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Rebecca B. Riggins - One of the best experts on this subject based on the ideXlab platform.
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ERRγ target genes are poor prognostic factors in Tamoxifen-treated breast cancer
Journal of Experimental & Clinical Cancer Research, 2015Co-Authors: Subha Madhavan, Yuriy Gusev, Salendra Singh, Rebecca B. RigginsAbstract:One-third of estrogen (ER+) and/or progesterone Receptor-positive (PGR+) breast tumors treated with Tamoxifen (TAM) do not respond to initial treatment, and the remaining 70% are at risk to relapse in the future. Estrogen-Related Receptor Gamma (ESRRG, ERRγ) is an orphan nuclear Receptor with broad, structural similarities to classical ER that is widely implicated in the transcriptional regulation of energy homeostasis. We have previously demonstrated that ERRγ induces resistance to TAM in ER+ breast cancer models, and that the Receptor’s transcriptional activity is modified by activation of the ERK/MAPK pathway. We hypothesize that hyper-activation or over-expression of ERRγ induces a pro-survival transcriptional program that impairs the ability of TAM to inhibit the growth of ER+ breast cancer. The goal of the present study is to determine whether ERRγ target genes are associated with reduced distant metastasis-free survival (DMFS) in ER+ breast cancer treated with TAM. Raw gene expression data was obtained from 3 publicly available breast cancer clinical studies of women with ER+ breast cancer who received TAM as their sole endocrine therapy. ERRγ target genes were selected from 2 studies that published validated chromatin immunoprecipitation (ChIP) analyses of ERRγ promoter occupancy. Kaplan-Meier estimation was used to determine the association of ERRγ target genes with DMFS, and selected genes were validated in ER+, MCF7 breast cancer cells that express exogenous ERRγ. Thirty-seven validated Receptor target genes were statistically significantly altered in women who experienced a DM within 5 years, and could classify several independent studies into poor vs. good DMFS. Two genes (EEF1A2 and PPIF) could similarly separate ER+, TAM-treated breast tumors by DMFS, and their protein levels were measured in an ER+ breast cancer cell line model with exogenous ERRγ. Finally, expression of ERRγ and these two target genes are elevated in models of ER+ breast cancer with hyperactivation of ERK/MAPK. ERRγ signaling is associated with poor DMFS in ER+, TAM-treated breast cancer, and ESRRG, EEF1A2, and PPIF comprise a 3-gene signaling node that may contribute to TAM resistance in the context of an active ERK/MAPK pathway.
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The pERK of being a target: Kinase regulation of the orphan nuclear Receptor ERRγ.
Receptors and clinical investigation, 2014Co-Authors: Rebecca B. RigginsAbstract:Estrogen-Related Receptors (ERRs) are orphan members of the nuclear Receptor superfamily that are important regulators of mitochondrial metabolism with emerging roles in cancer. In the absence of an endogenous ligand, ERRs are reliant upon other regulatory mechanisms that include protein/protein interactions and post-translational modification, though the cellular and clinical significance of this latter mechanism is unclear. We recently published a study in which we establish Estrogen-Related Receptor Gamma (ERRγ) as a target for extracellular signal-regulated kinase (ERK), and show that regulation of ERRγ by ERK has important consequences for the function of this Receptor in cellular models of estrogen Receptor-positive (ER+) breast cancer. In this Research Highlight, we discuss the implications of these findings from a molecular and clinical perspective.
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Abstract 3570: Phospho-dependent regulation of ERRγ expression, transcriptional activity, and Tamoxifen resistance in ER+ breast cancer.
Cancer Research, 2013Co-Authors: Rebecca B. Riggins, Subha Madhavan, Yuriy Gusev, Salendra Singh, Mary M. Heckler, Cara C. Schafer, Hemang Thakor, Ye Tian, Yue WangAbstract:Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Selective estrogen Receptor modulators (SERMs) such as Tamoxifen (TAM) can significantly improve breast cancer-specific survival for women with ER-positive (ER+) disease. However, resistance to TAM remains a major clinical problem. Estrogen-Related Receptor Gamma (ERRγ) is an orphan nuclear Receptor with broad, structural similarities to classical ER that is widely implicated in the transcriptional regulation of energy homeostasis. We previously reported that ERRγ is upregulated during the acquisition of TAM resistance in ER+ breast cancer cell lines, exogenous expression of ERRγ is sufficient to induce TAM resistance, and ERRγ mRNA is significantly increased in tumor samples from women with ER+ breast cancer who relapse following TAM treatment. Because ERRγ has no known ligand, our recent studies have focused on understanding how the expression and activity of this orphan nuclear Receptor is regulated, and how this contributes to the TAM resistant phenotype. We have found that TAM-resistant breast cancer cells in which endogenous ERRγ is upregulated show a concomitant hyper activation of p44/p42 ERK. Furthermore, ERK activity (but not that of JNK or p38 MAPK) directly enhances ERRγ protein stability via Serines 57, 81, and/or 219 of the Receptor. Phospho-deficient ERRγ is impaired in its ability to induce TAM resistance, and this is associated with a significant reduction in transcriptional activity at the Estrogen-Related response element (ERRE) half-site, in particular. This led us to hypothesize that ERRγ action at ERREs is most relevant to the development of TAM resistance. We examined a meta-list of validated, ERRE-containing ERR target genes in association with distant metastasis-free survival (DMFS) within 5 years of primary diagnosis in each of 3 publicly available clinical datasets comprised of ER+ breast cancer patients treated with TAM, and obtained a list of 37 differentially expressed targets. The proximal promoter regions of these 37 genes are enriched for binding sites for ELK1, a well-known ERK substrate. Sub-network analysis reveals enrichment of genes whose protein products regulate the mitochondrial unfolded protein response (UPRmito). We also performed differential dependency network (DDN) analysis in an independent dataset using the full meta-list of ERRγ target genes and also identified genes associated with UPRmito. These data suggest a potentially novel role for ERK-mediated regulation of ERRγ in mitochondrial protein folding in TAM-resistant breast cancer. Citation Format: Rebecca B. Riggins, Mary M. Heckler, Hemang Thakor, Cara C. Schafer, Salendra Singh, Ye Tian, Yuriy Gusev, Subha Madhavan, Yue Wang. Phospho-dependent regulation of ERRγ expression, transcriptional activity, and Tamoxifen resistance in ER+ breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3570. doi:10.1158/1538-7445.AM2013-3570
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ESRRG (Estrogen-Related Receptor Gamma)
Atlas of genetics and cytogenetics in oncology and haematology, 2011Co-Authors: Rebecca B. RigginsAbstract:Review on ESRRG (Estrogen-Related Receptor Gamma), with data on DNA, on the protein encoded, and where the gene is implicated.
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Abstract LB-29: Erk-mediated phosphorylation of the orphan nuclear Receptor ERRγ regulates Receptor stability and contributes to Tamoxifen resistance in ER+ breast cancer
Cancer Research, 2011Co-Authors: Rebecca B. Riggins, Mary M. Heckler, Cara C. SchaferAbstract:Estrogen Receptor alpha-positive (ER+) breast tumors comprise ∼70% of annually diagnosed breast cancers in the United States. While pro-tumorigenic ER signaling can be blocked by endocrine therapies that either inhibit the Receptor directly (Tamoxifen) or prevent synthesis of its ligand (aromatase inhibitors), de novo and acquired resistance to ER-targeted therapies is a major barrier to the successful treatment of ER+ breast cancer. One of the most common mechanisms of acquired or de novo endocrine resistance in ER+ breast cancer is increased reliance on alternative pro-proliferative and pro-survival pathways that circumvent ER. We have been studying the role of the orphan nuclear Receptor Estrogen-Related Receptor Gamma (ERRγ) in Tamoxifen-resistant breast cancer, increased expression of which induces Tamoxifen-resistant proliferation in multiple ER+ breast cancer cell lines. We have also reported that i . endogenous ERRγ shows increased levels of serine phosphorylation in Tamoxifen-resistant breast cancer cells, ii . this coincides with increased activation of extracellular signal-regulated kinase 2 (ERK2), and iii . pharmacological inhibition of the MEK/ERK pathway reduces ERRγ phosphorylation and transcriptional activity. This lead us to hypothesize that ERK-mediated phosphorylation of the orphan nuclear Receptor ERR contributes to Tamoxifen resistance in ER+ breast cancer . One way in which ERK-mediated phosphorylation can regulate its substrates is through changes in target protein stability. Co-transfection of wild-type ERRγ with either a constitutively active MEK (MEK-DD) or wild-type ERK2 led to an increase in ERRγ expression. Conversely, treatment of cells with the MEK inhibitor U0126 reduced transfected ERRγ expression. These data are also supported by mRNA data publicly available through ONCOMINE showing that i . relative to MCF7, BT-474 cells (which contain amplified HER2 and very high levels of active ERK) express significantly increased levels of ERRγ, and ii . treatment of BT-474 cells with the MEK inhibitor PD0325901 reduces ERRγ expression. To confirm that ERK-mediated phosphorylation of ERRγ regulates Receptor stability, we performed site-directed mutagenesis to change multiple Serine residues within ERK consensus sites to Alanine. These Ser-to-Ala ERRγ mutants are expressed at lower levels when compared to the wild-type Receptor, and co-transfection with MEK-DD is unable to increase their expression. Altogether, these data strongly suggest that direct ERK-mediated phosphorylation of ERR positively stabilizes Receptor expression. Ongoing studies are addressing the biochemical and biological consequences of ERK-mediated ERRγ phosphorylation in the context of Tamoxifen-resistant breast cancer; putative mechanisms include Receptor dimerization, DNA binding, and co-factor recruitment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-29. doi:10.1158/1538-7445.AM2011-LB-29
Manoochehr Tavassoli - One of the best experts on this subject based on the ideXlab platform.
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Association of the Polymorphism of the Estrogen-Related Receptor Gamma (ERRγ) Geneand the Risk of Breast Cancer in the Populationof Isfahan
2020Co-Authors: Padideh Karimi, Simin Hematti, Kamran Ghaedi, Elahe Kamali, Manoochehr TavassoliAbstract:Breast cancer is a hormone-dependent tumor which is regulated by steroid hormones including estrogen and progesterone. Therefore, Estrogen-Related Receptors (ERRs) which belong to orphan nuclear Receptor groups can interfere with the estrogen signaling pathway and cause the growth of solid tumors. In the present study, blood samples of 150 women with breast cancer and 150 healthy women were collected from Omid (Seyedoshohada) Cancer Hospital, Isfahan University of Medical Sciences and Clinical Laboratory, Alzahra Hospital, Isfahan University of Medical Sciences, Iran, respectively. DNA was extracted and amplified. Then, some of the alleles in variable sizes were sequenced and used as allele specific markers for exact determination of the number of AAAG repeats in other samples. This study was performed to determine the association between breast cancer risk and alleles of the tetranucleotide repeat (AAAG)n microsatellite in the intron of the ERRγ gene. Our results showed that women with short AAAG repeats were at higher risk of breast cancer (OR=7.14). These results suggest the possible involvement of the polymorphic AAAG repeat of the ERRγ gene in regulating its expression. Therefore, the shortest alleles of this polymorphism with 6 and 7 repeats of AAAG may be useful as a biomarker for breast cancer prognosis. Key words: Estrogen Related Receptor Gamma; Breast Neoplasms; Polymorphism, Genetic
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Association of the Polymorphism of the Estrogen-Related Receptor Gamma (ERRγ) Gene and the Risk of Breast Cancer in the Population of Isfahan
Genetics in the Third Millennium, 2013Co-Authors: Padideh Karimi, Simin Hematti, Kamran Ghaedi, Elahe Kamali, Manoochehr TavassoliAbstract:Breast cancer is a hormone-dependent tumor which is regulated by steroid hormones including estrogen and progesterone. Therefore, Estrogen-Related Receptors (ERRs) which belong to orphan nuclear Receptor groups can interfere with the estrogen signaling pathway and cause the growth of solid tumors. In the present study, blood samples of 150 women with breast cancer and 150 healthy women were collected from Omid (Seyedoshohada) Cancer Hospital, Isfahan University of Medical Sciences and Clinical Laboratory, Alzahra Hospital, Isfahan University of Medical Sciences, Iran, respectively. DNA was extracted and amplified. Then, some of the alleles in variable sizes were sequenced and used as allele specific markers for exact determination of the number of AAAG repeats in other samples. This study was performed to determine the association between breast cancer risk and alleles of the tetranucleotide repeat (AAAG)n microsatellite in the intron of the ERRγ gene. Our results showed that women with short AAAG repeats were at higher risk of breast cancer (OR=7.14). These results suggest the possible involvement of the polymorphic AAAG repeat of the ERRγ gene in regulating its expression. Therefore, the shortest alleles of this polymorphism with 6 and 7 repeats of AAAG may be useful as a biomarker for breast cancer prognosis.
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Polymorphic AAAG repeat length in Estrogen-Related Receptor Gamma (ERRγ) and risk of breast cancer in Iranian women.
Cancer Investigation, 2013Co-Authors: Padideh Karimi, Simin Hematti, Foruzan Safari, Manoochehr TavassoliAbstract:Estrogen-Related Receptors (ERRs) alpha, beta, and Gamma are orphan nuclear Receptors that modulate the estrogen signaling pathway and play roles in the regulation of breast cancer cell growth. To determine the association between breast cancer risk and alleles of the tetranucleotide repeat (AAAG)n in the intron of ERRγ gene, a case–control study of 200 breast cancer patients and 200 controls was performed in Iranian women. Our results demonstrate that women with short AAAG repeat are at higher risk of breast cancer (OR 7). This result suggests a possible involvement of polymorphic AAAG repeat of ERRγ gene in regulating its expression.
C. L. Galindo - One of the best experts on this subject based on the ideXlab platform.
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A long AAAG repeat allele in the 5′ UTR of the ERR-γ gene is correlated with breast cancer predisposition and drives promoter activity in MCF-7 breast cancer cells
Breast Cancer Research and Treatment, 2011Co-Authors: C. L. Galindo, J. F. Mccormick, V. J. Bubb, D. H. Abid Alkadem, Long-shan Li, L. J. Mciver, A. C. George, D. A. Boothman, J. P. Quinn, M. A. SkinnerAbstract:We sequenced the 5′ UTR of the Estrogen-Related Receptor Gamma gene ( ERR -γ) in ~500 patient and volunteer samples and found that longer alleles of the (AAAG)_ n microsatellite were statistically and significantly more likely to exist in the germlines of breast cancer patients when compared to healthy volunteers. This microsatellite region contains multiple binding sites for a number of transcription factors, and we hypothesized that the polymorphic AAAG-containing sequence in the 5′ UTR region of ERR-γ might modulate expression of ERR-γ. We found that the 369 bp PCR product containing the AAAG repeat drove expression of a reporter gene in estrogen Receptor positive breast cancer cells. Our results support a role for the 5′ UTR region in ERR-γ expression, which is potentially mediated via binding to the variable tandem AAAG repeat, the length of which correlates with breast cancer pre-disposition. Our study indicates that the AAAG tetranucleotide repeat polymorphism in ERR-γ gene 5′ UTR region may be a new biomarker for genetic susceptibility to breast cancer.
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Abstract P2-06-03: A Polymorphic AAAG Repeat in the Estrogen Receptor-Related-Gamma Gene May Represent a Breast Cancer Predisposition Biomarker
Cancer Research, 2010Co-Authors: Harold R. Garner, J. F. Mccormick, V. J. Bubb, Long-shan Li, L. J. Mciver, A. C. George, D. A. Boothman, J. P. Quinn, C. L. GalindoAbstract:Background: There is a strong genetic component to breast cancer, which is the most common neoplasm in women; however current risk markers are few, accounting for less than 10% of breast cancer cases. This means that the majority of familial breast cancers remain unexplained. Our laboratory has studied microsatellite polymorphisms for many years, and we developed techniques to assay these understudied regions of the genome en masse and individually via shot-gun methods to rapidly identify those that are likely to be polymorphic and therefore potentially contribute to phenotype. Material and Methods: Using these novel approaches, we identified a polymorphic AAAG microsatellite repeat in the Estrogen-Related Receptor Gamma (ERR-γ) that is expanded in -10% of the general population. We genotyped over 300 individuals and found a longer allelic version (13+ repeat copies) in 14.3% of breast cancer patients, compared to only 4.8% in cancer-free individuals. We computationally identified 22 transcription factors that could bind directly to this AAAG repeat and the surrounding region. We hypothesized that the AAAG-containing region might serve as a promoter for ERR-y. Results: We found a statistically significant number of breast cancer patients with the expanded AAAG allele, and preliminary experiments confirm that the AAAG-containing region of ERR-γ does indeed drive reporter gene expression in estrogen Receptor positive (ER+) MCF-7 breast cancer cells. This was not the case for the ER-breast cancer cells (MDA-MB-231) we also examined. Our initial assessments also revealed that SKBR-3 breast cancer cells are naturally heterozygotic for the long and short allelic versions of the AAAG repeat. Our ongoing studies involve knockdown of transcription factors in MCF-7 cells that abrogate the endogenous expression of ERR-γ. Discussion: The role of microsatellites in cancer is well defined for colon cancer, but few studies have been conducted to examine the contribution of these simple sequence repeats in breast cancer. We discovered a polymorphic AAAG repeat in the ERR-γ gene, and our studies indicate that a longer version of this repeat is more prevalent in the genomes of breast cancer patients. Based on our assessment, this allele carries a 2.98 relative risk for the development of breast cancer. The higher incidence of this putative biomarker in breast cancer patients may be a result of altered ERR-γ expression, as the AAAG-containing sequence can drive reporter expression. If the frequency of this potentially predictive marker is sustained in a larger population, and the mechanism by which it confers the cancer phenotype can be identified, it may contribute substantially as a biomarker offering surveillance, prophylactic surgery, and chemoprevention options to patients. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-06-03.
M. A. Skinner - One of the best experts on this subject based on the ideXlab platform.
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A long AAAG repeat allele in the 5′ UTR of the ERR-γ gene is correlated with breast cancer predisposition and drives promoter activity in MCF-7 breast cancer cells
Breast Cancer Research and Treatment, 2011Co-Authors: C. L. Galindo, J. F. Mccormick, V. J. Bubb, D. H. Abid Alkadem, Long-shan Li, L. J. Mciver, A. C. George, D. A. Boothman, J. P. Quinn, M. A. SkinnerAbstract:We sequenced the 5′ UTR of the Estrogen-Related Receptor Gamma gene ( ERR -γ) in ~500 patient and volunteer samples and found that longer alleles of the (AAAG)_ n microsatellite were statistically and significantly more likely to exist in the germlines of breast cancer patients when compared to healthy volunteers. This microsatellite region contains multiple binding sites for a number of transcription factors, and we hypothesized that the polymorphic AAAG-containing sequence in the 5′ UTR region of ERR-γ might modulate expression of ERR-γ. We found that the 369 bp PCR product containing the AAAG repeat drove expression of a reporter gene in estrogen Receptor positive breast cancer cells. Our results support a role for the 5′ UTR region in ERR-γ expression, which is potentially mediated via binding to the variable tandem AAAG repeat, the length of which correlates with breast cancer pre-disposition. Our study indicates that the AAAG tetranucleotide repeat polymorphism in ERR-γ gene 5′ UTR region may be a new biomarker for genetic susceptibility to breast cancer.
Hueng-sik Choi - One of the best experts on this subject based on the ideXlab platform.
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Emerging role of the orphan nuclear Receptor Estrogen-Related Receptor Gamma in liver metabolic diseases
Liver Research, 2019Co-Authors: Hueng-sik ChoiAbstract:Abstract Estrogen-Related Receptor Gamma (ERRγ) is one of three members of the ERR family and remains an orphan, as there are no known natural ligands. ERRγ is an inducible transcription factor, and its ligand-independent transcriptional activity is regulated by co-regulator interactions and post-transcriptional modifications. Recent findings from animal models show that ERRγ, as a downstream mediator of multiple extracellular signals, plays a key role in coordinating endocrine and metabolic signals, resulting in changes in glucose, alcohol, lipid, and iron metabolism in the liver. Therefore, dysregulation of this Receptor contributes to the pathogenesis of metabolic diseases such as hyperglycemia, insulin resistance, and alcoholic liver injury. Interestingly, ERRγ is also involved in responses to bacterial infection. These findings establish the importance of ERRγ in the endocrine and metabolic control of liver metabolism, and suggest that ERRγ may be a promising therapeutic target for metabolic diseases of the liver.
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Author Correction: Estrogen-Related Receptor Gamma functions as a tumor suppressor in gastric cancer.
Nature Communications, 2018Co-Authors: Myoung-hee Kang, Hueng-sik Choi, Hyunji Choi, Masanobu Oshima, Jae Ho Cheong, Young Soo Park, Mi-na Kweon, Chan-gi PackAbstract:The original version of this Article contained errors in Figs. 4, 5, and 6. In Fig. 4d, the x-axis label incorrectly read ‘blank, +, blank, +’, and in Fig. 5e, the bars of the second graph from the left were coloured blue-orange-blue-orange. Both of these errors have been fixed in the PDF and HTML versions of the Article. Furthermore, in Fig. 6a, the right-hand image of AGS cells treated with 5 µM DY131 was inadvertently replaced with a duplicate of the left-hand image. The correct version of this figure panel appears in the Author Correction associated with this Article. For transparency, the error has not been corrected in the PDF or HTML versions of the Article.
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Estrogen-Related Receptor Gamma functions as a tumor suppressor in gastric cancer
Nature Communications, 2018Co-Authors: Myoung-hee Kang, Hueng-sik Choi, Hyunji Choi, Masanobu Oshima, Jae Ho Cheong, Young Soo Park, Mi-na Kweon, Chan-gi PackAbstract:The principle factors underlying gastric cancer (GC) development and outcomes are not well characterized resulting in a paucity of validated therapeutic targets. To identify potential molecular targets, we analyze gene expression data from GC patients and identify the nuclear Receptor ESRRG as a candidate tumor suppressor. ESRRG expression is decreased in GC and is a predictor of a poor clinical outcome. Importantly, ESRRG suppresses GC cell growth and tumorigenesis. Gene expression profiling suggests that ESRRG antagonizes Wnt signaling via the suppression of TCF4/LEF1 binding to the CCND1 promoter. Indeed, ESRRG levels are found to be inversely correlated with Wnt signaling-associated genes in GC patients. Strikingly, the ESRRG agonist DY131 suppresses cancer growth and represses the expression of Wnt signaling genes. Our present findings thus demonstrate that ESRRG functions as a negative regulator of the Wnt signaling pathway in GC and is a potential therapeutic target for this cancer. Very little is known regarding the molecular mechanisms involved in gastric cancer development. Here the authors show Estrogen-Related Receptor Gamma (ESRRG) is a tumor suppressor in gastric cancer and suggest the mechanism of this tumor suppression function involves the inhibition of Wnt signaling.
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Estrogen Receptor-related Receptor γ regulates testicular steroidogenesis through direct and indirect regulation of steroidogenic gene expression.
Molecular and Cellular Endocrinology, 2017Co-Authors: Eunsook Park, Sudeep Kumar, Hueng-sik ChoiAbstract:Abstract Biosynthesis of testosterone, which mainly occurs in testicular Leydig cells, is controlled by steroidogenic proteins, such as StAR and P450c17. Although Estrogen-Related Receptor Gamma (ERRγ), an orphan nuclear Receptor, is expressed in the testis, its role is not well understood. In this study, we investigated the expression of ERRγ in Leydig cells and its molecular action on testicular steroidogenesis. ERRγ is expressed in mouse Leydig cells from pre-pubertal stages. ERRγ overexpression in primary Leydig cells elevated the production of testosterone with a marked increase of P450c17 expression at both mRNA and protein levels, albeit decreased expression of StAR. Promoter-reporter analyses showed that ERRγ directly regulated the P450c17 promoter. Further deletion mutant analyses of the P450c17 promoter revealed that ERRγ activated expression of the P450c17 gene by binding to an ERRγ response element within the P450c17 promoter. Meanwhile, ERRγ suppressed cAMP-induced activation of the StAR promoter, which was likely due to ERRγ-mediated inhibition of the transcriptional activity of Nur77, which is induced by cAMP and regulates StAR gene expression in Leydig cells. Interestingly, ERRγ coexpression also decreased the protein level of Nur77, which occurred through proteasomal degradation, suggesting ERRγ-mediated regulation of steroidogenesis at another level. Taken together, these findings suggest that ERRγ regulates testicular steroidogenesis, both directly controlling and indirectly fine-tuning the expression of steroidogenic genes.
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RORα switches transcriptional mode of ERRγ that results in transcriptional repression of CYP2E1 under ethanol-exposure.
Nucleic Acids Research, 2015Co-Authors: Tae-young Na, Na-lee Ka, Hueng-sik ChoiAbstract:Increased cytochrome P450 2E1 (CYP2E1) expression is the main cause of oxidative stress, which exacerbates alcoholic liver diseases (ALDs). Estrogen-Related Receptor Gamma (ERRγ) induces CYP2E1 expression and contributes to enhancing alcohol-induced liver injury. Retinoic acid-related orphan Receptor alpha (RORα) has antioxidative functions; however, potential cross-talk between ERRγ and RORα in the regulation of CYP2E1 has not been studied. We report that RORα suppressed ERRγ-mediated CYP2E1 expression. A physical interaction of RORα with ERRγ at the ERRγ−response element in the CYP2E1 promoter was critical in this suppression. At this site, coregulator recruitment of ERRγ was switched from coactivator p300 to the nuclear Receptor corepressor 1 in the presence of RORα. Cross-talk between ERRγ and RORα was demonstrated in vivo, in that administration of JC1–40, a RORα activator, significantly decreased both CYP2E1 expression and the signs of liver injury in ethanol-fed mice, and this was accompanied by coregulator switching. Thus, this non-classical RORα pathway switched the transcriptional mode of ERRγ, leading to repression of alcohol-induced CYP2E1 expression, and this finding may provide a new therapeutic strategy against ALDs.