scholarly journals Pharmacological Activators of the NR4A Nuclear Receptors Enhance LTP in a CREB/CBP-Dependent Manner

2016 ◽  
Vol 42 (6) ◽  
pp. 1243-1253 ◽  
Author(s):  
Morgan S Bridi ◽  
Joshua D Hawk ◽  
Snehajyoti Chatterjee ◽  
Stephen Safe ◽  
Ted Abel
Keyword(s):  
Nuclear Receptors ◽  
Dependent Manner ◽  
Nr4a Nuclear Receptors

scholarly journals Activating Signal Cointegrator 2 Belongs to a Novel Steady-State Complex That Contains a Subset of Trithorax Group Proteins

2003 ◽  
Vol 23 (1) ◽  
pp. 140-149 ◽  
Author(s):  
Young-Hwa Goo ◽  
Young Chang Sohn ◽  
Dae-Hwan Kim ◽  
Seung-Whan Kim ◽  
Min-Jung Kang ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Steady State ◽  
Nuclear Receptors ◽  
Transcriptional Activation ◽  
Retinoic Acid Receptor ◽  
Dependent Manner ◽  
Trithorax Group ◽  
Trithorax Group Proteins

ABSTRACT Many transcription coactivators interact with nuclear receptors in a ligand- and C-terminal transactivation function (AF2)-dependent manner. These include activating signal cointegrator 2 (ASC-2), a recently isolated transcriptional coactivator molecule, which is amplified in human cancers and stimulates transactivation by nuclear receptors and numerous other transcription factors. In this report, we show that ASC-2 belongs to a steady-state complex of approximately 2 MDa (ASC-2 complex [ASCOM]) in HeLa nuclei. ASCOM contains retinoblastoma-binding protein RBQ-3, α/β-tubulins, and trithorax group proteins ALR-1, ALR-2, HALR, and ASH2. In particular, ALR-1/2 and HALR contain a highly conserved 130- to 140-amino-acid motif termed the SET domain, which was recently implicated in histone H3 lysine-specific methylation activities. Indeed, recombinant ALR-1, HALR, and immunopurified ASCOM exhibit very weak but specific H3-lysine 4 methylation activities in vitro, and transactivation by retinoic acid receptor appears to involve ligand-dependent recruitment of ASCOM and subsequent transient H3-lysine 4 methylation of the promoter region in vivo. Thus, ASCOM may represent a distinct coactivator complex of nuclear receptors. Further characterization of ASCOM will lead to a better understanding of how nuclear receptors and other transcription factors mediate transcriptional activation.

scholarly journals GRIP1, a transcriptional coactivator for the AF-2 transactivation domain of steroid, thyroid, retinoid, and vitamin D receptors.

1997 ◽  
Vol 17 (5) ◽  
pp. 2735-2744 ◽  
Author(s):  
H Hong ◽  
K Kohli ◽  
M J Garabedian ◽  
M R Stallcup
Keyword(s):  
Vitamin D ◽  
Glucocorticoid Receptor ◽  
Nuclear Receptors ◽  
Steroid Hormone Receptors ◽  
Yeast Cells ◽  
Dependent Manner ◽  
Transactivation Domain ◽  
Transcriptional Coactivator ◽  
Vitamin D Receptors ◽  
Receptor Alpha

After binding to enhancer elements, transcription factors require transcriptional coactivator proteins to mediate their stimulation of transcription initiation. A search for possible coactivators for steroid hormone receptors resulted in identification of glucocorticoid receptor interacting protein 1 (GRIP1). The complete coding sequence for GRIP1, isolated from a mouse brain cDNA library, contains an open reading frame of 1,462 codons. GRIP1 is the probable ortholog of the subsequently identified human protein transcription intermediary factor 2 (TIF2) and is also partially homologous to steroid receptor coactivator 1 (SRC-1). The full-length GRIP1 interacted with the hormone binding domains (HBDs) of all five steroid receptors in a hormone-dependent manner and also with HBDs of class II nuclear receptors, including thyroid receptor alpha, vitamin D receptor, retinoic acid receptor alpha, and retinoid X receptor alpha. In contrast to agonists, glucocorticoid antagonists did not promote interaction between the glucocorticoid receptor and GRIP1. In yeast cells, GRIP1 dramatically enhanced the transcriptional activation function of proteins containing the HBDs of any of the above-named receptors fused to the GAL4 DNA binding domain and thus served as a transcriptional coactivator for them. This finding contrasts with previous reports of TIF2 and SRC-1, which in mammalian cells enhanced the transactivation activities of only a subset of the steroid and nuclear receptors that they physically interacted with. GRIP1 also enhanced the hormone-dependent transactivation activity of intact glucocorticoid receptor, estrogen receptor, and mineralocorticoid receptor. Experiments with glucocorticoid receptor truncation and point mutants indicated that GRIP1 interacted with and enhanced the activity of the C-terminal AF-2 but not the N-terminal AF-1 transactivation domain of the glucocorticoid receptor. These results demonstrate directly that AF-1 and AF-2 domains accomplish their transactivation activities through different mechanisms: AF-2 requires GRIP1 as a coactivator, but AF-1 does not.

scholarly journals Targeting Oncogenic Super Enhancers in MYC-Dependent AML Using a Small Molecule Activator of NR4A Nuclear Receptors

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
S. Greg Call ◽  
Ryan P. Duren ◽  
Anil K. Panigrahi ◽  
Loc Nguyen ◽  
Pablo R. Freire ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Small Molecule ◽  
Nr4a Nuclear Receptors

scholarly journals Decreased expression of NR4A nuclear receptors in adenomyosis impairs endometrial decidualization

2016 ◽  
Vol 22 (9) ◽  
pp. 655-668 ◽  
Author(s):  
Yue Jiang ◽  
Ruiwei Jiang ◽  
Xi Cheng ◽  
Qun Zhang ◽  
Yali Hu ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Nr4a Nuclear Receptors

Expression of the breast cancer resistance protein (Bcrp1/Abcg2) in tissues from pregnant mice: effects of pregnancy and correlations with nuclear receptors

2006 ◽  
Vol 291 (6) ◽  
pp. E1295-E1304 ◽  
Author(s):  
Honggang Wang ◽  
Xiaohui Wu ◽  
Kelly Hudkins ◽  
Andrei Mikheev ◽  
Huixia Zhang ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Small Intestine ◽  
Nuclear Receptors ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Cancer Resistance ◽  
Protein Levels ◽  
Pregnant Mice ◽  
Resistance Protein ◽  
Kidney Liver

The breastcancer resistance protein (BCRP) plays an important role in drug disposition, including limiting drug penetration across the placental barrier. Our goal was to investigate the effects of pregnancy on Bcrp1 expression in pregnant mice. We examined Bcrp1 expression in placenta, kidney, liver, and small intestine at various gestational ages. Bcrp1 protein levels peaked at gestation day ( gd) 15 in placenta, at gd 10 and 15 in kidney, and at gd 15 in liver; however, Bcrp1 protein levels in small intestine did not change significantly with gestational ages. Immunohistochemistry analysis revealed that the cellular localization of Bcrp1 in placenta, kidney, liver, and small intestine was not influenced by pregnancy. Bcrp1 mRNA levels were analyzed by quantitative real-time RT-PCR. In general, the effects of pregnancy on Bcrp1 protein somewhat lagged behind the effects on Bcrp1 mRNA. To further investigate the possible roles of nuclear receptors in the regulation of the Bcrp1 gene during pregnancy, we examined mRNA levels of aryl hydrocarbon receptor (AhR), hypoxia-inducible factor 1α (HIF1α), estrogen receptor α (ERα), estrogen receptor β (ERβ), or progesterone receptor and compared them with those of Bcrp1. Bcrp1 mRNA was significantly correlated with mRNA of AhR, HIF1α, and ERβ in placenta, with mRNA of HIF1α in kidney, and with mRNA of AhR and ERα in liver. These data suggest that Bcrp1 expression in mouse tissues can be altered by pregnancy in a gestational age-dependent manner. Such effects are likely mediated by certain nuclear receptors through a transcriptional mechanism.

scholarly journals Specific regulation of thermosensitive lipid droplet fusion by a nuclear hormone receptor pathway

2017 ◽  
Vol 114 (33) ◽  
pp. 8841-8846 ◽  
Author(s):  
Shiwei Li ◽  
Qi Li ◽  
Yuanyuan Kong ◽  
Shuang Wu ◽  
Qingpo Cui ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Lipid Droplets ◽  
Nuclear Hormone Receptor ◽  
Dependent Manner ◽  
Hormone Synthesis ◽  
C Elegans ◽  
Human Cytochrome ◽  
Specific Regulation ◽  
Regulatory Functions

Nuclear receptors play important roles in regulating fat metabolism and energy production in humans. The regulatory functions and endogenous ligands of many nuclear receptors are still unidentified, however. Here, we report that CYP-37A1 (ortholog of human cytochrome P450 CYP4V2), EMB-8 (ortholog of human P450 oxidoreductase POR), and DAF-12 (homolog of human nuclear receptors VDR/LXR) constitute a hormone synthesis and nuclear receptor pathway in Caenorhabditis elegans. This pathway specifically regulates the thermosensitive fusion of fat-storing lipid droplets. CYP-37A1, together with EMB-8, synthesizes a lipophilic hormone not identical to Δ7-dafachronic acid, which represses the fusion-promoting function of DAF-12. CYP-37A1 also negatively regulates thermotolerance and lifespan at high temperature in a DAF-12–dependent manner. Human CYP4V2 can substitute for CYP-37A1 in C. elegans. This finding suggests the existence of a conserved CYP4V2-POR–nuclear receptor pathway that functions in converting multilocular lipid droplets to unilocular ones in human cells; misregulation of this pathway may lead to pathogenic fat storage.

scholarly journals Drug targeting of NR4A nuclear receptors for treatment of acute myeloid leukemia

Leukemia ◽  
2018 ◽  
Vol 33 (1) ◽  
pp. 52-63 ◽  
Author(s):  
Seth P. Boudreaux ◽  
Ryan P. Duren ◽  
Steven G. Call ◽  
Loc Nguyen ◽  
Pablo R. Freire ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Nuclear Receptors ◽  
Drug Targeting ◽  
Myeloid Leukemia ◽  
Acute Myeloid ◽  
Nr4a Nuclear Receptors

scholarly journals Coregulator Function: A Key to Understanding Tissue Specificity of Selective Receptor Modulators

2004 ◽  
Vol 25 (1) ◽  
pp. 45-71 ◽  
Author(s):  
Carolyn L. Smith ◽  
Bert W. O’Malley
Keyword(s):  
Estrogen Receptor ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Critical Role ◽  
Dependent Manner ◽  
Nuclear Receptor Superfamily ◽  
Binding Domains ◽  
Receptor Modulator ◽  
Cellular Environment ◽  
Receptor Modulators

Ligands for the nuclear receptor superfamily control many aspects of biology, including development, reproduction, and homeostasis, through regulation of the transcriptional activity of their cognate receptors. Selective receptor modulators (SRMs) are receptor ligands that exhibit agonistic or antagonistic biocharacter in a cell- and tissue context-dependent manner. The prototypical SRM is tamoxifen, which as a selective estrogen receptor modulator, can activate or inhibit estrogen receptor action. SRM-induced alterations in the conformation of the ligand-binding domains of nuclear receptors influence their abilities to interact with other proteins, such as coactivators and corepressors. It has been postulated, therefore, that the relative balance of coactivator and corepressor expression within a given target cell determines the relative agonist vs. antagonist activity of SRMs. However, recent evidence reveals that the cellular environment also plays a critical role in determining SRM biocharacter. Cellular signaling influences the activity and subcellular localization of coactivators and corepressors as well as nuclear receptors, and this contributes to gene-, cell-, and tissue-specific responses to SRM ligands. Increased understanding of the effect of cellular environment on nuclear receptors and their coregulators has the potential to open the field of SRM discovery and research to many members of the nuclear receptor superfamily.

scholarly journals NR4A nuclear receptors in cardiac remodeling and neurohormonal regulation

2019 ◽  
Vol 29 (8) ◽  
pp. 429-437 ◽  
Author(s):  
Lejla Medzikovic ◽  
Carlie J.M. de Vries ◽  
Vivian de Waard
Keyword(s):  
Nuclear Receptors ◽  
Cardiac Remodeling ◽  
Nr4a Nuclear Receptors
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