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 Positive and Negative Regulation of Chicken Anemia Virus Transcription

2005 ◽  
Vol 79 (5) ◽  
pp. 2859-2868 ◽  
Author(s):  
Myrna M. Miller ◽  
Keith W. Jarosinski ◽  
Karel A. Schat
Keyword(s):  
Estrogen Receptor ◽  
Nuclear Receptor ◽  
Protein Translation ◽  
Chicken Anemia Virus ◽  
Egfp Expression ◽  
Start Site ◽  
Response Element ◽  
Nuclear Receptor Superfamily ◽  
Promoter Construct ◽  
Anemia Virus

ABSTRACT Chicken anemia virus (CAV) is a small circular single-stranded DNA virus with a single promoter-enhancer region containing four consensus cyclic AMP response element sequences (AGCTCA), which are similar to the estrogen response element (ERE) consensus half-sites (A)GGTCA. These sequences are arranged as direct repeats, an arrangement that can be recognized by members of the nuclear receptor superfamily. Transient-transfection assays which use a short CAV promoter construct that ended at the transcription start site and drive expression of enhanced green fluorescent protein (EGFP) showed high basal activity in DF-1, LMH, LMH/2A, and primary theca and granulosa cells. The estrogen receptor-enhanced cell line, LMH/2A, had significantly greater expression than LMH cells, and this expression was significantly increased with estrogen treatment. A long promoter construct which included GGTCA-like sequences downstream of the first CAV protein translation start site was found to have significantly less EGFP expression in DF-1 cells than the short promoter, which was largely due to decreased RNA transcription. DNA-protein binding assays indicated that proteins recognizing a consensus ERE palindrome also bind GGTCA-like sequences in the CAV promoter. Estrogen receptor and other members of the nuclear receptor superfamily may provide a mechanism to regulate CAV activity in situations of low virus copy number.

Selective estrogen receptor modulators suppress mesangial cell collagen synthesis

2000 ◽  
Vol 279 (2) ◽  
pp. F309-F318 ◽  
Author(s):  
Joel Neugarten ◽  
Anjali Acharya ◽  
Jun Lei ◽  
Sharon Silbiger
Keyword(s):  
Estrogen Receptor ◽  
Collagen Synthesis ◽  
Type Iv Collagen ◽  
Mesangial Cell ◽  
Type I ◽  
Dependent Manner ◽  
Type Iv ◽  
Estrogen Receptor Modulators ◽  
Receptor Modulators ◽  
Dose Dependent

Estrogen receptor modulators (SERMs) are “designer drugs” that exert estrogen-like actions in some cells but not in others. We examined the effects of the SERMs LY-117018 (an analog of raloxifene) and tamoxifen on mesangial cells synthesis of type I and type IV collagen. We found that LY-117018 and tamoxifen suppressed mesangial cell type IV collagen gene transcription and type IV collagen protein synthesis in a dose-dependent manner, with a potency identical to that of estradiol. Type I collagen synthesis was also suppressed by LY-117018 in a dose-dependent manner with a potency identical to that of estradiol but greater than that of tamoxifen. Genistein, which selectively binds to estrogen receptor-β in nanomolar concentrations, suppressed type I and type IV collagen synthesis, suggesting that estrogen receptor-β mediates the effects of estrogen on collagen synthesis. Because matrix accumulation is central to the development of glomerulosclerosis, second-generation SERMs may prove clinically useful in ameliorating progressive renal disease without the adverse effects of estrogen on reproductive tissues.

scholarly journals SERMs in the prevention and treatment of postmenopausal osteoporosis: an update

2010 ◽  
Vol 54 (2) ◽  
pp. 200-205 ◽  
Author(s):  
Jaime Kulak Júnior ◽  
Carolina Aguiar Moreira Kulak ◽  
Hugh S. Taylor
Keyword(s):  
Estrogen Receptor ◽  
Postmenopausal Osteoporosis ◽  
Single Agent ◽  
Clinical Development ◽  
Target Tissue ◽  
New Approach ◽  
Estrogen Receptor Modulators ◽  
Receptor Modulator ◽  
Prevention And Treatment ◽  
Receptor Modulators

Selective estrogen receptor modulators (SERMs) have the ability to bind the estrogen receptor (ER) and are known to confer ER agonist or antagonist effects depending on the target tissue. A number of newer SERMs, including bazedoxifene, lasofoxifene and ospemifene, are currently under clinical development for the prevention and treatment of postmenopausal osteoporosis and for other indications. Although the possibility of developing a single agent that has all of the desired characteristics of an ideal SERM seems to be unlikely, progress in the clinical development of SERMs targeted to the ER suggests that these newer compounds may have attributes that represent an improvement relative to existing SERMs. A new approach to menopausal therapy is the tissue selective estrogen complex or the pairing of a selective estrogen receptor modulator with estrogens. Further investigation will help to clarify relative benefits/risks of novel SERMs in development within specific indications.

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 Hormone receptor 4 is required in muscles and distinct ovarian cell types to regulate specific steps of Drosophila oogenesis

Development ◽  
2021 ◽  
pp. dev.198663
Author(s):  
Lesley N. Weaver ◽  
Daniela Drummond-Barbosa
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Hormone Receptor ◽  
Cell Types ◽  
Germline Stem Cell ◽  
Follicle Growth ◽  
Peripheral Tissues ◽  
Ovarian Cell ◽  
Nuclear Receptor Superfamily ◽  
Germline Cyst

The conserved nuclear receptor superfamily has critical roles in many processes, including reproduction. Nuclear receptors with known roles in oogenesis have been studied mostly in the context of their ovary-intrinsic requirement. Recent studies in Drosophila, however, have begun to reveal new roles of nuclear receptor signaling in peripheral tissues in controlling reproduction. Here, we identified Hormone receptor 4 (Hr4) as an oogenesis regulator required in the ovary and muscles. Global Hr4 knockdown leads to increased germline stem cell (GSC) loss, reduced GSC proliferation, early germline cyst death, slowed follicle growth, and vitellogenic follicle degeneration. Tissue-specific knockdown experiments uncovered ovary-intrinsic and peripheral tissue requirements for Hr4. In the ovary, Hr4 is required in the niche for GSC proliferation and in the germline for GSC maintenance. Hr4 functions in muscles to promote GSC maintenance and follicle growth. The specific tissues that require Hr4 for survival of early germline cysts and vitellogenic follicles remain unidentified. These results add to the few examples of muscles controlling gametogenesis and expand our understanding of the complexity of nuclear receptor regulation of various aspects of oogenesis.

scholarly journals A Retrospective on Nuclear Receptor Regulation of Inflammation: Lessons from GR and PPARs

PPAR Research ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Min-Dian Li ◽  
Xiaoyong Yang
Keyword(s):  
Glucocorticoid Receptor ◽  
Signaling Pathways ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Receptor Regulation ◽  
Peroxisome Proliferator ◽  
Novel Therapies ◽  
Nuclear Receptor Superfamily ◽  
Founding Member ◽  
Peroxisome Proliferator Activated Receptors

Members of the nuclear receptor superfamily have vital roles in regulating immunity and inflammation. The founding member, glucocorticoid receptor (GR), is the prototype to demonstrate immunomodulation via transrepression of the AP-1 and NF-κB signaling pathways. Peroxisome proliferator-activated receptors (PPARs) have emerged as key regulators of inflammation. This review examines the history and current advances in nuclear receptor regulation of inflammation by the crosstalk with AP-1 and NF-κB signaling, focusing on the roles of GR and PPARs. A better understanding of the molecular mechanism by which nuclear receptors inhibit proinflammatory signaling pathways will enable novel therapies to treat chronic inflammation.

scholarly journals Identification and Characterization of a Tissue-Specific Coactivator, GT198, That Interacts with the DNA-Binding Domains of Nuclear Receptors

2002 ◽  
Vol 22 (1) ◽  
pp. 357-369 ◽  
Author(s):  
Lan Ko ◽  
Guemalli R. Cardona ◽  
Alexandra Henrion-Caude ◽  
William W. Chin
Keyword(s):  
Protein Kinase ◽  
Dna Binding ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Thyroid Hormone Receptor ◽  
Pituitary Cells ◽  
Tissue Specific ◽  
Dna Binding Domains ◽  
Binding Domains

ABSTRACT Gene activation mediated by nuclear receptors is regulated in a tissue-specific manner and requires interactions between nuclear receptors and their cofactors. Here, we identified and characterized a tissue-specific coactivator, GT198, that interacts with the DNA-binding domains of nuclear receptors. GT198 was originally described as a genomic transcript that mapped to the human breast cancer susceptibility locus 17q12-q21 with unknown function. We show that GT198 exhibits a tissue-specific expression pattern in which its mRNA is elevated in testis, spleen, thymus, pituitary cells, and several cancer cell lines. GT198 is a 217-amino-acid nuclear protein that contains a leucine zipper required for its dimerization. In vitro binding and yeast two-hybrid assays indicated that GT198 interacted with nuclear receptors through their DNA-binding domains. GT198 potently stimulated transcription mediated by estrogen receptor α and β, thyroid hormone receptor β1, androgen receptor, glucocorticoid receptor, and progesterone receptor. However, the action of GT198 was distinguishable from that of the ligand-binding domain-interacting nuclear receptor coactivators, such as TRBP, CBP, and SRC-1, with respect to basal activation and hormone sensitivity. Furthermore, protein kinase A, protein kinase C, and mitogen-activated protein kinase can phosphorylate GT198 in vitro, and cotransfection of these kinases regulated the transcriptional activity of GT198. These data suggest that GT198 is a tissue-specific, kinase-regulated nuclear receptor coactivator that interacts with the DNA-binding domains of nuclear receptors.

scholarly journals Dimerization is required for transactivation by estrogen-receptor-related (ERR) orphan receptors: evidence from amphioxus ERR

2004 ◽  
Vol 33 (2) ◽  
pp. 493-509 ◽  
Author(s):  
B Horard ◽  
A Castet ◽  
P-L Bardet ◽  
V Laudet ◽  
V Cavailles ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Nuclear Receptor ◽  
Transcriptional Activation ◽  
Target Site ◽  
Estrogen Response Element ◽  
Orphan Receptors ◽  
Response Element ◽  
Nuclear Receptor Superfamily ◽  
Estrogen Response ◽  
Target Sites

The estrogen-receptor-related (ERR) receptors are orphan members of the nuclear receptor superfamily that bind to their specific DNA target sites as homodimers. However, it has not been shown whether this mode of binding is required for the transcriptional activation they drive. We here show that heterodimerization can also occur between these receptors. Furthermore, we demonstrate that the unique amphioxus ortholog of ERR genes (AmphiERR) is expressed as two isoforms differing by an in-frame insertion. While the short isoform behaves like its mammalian counterparts, the long isoform (AmphiERR(L)) displays divergent transcriptional properties according to the target site to which it binds. Indeed, AmphiERR(L) binds as a monomer but does not activate transcription through the SF1 response element (SFRE). On the contrary, this isoform binds as a homodimer and activates transcription through the classical estrogen-response element. Our results strongly suggest that dimerization is required for transactivation exerted by the ERR receptors.

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.

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