by which this agent affects fertility.

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