scholarly journals Nuclear receptors modulate the interaction of Sp1 and GC-rich DNA via ternary complex formation

2000 ◽  
Vol 352 (3) ◽  
pp. 763-772 ◽  
Author(s):  
Matthias HUSMANN ◽  
Yolanta DRAGNEVA ◽  
Eric ROMAHN ◽  
Petra JEHNICHEN
Keyword(s):  
Retinoic Acid ◽  
Complex Formation ◽  
Nuclear Receptors ◽  
Thyroid Hormone Receptor ◽  
Retinoic Acid Receptor ◽  
Ternary Complexes ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Retinoic Acid Response Element ◽  
Gc Box

Binding sites for transcription factor Sp1have been implicated in the transcriptional regulation of several genes by hormones or vitamins, and here we show that a GC-rich element contributes to the retinoic acid response of the interleukin 1β promoter. To explain such observations, it has been proposed that nuclear receptors can interact with Sp1 bound to GC-rich DNA. However, evidence supporting this model has remained indirect. So far, nuclear receptors have not been detected in a complex with Sp1 and GC-rich DNA, and the expected ternary complexes in non-denaturing gels were not seen. In search for these missing links we found that nuclear receptors [retinoic acid receptor (RAR), thyroid hormone receptor (TR), vitamin D3 receptor, peroxisome-proliferator-activated receptor and retinoic X receptor] induce an electrophoretic mobility increase of Sp1ŐGC-rich DNA complexes. Concomitantly, binding of Sp1 to the GC-box is enhanced. It is proposed that nuclear receptors may partially replace Sp1 in homo-oligomers at the GC-box. RARs and Sp1 can also combine into a complex with a retinoic acid-response element. The presence of RAR and Sp1 in complexes with either cognate site was revealed in supershift experiments. The C-terminus of Sp1 interacts with nuclear receptors. Both the ligand- and DNA-binding domains of the receptor are important for complex formation with Sp1 and GC-rich DNA. In spite of similar capacity to form ternary complexes, RAR but not TR up-regulated an Sp1-driven reporter in a ligand-dependent way. Thus additional factors limit the transcriptional response mediated by nuclear receptors and Sp1.

scholarly journals Nuclear Receptors as Potential Therapeutic Targets for Myeloid Leukemia

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1921
Author(s):  
Pan Pan ◽  
Xiao Chen
Keyword(s):  
Retinoic Acid ◽  
Myeloid Leukemia ◽  
Therapeutic Potential ◽  
Retinoic Acid Receptor ◽  
Therapeutic Targets ◽  
Leukemic Cells ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
All Trans Retinoic Acid ◽  
Research Findings

The nuclear receptor (NR) superfamily has been studied extensively in many solid tumors and some receptors have been targeted to develop therapies. However, their roles in leukemia are less clear and vary considerably among different types of leukemia. Some NRs participate in mediating the differentiation of myeloid cells, making them attractive therapeutic targets for myeloid leukemia. To date, the success of all-trans retinoic acid (ATRA) in treating acute promyelocytic leukemia (APL) remains a classical and unsurpassable example of cancer differentiation therapy. ATRA targets retinoic acid receptor (RAR) and forces differentiation and/or apoptosis of leukemic cells. In addition, ligands/agonists of vitamin D receptor (VDR) and peroxisome proliferator-activated receptor (PPAR) have also been shown to inhibit proliferation, induce differentiation, and promote apoptosis of leukemic cells. Encouragingly, combining different NR agonists or the addition of NR agonists to chemotherapies have shown some synergistic anti-leukemic effects. This review will summarize recent research findings and discuss the therapeutic potential of selected NRs in acute and chronic myeloid leukemia, focusing on RAR, VDR, PPAR, and retinoid X receptor (RXR). We believe that more mechanistic studies in this field will not only shed new lights on the roles of NRs in leukemia, but also further expand the clinical applications of existing therapeutic agents targeting NRs.

Pokemon decreases the transcriptional activity of RARα in the absence of ligand

2017 ◽  
Vol 398 (3) ◽  
pp. 331-340 ◽  
Author(s):  
Yutao Yang ◽  
Yueting Li ◽  
Fei Di ◽  
Jiajun Cui ◽  
Yue Wang ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Thyroid Hormone ◽  
Transcriptional Activity ◽  
Thyroid Hormone Receptor ◽  
Retinoic Acid Receptor ◽  
Potential Interaction ◽  
Retinoic Acid Receptor Alpha ◽  
Rare Element ◽  
Retinoic Acid Response Element

Abstract Pokemon is a transcriptional repressor that belongs to the POZ and Krüppel (POK) protein family. In this study, we investigated the potential interaction between Pokemon and retinoic acid receptor alpha (RARα) and determined the role of Pokemon in regulation of RARα transcriptional activity in the absence of ligand. We found that Pokemon could directly interact with RARα. Moreover, we demonstrated that Pokemon could decrease the transcriptional activity of RARα in the absence of ligand. Furthermore, we showed that Pokemon could repress the transcriptional activity of RARα by increasing the recruitment of nuclear receptor co-repressor (NCoR) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) to the retinoic acid response element (RARE) element. Taken together, these data suggest that Pokemon is a novel partner of RARα that acts as a co-repressor to regulate RARα transcriptional activity in the absence of ligand.

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.

scholarly journals Adiponectin, Retinoic Acid Receptor Responder 2, and Peroxisome Proliferator-Activated Receptor-γ Coativator-1 Genes and the Risk for Obesity

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Ana Carolina Proença da Fonseca ◽  
Alan Cleveland Ochioni ◽  
Raisa da Silva Martins ◽  
Verônica Marques Zembrzuski ◽  
Mario Campos Junior ◽  
...  
Keyword(s):  
Body Weight ◽  
Retinoic Acid ◽  
Waist Circumference ◽  
Retinoic Acid Receptor ◽  
Case Group ◽  
Peroxisome Proliferator ◽  
Nutritional Disorder ◽  
Peroxisome Proliferator Activated Receptor ◽  
Acid Receptor ◽  
Genotype Frequencies

Obesity is the most common nutritional disorder. This disease is a multifactorial disease influenced by environmental and genetic factors. This study investigated the relationship between common variants of adiponectin (ADIPOQ), retinoic acid receptor responder 2 (RARRES2), and peroxisome proliferator-activated receptor-γ coativator-1 (PPARGC1) and obesity-related traits and susceptibility. A total of 167 individuals with obesity and 165 normal-weight subjects were recruited. Genotype frequencies of rs182052 in ADIPOQ differed significantly between the groups. Genotype AA was observed at a higher frequency in case than in control subjects. Association analysis showed that the A allele was a risk factor for obesity. This polymorphism was associated with body weight, body mass index (BMI), and waist circumference. After stratification by BMI, eutrophic individuals with AA or AG genotypes had higher body weights and waist circumferences than those with GG genotypes. In the case group, no associations were observed, except for stratified subjects with morbid obesity that exhibited a progressive increase of body weight, BMI, and waist circumference when rs182052 A was present. No associations were observed between SNPs in RARRES2 and PPARGC1 and obesity or any other studied variables. The rs182052 polymorphism in ADIPOQ is associated with a higher risk for obesity and obesity-related parameters.

scholarly journals Alternative splicing determines the interaction of SMRT isoforms with nuclear receptor–DNA complexes

2009 ◽  
Vol 29 (3) ◽  
pp. 143-149 ◽  
Author(s):  
Flavie Faist ◽  
Stephen Short ◽  
G. Geoff Kneale ◽  
Colinb R. Sharpe
Keyword(s):  
Retinoic Acid ◽  
Alternative Splicing ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Thyroid Hormone Receptor ◽  
Retinoic Acid Receptor ◽  
Class Ii ◽  
Dna Complexes ◽  
Response Elements

Signalling by small molecules, such as retinoic acid, is mediated by heterodimers comprising a class II nuclear receptor and an RXR (retinoid X receptor) subunit. The receptors bind to DNA response elements and act as ligand-dependent transcription factors, but, in the absence of signal, the receptors bind the co-repressors SMRT [silencing mediator for RAR (retinoic acid receptor) and TR (thyroid hormone receptor)] and NCoR (nuclear receptor co-repressor) and repress gene expression. Alternative splicing of the SMRT transcript in mammals generates six isoforms containing 1, 2 or 3 CoRNR (co-repressor for nuclear receptor) box motifs which are responsible for the interactions with nuclear receptors. We show that human cell lines express all six SMRT isoforms and then determine the binding affinity of mouse SMRT isoforms for RAR/RXR and three additional class II nuclear receptor–DNA complexes. This approach demonstrates the importance of the full complement of CoRNR boxes within each SMRT protein, rather than the identity of individual CoRNR boxes, in directing the interaction of SMRT with nuclear receptors. Each class of SMRT isoform displays a distinct feature, as the 1-box isoform discriminates between DNA response elements, the 2-box isoforms promote high-affinity binding to TR complexes and the 3-box isoforms show differential binding to nuclear receptors. Consequently, the differential deployment of SMRT isoforms observed in vivo could significantly expand the regulatory capacity of nuclear receptor signalling.

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