scholarly journals Estrogen response element and the promoter context of the human and mouse lactoferrin genes influence estrogen receptor α-mediated transactivation activity in mammary gland cells

2004 ◽  
Vol 33 (2) ◽  
pp. 315-334 ◽  
Author(s):  
Kenya Stokes ◽  
Brenda Alston-Mills ◽  
Christina Teng
Keyword(s):  
Estrogen Receptor ◽  
Transcriptional Activity ◽  
Estrogen Receptor Α ◽  
Human Lactoferrin ◽  
Estrogen Response Element ◽  
Chimeric Mouse ◽  
Response Element ◽  
Estrogen Response ◽  
Lactoferrin Gene ◽  
Human And Mouse

A critical step in estrogen action is the recognition of estrogen responsive elements (EREs) by liganded estrogen receptor. Our current studies were designed to determine whether an extended estrogen response element half-site (ERRE) contributes to the differential estrogen responses of the human and mouse lactoferrin overlapping chicken ovalbumin upstream promoter/ERE sequences (estrogen response modules, ERMs) in the context of their natural promoters. Transient transfections of MCF-7 cells show that liganded estrogen receptor α (ERα) activates transcription of the human lactoferrin ERM fourfold higher than the mouse lactoferrin ERM in the context of their natural promoters. Since the ERRE of the human lactoferrin gene naturally occurs 18 bp upstream from the ERM and is absent in the mouse lactoferrin gene promoter, we created a chimeric mouse lactoferrin CAT reporter, which now encodes the ERRE in the identical location as in the human lactoferrin gene. The addition of the ERRE in the mouse lactoferrin gene rendered this reporter extremely responsive to estrogen stimulation. Using limited protease digestions and electrophoretic mobility shift assays, we showed that the binding and protease sensitivity of ERα bound to the mouse ERM with or without the ERRE, differed. Importantly, occupancy of additional nuclear receptors at the ERRE may contribute to ERα binding and activation. Furthermore, the presence of ERRE influences the selectivity of coactivators in liganded ERα-mediated transcriptional activity. When the receptor is bound to human and mouse plus genes, which contain the ERRE, steroid receptor coactivator (SRC)-2 was preferred, while SRC-1 and SRC-3 coactivators selectively enhanced the mouse lactoferrin gene activity. Moreover, peroxisome proliferator activated receptor-γ coactivator-1 (PGC-1α) and PGC-1-related estrogen receptor coactivator (PERC) robustly increase the transcriptional function of ERα in the presence of the ERRE. In conclusion, these data show that the context of the lactoferrin gene influences the ERα-mediated transcriptional activity.

scholarly journals Mouse Estrogen Receptor β Forms Estrogen Response Element-Binding Heterodimers with Estrogen Receptor α

1997 ◽  
Vol 11 (10) ◽  
pp. 1486-1496 ◽  
Author(s):  
Katarina Pettersson ◽  
Kaj Grandien ◽  
George G. J. M. Kuiper ◽  
Jan-Åke Gustafsson
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Α ◽  
Estrogen Receptor Β ◽  
Estrogen Response Element ◽  
Response Element ◽  
Estrogen Response

Regulation of HOXA10 expression by phytoestrogens

2007 ◽  
Vol 292 (2) ◽  
pp. E435-E442 ◽  
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.

scholarly journals The Conundrum of Estrogen Receptor Oscillatory Activity in the Search for an Appropriate Hormone Replacement Therapy

Endocrinology ◽  
2011 ◽  
Vol 152 (6) ◽  
pp. 2256-2265 ◽  
Author(s):  
Sara Della Torre ◽  
Andrea Biserni ◽  
Gianpaolo Rando ◽  
Giuseppina Monteleone ◽  
Paolo Ciana ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Transcriptional Activity ◽  
Hormone Replacement ◽  
Oscillatory Activity ◽  
Luciferase Reporter ◽  
Specific Gene ◽  
Estrogen Response Element ◽  
Response Element ◽  
Tissue Specific ◽  
Estrogen Response

By the use of in vivo imaging, we investigated the dynamics of estrogen receptor (ER) activity in intact, ovariectomized, and hormone-replaced estrogen response element-luciferase reporter mice. The study revealed the existence of a long-paced, noncircadian oscillation of ER transcriptional activity. Among the ER-expressing organs, this oscillation was asynchronous and its amplitude and period were tissue dependent. Ovariectomy affected the amplitude but did not suppress ER oscillations, suggesting the presence of tissue endogenous oscillators. Long-term administration of raloxifene, bazedoxifene, combined estrogens alone or with basedoxifene to ovariectomized estrogen response element-luciferase mice showed that each treatment induced a distinct spatiotemporal profile of ER activity, demonstrating that the phasing of ER activity among tissues may be regulated by the chemical nature and the concentration of circulating estrogen. This points to the possibility of a hierarchical organization of the tissue-specific pacemakers. Conceivably, the rhythm of ER transcriptional activity translates locally into the activation of specific gene networks enabling ER to significantly change its physiological activity according to circulating estrogens. In reproductive and nonreproductive organs this hierarchical regulation may provide ER with the signaling plasticity necessary to drive the complex metabolic changes occurring at each female reproductive status. We propose that the tissue-specific oscillatory activity here described is an important component of ER signaling necessary for the full hormone action including the beneficial effects reported for nonreproductive organs. Thus, this mechanism needs to be taken in due consideration to develop novel, more efficacious, and safer hormone replacement therapies.

scholarly journals POU Transcription Factors Brn-3a and Brn-3b Interact with the Estrogen Receptor and Differentially Regulate Transcriptional Activity via an Estrogen Response Element

1998 ◽  
Vol 18 (2) ◽  
pp. 1029-1041 ◽  
Author(s):  
Vishwanie Budhram-Mahadeo ◽  
Malcolm Parker ◽  
David S. Latchman
Keyword(s):  
Estrogen Receptor ◽  
Transcription Factors ◽  
Transcriptional Activity ◽  
Inhibitory Effect ◽  
Single Amino Acid ◽  
Estrogen Response Element ◽  
Response Element ◽  
Pou Domain ◽  
Estrogen Response ◽  
Repressive Effect

ABSTRACT The estrogen receptor (ER) modulates transcription by forming complexes with other proteins and then binding to the estrogen response element (ERE). We have identified a novel interaction of this receptor with the POU transcription factors Brn-3a and Brn-3b which was independent of ligand binding. By pull-down assays and the yeast two-hybrid system, the POU domain of Brn-3a and Brn-3b was shown to interact with the DNA-binding domain of the ER. Brn-3–ER interactions also affect transcriptional activity of an ERE-containing promoter, such that in estradiol-stimulated cells, Brn-3b strongly activated the promoter via the ERE, while Brn-3a had a mild inhibitory effect. The POU domain of Brn-3b which interacts with the ER was sufficient to confer this activation potential, and the change of a single amino acid in the first helix of the POU homeodomain of Brn-3a to its equivalent in Brn-3b can change the mild repressive effect of Brn-3a to a stimulatory Brn-3b-like effect. These observations and their implications for transcriptional regulation by the ER are discussed.

scholarly journals 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 ◽  
2007 ◽  
Vol 148 (10) ◽  
pp. 4634-4641 ◽  
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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