Nuclear receptors in disease: thyroid receptor beta, peroxisome-proliferator-activated receptor gamma and orphan receptors

2004 ◽  
Vol 40 ◽  
pp. 169-189 ◽  
Author(s):  
Mark Gurnell ◽  
V Krishna K Chatterjee
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Molecular Mechanisms ◽  
Thyroid Hormone Receptor ◽  
Human Subjects ◽  
Peroxisome Proliferator ◽  
Related Factor ◽  
Orphan Receptors ◽  
Peroxisome Proliferator Activated Receptor ◽  
Receptor Beta

The nuclear receptor superfamily comprises a group of proteins that includes the molecular targets for classical steroid hormones such as glucocorticoids, androgens and vitamin D, together with a number of so-called 'orphan' receptors whose ligands and/or function remain to be determined. Many of the world's most commonly prescribed drugs act via nuclear receptors, attesting to their importance as therapeutic targets in human disease [for example, the novel anti-diabetic thiazolidinediones rosiglitazone and pioglitazone are high-affinity ligands for peroxisome-proliferator-activated receptor gamma (PPARgamma)]. The study of transgenic mice harbouring global and tissue-specific alterations in nuclear receptor genes has greatly enhanced our understanding of the roles that these receptors play in mammalian physiology. In many cases, these findings have been complemented by the study of human subjects harbouring naturally occurring mutations within the corresponding receptor, whereas in others, such studies have served to highlight important differences that exist between human and mouse physiology especially, for example, in relation to aspects of metabolism. Here we review the diverse clinical phenotypes that have been reported in subjects found to have germline mutations in thyroid hormone receptor beta, PPARgamma, hepatocyte nuclear factor 4alpha, small heterodimer partner, steroidogenic factor 1, DAX1, photoreceptor-specific nuclear receptor and NUR-related factor 1, and consider the molecular mechanisms through which aberrant signalling by mutant receptors might contribute to the pathogenesis of the associated disorders.

scholarly journals Alternative Mechanisms by Which Mediator Subunit MED1/TRAP220 Regulates Peroxisome Proliferator-Activated Receptor γ-Stimulated Adipogenesis and Target Gene Expression

2007 ◽  
Vol 28 (3) ◽  
pp. 1081-1091 ◽  
Author(s):  
Kai Ge ◽  
Young-Wook Cho ◽  
Hong Guo ◽  
Teresa B. Hong ◽  
Mohamed Guermah ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Polymerase Ii ◽  
Nuclear Receptor ◽  
Transcriptional Activity ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cultured Fibroblasts ◽  
Target Gene Expression

ABSTRACT Mediator is a general coactivator complex connecting transcription activators and RNA polymerase II. Recent work has shown that the nuclear receptor-interacting MED1/TRAP220 subunit of Mediator is required for peroxisome proliferator-activated receptor γ (PPARγ)-stimulated adipogenesis of mouse embryonic fibroblasts (MEFs). However, the molecular mechanisms remain undefined. Here, we show an intracellular PPARγ-Mediator interaction that requires the two LXXLL nuclear receptor recognition motifs on MED1/TRAP220 and, furthermore, we show that the intact LXXLL motifs are essential for optimal PPARγ function in a reconstituted cell-free transcription system. Surprisingly, a conserved N-terminal region of MED1/TRAP220 that lacks the LXXLL motifs but gets incorporated into Mediator fully supports PPARγ-stimulated adipogenesis. Moreover, in undifferentiated MEFs, MED1/TRAP220 is dispensable both for PPARγ-mediated target gene activation and for recruitment of Mediator to a PPAR response element on the aP2 target gene promoter. However, PPARγ shows significantly reduced transcriptional activity in cells deficient for a subunit (MED24/TRAP100) important for the integrity of the Mediator complex, indicating a general Mediator requirement for PPARγ function. These results indicate that there is a conditional requirement for MED1/TRAP220 and that a direct interaction between PPARγ and Mediator through MED1/TRAP220 is not essential either for PPARγ-stimulated adipogenesis or for PPARγ target gene expression in cultured fibroblasts. As Mediator is apparently essential for PPARγ transcriptional activity, our data indicate the presence of alternative mechanisms for Mediator recruitment, possibly through intermediate cofactors or other cofactors that are functionally redundant with MED1/TRAP220.

scholarly journals Definition of functionally and structurally distinct repressive states in the nuclear receptor PPARγ

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Zahra Heidari ◽  
Ian M. Chrisman ◽  
Michelle D. Nemetchek ◽  
Scott J. Novick ◽  
Anne-Laure Blayo ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Salt Bridge ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Exchange Mass Spectrometry ◽  
Omega Loop ◽  
Hydrogen Deuterium ◽  
Definition Of

AbstractThe repressive states of nuclear receptors (i.e., apo or bound to antagonists or inverse agonists) are poorly defined, despite the fact that nuclear receptors are a major drug target. Most ligand bound structures of nuclear receptors, including peroxisome proliferator-activated receptor γ (PPARγ), are similar to the apo structure. Here we use NMR, accelerated molecular dynamics and hydrogen-deuterium exchange mass spectrometry to define the PPARγ structural ensemble. We find that the helix 3 charge clamp positioning varies widely in apo and is stabilized by efficacious ligand binding. We also reveal a previously undescribed mechanism for inverse agonism involving an omega loop to helix switch which induces disruption of a tripartite salt-bridge network. We demonstrate that ligand binding can induce multiple structurally distinct repressive states. One state recruits peptides from two different corepressors, while another recruits just one, providing structural evidence of ligand bias in a nuclear receptor.

scholarly journals The role of the amino-terminal domain in the interaction of unliganded peroxisome proliferator-activated receptor γ-2 with nuclear receptor co-repressor

2010 ◽  
Vol 45 (3) ◽  
pp. 133-145 ◽  
Author(s):  
Sadako Suzuki ◽  
Shigekazu Sasaki ◽  
Hiroshi Morita ◽  
Yutaka Oki ◽  
Daisuke Turiya ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Nuclear Receptor ◽  
Thyroid Hormone Receptor ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Amino Terminal

Peroxisome proliferator-activated receptor γ-2 (PPARG2) is a ligand-dependent transcriptional factor involved in the pathogenesis of insulin resistance. In the presence of a ligand, PPARG2 associates with co-activators, while it recruits co-repressors (CoRs) in the absence of a ligand. It has been reported that the interaction of liganded PPARG2 with co-activators is regulated by the amino-terminal A/B domain (NTD) via inter-domain communication. However, the role of the NTD is unknown in the case of the interaction between unliganded PPARG2 and CoRs. To elucidate this, total elimination of the influence of ligands is required, but the endogenous ligands of PPARG2 have not been fully defined. PPARG1-P467L, a naturally occurring mutant of PPARG1, was identified in a patient with severe insulin resistance. Reflecting its very low affinity for various ligands, this mutant does not have transcriptional activity in the PPAR response element, but exhibits dominant negative effects (DNEs) on liganded wild-type PPARG2-mediated transactivation. Using the corresponding PPARG2 mutant, PPARG2-P495L, we evaluated the role of the NTD in the interaction between unliganded PPARG2 and CoRs. Interestingly, the DNE of PPARG2-P495L was increased by the truncation of its NTD. NTD deletion also enhanced the DNE of a chimeric receptor, PT, in which the ligand-binding domain of PPARG2 was replaced with that of thyroid hormone receptor β-1. Moreover, NTD deletion facilitated the in vitro binding of nuclear receptor CoR with wild-type PPARG2, mutant P495L, and the PT chimera (PPARG2-THRB). Inter-domain communication in PPARG2 regulates not only ligand-dependent transactivation but also ligand-independent silencing.

scholarly journals Nongenomic signaling of the retinoid X receptor through binding and inhibiting Gq in human platelets

Blood ◽  
2007 ◽  
Vol 109 (9) ◽  
pp. 3741-3744 ◽  
Author(s):  
Leonardo A. Moraes ◽  
Karen E. Swales ◽  
Jessica A. Wray ◽  
Amilcar Damazo ◽  
Jonathan M. Gibbins ◽  
...  
Keyword(s):  
G Protein ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Hormone Receptors ◽  
Calcium Release ◽  
Human Platelets ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
X Receptors

Abstract Retinoid X receptors (RXRs) are important transcriptional nuclear hormone receptors, acting as either homodimers or the binding partner for at least one fourth of all the known human nuclear receptors. Functional nongenomic effects of nuclear receptors are poorly understood; however, recently peroxisome proliferator-activated receptor (PPAR) \#947;, PPAR\#946;, and the glucocorticoid receptor have all been found active in human platelets. Human platelets express RXR\#945; and RXR\#946;. RXR ligands inhibit platelet aggregation and TXA2 release to ADP and the TXA2 receptors, but only weakly to collagen. ADP and TXA2 both signal via the G protein, Gq. RXR rapidly binds Gq but not Gi/z/o/t/gust in a ligand-dependent manner and inhibits Gq-induced Rac activation and intracellular calcium release. We propose that RXR ligands may have beneficial clinical actions through inhibition of platelet activation. Furthermore, our results demonstrate a novel nongenomic mode for nuclear receptor action and a functional cross-talk between G-protein and nuclear receptor signaling families.

scholarly journals Estrogen-related receptor-γ and peroxisome proliferator-activated receptor-γ coactivator-1α regulate estrogen-related receptor-α gene expression via a conserved multi-hormone response element

2005 ◽  
Vol 34 (2) ◽  
pp. 473-487 ◽  
Author(s):  
D Liu ◽  
Z Zhang ◽  
C T Teng
Keyword(s):  
Nuclear Receptors ◽  
Molecular Mechanisms ◽  
Ectopic Expression ◽  
Peroxisome Proliferator ◽  
Hormone Response ◽  
Core Element ◽  
Response Element ◽  
Peroxisome Proliferator Activated Receptor ◽  
Hormone Response Element ◽  
Estrogen Related Receptor

The expression of estrogen-related receptor-α (ERRα) is stimulated by estrogen in selective tissues. Recently, a correlation between ERRα expression and the induction of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in the liver of fasting animals and in cold-stressed brown-fat tissues and skeletal muscle was shown. To explore the molecular mechanisms of ERRα regulation by diverse signals, the promoter of the human ERRα gene was cloned and characterized. Mutation and deletion analyses revealed that a 53 bp region containing repeated core element AGGTCA motifs of the ERRα gene serves as a multi-hormone response element (MHRE) for several nuclear receptors in transient co-transfection studies of human endometrial carcinoma (HEC-1B) cells. Among the nuclear receptors tested, ERRγ bound to and robustly stimulated the transcription of reporters containing at least two AGGTCA motifs. Ectopic expression of PGC-1α in HEC-1B cells strongly activated the reporter containing the MHRE, presumably via the endogenous nuclear receptor binding to the element. Reducing the endogenous level of ERRγ by small interfering RNA, and increasing the ERRγ level by ectopic expression, substantially decreased and increased respectively the transactivation capability of PGC-1α. The activation function 2 domain of the ERRγ and the L2 and L3 motifs of PGC-1α were essential to transactivate the MHRE. Additionally, PGC-1α increases the amount of endogenous ERRγ bound to the MHRE region as determined by a chromatin immunoprecipitation assay. The present study demonstrates that the MHRE of the ERRα gene is a target for ERRγ transactivation, which is enhanced by PGC-1α.

scholarly journals A Novel Role for Helix 12 of Retinoid X Receptor in Regulating Repression

1999 ◽  
Vol 19 (9) ◽  
pp. 6448-6457 ◽  
Author(s):  
Jinsong Zhang ◽  
Xiao Hu ◽  
Mitchell A. Lazar
Keyword(s):  
Binding Site ◽  
Nuclear Receptors ◽  
Thyroid Hormone Receptor ◽  
Specific Interaction ◽  
Retinoid X Receptor ◽  
Peroxisome Proliferator ◽  
Specific Sequence ◽  
Peroxisome Proliferator Activated Receptor ◽  
Binding Surface ◽  
Helix 12

ABSTRACT Nutrients, drugs, and hormones influence transcription during differentiation and metabolism by binding to high-affinity nuclear receptors. In the absence of ligand, some but not all nuclear receptors repress transcription as a heterodimer with retinoid X receptor (RXR). Here we define a novel role for helix 12 (H12) in sterically masking the corepressor (CoR) binding site in apo-RXR. Removing H12 converts RXR to a potent transcriptional repressor. The length but not the specific sequence of H12 is critical for masking RXR’s intrinsic repression function. This contrasts with the amphipathic character required for mediating ligand-dependent activation and coactivator recruitment. Physiologically, we show that heterodimerization of RXR with apo-thyroid hormone receptor (TR) unmasks the CoR binding site in RXR and allows the TR-RXR heterodimer to repress. A molecular mechanism that involves sequence-specific interaction between RXR H12 and the coactivator-binding surface of the nuclear receptor is proposed for this heterodimerization-mediated unmasking. Peroxisome proliferator-activated receptor γ does not interact as well with RXR H12, thus explaining its inability to repress transcription as an RXR heterodimer. The requirement to unmask RXR’s latent repression function explains why only certain RXR partners repress transcription.

scholarly journals Functional interference between estrogen-related receptor alpha and peroxisome proliferator-activated receptor alpha/9-cis-retinoic acid receptor alpha heterodimer complex in the nuclear receptor response element-1 of the medium chain acyl-coenzyme A dehydrogenase gene

2003 ◽  
Vol 31 (1) ◽  
pp. 47-60 ◽  
Author(s):  
K Maehara ◽  
T Hida ◽  
Y Abe ◽  
A Koga ◽  
K Ota ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Retinoic Acid Receptor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Receptor Alpha ◽  
Receptor Response ◽  
Chain Acyl ◽  
Acyl Coenzyme A ◽  
Estrogen Related Receptor

We undertook a study of molecular interference of nuclear orphan receptors. Nuclear receptor response element-1 (NRRE-1) from the human medium-chain acyl coenzyme A dehydrogenase (MCAD) gene promoter was shown to contain three hexamer elements (site 1 through 3) that are known to interact with a number of nuclear receptors including chicken ovalbumin upstream promoter transcription factor (COUP-TF) and estrogen-related receptor alpha (ERRalpha). We demonstrated that the peroxisome proliferator-activated receptor alpha/9-cis-retinoic acid receptor alpha (PPARalpha/RXRalpha) heterodimer complex can also bind to the two hexamer repeat sequences (between site 1 and site 3) arranged as an everted imperfect repeat separated by 14 bp (ER14). Mutations of the putative core elements have shown that these three sites are differentially involved in ERRalpha and PPARalpha/RXRalpha binding. Homodimer of ERRalpha was shown to interact between site 1 and site 3 (ER14). To date, no nuclear receptor is known to bind to response elements over such long intervals. Interestingly, site 1 was shown to be essential for ERRalpha binding while site 3 supports its binding only in the presence of site 1. Furthermore, it was shown that the binding profile of ERRalpha and PPARalpha/RXRalpha are competitive rather than making a high order complex within NRRE-1. At the cellular level, transcriptional activation driven by the PPARalpha/RXRalpha complex was counteracted by the expression of ERRalpha in HeLa cells. These results suggest that ERRalpha and PPARalpha/RXRalpha could interfere with each other's function through binding to similar DNA elements, thereby finetuning the transcriptional outcome of the target gene. Our findings suggest a mechanism whereby multiple nuclear receptors can activate or repress DNA binding or transcription via a single pleiotropic regulatory element.

Interleukin enhancer-binding factor 3 functions as a liver receptor homologue-1 co-activator in synergy with the nuclear receptor co-activators PRMT1 and PGC-1α

2011 ◽  
Vol 437 (3) ◽  
pp. 531-540 ◽  
Author(s):  
Masae Ohno ◽  
Jun Komakine ◽  
Eiko Suzuki ◽  
Makoto Nishizuka ◽  
Shigehiro Osada ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nuclear Receptor ◽  
Transcriptional Control ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Peroxisome Proliferator ◽  
Gene Encoding ◽  
Peroxisome Proliferator Activated Receptor ◽  
Binding Factor ◽  
Protein Arginine Methyltransferase 1

LRH-1 (liver receptor homologue-1), a transcription factor and member of the nuclear receptor superfamily, regulates the expression of its target genes, which are involved in bile acid and cholesterol homoeostasis. However, the molecular mechanisms of transcriptional control by LRH-1 are not completely understood. Previously, we identified Ku80 and Ku70 as LRH-1-binding proteins and reported that they function as co-repressors. In the present study, we identified an additional LRH-1-binding protein, ILF3 (interleukin enhancer-binding factor 3). ILF3 formed a complex with LRH-1 and the other two nuclear receptor co-activators PRMT1 (protein arginine methyltransferase 1) and PGC-1α (peroxisome proliferator-activated receptor γ co-activator-1α). We demonstrated that ILF3, PRMT1 and PGC-1α were recruited to the promoter region of the LRH-1-regulated SHP (small heterodimer partner) gene, encoding one of the nuclear receptors. ILF3 enhanced SHP gene expression in co-operation with PRMT1 and PGC-1α through the C-terminal region of ILF3. In addition, we found that the small interfering RNA-mediated down-regulation of ILF3 expression led to a reduction in the occupancy of PGC-1α at the SHP promoter and SHP expression. Taken together, our results suggest that ILF3 functions as a novel LRH-1 co-activator by acting synergistically with PRMT1 and PGC-1α, thereby promoting LRH-1-dependent gene expression.

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