Sex steroid receptor regulation by genistein in the prepubertal rat uterus

Cotroneo, Michelle S.; Wang, Jun; Eltoum, Isam-Eldin; Lamartiniere, Coral A.

doi:10.1016/s0303-7207(00)00405-6

Cited by 50 publications

(40 citation statements)

References 46 publications

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“…An earlier study had postulated that TCDD may promote this effect by inducing an enzyme that acts in concert with E2 to target the ER to the ubiquitin proteasome pathway (2), a model similar to what we propose with the GR. In another study, exposure to genistein was shown to down regulate androgen receptors in the rat prostate (18) and uterus (11). These studies support a role of ER signaling in regulation of steroid hormone receptor protein stability.…”

Section: Discussionmentioning

confidence: 78%

Estrogen Receptor-Dependent Proteasomal Degradation of the Glucocorticoid Receptor Is Coupled to an Increase in Mdm2 Protein Expression

Kinyamu

Archer

2003

Molecular and Cellular Biology

143

133

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Glucocorticoids and estrogens regulate a number of vital physiological processes. We developed a model breast cancer cell line, MCF-7 M, to examine potential mechanisms by which the ligand-bound estrogen receptor (ER) regulates glucocorticoid receptor (GR)-mediated transcription. MCF-7 cells, which endogenously express ER␣, were stably transfected with mouse mammary tumor virus promoter-luciferase (MMTV-LUC) reporter and GR expression constructs. Our results demonstrate that treatment with estrogen agonists (17␤-estradiol [E2], diethylstilbestrol, genistein), but not antagonists (tamoxifen or raloxifene), for 48 h inhibits GR-mediated MMTV-LUC transcription and chromatin remodeling. Furthermore, estrogen agonists inhibit glucocorticoid induction of p21 mRNA and protein levels, suggesting that the repressive effect applies to other GR-regulated genes and proteins in MCF-7 cells. Importantly, GR transcriptional activity is compromised because treatment with estrogen agonists down regulates GR protein levels. The protein synthesis inhibitor cycloheximide and the proteasome inhibitor MG132 block E2-mediated decrease in GR protein levels, suggesting that estrogen agonists down regulate the GR via the proteasomal degradation pathway. In support of this, we demonstrate that E2-mediated GR degradation is coupled to an increase in p53 and its key regulator protein Mdm2 (murine double minute 2), an E3 ubiquitin ligase shown to target the GR for degradation. Using the chromatin immunoprecipitation assay, we demonstrate an E2-dependent recruitment of ER␣ to the Mdm2 promoter, suggesting a role of ER in the regulation of Mdm2 protein expression and hence the enhanced GR degradation in the presence of estrogen agonists. Our study shows that cross talk between the GR and ER involves multiple signaling pathways, indicative of the mechanistic diversity within steroid receptor-regulated transcription.Physiological and therapeutic activities of glucocorticoids and estrogens are mediated by the glucocorticoid receptor (GR) and estrogen receptor (ER), respectively. As mediators of glucocorticoid and estrogenic hormones, the GR and ER play a critical role in a diverse array of physiological processes, including metabolism, immunity, cell growth and proliferation, reproduction, and development (12, 58). Both GR and ER exert important actions in tissues other than their primary target tissues. In tissues that express both receptors, glucocorticoids often oppose the actions of estrogens. For example, in the mammary gland, glucocorticoids exert antiproliferative effects, whereas estrogens promote cell growth and proliferation (69, 79). In contrast, in bone, glucocorticoids induce bone resorption (57), whereas estrogens inhibit this action (23). Although glucocorticoids and estrogens act within the same cellular context in these biological processes, little is known about the cross talk between the GR and ER signaling pathways.The GR and ER are both members of the steroid hormone receptor superfamily of nuclear receptors that includes the...

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Section: Discussionmentioning

confidence: 78%

Estrogen Receptor-Dependent Proteasomal Degradation of the Glucocorticoid Receptor Is Coupled to an Increase in Mdm2 Protein Expression

Kinyamu

Archer

2003

Molecular and Cellular Biology

143

133

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“…Similar to the present result, ERb immunoreaction was not affected by androgen/estrogen withdrawal or by steroid replacement in rat testis and prostate . Also, exposure of rats to the phytoestrogen genistein (Cotroneo et al 2001) and diethylstilbestrol caused an alteration in ERa expression, but not ERb, in the female and male tract respectively. However, in contrast to the efferent ductules, ERb mRNA may be regulated by androgens in the prostate.…”

Section: Discussionmentioning

confidence: 96%

Differential hormonal regulation of estrogen receptors ERα and ERβ and androgen receptor expression in rat efferent ductules

et al. 2004

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Estrogen receptors, in addition to the androgen receptor (AR), are expressed at high levels in efferent ductules of the male reproductive tract and it is now well recognized that estrogen receptor (ER) a is required for the maintenance of normal structure and function of the ductules. However, little is known regarding the hormonal regulation of the receptors themselves in the male. In the present study, efferent ductule ligation and castration, followed by replacement with testosterone, dihydrotestosterone (DHT) or estradiol was used to investigate the relative importance of circulating and luminal sources of steroid for the modulation of ERa, ERb and AR in rat efferent ductules. Uni-or bilateral castration and ligation did not affect the expression of ERa and ERb, but bilateral castration caused down-regulation of AR. Replacement with DHT and testosterone alone or in combination with estradiol caused the recovery of AR expression to control levels. A slight recovery of AR was also observed after estrogen replacement. ERa expression was decreased to nearly undetectable levels after estrogen replacement. On the other hand, ERb did not show evident effects following any of the treatments, suggesting a constitutive expression of this receptor. This differential modulation of the steroid hormone receptors highlights the importance of maintaining a physiological androgen-estrogen balance to regulate the structure and function of efferent ductules in the male.

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“…The low levels of ER␣ protein observed are in accordance with previous studies where it was shown that (i) the ER␣ protein displays a shorter half-life after ligand binding (46), (ii) ER␣ is subject to degradation induced by its antagonist ICI 182780 (47), and (iii) ER␣ may be down-regulated by the genistein treatment. It has been proposed that proteasomal degradation of ER␣ protein is increased in the presence of the co-regulated proteins KRT18 and KRT8 (48,49). Upregulation of these cytokeratins (Tables III and V) attracts the receptor into close proximity to nuclear matrix-associated proteasomes for degradation as has been described after treatment with ICI 182780 (50).…”

Section: Discussionmentioning

confidence: 99%

“…Upregulation of these cytokeratins (Tables III and V) attracts the receptor into close proximity to nuclear matrix-associated proteasomes for degradation as has been described after treatment with ICI 182780 (50). In the samples treated with genistein, expression of ER␣, after ICI withdrawal, could return to low basal levels (46,48,49) because genistein influences the expression of ER␣. This observation is supported by the co-regulation of ER␣ and c-MYC proteins.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Proteomics and Transcriptomics Addressing the Estrogen Receptor Subtype-mediated Effects in T47D Breast Cancer Cells Exposed to the Phytoestrogen Genistein

Sotoca

Gelpke²,

Boeren

et al. 2011

Molecular & Cellular Proteomics

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The present study addresses, by transcriptomics and quantitative stable isotope labeling by amino acids in cell culture (SILAC)-based proteomics, the estrogen receptor ␣ (ER␣) and ␤ (ER␤)-mediated effects on gene and protein expression in T47D breast cancer cells exposed to the phytoestrogen genistein. Using the T47D human breast cancer cell line with tetracycline-dependent ER␤ expression (T47D-ER␤), the effect of a varying intracellular ER␣/ ER␤ ratio on genistein-induced gene and protein expression was characterized. Results obtained reveal that in ER␣-expressing T47D-ER␤ cells with inhibited ER␤ expression genistein induces transcriptomics and proteomics signatures pointing at rapid cell growth and migration by dynamic activation of cytoskeleton remodeling. The data reveal an interplay between integrins, focal adhesion kinase, CDC42, and actin cytoskeleton signaling cascades, occurring upon genistein treatment, in the T47D-ER␤ breast cancer cells with low levels of ER␣ and no expression of ER␤. In addition, data from our study indicate that ER␤-mediated gene and protein expression counteracts ER␣-mediated effects because in T47D-ER␤ cells expressing ER␤ and exposed to genistein transcriptomics and proteomics signatures pointing at a clear down-regulation of cell growth and induction of cell cycle arrest and apoptosis were demonstrated. These results suggest that ER␤ decreases cell motility and metastatic potential as well as cell survival of the breast cancer cell line. It is concluded that the effects of genistein on proteomics and transcriptomics end points in the T47D-ER␤ cell model are comparable with those reported previously for estradiol with the ultimate estrogenic effect being dependent on the relative affinity for both receptors and on the receptor phenotype (ER␣/ER␤ ratio)

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Sex steroid receptor regulation by genistein in the prepubertal rat uterus

Cited by 50 publications

References 46 publications

Estrogen Receptor-Dependent Proteasomal Degradation of the Glucocorticoid Receptor Is Coupled to an Increase in Mdm2 Protein Expression

Estrogen Receptor-Dependent Proteasomal Degradation of the Glucocorticoid Receptor Is Coupled to an Increase in Mdm2 Protein Expression

Differential hormonal regulation of estrogen receptors ERα and ERβ and androgen receptor expression in rat efferent ductules

Quantitative Proteomics and Transcriptomics Addressing the Estrogen Receptor Subtype-mediated Effects in T47D Breast Cancer Cells Exposed to the Phytoestrogen Genistein

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