Identification of a nuclear receptor/coactivator developmental signaling pathway in the nematode parasite Strongyloides stercoralis

DAF-12 is nematode-specific nuclear receptor that has been proposed to govern development of the infectious stage of parasitic species, including Strongyloides stercoralis. Here, we identified a parasite-specific coactivator, called DAF-12 interacting protein-1 (DIP-1), that is required for DAF-12 ligand-dependent transcriptional activity. DIP-1 is found only in Strongyloides spp. and selectively interacts with DAF-12 through an atypical receptor binding motif. Using CRISPR/Cas9-directed mutagenesis, we demonstrate that DAF-12 is required for the requisite developmental arrest and the ligand-dependent reactivation of infectious S. stercoralis infective third-stage larvae, and that these effects require the DIP-1 coactivator. These studies reveal the existence of a distinct nuclear receptor/coactivator signaling pathway that governs parasite development.

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Inactivation of the Nuclear Receptor Coactivator RAP250 in Mice Results in Placental Vascular Dysfunction

Molecular and Cellular Biology ◽

10.1128/mcb.23.4.1260-1268.2003 ◽

2003 ◽

Vol 23 (4) ◽

pp. 1260-1268 ◽

Cited By ~ 72

Author(s):

Per Antonson ◽

Gertrud U. Schuster ◽

Ling Wang ◽

Björn Rozell ◽

Elin Holter ◽

...

Keyword(s):

Nuclear Receptors ◽

Nuclear Receptor ◽

Blood Circulation ◽

Transcriptional Activity ◽

Vascular Dysfunction ◽

Diverse Group ◽

Placental Development ◽

Nuclear Receptor Coactivator ◽

The Past ◽

Placental Blood

ABSTRACT Coactivators constitute a diverse group of proteins that are essential for optimal transcriptional activity of nuclear receptors. In the past few years many coactivators have been identified but it is still unclear whether these proteins interact indiscriminately with all nuclear receptors and whether there is some redundancy in their functions. We have previously cloned and characterized RAP250 (ASC-2/PRIP/TRBP/NRC), an LXXLL-containing coactivator for nuclear receptors. In order to study its biological role, Rap250 null mice were generated by gene targeting. Here we show that genetic disruption of Rap250 results in embryonic lethality at embryonic day (E) 13.5. Histological examination of placentas revealed a dramatically reduced spongiotrophoblast layer, a collapse of blood vessels in the region bordering the spongiotrophoblast, and labyrinthine layers in placentas from Rap250−/− embryos. These findings suggest that the lethality of Rap250−/− embryos is the result of obstructed placental blood circulation. Moreover, the transcriptional activity of PPARγ is reduced in fibroblasts derived from Rap250−/− embryos, suggesting that RAP250 is an essential coactivator for this nuclear receptor in the placenta. Our results demonstrate that RAP250 is necessary for placental development and thus essential for embryonic development.

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Multiple Signal Input and Output Domains of the 160-Kilodalton Nuclear Receptor Coactivator Proteins

Molecular and Cellular Biology ◽

10.1128/mcb.19.9.6164 ◽

1999 ◽

Vol 19 (9) ◽

pp. 6164-6173 ◽

Cited By ~ 169

Author(s):

Han Ma ◽

Heng Hong ◽

Shih-Ming Huang ◽

Ryan A. Irvine ◽

Paul Webb ◽

...

Keyword(s):

Nuclear Receptor ◽

Transcriptional Activation ◽

Thyroid Hormone Receptor ◽

Activation Function ◽

Creb Binding Protein ◽

Activation Domain ◽

Nuclear Receptor Coactivator ◽

Interacting Protein ◽

Binding Domains ◽

Signal Input

ABSTRACT Members of the 160-kDa nuclear receptor coactivator family (p160 coactivators) bind to the conserved AF-2 activation function found in the hormone binding domains of nuclear receptors (NR) and are potent transcriptional coactivators for NRs. Here we report that the C-terminal region of p160 coactivators glucocorticoid receptor interacting protein 1 (GRIP1), steroid receptor coactivator 1 (SRC-1a), and SRC-1e binds the N-terminal AF-1 activation function of the androgen receptor (AR), and p160 coactivators can thereby enhance transcriptional activation by AR. While they all interact efficiently with AR AF-1, these same coactivators have vastly different binding strengths with and coactivator effects on AR AF-2. p160 activation domain AD1, which binds secondary coactivators CREB binding protein (CBP) and p300, was previously implicated as the principal domain for transmitting the activating signal to the transcription machinery. We identified a new highly conserved motif in the AD1 region which is important for CBP/p300 binding. Deletion of AD1 only partially reduced p160 coactivator function, due to signaling through AD2, another activation domain located at the C-terminal end of p160 coactivators. C-terminal coactivator fragments lacking AD1 but containing AD2 and the AR AF-1 binding site served as efficient coactivators for full-length AR and AR AF-1. The two signal input domains (one that binds NR AF-2 domains and one that binds AF-1 domains of some but not all NRs) and the two signal output domains (AD1 and AD2) of p160 coactivators played different relative roles for two different NRs: AR and thyroid hormone receptor.

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Activities in Pit-1 Determine Whether Receptor Interacting Protein 140 Activates or Inhibits Pit-1/Nuclear Receptor Transcriptional Synergy

Molecular Endocrinology ◽

10.1210/mend.11.9.9978 ◽

1997 ◽

Vol 11 (9) ◽

pp. 1332-1341 ◽

Cited By ~ 19

Author(s):

F. Max Chuang ◽

Brian L. West ◽

John D. Baxter ◽

Fred Schaufele

Keyword(s):

Amino Acids ◽

Nuclear Receptor ◽

Thyroid Hormone Receptor ◽

Activation Function ◽

Activation Functions ◽

Nuclear Receptor Coactivator ◽

Interacting Protein ◽

Synergistic Interactions ◽

Synergistic Activation ◽

Context Specific

Abstract Pituitary-specific transcription of the evolutionarily related rat (r) GH and PRL genes involves synergistic interactions between Pit-1 and other promoter-binding factors including nuclear receptors. We show that Pit-1/thyroid hormone receptor (TR) and Pit-1/estrogen receptor (ER) synergistic activation of the rGH and rPRL promoters are globally similar. Both synergies depend upon the same activation functions in Pit-1 and also require activation function-2 conserved in TR and ER. The activation function-2 binding protein, RIP140, previously thought to be a nuclear receptor coactivator, strongly inhibits both Pit-1/TR and Pit-1/ER synergy. RIP140 inhibition is profoundly influenced, in a promoter-specific fashion, by a synergism-selective function in Pit-1: deletion of Pit-1 amino acids 72–100 switches RIP140 to an activator of Pit-1/ER and Pit-1/TR synergy at the rPRL promoter but not at the rGH promoter. Pit-1 amino acids 101–125 are required for RIP140 inhibition or activation again only at the rPRL promoter. Therefore, functions within one factor can determine the activity of a coactivator binding to its synergistic partner. This promoter context-specific synergistic interplay between transcription factors and coactivators is likely an essential determinant of cell-specific transcriptional regulation.

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Development of Peptide Antagonists for the Androgen Receptor Using Combinatorial Peptide Phage Display

Molecular Endocrinology ◽

10.1210/me.2005-0072 ◽

2005 ◽

Vol 19 (10) ◽

pp. 2478-2490 ◽

Cited By ~ 53

Author(s):

Ching-yi Chang ◽

Jennifer Abdo ◽

Tanya Hartney ◽

Donald P. McDonnell

Keyword(s):

Androgen Receptor ◽

Phage Display ◽

Nuclear Receptors ◽

Nuclear Receptor ◽

Transcriptional Activity ◽

Binding Pocket ◽

Orphan Nuclear Receptors ◽

Nuclear Receptor Coactivator ◽

Pharmacological Significance ◽

Peptide Phage Display

Abstract Under the auspices of the Nuclear Receptor Signaling Atlas (NURSA) , we have undertaken to evaluate the feasibility of targeting nuclear receptor-coactivator surfaces for new drug discovery. The underlying objective of this approach is to provide the research community with reagents that can be used to modulate the transcriptional activity of nuclear receptors. Using combinatorial peptide phage display, we have been able to develop peptide antagonists that target specific nuclear receptor (NR)-coactivator binding surfaces. It can be appreciated that reagents of this nature will be of use in the study of orphan nuclear receptors for whom classical ligands have not yet been identified. In addition, because the interaction of coactivators with the receptor is an obligate step for NR transcriptional activity, it is anticipated that peptides that block these interactions will enable the definition of the biological and pharmacological significance of individual NR-coactivator interactions. In this report, we describe the use of this approach to develop antagonists of the androgen receptor by targeting its coactivator-binding pocket and their use to study the coactivator-binding surface of this receptor. Based on our findings, we believe that molecules that function by disrupting the androgen receptor-cofactor interactions will have use in the treatment of prostate cancer.

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Knockdown of NCOA2 Inhibits the Growth and Progression of Gastric Cancer by Affecting the Wnt Signaling Pathway–Related Protein Expression

Technology in Cancer Research & Treatment ◽

10.1177/1533033820928072 ◽

2020 ◽

Vol 19 ◽

pp. 153303382092807

Author(s):

Zhenlv Lin ◽

Fan Yang ◽

Dong Lu ◽

Wenjie Sun ◽

Guangwei Zhu ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

Signaling Pathway ◽

Nuclear Receptor ◽

Wnt Signaling Pathway ◽

Related Protein ◽

Gastric Cancer Cells ◽

Nuclear Receptor Coactivator ◽

Proliferation And Invasion

Objective: The aim of the study is to determine the role of nuclear receptor coactivator 2 in cell proliferation and invasion ability of gastric cancer cells and to explore its possible mechanisms. Methods: Immunohistochemical staining was used to determine NCOA2 gene expression in gastric cancer. Western blotting was used to detect Wnt signal pathways–related protein expression. Colony formation assays, Cell Counting Kit-8 assays, and transwell assays were used to determine cell proliferation, metastasis, and invasion ability of gastric cancer cells. A flow cytometric apoptosis tests determine gastric cancer cell apoptosis ability after inhibition of the expression of nuclear receptor coactivator 2. Subcutaneous mouse models were used to determine the gastric cancer growth and peritoneal metastasis differences after inhibition the expression of nuclear receptor coactivator 2. Results: The expression of nuclear receptor coactivator 2 in gastric cancer cells is high ( P < .01), including lymph node metastasis, TNM staging, and gender differences in nuclear receptor coactivator 2 expression were statistically significant ( P < .01). Short interfering nuclear receptor coactivator 2 could inhibit the proliferation and invasion ability of gastric cancer cells. Short interfering nuclear receptor coactivator 2 promotes the apoptosis of gastric cancer cells. Animal experiments showed that short interfering nuclear receptor coactivator 2 could inhibit the growth and invasion of gastric cancer-transplantable tumors. Knockdown of the expression of nuclear receptor coactivator 2 inhibited the Wnt/β-catenin signaling pathway in the gastric cancer cells. Conclusions: Knockdown of the expression of nuclear receptor coactivator 2 can inhibit the proliferation and invasion of human gastric cancer in vitro and in vivo. The underlying mechanism of NOCA2 affects the Wnt signaling pathway.

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Association Between Nuclear Receptor Coactivator 1 and Stem Cell Signaling Pathway and Identification of Natural NCOA1 Inhibitors: An in-silico Study

Phytochemistry: An in-silico and in-vitro Update ◽

10.1007/978-981-13-6920-9_30 ◽

2019 ◽

pp. 545-564

Author(s):

Pushpendra Singh ◽

Prem P. Kushwaha ◽

Atul K. Singh ◽

Shashank Kumar

Keyword(s):

Stem Cell ◽

Cell Signaling ◽

Signaling Pathway ◽

Nuclear Receptor ◽

In Silico ◽

Nuclear Receptor Coactivator ◽

Cell Signaling Pathway ◽

In Silico Study

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The enhancement of nuclear receptor transcriptional activation by a mouse actin-binding protein, alpha actinin 2

Journal of Molecular Endocrinology ◽

10.1677/jme.0.0320481 ◽

2004 ◽

Vol 32 (2) ◽

pp. 481-496 ◽

Cited By ~ 32

Author(s):

SM Huang ◽

CJ Huang ◽

WM Wang ◽

JC Kang ◽

WC Hsu

Keyword(s):

Nuclear Receptor ◽

Transcriptional Activation ◽

Retinoic Acid Receptor ◽

Binding Protein ◽

Actin Binding ◽

Binding Motif ◽

Interacting Protein ◽

Activation Domains ◽

Actin Binding Protein ◽

Steroid Receptor Coactivator

The p160 coactivators, steroid receptor coactivator 1, glucocorticoid receptor interacting protein 1 (GRIP1) and the activator of thyroid and retinoic acid receptor, have two activation domains, AD1 and AD2, which transmit the activation signal from the DNA-bound nuclear receptor to the chromatin and/or transcription machinery. In screening for mammalian proteins that bind the AD2 of GRIP1, we identified a mouse actin-binding protein, alpha actinin 2 (mACTN2). mACTN2 was expressed in the heart, skeletal muscle, lung, brain and testis, but there was no expression in the spleen, liver or kidney. Interestingly, the expression level of mACTN2 in the developing embryo depended on the embryonic stage. We further demonstrated that mACTN2 could enhance two transactivation activities of GRIP1, which in turn could enhance the homodimerization of mACTN2. Importantly, mACTN2 not only served as a primary coactivator for androgen receptor, estrogen receptor and thyroid receptor activities, but also acted synergistically with GRIP1 to enhance these nuclear receptor (NR) functions. However, the NR binding motif, LXXLL, conserved in mACTN2 and other actinin family proteins, might be a dispensable domain for its coactivator roles in NRs. These findings suggested that mACTN2 might play an important role in GRIP1-induced NR coactivator functions.

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The Nuclear Receptor-Coactivator Interaction Surface as a Target for Peptide Antagonists of the Peroxisome Proliferator-Activated Receptors

Molecular Endocrinology ◽

10.1210/me.2007-0201 ◽

2007 ◽

Vol 21 (10) ◽

pp. 2361-2377 ◽

Cited By ~ 32

Author(s):

Niharika B. Mettu ◽

Thomas B. Stanley ◽

Mary A. Dwyer ◽

Michelle S. Jansen ◽

John E. Allen ◽

...

Keyword(s):

Nuclear Receptors ◽

Nuclear Receptor ◽

Target Genes ◽

Binding Motif ◽

Peroxisome Proliferator ◽

Constitutive Activity ◽

Phage Display Technology ◽

Nuclear Receptor Coactivator ◽

Peroxisome Proliferator Activated Receptors ◽

Interaction Surface

Abstract The peroxisome proliferator-activated receptors (PPARα, PPARδ, and PPARγ) constitute a family of nuclear receptors that regulates metabolic processes involved in lipid and glucose homeostasis. Although generally considered to function as ligand-regulated receptors, all three PPARs exhibit a high level of constitutive activity that may result from their stimulation by intracellularly produced endogenous ligands. Consequently, complete inhibition of PPAR signaling requires the development of inverse agonists. However, the currently available small molecule antagonists for the PPARs function only as partial agonists, or their efficacy is not sufficient to inhibit the constitutive activity of these receptors. Due to the lack of efficacious antagonists that interact with the ligand-binding domain of the PPARs, we decided to target an interaction that is central to nuclear receptor-mediated gene transcription: the nuclear receptor-coactivator interaction. We utilized phage display technology to identify short LXXLL-containing peptides that bind to the PPARs. Analysis of these peptides revealed a consensus binding motif consisting of HPLLXXLL. Cross-screening of these peptides for binding to other nuclear receptors enabled the identification of a high-affinity PPAR-selective peptide that has the ability to repress PPARγ1-dependent transcription of transfected reporter genes. Most importantly, when introduced into HepG2 cells, the peptide inhibited the expression of endogenous PPARγ1 target genes, adipose differentiation-related protein and mitochondrial 3-hydroxy-3-methylglutaryl coenzyme A synthase 2. This work lends support for the rational development of peptidomimetics that block receptor-mediated transcription by targeting the nuclear receptor-coactivator interaction surface.

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