scholarly journals Definition of the Molecular Basis for Estrogen Receptor-Related Receptor-α-Cofactor Interactions

2007 ◽  
Vol 21 (1) ◽  
pp. 62-76 ◽  
Author(s):  
Stéphanie Gaillard ◽  
Mary A. Dwyer ◽  
Donald P. McDonnell
Keyword(s):  
Estrogen Receptor ◽  
Nuclear Receptor ◽  
Target Genes ◽  
Activation Function ◽  
Peroxisome Proliferator ◽  
Orphan Nuclear Receptor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Hormone Response Elements ◽  
Phage Libraries ◽  
Definition Of

Abstract Estrogen receptor-related receptor-α (ERRα) is an orphan nuclear receptor that does not appear to require a classical small molecule ligand to facilitate its interaction with coactivators and/or hormone response elements within target genes. Instead, the apo-receptor is capable of interacting in a constitutive manner with coactivators that stimulate transcription by acting as protein ligands. We have screened combinatorial phage libraries for peptides that selectively interact with ERRα to probe the architecture of the ERRα-coactivator pocket. In this manner, we have uncovered a fundamental difference in the mechanism by which this receptor interacts with peroxisome proliferator-activated receptor-γ coactivator-1α, as compared with members of the steroid receptor coactivator subfamily of coactivators. Our findings suggest that it may be possible to develop ERRα ligands that exhibit different pharmacological activities as a consequence of their ability to differentially regulate coactivator recruitment. In addition, these findings have implications beyond ERRα because they suggest that subtle alterations in the structure of the activation function-2 pocket within any nuclear receptor may enable differential recruitment of coactivators, an observation of notable pharmaceutical importance.

Transcriptional ERRγ2-mediated activation is regulated by sentrin-specific proteases

2009 ◽  
Vol 419 (1) ◽  
pp. 167-176 ◽  
Author(s):  
Moritz Hentschke ◽  
Ute Süsens ◽  
Uwe Borgmeyer
Keyword(s):  
Nuclear Receptor ◽  
Mutational Analysis ◽  
Activation Function ◽  
Peroxisome Proliferator ◽  
Orphan Nuclear Receptor ◽  
Mobility Shift ◽  
Peroxisome Proliferator Activated Receptor ◽  
Specific Protease ◽  
Mobility Shift Assay ◽  
Group B

Modification with SUMOs (small ubiquitin-related modifiers) has emerged as an important means of regulating the activity of transcription factors, often by repressing their activity. The ERRγ [oestrogen receptor-related receptor γ; ERR3 or NR3B3 (nuclear receptor subfamily 3, group B, gene3)] is a constitutively active orphan nuclear receptor. A PDSM, (phosphorylation-dependent sumoylation motif) is located in the close vicinity of the N-terminally located ERRγ2-specific AF-1 (activation function-1). Its function can be replaced by an NDSM (negatively charged amino acid-dependent sumoylation motif). A mutational analysis reveals that ERRγ2 activity is modulated through sumoylation of a lysine residue at position 40, which in turn is regulated by phosphorylation. Phosphorylation at the +5 position relative to the sumoylation target is directly visualized by a high-resolution EMSA (electrophoretic mobility-shift assay). Sumoylation represses the activity of ERRγ both with and without forced expression of the PGC-1β (peroxisome-proliferator-activated receptor γ co-activator-1β). Fusion proteins of a heterologous DNA-binding domain with the ERRγ2 N-terminus demonstrate the function of the PDSM as the RF-1 (repression function-1) for the neighbouring AF-1. De-repression is achieved by co-expression of sentrin/SENP (sentrin-specific protease) family members. Together, our results demonstrate reversible phosphorylation-dependent sumoylation as a means to regulate the activity of an orphan nuclear receptor.

scholarly journals PRIC295, a Nuclear Receptor Coactivator, Identified from PPAR-Interacting Cofactor Complex

PPAR Research ◽  
2010 ◽  
Vol 2010 ◽  
pp. 1-16 ◽  
Author(s):  
Sean R. Pyper ◽  
Navin Viswakarma ◽  
Yuzhi Jia ◽  
Yi-Jun Zhu ◽  
Joseph D. Fondell ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Target Genes ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nuclear Receptor Coactivator ◽  
Evolutionarily Conserved

The peroxisome proliferator-activated receptor- (PPAR) plays a key role in lipid metabolism and energy combustion. Chronic activation of PPAR in rodents leads to the development of hepatocellular carcinomas. The ability of PPAR to induce expression of its target genes depends on Mediator, an evolutionarily conserved complex of cofactors and, in particular, the subunit 1 (Med1) of this complex. Here, we report the identification and characterization of PPAR-interacting cofactor (PRIC)-295 (PRIC295), a novel coactivator protein, and show that it interacts with the Med1 and Med24 subunits of the Mediator complex. PRIC295 contains 10 LXXLL signature motifs that facilitate nuclear receptor binding and interacts with PPAR and five other members of the nuclear receptor superfamily in a ligand-dependent manner. PRIC295 enhances the transactivation function of PPAR, PPAR, and ER. These data demonstrate that PRIC295 interacts with nuclear receptors such as PPAR and functions as a transcription coactivator underin vitroconditions and may play an important role in mediating the effectsin vivoas a member of the PRIC complex with Med1 and Med24.

scholarly journals Small Heterodimer Partner, an Orphan Nuclear Receptor, Augments Peroxisome Proliferator-activated Receptor γ Transactivation

2001 ◽  
Vol 277 (2) ◽  
pp. 1586-1592 ◽  
Author(s):  
Hitoshi Nishizawa ◽  
Kazuya Yamagata ◽  
Iichiro Shimomura ◽  
Masahiko Takahashi ◽  
Hiroshi Kuriyama ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Peroxisome Proliferator ◽  
Orphan Nuclear Receptor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Small Heterodimer Partner

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 Cyclin D3 Promotes Adipogenesis through Activation of Peroxisome Proliferator-Activated Receptor γ

2005 ◽  
Vol 25 (22) ◽  
pp. 9985-9995 ◽  
Author(s):  
David A. Sarruf ◽  
Irena Iankova ◽  
Anna Abella ◽  
Said Assou ◽  
Stéphanie Miard ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Nuclear Receptor ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Direct Interaction ◽  
Mitotic Division ◽  
Cyclin D3 ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Diet Induced Obesity

ABSTRACT In addition to their role in cell cycle progression, new data reveal an emerging role of D-type cyclins in transcriptional regulation and cellular differentiation processes. Using 3T3-L1 cell lines to study adipogenesis, we observed an up-regulation of cyclin D3 expression throughout the differentiation process. Surprisingly, cyclin D3 was only minimally expressed during the initial stages of adipogenesis, when mitotic division is prevalent. This seemingly paradoxical expression led us to investigate a potential cell cycle-independent role for cyclin D3 during adipogenesis. We show here a direct interaction between cyclin D3 and the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ). Our experiments reveal cyclin D3 acts as a ligand-dependent PPARγ coactivator, which, together with its cyclin-dependent kinase partner, phosphorylates the A-B domain of the nuclear receptor. Overexpression and knockdown studies with cyclin D3 had marked effects on PPARγ activity and subsequently on adipogenesis. Chromatin immunoprecipitation assays confirm the participation of cyclin D3 in the regulation of PPARγ target genes. We show that cyclin D3 mutant mice are protected from diet-induced obesity, display smaller adipocytes, have reduced adipogenic gene expression, and are insulin sensitive. Our results indicate that cyclin D3 is an important factor governing adipogenesis and obesity.

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.

scholarly journals Ligand-Dependent Corepressor (LCoR) Is a Rexinoid-Inhibited Peroxisome Proliferator-Activated Receptor γ–Retinoid X Receptor α Coactivator

2018 ◽  
Vol 38 (9) ◽  
Author(s):  
Tali Shalom-Barak ◽  
Jaclyn Liersemann ◽  
Babak Memari ◽  
Lawrence Flechner ◽  
Caitlin E. Devor ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Activation Function ◽  
Retinoid X Receptor ◽  
Peroxisome Proliferator ◽  
Receptor Function ◽  
Placental Development ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Motifs ◽  
Transcription Cofactor ◽  
Target Activation

ABSTRACTThe 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 theMuc1promoter. 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 ofMuc1by 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 thatMuc1activation entails altered AF2 structures of both PPARγ and RXRα. This unique regulation ofMuc1reflects specific coactivation of PPARγ-RXRα heterodimers by the transcription cofactor ligand-dependent corepressor (LCoR), corroborated by significant downregulation ofMuc1inLcor-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 Krüppel-like factor 6 (KLF6) as a critical regulator of placental development and a component ofMuc1regulation 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.

scholarly journals The Adipogenic Acetyltransferase Tip60 Targets Activation Function 1 of Peroxisome Proliferator-Activated Receptor γ

Endocrinology ◽  
2007 ◽  
Vol 149 (4) ◽  
pp. 1840-1849 ◽  
Author(s):  
Olivier van Beekum ◽  
Arjan B. Brenkman ◽  
Lars Grøntved ◽  
Nicole Hamers ◽  
Niels J. F. van den Broek ◽  
...  
Keyword(s):  
Transcriptional Activity ◽  
Target Genes ◽  
Activation Function ◽  
Specific Gene ◽  
Chimeric Proteins ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Interacting Protein ◽  
And Function ◽  
Interfering Rna

The transcription factor peroxisome proliferator-activated receptor γ (PPARγ) plays a key role in the regulation of lipid and glucose metabolism in adipocytes, by regulating their differentiation, maintenance, and function. The transcriptional activity of PPARγ is dictated by the set of proteins with which this nuclear receptor interacts under specific conditions. Here we identify the HIV-1 Tat-interacting protein 60 (Tip60) as a novel positive regulator of PPARγ transcriptional activity. Using tandem mass spectrometry, we found that PPARγ and the acetyltransferase Tip60 interact in cells, and through use of chimeric proteins, we established that coactivation by Tip60 critically depends on the N-terminal activation function 1 of PPARγ, a domain involved in isotype-specific gene expression and adipogenesis. Chromatin immunoprecipitation experiments showed that the endogenous Tip60 protein is recruited to PPARγ target genes in mature 3T3-L1 adipocytes but not in preadipocytes, indicating that Tip60 requires PPARγ for its recruitment to PPARγ target genes. Importantly, we show that in common with disruption of PPARγ function, small interfering RNA-mediated reduction of Tip60 protein impairs differentiation of 3T3-L1 preadipocytes. Taken together, these findings qualify the acetyltransferase Tip60 as a novel adipogenic factor.

scholarly journals The Tailless Nuclear Receptor Acts as a Dedicated Repressor in the Early Drosophila Embryo

2006 ◽  
Vol 26 (9) ◽  
pp. 3446-3454 ◽  
Author(s):  
Érica Morán ◽  
Gerardo Jiménez
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Target Genes ◽  
Activation Function ◽  
Drosophila Embryo ◽  
Intact Protein ◽  
Positive Interactions ◽  
Orphan Nuclear Receptor ◽  
Loss Of Function ◽  
Early Drosophila Embryo

ABSTRACT Tailless is an orphan nuclear receptor that controls terminal body patterning in Drosophila. Genetic analyses have revealed both positive and negative regulatory interactions of Tailless with various target genes, leading to the idea that, like many other nuclear receptors, Tailless mediates both activation and repression of transcription. In this paper, we have examined the consequences of converting Tailless into an obligate repressor and compared the activities of the resulting protein with those of wild-type Tailless. We find that this repressor form of Tailless behaves like the intact protein in gain- and loss-of-function experiments, being sufficient to support normal embryonic development and establish accurate patterns of gene expression even for positive Tailless targets such as hunchback and brachyenteron. This suggests that Tailless functions exclusively as a transcriptional repressor in the embryo and that the observed positive interactions of Tailless with specific targets are secondary effects involving repression of repressors. We provide evidence that knirps is one such repressor gene acting between Tailless and its indirect positive targets. Finally, our results indicate that Tailless exerts an active mechanism of repression via its ligand-binding domain and that this activity is largely independent of the activation function 2 (AF2) motif characteristic of most nuclear receptors.

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