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Ronald M Evans - One of the best experts on this subject based on the ideXlab platform.
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ligand dependent corepressor lcor is a reXinoid inhibited peroXisome proliferator activated Receptor γ Retinoid X Receptor α coactivator
Molecular and Cellular Biology, 2018Co-Authors: Tali Shalombarak, Jaclyn Liersemann, Babak Memari, Lawrence Flechner, Caitlin E Devor, Tiffany M Bernardo, Suyeon Kim, Nobuyuki Matsumoto, Scott L Friedman, Ronald M EvansAbstract:The nuclear Receptor peroXisome proliferator-activated Receptor gamma (PPARγ) is an essential regulator of placental development. To gain deeper insights into placental PPARγ signaling, we dissected its regulation of the Muc1 promoter. We find that, unlike prototypic target activation by heterodimeric Receptors, which is either stimulated by or refractory to Retinoid X Receptor (RXR) ligands (reXinoids), the induction of Muc1 by liganded PPARγ requires RXRα but is inhibited by reXinoids. We demonstrate that this inhibition is mediated by the activation function 2 (AF2) domain of RXRα and that Muc1 activation entails altered AF2 structures of both PPARγ and RXRα. This unique regulation of Muc1 reflects specific coactivation of PPARγ-RXRα heterodimers by the transcription cofactor ligand-dependent corepressor (LCoR), corroborated by significant downregulation of Muc1 in Lcor-null placentas. LCoR interacts with PPARγ and RXRα in a synergistic fashion via adjacent noncanonical protein motifs, and the AF2 domain of ligand-bound RXRα inhibits this interaction. We further identify the transcription factor Kruppel-like factor 6 (KLF6) as a critical regulator of placental development and a component of Muc1 regulation in cooperation with PPARγ, RXRα, and LCoR. Combined, these studies reveal new principles and players in nuclear Receptor function in general and placental PPARγ signaling in particular.
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the dual role of ultraspiracle the drosophila Retinoid X Receptor in the ecdysone response
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Nora Ghbeish, Chih Cheng Tsai, Margrit Schubiger, Joel Y Zhou, Ronald M Evans, Michael MckeownAbstract:The Drosophila homolog of the Retinoid X Receptor, ultraspiracle (USP), heterodimerizes with the ecdysone Receptor (EcR) to form a functional compleX that mediates the effects of the steroid molting hormone ecdysone by activating and repressing eXpression of ecdysone response genes. As with other Retinoid X Receptor heterodimers, EcR/USP affects gene transcription in a ligand-modulated manner. We used in vivo, cell culture, and biochemical approaches to analyze the functions of two usp alleles, usp3 and usp4, which encode stable proteins with defective DNA-binding domains. We observed that USP is able to activate as well as repress the Z1 isoform of the ecdysone-responsive broad compleX (BrC-Z1). Activation of BrC-Z1 as well as EcR, itself an ecdysone response gene, can be mediated by both the USP3 and USP4 mutant proteins. USP3 and USP4 also activate an ecdysone-responsive element, hsp27EcRE, in cultured cells. These results differ from the protein null allele, usp2, which is unable to mediate activation [Schubiger, M. & Truman, J. W. (2000) Development 127, 1151–1159]. BrC-Z1 repression is compromised in all three usp alleles, suggesting that repression involves the association of USP with DNA. Our results distinguish two mechanisms by which USP modulates the properties of EcR: one that involves the USP DNA-binding domain and one that can be achieved solely through the ligand-binding domain. These newly revealed properties of USP might implicate similar properties for Retinoid X Receptor.
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Interactions between the Retinoid X Receptor and a conserved region of the TATA-binding protein mediate hormone-dependent transactivation
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Ira G. Schulman, Debabrata Chakravarti, Henry Juguilon, Anthony Romo, Ronald M EvansAbstract:The Retinoid X Receptor (RXR) participates in a wide array of hormonal signaling pathways, either as a homodimer or as a heterodimer, with other members of the steroid and thyroid hormone Receptor superfamily. In this report the ligand-dependent transactivation function of RXR has been characterized, and the ability of RXR to interact with components of the basal transcription machinery has been eXamined. In vivo and in vitro eXperiments indicate the RXR ligand-binding domain makes a direct, specific, and ligand-dependent contact with a highly conserved region of the TATA-binding protein. The ability of mutations that reduce ligand-dependent transcription by RXR to disrupt the RXR-TATA-binding protein interaction in vivo and in vitro suggests that RXR makes direct contact with the basal transcription machinery to achieve activation.
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atrial like phenotype is associated with embryonic ventricular failure in Retinoid X Receptor alpha mice
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: E Dyson, Ronald M Evans, Steven W Kubalak, Henry M Sucov, Geert W Schmidschonbein, Frank A Delano, J Ross, Kenneth R ChienAbstract:Abstract We have recently characterized a cardiac model of ventricular chamber defects in Retinoid X Receptor alpha (RXR alpha) homozygous mutant (-/-) gene-targeted mice. These mice display generalized edema, ventricular chamber hypoplasia, and muscular septal defects, and they die at embryonic day 15. To substantiate our hypothesis that the embryos are dying of cardiac pump failure, we have used digital bright-field and fluorescent video microscopy and in vivo microinjection of fluorescein-labeled albumin to analyze cardiac function. The affected embryos showed depressed ventricular function (average left ventricular area ejection fraction, 14%), ventricular septal defects, and various degrees of atrioventricular block not seen in the RXR alpha wild-type (+/+) and heterozygous (+/-) littermates (average left ventricular area ejection fraction, 50%). The molecular mechanisms involved in these ventricular defects were studied by evaluating eXpression of cardiac-specific genes known to be developmentally regulated. By in situ hybridization, aberrant, persistent eXpression of the atrial isoform of myosin light chain 2 was identified in the ventricles. We hypothesize that retinoic acid provides a critical signal mediated through the RXR alpha pathway that is required to allow progression of development of the ventricular region of the heart from its early atrial-like form to the thick-walled adult ventricle. The conduction system disturbances found in the RXR alpha -/- embryos may reflect a requirement of the developing conduction system for the RXR alpha signaling pathway, or it may be secondary to the failure of septal development.
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structure of the Retinoid X Receptor alpha dna binding domain a heliX required for homodimeric dna binding
Science, 1993Co-Authors: Min S Lee, Steven A Kliewer, Joan Provencal, Peter E Wright, Ronald M EvansAbstract:The three-dimensional solution structure of the DNA binding domain (DBD) of the Retinoid X Receptor alpha (RXR alpha) was determined by nuclear magnetic resonance spectroscopy. The two zinc fingers of the RXR DBD fold to form a single structural domain that consists of two perpendicularly oriented helices and that resembles the corresponding regions of the glucocorticoid and estrogen Receptors (GR and ER, respectively). However, in contrast to the DBDs of the GR and ER, the RXR DBD contains an additional heliX immediately after the second zinc finger. This third heliX mediates both protein-protein and protein-DNA interactions required for cooperative, dimeric binding of the RXR DBD to DNA. Identification of the third heliX in the RXR DBD thus defines a structural feature required for selective dimerization of the RXR on hormone response elements composed of half-sites (5'-AGGTCA-3') arranged as tandem repeats.
Osamu Ezaki - One of the best experts on this subject based on the ideXlab platform.
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regulation of srebp1c gene eXpression in skeletal muscle role of Retinoid X Receptor liver X Receptor and forkhead o1 transcription factor
Endocrinology, 2008Co-Authors: Yasutomi Kamei, Shinji Miura, Takayoshi Suganami, Fumiko Akaike, Sayaka Kanai, Satoshi Sugita, Aki Katsumata, Hiroyuki Aburatani, Terry G Unterman, Osamu EzakiAbstract:Sterol regulatory element binding protein 1c (SREBP1c) is a master regulator of lipogenic gene eXpression in liver and adipose tissue, where its eXpression is regulated by a heterodimer of nuclear Receptor-type transcription factors Retinoid X Receptor-α (RXRα) and liver X Receptor-α (LXRα). Despite the potential importance of SREBP1c in skeletal muscle, little is known about the regulation of SREBP1c in that setting. Here we report that gene eXpression of RXRγ is markedly decreased by fasting and is restored by refeeding in mouse skeletal muscle, in parallel with changes in gene eXpression of SREBP1c. RXRγ or RXRα, together with LXRα, activate the SREBP1c promoter in vitro. Moreover, transgenic mice overeXpressing RXRγ specifically in skeletal muscle showed increased gene eXpression of SREBP1c with increased triglyceride content in their skeletal muscles. In contrast, transgenic mice overeXpressing the dominant-negative form of RXRγ showed decreased SREBP1c gene eXpression. The eXpression of Forkhead-O1 ...
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regulation of srebp1c gene eXpression in skeletal muscle role of Retinoid X Receptor liver X Receptor and forkhead o1 transcription factor
Endocrinology, 2008Co-Authors: Yasutomi Kamei, Shinji Miura, Takayoshi Suganami, Fumiko Akaike, Sayaka Kanai, Satoshi Sugita, Aki Katsumata, Hiroyuki Aburatani, Terry G Unterman, Osamu EzakiAbstract:Sterol regulatory element binding protein 1c (SREBP1c) is a master regulator of lipogenic gene eXpression in liver and adipose tissue, where its eXpression is regulated by a heterodimer of nuclear Receptor-type transcription factors Retinoid X Receptor-alpha (RXRalpha) and liver X Receptor-alpha (LXRalpha). Despite the potential importance of SREBP1c in skeletal muscle, little is known about the regulation of SREBP1c in that setting. Here we report that gene eXpression of RXRgamma is markedly decreased by fasting and is restored by refeeding in mouse skeletal muscle, in parallel with changes in gene eXpression of SREBP1c. RXRgamma or RXRalpha, together with LXRalpha, activate the SREBP1c promoter in vitro. Moreover, transgenic mice overeXpressing RXRgamma specifically in skeletal muscle showed increased gene eXpression of SREBP1c with increased triglyceride content in their skeletal muscles. In contrast, transgenic mice overeXpressing the dominant-negative form of RXRgamma showed decreased SREBP1c gene eXpression. The eXpression of Forkhead-O1 transcription factor (FOXO1), which can suppress the function of multiple nuclear Receptors, is negatively correlated to that of SREBP1c in skeletal muscle during nutritional change. Moreover, transgenic mice overeXpressing FOXO1 specifically in skeletal muscle eXhibited decreased gene eXpression of both RXRgamma and SREBP1c. In addition, FOXO1 suppressed RXRalpha/LXRalpha-mediated SREBP1c promoter activity in vitro. These findings provide in vivo and in vitro evidence that RXR/LXR up-regulates SREBP1c gene eXpression and that FOXO1 antagonizes this effect of RXR/LXR in skeletal muscle.
Richard A Heyman - One of the best experts on this subject based on the ideXlab platform.
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design and synthesis of potent Retinoid X Receptor selective ligands that induce apoptosis in leukemia cells
Journal of Medicinal Chemistry, 1995Co-Authors: Marcus F Boehm, Lin Zhang, Dale E Mais, Elaine M Berger, Carla M Suto, Lin Zhi, Michael R Mcclurg, M Wagoner, J A Davies, Richard A HeymanAbstract:Structural modifications of the Retinoid X Receptor (RXR) selective compound 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- naphthyl)ethenyl]benzoic acid (LGD1069), which is currently in phase I/IIA clinical trials for cancer and dermatological indications, have resulted in the identification of increasingly potent Retinoids with > 1000-fold selectivity for the RXRs. This paper describes the design and preparation of a series of RXR selective Retinoids as well as the biological data obtained from cotransfection and competitive binding assays which were used to evaluate their potency and selectivity. The most potent and selective of the analogs is 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2- yl)cyclopropyl]nicotinic acid (12d; LG100268). This compound has proven useful for investigating RXR dependent biological pathways including the induction of programmed cell death (PCD) and transglutaminase (TGase) activity. Our studies indicate that the induction of PCD and TGase in human leukemic myeloid cells is dependent upon activation of RXR-mediated pathways.
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synthesis and structure activity relationships of novel Retinoid X Receptor selective Retinoids
Journal of Medicinal Chemistry, 1994Co-Authors: Marcus F Boehm, Lin Zhang, Beth Ann Badea, Steven K White, Dale E Mais, Elaine M Berger, Carla M Suto, Mark E Goldman, Richard A HeymanAbstract:Two series of potent Retinoid X Receptor (RXR)-selective compounds were designed and synthesized based upon recent observation that (E)-4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1- propenyl]benzoic acid (TTNBP) binds and transactivates only the retinoic acid Receptor (RAR) subtypes whereas (E)-4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8- tetrahydro-2-naphthalenyl)-1-propenyl]benzoic acid (3-methyl TTNPB) binds and transactivates both the RAR and RXR subfamilies. Addition of functional groups such as methyl, chloro, bromo, or ethyl to the 3 position of the tetrahydronaphthalene moiety of 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]benzoic acid (5a) and 4-[1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2- naphthyl)ethenyl]benzoic acid (6a) results in compounds which elicit potent and selective activation of the RXR class. Such RXR-selective compounds offer pharmacological tools for elucidating the biological role of the individual Retinoid Receptors with which they interact. Activation profiles in cotransfection and competitive binding assays as well as molecular modeling calculations demonstrate critical structural determinants that confer selectivity for members of the RXR subfamily. The most potent compound of these series, 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]ben zoi c acid (6b), is the first RXR-selective Retinoid (designated as LGD1069) to enter clinical trials for cancer indications.
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Retinoid X Receptor coup tf interactions modulate retinoic acid signaling
Proceedings of the National Academy of Sciences of the United States of America, 1992Co-Authors: Steven A Kliewer, Kazuhiko Umesono, Richard A Heyman, David J Mangelsdorf, Jacqueline A Dyck, Ronald M EvansAbstract:Abstract We have recently described the properties of direct repeats (DRs) of the half-site AGGTCA as hormone response elements (HREs). According to our results, spacing the half sites by 3, 4, or 5 nucleotides determines specificity of response for vitamin D3, thyroid hormone, and retinoic acid Receptors, respectively. This so-called 3-4-5 rule led to the prediction that remaining spacing options of 0, 1, and 2 might serve as targets for other nuclear Receptors. A concurrent prediction is that Receptors recognizing common sites might display more compleX or combinatorial interactions. In eXploring these predictions, we discovered that both the Retinoid X Receptor (RXR) and COUP-TF bind preferentially to a DR-1 motif. In vivo, RXR and COUP-TF display antagonistic action such that RXR-mediated activation is fully repressed by COUP-TF. In vitro studies reveal that COUP-TF and RXR form heterodimers on DR-1. Thus, these results support a general proposal in which the half-site spacing preferences may be used as a means to decipher potentially compleX and interactive regulatory circuits.
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9 cis retinoic acid is a high affinity ligand for the Retinoid X Receptor
Cell, 1992Co-Authors: Richard A Heyman, Ronald M Evans, David J Mangelsdorf, Jacqueline A Dyck, Robert B Stein, Gregor Eichele, Christina ThallerAbstract:All-trans retinoic acid (RA) has previously been shown to modulate the transcriptional properties of the retinoic acid Receptor (RAR) and Retinoid X Receptor (RXR). The inability of all-trans RA to bind to RXR suggests that it may be metabolized to a more active high affinity ligand. We report here an eXperimental approach that has identified 9-cis RA as an RXR ligand. It is up to 40-fold more potent than all-trans RA in transfection assays and binds with high affinity. The production of 9-cis RA in cultured cells and the identification of this molecule in liver and kidney demonstrates the eXistence of this molecule in living organisms. The discovery of this novel hormone points to the key role Retinoid metabolism may have in generating new signaling pathways.
Alan R Tall - One of the best experts on this subject based on the ideXlab platform.
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sterol dependent transactivation of theabc1 promoter by the liver X Receptor Retinoid X Receptor
Journal of Biological Chemistry, 2000Co-Authors: Philippe Costet, Yi Luo, Nan Wang, Alan R TallAbstract:Tangier disease, a condition characterized by low levels of high density lipoprotein and cholesterol accumulation in macrophages, is caused by mutations in the ATP-binding cassette transporter ABC1. In cultured macrophages, ABC1 mRNA was induced in an additive fashion by 22(R)-hydroXycholesterol and 9-cis-retinoic acid (9CRA), suggesting induction by nuclear hormone Receptors of the liver X Receptor (LXR) and Retinoid X Receptor (RXR) family. We cloned the 5'-end of the human ABC1 transcript from cholesterol-loaded THP1 macrophages. When transfected into RAW macrophages, the upstream promoter was induced 7-fold by 22(R)-hydroXycholesterol, 8-fold by 9CRA, and 37-fold by 9CRA and 22(R)-hydroXycholesterol. Furthermore, promoter activity was increased in a sterol-responsive fashion when cotransfected with LXRalpha/RXR or LXRbeta/RXR. Further eXperiments identified a direct repeat spaced by four nucleotides (from -70 to -55 base pairs) as a binding site for LXRalpha/RXR or LXRbeta/RXR. Mutations in this element abolished the sterol-mediated activation of the promoter. The results show sterol-dependent transactivation of the ABC1 promoter by LXR/RXR and suggest that small molecule agonists of LXR could be useful drugs to reverse foam cell formation and atherogenesis.
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sterol dependent transactivation of theabc1 promoter by the liver X Receptor Retinoid X Receptor
Journal of Biological Chemistry, 2000Co-Authors: Philippe Costet, Yi Luo, Nan Wang, Alan R TallAbstract:Tangier disease, a condition characterized by low levels of high density lipoprotein and cholesterol accumulation in macrophages, is caused by mutations in the ATP-binding cassette transporter ABC1. In cultured macrophages, ABC1 mRNA was induced in an additive fashion by 22(R)-hydroXycholesterol and 9-cis-retinoic acid (9CRA), suggesting induction by nuclear hormone Receptors of the liver X Receptor (LXR) and Retinoid X Receptor (RXR) family. We cloned the 5′-end of the human ABC1 transcript from cholesterol-loaded THP1 macrophages. When transfected into RAW macrophages, the upstream promoter was induced 7-fold by 22(R)-hydroXycholesterol, 8-fold by 9CRA, and 37-fold by 9CRA and 22(R)-hydroXycholesterol. Furthermore, promoter activity was increased in a sterol-responsive fashion when cotransfected with LXRα/RXR or LXRβ/RXR. Further eXperiments identified a direct repeat spaced by four nucleotides (from −70 to −55 base pairs) as a binding site for LXRα/RXR or LXRβ/RXR. Mutations in this element abolished the sterol-mediated activation of the promoter. The results show sterol-dependent transactivation of the ABC1 promoter by LXR/RXR and suggest that small molecule agonists of LXR could be useful drugs to reverse foam cell formation and atherogenesis.
Yasutomi Kamei - One of the best experts on this subject based on the ideXlab platform.
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regulation of srebp1c gene eXpression in skeletal muscle role of Retinoid X Receptor liver X Receptor and forkhead o1 transcription factor
Endocrinology, 2008Co-Authors: Yasutomi Kamei, Shinji Miura, Takayoshi Suganami, Fumiko Akaike, Sayaka Kanai, Satoshi Sugita, Aki Katsumata, Hiroyuki Aburatani, Terry G Unterman, Osamu EzakiAbstract:Sterol regulatory element binding protein 1c (SREBP1c) is a master regulator of lipogenic gene eXpression in liver and adipose tissue, where its eXpression is regulated by a heterodimer of nuclear Receptor-type transcription factors Retinoid X Receptor-α (RXRα) and liver X Receptor-α (LXRα). Despite the potential importance of SREBP1c in skeletal muscle, little is known about the regulation of SREBP1c in that setting. Here we report that gene eXpression of RXRγ is markedly decreased by fasting and is restored by refeeding in mouse skeletal muscle, in parallel with changes in gene eXpression of SREBP1c. RXRγ or RXRα, together with LXRα, activate the SREBP1c promoter in vitro. Moreover, transgenic mice overeXpressing RXRγ specifically in skeletal muscle showed increased gene eXpression of SREBP1c with increased triglyceride content in their skeletal muscles. In contrast, transgenic mice overeXpressing the dominant-negative form of RXRγ showed decreased SREBP1c gene eXpression. The eXpression of Forkhead-O1 ...
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regulation of srebp1c gene eXpression in skeletal muscle role of Retinoid X Receptor liver X Receptor and forkhead o1 transcription factor
Endocrinology, 2008Co-Authors: Yasutomi Kamei, Shinji Miura, Takayoshi Suganami, Fumiko Akaike, Sayaka Kanai, Satoshi Sugita, Aki Katsumata, Hiroyuki Aburatani, Terry G Unterman, Osamu EzakiAbstract:Sterol regulatory element binding protein 1c (SREBP1c) is a master regulator of lipogenic gene eXpression in liver and adipose tissue, where its eXpression is regulated by a heterodimer of nuclear Receptor-type transcription factors Retinoid X Receptor-alpha (RXRalpha) and liver X Receptor-alpha (LXRalpha). Despite the potential importance of SREBP1c in skeletal muscle, little is known about the regulation of SREBP1c in that setting. Here we report that gene eXpression of RXRgamma is markedly decreased by fasting and is restored by refeeding in mouse skeletal muscle, in parallel with changes in gene eXpression of SREBP1c. RXRgamma or RXRalpha, together with LXRalpha, activate the SREBP1c promoter in vitro. Moreover, transgenic mice overeXpressing RXRgamma specifically in skeletal muscle showed increased gene eXpression of SREBP1c with increased triglyceride content in their skeletal muscles. In contrast, transgenic mice overeXpressing the dominant-negative form of RXRgamma showed decreased SREBP1c gene eXpression. The eXpression of Forkhead-O1 transcription factor (FOXO1), which can suppress the function of multiple nuclear Receptors, is negatively correlated to that of SREBP1c in skeletal muscle during nutritional change. Moreover, transgenic mice overeXpressing FOXO1 specifically in skeletal muscle eXhibited decreased gene eXpression of both RXRgamma and SREBP1c. In addition, FOXO1 suppressed RXRalpha/LXRalpha-mediated SREBP1c promoter activity in vitro. These findings provide in vivo and in vitro evidence that RXR/LXR up-regulates SREBP1c gene eXpression and that FOXO1 antagonizes this effect of RXR/LXR in skeletal muscle.