scholarly journals Familial Focal Segmental Glomerulosclerosis (FSGS)-linked α-Actinin 4 (ACTN4) Protein Mutants Lose Ability to Activate Transcription by Nuclear Hormone Receptors

2012 ◽  
Vol 287 (15) ◽  
pp. 12027-12035 ◽  
Author(s):  
Simran Khurana ◽  
Sharmistha Chakraborty ◽  
Minh Lam ◽  
Yu Liu ◽  
Yu-Ting Su ◽  
...  
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Nuclear Receptors ◽  
Transcriptional Activation ◽  
Transcriptional Activity ◽  
Hormone Receptors ◽  
Retinoic Acid Receptor ◽  
Nuclear Hormone Receptors ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Segmental Glomerulosclerosis

Mutations in α-actinin 4 (ACTN4) are linked to familial forms of focal segmental glomerulosclerosis (FSGS), a kidney disease characterized by proteinuria due to podocyte injury. The mechanisms underlying ACTN4 mutant-associated FSGS are not completely understood. Although α-actinins are better known to cross-link actin filaments and modulate cytoskeletal organization, we have previously shown that ACTN4 interacts with transcription factors including estrogen receptor and MEF2s and potentiates their transcriptional activity. Nuclear receptors including retinoic acid receptor (RAR) have been proposed to play a protective role in podocytes. We show here that ACTN4 interacts with and enhances transcriptional activation by RARα. In addition, FSGS-linked ACTN4 mutants not only mislocalized to the cytoplasm, but also lost their ability to associate with nuclear receptors. Consequently, FSGS-linked ACTN4 mutants failed to potentiate transcriptional activation by nuclear hormone receptors in podocytes. In addition, overexpression of these mutants suppressed the transcriptional activity mediated by endogenous wild-type ACTN4 possibly by a cytoplasmic sequestration mechanism. Our data provide the first link between FSGS-linked ACTN4 mutants and transcriptional activation by nuclear receptor such as RARα and peroxisome proliferator-activated receptor γ.

Peroxisomal bifunctional enzyme binds and activates the activationfunction-1 region of the peroxisome proliferator-activated receptor α

2001 ◽  
Vol 353 (2) ◽  
pp. 253-258 ◽  
Author(s):  
Cristiana E. JUGE-AUBRY ◽  
Stéphane KUENZLI ◽  
Jean-Charles SANCHEZ ◽  
Denis HOCHSTRASSER ◽  
Christoph A. MEIER
Keyword(s):  
Amino Acids ◽  
Transcriptional Activity ◽  
Hormone Receptors ◽  
Affinity Purification ◽  
Fold Increase ◽  
Activation Function ◽  
Bifunctional Enzyme ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor

The transcriptional activity of peroxisome proliferator-activated receptors (PPARs), and of nuclear hormone receptors in general, is subject to modulation by cofactors. However, most currently known co-activating proteins interact in a ligand-dependent manner with the C-terminal ligand-regulated activation function (AF)-2 domain of nuclear receptors. Since PPARα exhibits a strong constitutive transactivating function contained within an N-terminal AF-1 region, it can be speculated that a different set of cofactors might interact with this region of PPARs. An affinity purification approach was used to identify the peroxisomal enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase (bifunctional enzyme, BFE) as a protein which strongly and specifically interacted with the N-terminal 92 amino acids of PPARα. ProteinŐprotein interaction assays with the cloned BFE confirmed this interaction, which could be mapped to amino acids 307Ő514 of the BFE and the N-terminal 70 amino acids of PPARα. Moreover, transient transfection experiments in hepatoma cells revealed a 2.2-fold increase in the basal and ligand-stimulated transcriptional activity of PPARα in the presence of BFE. This stimulatory effect is preferentially observed for the PPARα isoform and it is significantly stronger (4.8-fold) in non-hepatic cells, which presumably express lower levels of endogenous BFE. Hence, the BFE represents the first known cofactor capable of activating the AF-1 domain of PPAR without requiring additional regions of this receptor. These data are compatible with a model whereby the PPAR-regulated BFE is able to modulate its own expression through an enhancement of the activity of PPARα, representing a novel peroxisomalŐnuclear feed-forward regulatory loop.

scholarly journals Specific Structural Motifs Determine TRAP220 Interactions with Nuclear Hormone Receptors

2000 ◽  
Vol 20 (15) ◽  
pp. 5433-5446 ◽  
Author(s):  
Yunsheng Ren ◽  
Evan Behre ◽  
Zhaojun Ren ◽  
Jiachang Zhang ◽  
Qianben Wang ◽  
...  
Keyword(s):  
Single Molecule ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Activation Function ◽  
Site Directed Mutagenesis ◽  
Nuclear Hormone Receptors ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Amino Terminal ◽  
Binding Domains

ABSTRACT The TRAP coactivator complex is a large, multisubunit complex of nuclear proteins which associates with nuclear hormone receptors (NRs) in the presence of cognate ligand and stimulates NR-mediated transcription. A single subunit, TRAP220, is thought to target the entire complex to a liganded receptor through a domain containing two of the signature LXXLL motifs shown previously in other types of coactivator proteins to be essential for mediating NR binding. In this work, we demonstrate that each of the two LXXLL-containing regions, termed receptor binding domains 1 and 2 (RBD-1 and RBD-2), is differentially preferred by specific NRs. The retinoid X receptor (RXR) displays a weak yet specific activation function 2 (AF2)-dependent preference for RBD-1, while the thyroid hormone receptor (TR), vitamin D3 receptor (VDR), and peroxisome proliferator-activated receptor all exhibit a strong AF2-dependent preference for RBD-2. Using site-directed mutagenesis, we show that preference for RBD-2 is due to the presence of basic-polar residues on the amino-terminal end of the core LXXLL motif. Furthermore, we show that the presence and proper spacing of both RBD-1 and RBD-2 are required for an optimal association of TRAP220 with RXR-TR or RXR-VDR heterodimers bound to DNA and for TRAP220 coactivator function. On the basis of these results, we suggest that a single molecule of TRAP220 can interact with both subunits of a DNA-bound NR heterodimer.

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.

Ginseng on Nuclear Hormone Receptors

2017 ◽  
Vol 45 (06) ◽  
pp. 1147-1156 ◽  
Author(s):  
Joonwoo Park ◽  
Phuong T. C. Bui ◽  
Heewon Song ◽  
Si-Kwan Kim ◽  
Dong-Kwon Rhee ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Hormone Receptors ◽  
Specific Binding ◽  
First Record ◽  
Scientific Basis ◽  
Nuclear Hormone Receptors ◽  
Peroxisome Proliferator ◽  
Cellular Targets ◽  
Beneficial Effects ◽  
Bioactive Ingredients

The first record of ginseng use dates back over two millennia, and ginseng is now popular in more than 35 countries. Ginsenosides are the pharmacological constituents responsible for the beneficial effects of ginseng. There is increasing evidence that ginseng and its bioactive ingredients are involved in the regulation of nuclear receptors, molecules that act in response to the specific binding of hormones, which link to a diverse array of signaling pathways, such as the ERK and PI3K/Akt pathways. Knowledge of the mechanism of how ginseng mediates these complexes is essential for the development of multi-target phytomedicine as possible therapy for different diseases. Here, we discuss the literature on the effects of ginseng and its constituents on estrogen, glucocorticoid, peroxisome proliferator-activated, and androgen nuclear hormone receptors, as well as how ginseng and its constituents exert their biological function in the treatment of cancer, obesity, and cardiovascular and neurological disorders. The accumulated results definitely show that the nuclear receptors are cellular targets of ginsenosides, but more rigorous data are required to establish and provide a scientific basis to confirm the suggested efficacy of ginseng or products with ginsenosides.

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.

scholarly journals Mechanistic Principles in NR Box-Dependent Interaction between Nuclear Hormone Receptors and the Coactivator TIF2

1998 ◽  
Vol 18 (10) ◽  
pp. 6001-6013 ◽  
Author(s):  
Jörg Leers ◽  
Eckardt Treuter ◽  
Jan-Åke Gustafsson
Keyword(s):  
Transcriptional Activation ◽  
Hormone Receptors ◽  
Target Genes ◽  
Nuclear Hormone Receptors ◽  
Receptor Interaction ◽  
Peroxisome Proliferator ◽  
Interaction Domain ◽  
Interacting Protein ◽  
Necessary And Sufficient ◽  
Dependent Interaction

ABSTRACT Nuclear hormone receptors exert transcriptional activation of target genes upon hormone induction via interactions with the basal transcription machinery. This interaction is mediated by cofactors which physically bind to receptors, thereby acting as coactivators or corepressors leading to activation or repression, respectively. Here we report the screening for and cloning of a peroxisome proliferator receptor-interacting protein, the rat homolog of TIF2. By sequence comparison with the related coactivator SRC-1, we identified three short conserved motifs (NR boxes) in both proteins which are the putative binding sites of TIF2 to nuclear hormone receptors. We demonstrate here by generation of amino acid exchanges within the NR boxes that all three boxes located in the receptor interaction domain of TIF2 are necessary and sufficient for interaction. The three boxes individually can bind to hormone receptors but display preferences in binding for certain receptors. In addition, we show that the interaction domain of TIF2 can compete with other AF-2-dependent cofactors for binding to receptors. Finally, we demonstrate cooperative binding of two TIF2 molecules to a heterodimeric nuclear receptor complex even in the presence of only one cognate ligand, indicating an allosteric effect on the heterodimeric partner upon coactivator binding.

scholarly journals PPARS - Peroxisome Proliferator Activated Receptor Activators and Fibrates Actions

2021 ◽  
Vol 5 (2) ◽  
Author(s):  
Sidney Carvalho Fernandes ◽  
Anita L. R. Saldanha ◽  
Ana Paula Pantoja Margeotto ◽  
André Luiz Valera Gasparoto ◽  
Tania Leme da Rocha Martinez
Keyword(s):  
Hormone Receptors ◽  
Retinoic Acid Receptor ◽  
Microvascular Disease ◽  
Small Variation ◽  
Lipid Lowering ◽  
Diabetic Patients ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Low Hdl ◽  
1960S And 1970S

Peroxisome Proliferator Activated Receptor sits part of the family of nuclear receptors, which has about 50 known receptors, including thyroid hormone receptors, which have the function of regulating metabolism and metabolizing and eliminating substances. These receptors, to act, must be activated by ligands, form a heterodmer with the retinoic acid receptor, recruit activating cofactors, release inhibitory cofactors to which they are bound, and then act on the responsive element of target gene. Three species of peroxisome proliferator activated receptor are known: PPARa, PPARγ and PPARβ (also known as PPARd or β/d). The prototypes of PPARa activators are the derivatives of fibricacid, of which the first representative was clofibrate, used as a lipid-lowering factor in the 1960s and 1970s. Although there may be a small variation among the various fibrates regarding the mechanism of action, these drugs are basically PPARa activators. In the action of fibrates, there is a reduction of triglycerides, with a decrease in the synthesis of VLDL, increase of HDL particles and transformation of small and dense LDL into larger, less dense LDL and with lower atherogenic potential. Fibrates are second-choice substances, and statins are the first for the treatment of hypertriglyceridemia. Fibrates are efficient for the treatment of patients with low HDL-C, decrease macro and microvascular disease of diabetic patients. The recommendation is do not associate gemfibrozil with statins. Other fibrates may be associated, and preference should be given to the association of statins that are not metabolized by CYP3A4: rosvastatin, pravastatin and fluvastatin.

scholarly journals Scaffold attachment factor B1 directly interacts with nuclear receptors in living cells and represses transcriptional activity

2005 ◽  
Vol 35 (3) ◽  
pp. 503-517 ◽  
Author(s):  
M-B Debril ◽  
L Dubuquoy ◽  
J-N Feige ◽  
W Wahli ◽  
B Desvergne ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Transcriptional Activity ◽  
Resonance Energy ◽  
Human Adipose Tissue ◽  
Estrogen Receptor Α ◽  
Living Cells ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Attachment Factor

Transcriptional activity relies on coregulators that modify the chromatin structure and serve as bridging factors between transcription factors and the basal transcription machinery. Using the DE domain of human peroxisome proliferator-activated receptor gamma (PPARγ) as bait in a yeast two-hybrid screen of a human adipose tissue library, we isolated the scaffold attachment factor B1 (SAFB1/HET/HAP), which was previously shown to be a corepressor of estrogen receptor α. We show here that SAFB1 has a very broad tissue expression profile in human and is also expressed all along mouse embryogenesis. SAFB1 interacts in pull-down assays not only with PPARγ but also with all nuclear receptors tested so far, albeit with different affinities. The association of SAFB1 and PPARγ in vivo is further demonstrated by fluorescence resonance energy transfer (FRET) experiments in living cells. We finally show that SAFB1 is a rather general corepressor for nuclear receptors. Its change in expression during the early phases of adipocyte and enterocyte differentiation suggests that SAFB1 potentially influences cell proliferation and differentiation decisions.

scholarly journals Agonist binding directs dynamic competition among nuclear receptors for heterodimerization with retinoid X receptor

2020 ◽  
Vol 295 (29) ◽  
pp. 10045-10061
Author(s):  
Lina Fadel ◽  
Bálint Rehó ◽  
Julianna Volkó ◽  
Dóra Bojcsuk ◽  
Zsuzsanna Kolostyák ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Cellular Response ◽  
Nuclear Translocation ◽  
Retinoic Acid Receptor ◽  
Retinoid X Receptor ◽  
Peroxisome Proliferator ◽  
Dynamic Competition ◽  
Peroxisome Proliferator Activated Receptor ◽  
Imaging Model ◽  
Translocation Assay

Retinoid X receptor (RXR) plays a pivotal role as a transcriptional regulator and serves as an obligatory heterodimerization partner for at least 20 other nuclear receptors (NRs). Given a potentially limiting/sequestered pool of RXR and simultaneous expression of several RXR partners, we hypothesized that NRs compete for binding to RXR and that this competition is directed by specific agonist treatment. Here, we tested this hypothesis on three NRs: peroxisome proliferator-activated receptor gamma (PPARγ), vitamin D receptor (VDR), and retinoic acid receptor alpha (RARα). The evaluation of competition relied on a nuclear translocation assay applied in a three-color imaging model system by detecting changes in heterodimerization between RXRα and one of its partners (NR1) in the presence of another competing partner (NR2). Our results indicated dynamic competition between the NRs governed by two mechanisms. First, in the absence of agonist treatment, there is a hierarchy of affinities between RXRα and its partners in the following order: RARα > PPARγ > VDR. Second, upon agonist treatment, RXRα favors the liganded partner. We conclude that recruiting RXRα by the liganded NR not only facilitates a stimulus-specific cellular response but also might impede other NR pathways involving RXRα.

scholarly journals Prothymosin Alpha Selectively Enhances Estrogen Receptor Transcriptional Activity by Interacting with a Repressor of Estrogen Receptor Activity

2000 ◽  
Vol 20 (17) ◽  
pp. 6224-6232 ◽  
Author(s):  
Paolo G. V. Martini ◽  
Regis Delage-Mourroux ◽  
Dennis M. Kraichely ◽  
Benita S. Katzenellenbogen
Keyword(s):  
Estrogen Receptor ◽  
Transcriptional Activation ◽  
Transcriptional Activity ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Receptor Activity ◽  
Nuclear Hormone Receptors ◽  
Prothymosin Alpha ◽  
Estrogen Receptor Activity ◽  
Two Hybrid

ABSTRACT We find that prothymosin alpha (PTα) selectively enhances transcriptional activation by the estrogen receptor (ER) but not transcriptional activity of other nuclear hormone receptors. This selectivity for ER is explained by PTα interaction not with ER, but with a 37-kDa protein denoted REA, for repressor of estrogen receptor activity, a protein that we have previously shown binds to ER, blocking coactivator binding to ER. We isolated PTα, known to be a chromatin-remodeling protein associated with cell proliferation, using REA as bait in a yeast two-hybrid screen with a cDNA library from MCF-7 human breast cancer cells. PTα increases the magnitude of ERα transcriptional activity three- to fourfold. It shows lesser enhancement of ERβ transcriptional activity and has no influence on the transcriptional activity of other nuclear hormone receptors (progesterone receptor, glucocorticoid receptor, thyroid hormone receptor, or retinoic acid receptor) or on the basal activity of ERs. In contrast, the steroid receptor coactivator SRC-1 increases transcriptional activity of all of these receptors. Cotransfection of PTα or SRC-1 with increasing amounts of REA, as well as competitive glutathione S-transferase pulldown and mammalian two-hybrid studies, show that REA competes with PTα (or SRC-1) for regulation of ER transcriptional activity and suppresses the ER stimulation by PTα or SRC-1, indicating that REA can function as an anticoactivator in cells. Our data support a model in which PTα, which does not interact with ER, selectively enhances the transcriptional activity of the ER but not that of other nuclear receptors by recruiting the repressive REA protein away from ER, thereby allowing effective coactivation of ER with SRC-1 or other coregulators. The ability of PTα to directly interact in vitro and in vivo with REA, a selective coregulator of the ER, thereby enabling the interaction of ER with coactivators, appears to explain its ability to selectively enhance ER transcriptional activity. These findings highlight a new role for PTα as a coregulator activity-modulating protein that confers receptor specificity. Proteins such as PTα represent an additional regulatory component that defines a novel paradigm enabling receptor-selective enhancement of transcriptional activity by coactivators.

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