Unliganded estrogen receptor-α activates transcription of the mammary gland Na+/I− symporter gene

Alotaibi, Hani; Yaman, Elif; Demirpençe, Ediz; Tazebay, Uygar Halis

doi:10.1016/j.bbrc.2006.05.049

Cited by 20 publications

(31 citation statements)

References 35 publications

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“…Interestingly, we detected ERα binding to the Kiss1 promoter region taken from the ARC of OVX mice without E2 treatment (Fig. 2C), suggesting that unliganded ERα may have a role in Kiss1 regulation, as previously reported (34)(35)(36). The ligand-independent ERα activity was increased by phosphorylation at specific serine residues in the N-terminal domain as activated by the growth factor pathway (37,38).…”

Section: Discussionsupporting

confidence: 58%

Epigenetic regulation of Kiss1 gene expression mediating estrogen-positive feedback action in the mouse brain

Tomikawa¹,

Uenoyama²,

Ozawa³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

132

118

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This study aims to determine the epigenetic mechanism regulating Kiss1 gene expression in the anteroventral periventricular nucleus (AVPV) to understand the mechanism underlying estrogen-positive feedback action on gonadotropin-releasing hormone/gonadotropin surge. We investigated estrogen regulation of the epigenetic status of the mouse AVPV Kiss1 gene locus in comparison with the arcuate nucleus (ARC), in which Kiss1 expression is down-regulated by estrogen. Histone of AVPV Kiss1 promoter region was highly acetylated, and estrogen receptor α was highly recruited at the region by estrogen. In contrast, the histone of ARC Kiss1 promoter region was deacetylated by estrogen. Inhibition of histone deacetylation upregulated in vitro Kiss1 expression in a hypothalamic non-Kiss1-expressing cell line. Gene conformation analysis indicated that estrogen induced formation of a chromatin loop between Kiss1 promoter and the 3′ intergenic region, suggesting that the intergenic region serves to enhance estrogen-dependent Kiss1 expression in the AVPV. This notion was proved, because transgenic reporter mice with a complete Kiss1 locus sequence showed kisspeptin neuronspecific GFP expression in both the AVPV and ARC, but the deletion of the 3′ region resulted in greatly reduced GFP expression only in the AVPV. Taken together, these results demonstrate that estrogen induces recruitment of estrogen receptor α and histone acetylation in the Kiss1 promoter region of the AVPV and consequently enhances chromatin loop formation of Kiss1 promoter and Kiss1 gene enhancer, resulting in an increase in AVPV-specific Kiss1 gene expression. These results indicate that epigenetic regulation of the Kiss1 gene is involved in estrogen-positive feedback to generate the gonadotropin-releasing hormone/gonadotropin surge.

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Section: Discussionsupporting

confidence: 58%

Epigenetic regulation of Kiss1 gene expression mediating estrogen-positive feedback action in the mouse brain

Tomikawa¹,

Uenoyama²,

Ozawa³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

132

118

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“…First, ER␣ could elicit some of the downstream effects in a ligand-independent manner. Although data supporting the importance of this mechanism in vivo are scarce, several observations in cultured cells established the significance of this pathway in dynamic regulation of transcription by ER␣ (17)(18)(19). In the absence of estrogen, ER␣ can modulate expression of selected genes by recruiting both transcriptional repressors and activators as well as by remodeling chromatin structure (17,20).…”

Section: Discussionmentioning

confidence: 99%

“…Although data supporting the importance of this mechanism in vivo are scarce, several observations in cultured cells established the significance of this pathway in dynamic regulation of transcription by ER␣ (17)(18)(19). In the absence of estrogen, ER␣ can modulate expression of selected genes by recruiting both transcriptional repressors and activators as well as by remodeling chromatin structure (17,20). Notably, some of these events appear to depend on interaction of unliganded ER␣ with DNA sequences that are distinct from classical consensus sites recognized by estrogenbound ER␣ (17).…”

Section: Discussionmentioning

confidence: 99%

“…In the absence of estrogen, ER␣ can modulate expression of selected genes by recruiting both transcriptional repressors and activators as well as by remodeling chromatin structure (17,20). Notably, some of these events appear to depend on interaction of unliganded ER␣ with DNA sequences that are distinct from classical consensus sites recognized by estrogenbound ER␣ (17).…”

Section: Discussionmentioning

confidence: 99%

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Silencing of estrogen receptor α in the ventromedial nucleus of hypothalamus leads to metabolic syndrome

Musatov

Chen

Pfaff

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

464

373

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Estrogen receptor ␣ (ER␣) plays a pivotal role in the regulation of food intake and energy expenditure by estrogens. Although it is well documented that a disruption of ER␣ signaling in ER␣ knockout (ERKO) mice leads to an obese phenotype, the sites of estrogen action and mechanisms underlying this phenomenon are still largely unknown. In the present study, we exploited RNA interference mediated by adeno-associated viral vectors to achieve focused silencing of ER␣ in the ventromedial nucleus of the hypothalamus, a key center of energy homeostasis. After suppression of ER␣ expression in this nucleus, female mice and rats developed a phenotype characteristic for metabolic syndrome and marked by obesity, hyperphagia, impaired tolerance to glucose, and reduced energy expenditure. This phenotype persisted despite normal ER␣ levels elsewhere in the brain. Although an increase in food intake preceded weight gain, our data suggest that a leading factor of obesity in this model is likely a decline in energy expenditure with all three major constituents being affected, including voluntary activity, basal metabolic rate, and diet-induced thermogenesis. Together, these findings indicate that ER␣ in the ventromedial nucleus of the hypothalamus neurons plays an essential role in the control of energy balance and the maintenance of normal body weight.adeno-associated virus ͉ body weight ͉ energy metabolism ͉ obesity ͉ RNA interference E strogen receptor ␣ (ER␣) is the main mediator of estrogen effects on energy homeostasis. ER␣ knockout (ERKO) mice with targeted deletion of this receptor develop several hallmark features often associated with obesity including increased visceral adiposity, elevated insulin levels, and impaired glucose tolerance (1). Although the nature of events leading to this phenotype is unclear, hyperphagia does not seem to be the cause because food consumption was not altered in ERKO mice. Instead, several observations suggest that the weight gain in this model is due to a decrease in energy expenditure, which given the normal food intake would result in a state of positive energy balance (1, 2). In this respect, this condition partially resembles an obesity syndrome following lesions of the ventromedial nucleus of hypothalamus (VMN), which is also marked by a significant weight gain due to an accumulation of visceral fat, impaired glucose homeostasis, and reduced energy expenditure (3, 4). Although VMN-lesioned animals initially become hyperphagic as well, when tube-pair-fed with control animals to ensure equal food consumption, lesioned rats still gained more weight and accumulated more fat, albeit to a lesser extent than rats fed ad libitum (3, 5). There are additional lines of evidence that are consistent with a functional role of VMN ER␣ in the regulation of body weight. VMN has a high density of estrogenbinding sites (6), and the neurons in this nucleus express ER␣ at high levels (7). Although VMN lesioning or ovariectomy both lead to increased food intake and body weight, the effect does not appear...

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“…MDA-66 was produced by stable transfection of MDA-MB-231 with human ER expression vector (pCMV-ERα) (Alotaibi et al, 2006).…”

Section: Cell Lines and Culturementioning

confidence: 99%

Alteration in the subcellular location of the inhibitor of growth proteinp33(ING1b) in estrogen receptor alpha positive breast carcinoma cells

Kunter¹,

Kandemiş²,

Alotaibi³

et al. 2017

Turk J Biol

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ING1 has regulatory roles in the expression of genes associated with proliferation, apoptosis, and senescence. p33(ING1b) is the most widely expressed isoform of the gene. Downregulation of its nuclear expression is involved in differentiation and pathogenesis in invasive breast carcinoma. Yet the mechanism(s) by which p33 nuclear targeting is regulated remains unknown. In this study, we analyzed human invasive breast carcinoma tissue samples by immunostaining with p33 and correlating p33 location with the presence of ERα. Our findings show the expression of p33 protein in ERα-positive tumor samples was in the nucleus alone, while the expression was mainly in the cytoplasm in ERα-negative tumor samples. Examination of the localization of p33 in the nucleus and/or cytoplasm in several different cell lines demonstrated 17β-estradiol (E2) treatment causes dramatic compartmental shift in p33 protein from the cytoplasm to the nucleus in ERα-positive MDA-66 cells. No significant differences in ERα-negative MDA-MB-231 cells in the same conditions were observed. We show for the first time nuclear localization of p33 is regulated by estradiol induction in ERα-positive breast cancer cells. These results suggest compartmental shift in p33 by ER signaling may be an important molecular event in the differentiation and pathogenesis of invasive breast cancer.

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Unliganded estrogen receptor-α activates transcription of the mammary gland Na+/I− symporter gene

Cited by 20 publications

References 35 publications

Epigenetic regulation of Kiss1 gene expression mediating estrogen-positive feedback action in the mouse brain

Epigenetic regulation of Kiss1 gene expression mediating estrogen-positive feedback action in the mouse brain

Silencing of estrogen receptor α in the ventromedial nucleus of hypothalamus leads to metabolic syndrome

Alteration in the subcellular location of the inhibitor of growth proteinp33(ING1b) in estrogen receptor alpha positive breast carcinoma cells

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