scholarly journals MTA family of coregulators in nuclear receptor biology and pathology

2007 ◽  
Vol 5 (1) ◽  
pp. nrs.05010 ◽  
Author(s):  
Bramanandam Manavathi ◽  
Kamini Singh ◽  
Rakesh Kumar
Keyword(s):  
Estrogen Receptor ◽  
Nuclear Receptors ◽  
Histone Deacetylases ◽  
Target Genes ◽  
Estrogen Signaling ◽  
Dependent Manner ◽  
Nucleosome Remodeling ◽  
Associated Proteins ◽  
Receptor Biology ◽  
Receptor Transactivation

Nuclear receptors (NRs) rely on coregulators (coactivators and corepressors) to modulate the transcription of target genes. By interacting with nucleosome remodeling complexes, NR coactivators potentiate transcription, whereas corepressors inhibit transcription of the target genes. Metastasis-associated proteins (MTA) represent an emerging family of novel NR coregulators. In general, MTA family members form independent nucleosome remodeling and deacetylation (NuRD) complexes and repress the transcription of different genes by recruiting histone deacetylases onto their target genes. However, MTA1 also acts as a coactivator in a promoter-context dependent manner. Recent findings that repression of estrogen receptor transactivation functions by MTA1, MTA1s, and MTA2 and regulation of MTA3 by estrogen signaling have indicated the significance of these proteins in NR signaling. Here, we highlight the action of MTA proteins on NR signaling and their roles in pathophysiological conditions.

scholarly journals Poly-ADP-Ribosylation of Estrogen Receptor-Alpha by PARP1 Mediates Antiestrogen Resistance in Human Breast Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 43 ◽  
Author(s):  
Nicholas Pulliam ◽  
Jessica Tang ◽  
Weini Wang ◽  
Fang Fang ◽  
Riddhi Sood ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Oxidative Stress ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Target Genes ◽  
Tamoxifen Resistance ◽  
Tamoxifen Treatment ◽  
Dependent Manner ◽  
Tamoxifen Resistant

Therapeutic targeting of estrogen receptor-α (ERα) by the anti-estrogen tamoxifen is standard of care for premenopausal breast cancer patients and remains a key component of treatment strategies for postmenopausal patients. While tamoxifen significantly increases overall survival, tamoxifen resistance remains a major limitation despite continued expression of ERα in resistant tumors. Previous reports have described increased oxidative stress in tamoxifen resistant versus sensitive breast cancer and a role for PARP1 in mediating oxidative damage repair. We hypothesized that PARP1 activity mediated tamoxifen resistance in ERα-positive breast cancer and that combining the antiestrogen tamoxifen with a PARP1 inhibitor (PARPi) would sensitize tamoxifen resistant cells to tamoxifen therapy. In tamoxifen-resistant vs. -sensitive breast cancer cells, oxidative stress and PARP1 overexpression were increased. Furthermore, differential PARylation of ERα was observed in tamoxifen-resistant versus -sensitive cells, and ERα PARylation was increased by tamoxifen treatment. Loss of ERα PARylation following treatment with a PARP inhibitor (talazoparib) augmented tamoxifen sensitivity and decreased localization of both ERα and PARP1 to ERα-target genes. Co-administration of talazoparib plus tamoxifen increased DNA damage accumulation and decreased cell survival in a dose-dependent manner. The ability of PARPi to overcome tamoxifen resistance was dependent on ERα, as lack of ERα-mediated estrogen signaling expression and showed no response to tamoxifen-PARPi treatment. These results correlate ERα PARylation with tamoxifen resistance and indicate a novel mechanism-based approach to overcome tamoxifen resistance in ER+ breast cancer.

Membrane-Initiated Estradiol Signaling in the Central Nervous System

2019 ◽  
Author(s):  
Paul E. Micevych ◽  
Melinda A. Mittelman-Smith
Keyword(s):  
Nervous System ◽  
Estrogen Receptor ◽  
Estrogen Receptors ◽  
G Protein ◽  
Nuclear Receptors ◽  
Signaling Cascades ◽  
Estrogen Signaling ◽  
Female Reproduction ◽  
Brain Physiology ◽  
The Brain

In the last two decades of the 20th century, key findings in the field of estrogen signaling completely changed our understanding of hormones: first, steroidogenesis was demonstrated in the CNS; second, a vast majority of cells in the nervous system were shown to have estrogen receptors; third, a second nuclear estrogen receptor (ERß) was cloned; and finally, “nuclear” receptors were shown to be present and functional in the cell membrane. Shortly thereafter, even more membrane estrogen receptors were discovered. Steroids (estrogens, in particular) began to be considered as neurotransmitters and their receptors were tethered to G protein-coupled receptor signaling cascades. In some parts of the brain, levels of steroids appeared to be independent of those found in the circulation and yet, circulating steroids had profound actions on the brain physiology. In this review, we discuss the interaction of peripheral and central estrogen action in the context of female reproduction—one of the best-studied aspects of steroid action. In addition to reviewing the evidence for steroidogenesis in the hypothalamus, we review membrane-localized nuclear receptors coupling to G protein-signaling cascades and the downstream physiological consequences for reproduction. We will also introduce newer work that demonstrates cell signaling for a common splice variant of estrogen receptor-α (ERα), and membrane action of neuroprogesterone in regulating estrogen positive feedback.

scholarly journals Inhibition of Estrogen Receptor Action by the Orphan Receptor SHP (Short Heterodimer Partner)

1998 ◽  
Vol 12 (10) ◽  
pp. 1551-1557 ◽  
Author(s):  
Wongi Seol ◽  
Bettina Hanstein ◽  
Myles Brown ◽  
David D. Moore
Keyword(s):  
Estrogen Receptor ◽  
Thyroid Hormone ◽  
Transcriptional Activation ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Orphan Receptor ◽  
Estrogen Signaling ◽  
Dependent Manner ◽  
Interaction Domain ◽  
Short Heterodimer Partner

Abstract SHP (short heterodimer partner) is an unusual orphan receptor that lacks a conventional DNA-binding domain. Previous results have shown that it interacts with several other nuclear hormone receptors, including the retinoid and thyroid hormone receptors, and inhibits their ligand-dependent transcriptional activation. Here we show that SHP also interacts with estrogen receptors and inhibits their function. In mammalian and yeast two-hybrid systems as well as glutathione-S-transferase pull-down assays, SHP interacts specifically with estrogen receptor-α (ERα) in an agonist-dependent manner. The same assay systems using various deletion mutants of SHP map the interaction domain with ERα to the same SHP sequences required for interaction with the nonsteroid hormone receptors such as retinoid X receptor and thyroid hormone receptor. In transient cotransfection assays, SHP inhibits estradiol -dependent activation by ERα by about 5-fold. In contrast, SHP interacts with ERβ independent of ligand and reduces its ability to activate transcription by only 50%. These data suggest that SHP functions to regulate estrogen signaling through a direct interaction with ERα.

scholarly journals Estrogen Receptor β: An Overview and Update

2008 ◽  
Vol 6 (1) ◽  
pp. nrs.06003 ◽  
Author(s):  
Chunyan Zhao ◽  
Karin Dahlman-Wright ◽  
Jan-Åke Gustafsson
Keyword(s):  
Estrogen Receptor ◽  
Target Genes ◽  
Expression Patterns ◽  
Estrogen Signaling ◽  
Receptor Subtypes ◽  
Specific Expression ◽  
Microarray Experiments ◽  
Downstream Target ◽  
Animal Disease Models ◽  
Selective Ligands

The discovery of a second estrogen receptor (ER), designated ERβ (NR3A2), has redefined our knowledge about the mechanisms underlying cellular signaling by estrogens and has broad implications for our understanding of regulation of estrogen-responsive tissues. Highly variable and even contrasting effects of estrogens in different tissues seem to be at least partially explained by different estrogen signaling pathways, involving ERα (NR3A1) and/or ERβ. To date, two key conclusions can be drawn from the significant body of work carried out on the specific roles of the two receptor subtypes in diverse estrogen target tissues. First, ERα and ERβ have different biological functions, as indicated by their specific expression patterns and the distinct phenotypes observed in ERα and ERβ knockout (αERKO and βERKO) mice. Second, ERα and ERβ appear to have overlapping but also unique sets of downstream target genes, as judged from a set of microarray experiments. Thus, ERα and ERβ have different transcriptional activities in certain ligand, cell-type, and promoter contexts, which may help to explain some of the major differences in their tissue-specific biological actions. The phenotypes observed for βERKO mice have suggested certain therapeutic areas to be further explored. The development of ERβ-selective ligands active in animal disease models indicates new avenues for clinical exploration. ERβ agonists are being explored and validated as drugs for a growing number of indications. Hopefully, some ERβ targeted drugs will prove to be efficient in enhancing human health.

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 Sex- and Age-Related Estrogen Signaling Alteration in Inflammatory Bowel Diseases: Modulatory Role of Estrogen Receptors

2019 ◽  
Vol 20 (13) ◽  
pp. 3175 ◽  
Author(s):  
Damian Jacenik ◽  
Adam I. Cygankiewicz ◽  
Anna Mokrowiecka ◽  
Ewa Małecka-Panas ◽  
Jakub Fichna ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptors ◽  
Inflammatory Bowel Diseases ◽  
Protein Level ◽  
Estrogen Signaling ◽  
Dependent Manner ◽  
Tissue Samples ◽  
Age Related ◽  
Bowel Diseases ◽  
Inflammatory Bowel

The pathogenesis of inflammatory bowel diseases (IBD) seems to be associated with alterations of immunoregulation. Several lines of evidence suggest that estrogens play a role in the modulation of immune responses and may be related to the etiology of IBD. The purpose of this work was to examine the involvement of G protein-coupled estrogen receptor (GPER), estrogen receptor α (ERα), estrogen receptor β (ERβ) and ERα spliced variants ERα36 and ERα46 in Crohn’s disease (CD) and ulcerative colitis (UC). The studied group included 73 patients with IBD and 31 sex and age-related controls. No differences in serum levels of 17β-estradiol nor of CYP1A1 and SULT1E1 enzymes involved in estrogen catabolism were stated. The expression pattern of estrogen receptors in tissue samples was quantified using real-time PCR and Western blotting. Statistically significant up-regulation of GPER and ERα in both CD and UC as well as down-regulation of ERβ in CD patients was found. However, differences in the expression of estrogen receptors in CD and UC have been identified, depending on the sex and age of patients. In men, up-regulation of GPER, ERα and ERα46 expression was shown in CD and UC patients. In women under 50 years of age, GPER protein level increased in UC whereas ERβ expression tended to decrease in CD and UC patients. In turn, in women over 50 the protein level of ERα increased in UC while ERβ expression decreased in CD patients. Dysregulation of estrogen receptors in the intestinal mucosa of patients with CD and UC indicates that estrogen signaling may play a role in the local immune response and maintain epithelial homeostasis in a gender- and age-dependent manner.

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 The SWI/SNF ATP-Dependent Chromatin Remodeling Complex in Arabidopsis Responds to Environmental Changes in Temperature-Dependent Manner

2020 ◽  
Vol 21 (3) ◽  
pp. 762 ◽  
Author(s):  
Dominika M. Gratkowska-Zmuda ◽  
Szymon Kubala ◽  
Elzbieta Sarnowska ◽  
Pawel Cwiek ◽  
Paulina Oksinska ◽  
...  
Keyword(s):  
Plant Growth ◽  
Chromatin Remodeling ◽  
Target Genes ◽  
Environmental Changes ◽  
Fine Tuning ◽  
Regulation Of Transcription ◽  
Dependent Manner ◽  
Growth Responses ◽  
Nucleosome Remodeling ◽  
The Core

SWI/SNF ATP-dependent chromatin remodeling complexes (CRCs) play important roles in the regulation of transcription, cell cycle, DNA replication, repair, and hormone signaling in eukaryotes. The core of SWI/SNF CRCs composed of a SWI2/SNF2 type ATPase, a SNF5 and two of SWI3 subunits is sufficient for execution of nucleosome remodeling in vitro. The Arabidopsis genome encodes four SWI2/SNF2 ATPases, four SWI3, a single SNF5 and two SWP73 subunits. Genes of the core SWI/SNF components have critical but not fully overlapping roles during plant growth, embryogenesis, and sporophyte development. Here we show that the Arabidopsis swi3c mutant exhibits a phenotypic reversion when grown at lower temperature resulting in partial restoration of its embryo, root development and fertility defects. Our data indicates that the swi3c mutation alters the expression of several genes engaged in low temperature responses. The location of SWI3C-containing SWI/SNF CRCs on the ICE1, MYB15 and CBF1 target genes depends on the temperature conditions, and the swi3c mutation thus also influences the transcription of several cold-responsive (COR) genes. These findings, together with genetic analysis of swi3c/ice1 double mutant and enhanced freezing tolerance of swi3c plants illustrate that SWI/SNF CRCs contribute to fine-tuning of plant growth responses to different temperature regimes.

scholarly journals Expression Levels of Estrogen Receptor β Are Modulated by Components of the Molecular Clock

2007 ◽  
Vol 28 (2) ◽  
pp. 784-793 ◽  
Author(s):  
Wen Cai ◽  
Juliette Rambaud ◽  
Michèle Teboul ◽  
Ingrid Masse ◽  
Gerard Benoit ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Target Genes ◽  
Regulation Of Gene Expression ◽  
Estrogen Receptor Beta ◽  
Circadian System ◽  
Estrogen Signaling ◽  
Mrna Levels ◽  
Peripheral Tissues ◽  
Regulatory Factors ◽  
Expression Levels

ABSTRACT Circadian regulation of gene expression plays a major role in health and disease. The precise role of the circadian system remains to be clarified, but it is known that circadian proteins generate physiological rhythms in organisms by regulating clock-controlled target genes. The estrogen receptor beta (ERβ) is, together with ERα, a member of the nuclear receptor superfamily and a key mediator of estrogen action. Interestingly, recent studies show that disturbed circadian rhythmicity in humans can increase the risk of reproductive malfunctions, suggesting a link between the circadian system and ER-mediated transcription pathways. Here, we identify a novel level of regulation of estrogen signaling where ERβ, but not ERα, is controlled by circadian clock proteins. We show that ERβ mRNA levels fluctuate in different peripheral tissues following a robust circadian pattern, with a peak at the light-dark transition, which is maintained under free-running conditions. Interestingly, this oscillation is abolished in clock-deficient BMAL1 knockout mice. Circadian control of ERβ expression is exerted through a conserved E-box element in the ERβ promoter region that recruits circadian regulatory factors. Furthermore, using small interfering RNA-mediated knockdown assays, we show that the expression levels of the circadian regulatory factors directly influence estrogen signaling by regulating the intracellular levels of endogenous ERβ.

scholarly journals GAC63, a GRIP1-Dependent Nuclear Receptor Coactivator

2005 ◽  
Vol 25 (14) ◽  
pp. 5965-5972 ◽  
Author(s):  
Yong-Heng Chen ◽  
Jeong Hoon Kim ◽  
Michael R. Stallcup
Keyword(s):  
Estrogen Receptor ◽  
Protein Interactions ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Gene Promoter ◽  
Dependent Manner ◽  
Protein Protein Interactions ◽  
Promoter Regions ◽  
Nuclear Receptor Coactivator ◽  
Binding Domains

ABSTRACT Nuclear receptors (NRs) regulate target gene transcription through the recruitment of multiple coactivator complexes to the promoter regions of target genes. One important coactivator complex includes a p160 coactivator (GRIP1, SRC-1, or ACTR) and its downstream coactivators (e.g., p300, CARM1, CoCoA, and Fli-I), which contribute to transcriptional activation by protein acetylation, protein methylation, and protein-protein interactions. In this study, we identified a novel NR coactivator, GAC63, which binds to the N-terminal region of p160 coactivators as well as the ligand binding domains of some NRs. GAC63 enhanced transcriptional activation by NRs in a hormone-dependent and GRIP1-dependent manner in transient transfection assays and cooperated synergistically and selectively with other NR coactivators, including GRIP1 and CARM1, to enhance estrogen receptor function. Endogenous GAC63 was recruited to the estrogen-responsive pS2 gene promoter of MCF-7 cells in response to the hormone. Reduction of the endogenous GAC63 level by small interfering RNA inhibited transcriptional activation by the hormone-activated estrogen receptor. Thus, GAC63 is a physiologically relevant part of the p160 coactivator signaling pathway that mediates transcriptional activation by NRs.

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