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Donald P. Mcdonnell - One of the best experts on this subject based on the ideXlab platform.
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Molecular Pathways: The Metabolic Regulator Estrogen-Related Receptor α as a Therapeutic Target in Cancer
Clinical cancer research : an official journal of the American Association for Cancer Research, 2012Co-Authors: Ching-yi Chang, Donald P. McdonnellAbstract:The Estrogen Related Receptor alpha (ERRα) is an orphan member of the nuclear Receptor superfamily of transcription factors whose activity is regulated by the expression level and/or activity of its obligate coregulators, peroxisome proliferator activated Receptor gamma coactivator-1 alpha and beta (PGC-1α or PGC-1β). Under normal physiological conditions, and in responding to different environmental stimuli, the ERRα/PGC-1 complex is involved in regulating metabolic homeostasis under conditions of high energy demand in brown adipocytes, proliferating T-cells and in muscle. Interestingly, increased expression/activity of the ERRα/PGC-1 axis has also been shown to correlate with unfavorable clinical outcome in both breast and ovarian tumors. The observation that ERRα activity is manifest in all breast tumor sub-types with particularly high activity being evident in ERα-negative, HER2 positive and triple negative breast cancers has raised significant interest in targeting this Receptor for the treatment of those breast cancers where therapeutic options are limited.
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On the intractability of Estrogen-Related Receptor α as a target for activation by small molecules
Journal of medicinal chemistry, 2007Co-Authors: Stephen M. Hyatt, Rebecca A. Stein, Donald P. Mcdonnell, Elizabeth L. Lockamy, Aaron B. Miller, Lisa A. Orband-miller, Timothy M. Willson, William J. ZuercherAbstract:The Estrogen-Related Receptor α (ERRα) is a potential target for activation in the treatment of metabolic disease. To date, no small-molecule agonists of ERRα have been identified despite several high-throughput screening campaigns. We describe the synthesis and profiling of a small array of compounds designed on the basis of a previously reported agonist-bound crystal structure of the closely related Receptor ERRγ. The results suggest that ERRα may be intractable as a direct target for pharmacologic activation.
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Estrogen-Related Receptor α as a therapeutic target in cancer
Endocrine-related cancer, 2006Co-Authors: Rebecca A. Stein, Donald P. McdonnellAbstract:The orphan Receptor Estrogen-Related Receptor alpha (ERR alpha) is a member of the nuclear Receptor superfamily of ligand-regulated transcription factors. This protein is structurally most related to the canonical estrogen Receptor and has been shown to modulate estrogen signaling in some contexts. These observations have heightened interest in ERR alpha as a therapeutic target in both breast and ovarian cancer and in other estrogenopathies. This review details our present understanding of ERR alpha action with a view to highlight specific aspects of its signal-transduction pathway in breast cancer that may be amenable to pharmaceutical manipulation.
Duk-hwa Kwon - One of the best experts on this subject based on the ideXlab platform.
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Estrogen-Related Receptor gamma induces cardiac hypertrophy by activating GATA4.
Journal of Molecular and Cellular Cardiology, 2013Co-Authors: Duk-hwa KwonAbstract:Abstract Estrogen-Related Receptor gamma (ERRγ) is an orphan nuclear Receptor that has biological roles mainly in metabolism and that controls metabolic switching in perinatal heart. In adult heart diseases, however, the functional roles of ERRγ have not yet been elucidated. In the present study, we aimed to characterize the role of ERRγ in cardiac hypertrophy. The functional roles of ERRγ in the development of cardiac hypertrophy were examined in primary cultured cardiomyocytes and in animal models. ERRγ expression was increased in hearts from human hypertrophic cardiomyopathy patients and in both cellular and animal models of cardiac hypertrophy. Transgenic overexpression in mouse heart as well as forced expression of ERRγ in cardiomyocytes induced hypertrophic phenotypes. Knock-down of ERRγ blocked agonist-induced hypertrophic phenotypes. ERRγ bound directly to the proximal ERR-responsive element in the GATA4 promoter in a sequence-specific manner and thereby induced transcription. ERRγ-induced hypertrophy was blocked by inhibition of GATA4. GSK-5182, an inverse agonist of ERRγ, completely blocked cardiac hypertrophy in cardiomyocytes. It also prevented aortic banding-induced cardiac hypertrophy and fibrosis in mouse heart. These findings demonstrate a novel ERRγ/GATA4 signal cascade in the development of cardiac hypertrophy and suggest GSK-5182 as a possible therapeutic.
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Abstract 071: Estrogen-Related Receptor Gamma Induces Cardiac Hypertrophy By Activating Gata4
Circulation Research, 2013Co-Authors: Duk-hwa Kwon, Jeong-hyeon Ko, Sera Shin, Nakwon ChoeAbstract:Introduction— Estrogen-Related Receptor gamma (ERRγ) is an orphan nuclear Receptor that has biological roles mainly in metabolism and it controls metabolic switching in perinatal heart. In adult heart diseases, however, the functional roles of ERRγ have not yet been elucidated. Hypothesis— In the present study, we aimed to characterize the role of ERRγ in cardiac hypertrophy. Here we show that ERRγ provokes cardiac hypertrophy by inducing GATA4 and that its inverse agonist, GSK-5182, prevents cardiac hypertrophy. Methods and Results— The functional roles of ERRγ in association with development of cardiac hypertrophy were examined in primarily cultured cardiomyocytes, in animal models, and in heart samples from human hypertrophic cardiomyopathy patients. ERRγ expression was increased in hearts obtained from human hypertrophic cardiomyopathy patients and in both agonist-induced cellular models and aortic banding-induced animal models of cardiac hypertrophy. Transgenic overexpression in mouse heart as well as forced expression of ERRγ in cardiomyocytes induced hypertrophic phenotypes. Knock-down of ERRγ blocked agonist-induced hypertrophic phenotypes. ERRγ directly bound to the proximal ERR-responsive element in the GATA4 promoter in a sequence-specific manner and thereby induced transcription. ERRγ-induced hypertrophy was blocked by inhibition of GATA4. GSK-5182 completely blocked cardiac hypertrophy in cardiomyocytes. It also prevented aortic banding-induced cardiac hypertrophy and fibrosis in mouse heart. Conclusion— These findings demonstrate a novel ERRγ/GATA4 signal cascade in the development of cardiac hypertrophy and suggest GSK-5182 as a possible therapeutic.
Rebecca A. Stein - One of the best experts on this subject based on the ideXlab platform.
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On the intractability of Estrogen-Related Receptor α as a target for activation by small molecules
Journal of medicinal chemistry, 2007Co-Authors: Stephen M. Hyatt, Rebecca A. Stein, Donald P. Mcdonnell, Elizabeth L. Lockamy, Aaron B. Miller, Lisa A. Orband-miller, Timothy M. Willson, William J. ZuercherAbstract:The Estrogen-Related Receptor α (ERRα) is a potential target for activation in the treatment of metabolic disease. To date, no small-molecule agonists of ERRα have been identified despite several high-throughput screening campaigns. We describe the synthesis and profiling of a small array of compounds designed on the basis of a previously reported agonist-bound crystal structure of the closely related Receptor ERRγ. The results suggest that ERRα may be intractable as a direct target for pharmacologic activation.
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Estrogen-Related Receptor α as a therapeutic target in cancer
Endocrine-related cancer, 2006Co-Authors: Rebecca A. Stein, Donald P. McdonnellAbstract:The orphan Receptor Estrogen-Related Receptor alpha (ERR alpha) is a member of the nuclear Receptor superfamily of ligand-regulated transcription factors. This protein is structurally most related to the canonical estrogen Receptor and has been shown to modulate estrogen signaling in some contexts. These observations have heightened interest in ERR alpha as a therapeutic target in both breast and ovarian cancer and in other estrogenopathies. This review details our present understanding of ERR alpha action with a view to highlight specific aspects of its signal-transduction pathway in breast cancer that may be amenable to pharmaceutical manipulation.
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Estrogen-Related Receptor a as a therapeutic target in cancer
2006Co-Authors: Rebecca A. Stein, Dp McdonnellAbstract:The orphan Receptor Estrogen-Related Receptor a (ERRa) is a member of the nuclear Receptor superfamily of ligand-regulated transcription factors. This protein is structurally most related to the canonical estrogen Receptor and has been shown to modulate estrogen signaling in some contexts. These observations have heightened interest in ERRa as a therapeutic target in both breast and ovarian cancer and in other estrogenopathies. This review details our present understanding of ERRa action with a view to highlight specific aspects of its signal-transduction pathway in breast cancer that may be amenable to pharmaceutical manipulation. Endocrine-Related Cancer (2006) 13 S25‐S32
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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Estrogen-Related Receptor gamma functions as a tumor suppressor in gastric cancer
Nature Communications, 2018Co-Authors: Myoung-hee Kang, Hyunji Choi, Masanobu Oshima, Mi-na Kweon, Hueng Sik Choi, Young Soo Park, Jae Ho Cheong, 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-Related Receptor γ causes osteoarthritis by upregulating extracellular matrix-degrading enzymes.
Nature communications, 2017Co-Authors: Young-ok Son, Seulki Park, Ji-sun Kwak, Yoonkyung Won, Wan-su Choi, Jinseol Rhee, Churl-hong Chun, Je-hwang Ryu, Don-kyu Kim, Hueng Sik ChoiAbstract:The Estrogen-Related Receptor (ERR) family of orphan nuclear Receptor is composed of ERRα, ERRβ, and ERRγ, which are known to regulate various isoform-specific functions under normal and pathophysiological conditions. Here, we investigate the involvement of ERRs in the pathogenesis of osteoarthritis (OA) in mice. Among ERR family members, ERRγ is markedly upregulated in cartilage from human OA patients and various mouse models of OA. Adenovirus-mediated overexpression of ERRγ in mouse knee joint or transgenic expression of ERRγ in cartilage leads to OA. ERRγ overexpression in chondrocytes directly upregulates matrix metalloproteinase (MMP)-3 and MMP13, which are known to play crucial roles in cartilage destruction in OA. In contrast, genetic ablation of Esrrg or shRNA-mediated downregulation of Esrrg in joint tissues abrogates experimental OA in mice. Our results collectively indicate that ERRγ is a novel catabolic regulator of OA pathogenesis.
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Estrogen-Related Receptor gamma regulates dopaminergic neuronal phenotype by activating GSK3β/NFAT signaling in SH-SY5Y cells.
Journal of Neurochemistry, 2015Co-Authors: Hueng Sik Choi, Hyun Jin ChoiAbstract:The orphan nuclear Receptor Estrogen-Related Receptor gamma (ERRγ) is highly expressed in the nervous system during embryogenesis and in adult brains, but its physiological role in neuronal development remains unknown. In this study, we evaluated the relevance of ERRγ in regulating dopaminergic (DAergic) phenotype and the corresponding signaling pathway. We used retinoic acid (RA) to differentiate human neuroblastoma SH-SY5Y cells. RA induced neurite outgrowth of SH-SY5Y cells with an increase in DAergic neuron-like properties, including up-regulation of tyrosine hydroxylase, dopamine transporter, and vesicular monoamine transporter 2. ERRγ, but not ERRα, was up-regulated by RA, and participated in RA effect on SH-SY5Y cells. ERRγ over-expression enhanced mature DAergic neuronal phenotype with neurite outgrowth as with RA treatment; and RA-induced increase in DAergic phenotype was attenuated by silencing ERRγ expression. ERRγ appears to have a crucial role in morphological and functional regulation of cells that is selective for DAergic neurons. Polo-like kinase 2 was up-regulated in ERRγ-over-expressing SH-SY5Y cells, which was involved in phosphorylation of glycogen synthase kinase 3β and resulting downstream activation of nuclear factor of activated T cells. The likely involvement of ERRγ in regulating the DAergic neuronal phenotype makes this orphan nuclear Receptor a novel target for understanding DAergic neuronal differentiation. We propose the relevance of Estrogen-Related Receptor gamma (ERRγ) in regulating dopaminergic neuronal phenotype: ERRγ is up-regulated by retinoic acid in SH-SY5Y cells, and enhances dopaminergic phenotypes and induces neurite outgrowth; Polo-like kinase 2 (PLK2) and glycogen synthase kinase 3 beta/nuclear factor of activated T cells (GSK3β/NFAT) signaling are responsible for the ERRγ effect. Our findings provide the first insights into the role of ERRγ in the brain, as a novel approach toward understanding dopaminergic differentiation.
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the estrogen related Receptor alpha upregulates secretin expressions in response to hypertonicity and angiotensin ii stimulation
PLOS ONE, 2012Co-Authors: Vien H Y Lee, Hueng Sik Choi, Ian P Y Lam, Billy K C Chow, Leo T O LeeAbstract:Osmoregulation via maintenance of water and salt homeostasis is a vital process. In the brain, a functional secretin (SCT) and secretin Receptor (SCTR) axis has recently been shown to mediate central actions of angiotensin II (ANGII), including initiation of water intake and stimulation of vasopressin (VP) expression and release. In this report, we provide evidence that Estrogen-Related Receptor α (ERRα, NR3B1), a transcription factor mainly involved in metabolism, acts as an upstream activator of the SCT gene. In vitro studies using mouse hypothalamic cell line N-42 show that ERRα upregulates SCT promoter and gene expression. More importantly, knockdown of endogenous ERRα abolishes SCT promoter activation in response to hypertonic and ANGII stimulations. In mouse brain, ERRα coexpresses with SCT in various osmoregulatory brain regions, including the lamina terminalis and the paraventricular nucleus of the hypothalamus, and its expression is induced by hyperosmotic and ANGII treatments. Based on our data, we propose that both the upregulation of ERRα and/or the increased binding of ERRα to the mouse SCT promoter are two possible mechanisms for the elevated SCT expression upon hyperosmolality and central ANGII stimulation.
Odile Damour - One of the best experts on this subject based on the ideXlab platform.
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Expression of Estrogen-Related Receptor gamma (ERRgamma) in human skin.
European Journal of Dermatology, 2008Co-Authors: Elodie Krahn-bertil, Isabelle Orly, Valerie Andre, Jean Kanitakis, Marie-alexandrine Bolzinger, Patricia Rousselle, Odile DamourAbstract:Skin is a non-classical target for estrogens. Despite evidence showing that estrogen Receptors (ER) are expressed in skin, there are still extensive gaps in our understanding of how estrogens exert their action in non-reproductive tissues. Estrogen-Related Receptor γ (ERRγ), an orphan member of the nuclear Receptor superfamily, shows a strong sequence homology with estrogen Receptor α but it does not bind estradiol. Here, for the first time, we demonstrate the expression of ERRγ in adult human skin. ERRγ mRNA was detected in the keratinocytes and fibroblasts of 8 female donor skins using RT-PCR. The presence of the protein was confirmed using immunohistochemistry on 11 adult human skins and Western Blotting on monolayer-cultures of fibroblasts and keratinocytes from respectively 4 and 2 donors. This study shows that ERRγ is expressed in human skin and could intervene in a potentially new estrogen signaling pathway in the skin.
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Expression of Estrogen-Related Receptor gamma (ERRgamma) in human skin.
Eur J Dermatol, 2008Co-Authors: Elodie Krahn-bertil, Isabelle Orly, Valerie Andre, Jean Kanitakis, Marie-alexandrine Bolzinger, Patricia Rousselle, Odile DamourAbstract:Skin is a non-classical target for estrogens. Despite evidence showing that estrogen Receptors (ER) are expressed in skin, there are still extensive gaps in our understanding of how estrogens exert their action in non-reproductive tissues. Estrogen-Related Receptor gamma (ERRgamma), an orphan member of the nuclear Receptor superfamily, shows a strong sequence homology with estrogen Receptor alpha but it does not bind estradiol. Here, for the first time, we demonstrate the expression of ERRgamma in adult human skin. ERRgamma mRNA was detected in the keratinocytes and fibroblasts of 8 female donor skins using RT-PCR. The presence of the protein was confirmed using immunohistochemistry on 11 adult human skins and Western Blotting on monolayer-cultures of fibroblasts and keratinocytes from respectively 4 and 2 donors. This study shows that ERRgamma is expressed in human skin and could intervene in a potentially new estrogen signaling pathway in the skin.Skin is a non-classical target for estrogens. Despite evidence showing that estrogen Receptors (ER) are expressed in skin, there are still extensive gaps in our understanding of how estrogens exert their action in non-reproductive tissues. Estrogen-Related Receptor gamma (ERRgamma), an orphan member of the nuclear Receptor superfamily, shows a strong sequence homology with estrogen Receptor alpha but it does not bind estradiol. Here, for the first time, we demonstrate the expression of ERRgamma in adult human skin. ERRgamma mRNA was detected in the keratinocytes and fibroblasts of 8 female donor skins using RT-PCR. The presence of the protein was confirmed using immunohistochemistry on 11 adult human skins and Western Blotting on monolayer-cultures of fibroblasts and keratinocytes from respectively 4 and 2 donors. This study shows that ERRgamma is expressed in human skin and could intervene in a potentially new estrogen signaling pathway in the skin.