scholarly journals The Nuclear Hormone Receptor Coactivator NRC Is a Pleiotropic Modulator Affecting Growth, Development, Apoptosis, Reproduction, and Wound Repair

2004 ◽  
Vol 24 (11) ◽  
pp. 4994-5004 ◽  
Author(s):  
Muktar A. Mahajan ◽  
Sharmistha Das ◽  
Hong Zhu ◽  
Marjana Tomic-Canic ◽  
Herbert H. Samuels
Keyword(s):  
Hormone Receptor ◽  
Wound Repair ◽  
Hormone Receptors ◽  
Homozygous Deletion ◽  
Nuclear Hormone Receptor ◽  
High Rate ◽  
Wild Type ◽  
Postnatal Mortality ◽  
Wild Type Mefs ◽  
Interfering Rna

ABSTRACT Nuclear hormone receptor coregulator (NRC) is a 2,063-amino-acid coregulator of nuclear hormone receptors and other transcription factors (e.g., c-Fos, c-Jun, and NF-κB). We and others have generated C57BL/6-129S6 hybrid (C57/129) NRC+/− mice that appear outwardly normal and grow and reproduce. In contrast, homozygous deletion of the NRC gene is embryonic lethal. NRC−/− embryos are always smaller than NRC+/+ embryos, and NRC−/− embryos die between 8.5 and 12.5 days postcoitus (dpc), suggesting that NRC has a pleotrophic effect on growth. To study this, we derived mouse embryonic fibroblasts (MEFs) from 12.5-dpc embryos, which revealed that NRC−/− MEFs exhibit a high rate of apoptosis. Furthermore, a small interfering RNA that targets mouse NRC leads to enhanced apoptosis of wild-type MEFs. The finding that C57/129 NRC+/− mice exhibit no apparent phenotype prompted us to develop 129S6 NRC+/− mice, since the phenotype(s) of certain gene deletions may be strain dependent. In contrast with C57/129 NRC+/− females, 20% of 129S6 NRC+/− females are infertile while 80% are hypofertile. The 129S6 NRC+/− males produce offspring when crossed with wild-type 129S6 females, although fertility is reduced. The 129S6 NRC+/− mice tend to be stunted in their growth compared with their wild-type littermates and exhibit increased postnatal mortality. Lastly, both C57/129 NRC+/− and 129S6 NRC+/− mice exhibit a spontaneous wound healing defect, indicating that NRC plays an important role in that process. Our findings reveal that NRC is a coregulator that controls many cellular and physiologic processes ranging from growth and development to reproduction and wound repair.

Abstract P244: Transcriptional Regulation of Cardiac Gene Expression by Med13 Alters Global Energy Balance

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Chad E Grueter ◽  
Brett A Johnson ◽  
Xiaoxia Qi ◽  
John McAnally ◽  
Rhonda Bassel-Duby ◽  
...  
Keyword(s):  
Gene Expression ◽  
Energy Balance ◽  
Hormone Receptor ◽  
Hormone Receptors ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Cardiac Contractility ◽  
Nuclear Hormone Receptor ◽  
Mediator Complex

Aberrant cardiac metabolism is associated with obesity, type 2 diabetes and heart failure. The heart requires highly efficient metabolism to maintain the levels of ATP needed for contractility and pump function, however little is known about the role of the heart as a metabolic organ. Nuclear hormone receptors, such as thyroid hormone receptor play an important role in cardiovascular disease by significantly altering expression of genes involved in maintaining metabolic activity. The Mediator, a large multiprotein complex functions as a hub to control gene expression through association with transcriptional activators and repressors. We tested the hypothesis that Med13, a component of the Mediator complex, regulates cardiac function in a gain-of-function mouse model. Trangsenic mice overexpressing Med13 in the heart are lean, have increased energy expenditure, are resistant to high fat diet-induced obesity and have enhanced cardiac contractility. Microarray analysis and biochemical assays show that in vivo and in vitro Med13 selectively inhibits nuclear hormone receptor target genes of energy metabolism. These results implicate the Mediator complex regulates energy balance and cardiac contractility and suggests that the heart may function as a key component of mammalian energy homeostasis.

scholarly journals The Angelman Syndrome-Associated Protein, E6-AP, Is a Coactivator for the Nuclear Hormone Receptor Superfamily

1999 ◽  
Vol 19 (2) ◽  
pp. 1182-1189 ◽  
Author(s):  
Zafar Nawaz ◽  
David M. Lonard ◽  
Carolyn L. Smith ◽  
Efrat Lev-Lehman ◽  
Sophia Y. Tsai ◽  
...  
Keyword(s):  
Angelman Syndrome ◽  
Hormone Receptor ◽  
Hormone Receptors ◽  
Degradation Pathway ◽  
Nuclear Hormone Receptor ◽  
Dependent Manner ◽  
Speech Impairment ◽  
Ubiquitin Protein Ligase ◽  
Independent Functions ◽  
Ligase Function

ABSTRACT In this study, we found that the E6-associated protein (E6-AP/UBE3A) directly interacts with and coactivates the transcriptional activity of the human progesterone receptor (PR) in a hormone-dependent manner. E6-AP also coactivates the hormone-dependent transcriptional activities of the other members of the nuclear hormone receptor superfamily. Previously, it was shown that E6-AP serves the role of a ubiquitin-protein ligase (E3) in the presence of the E6 protein from human papillomavirus types 16 and 18. Our data show that the ubiquitin-protein ligase function of E6-AP is dispensable for its ability to coactivate nuclear hormone receptors, showing that E6-AP possesses two separable independent functions, as both a coactivator and a ubiquitin-protein ligase. Disruption of the maternal copy of E6-AP is correlated with Angelman syndrome (AS), a genetic neurological disorder characterized by severe mental retardation, seizures, speech impairment, and other symptoms. However, the exact mechanism by which the defective E6-AP gene causes AS remains unknown. To correlate the E6-AP coactivator function and ubiquitin-protein ligase functions with the AS phenotype, we expressed mutant forms of E6-AP isolated from AS patients and assessed the ability of each of these mutant proteins to coactivate PR or provide ubiquitin-protein ligase activity. This analysis revealed that in the majority of the AS patients examined, the ubiquitin-protein ligase function of E6-AP was defective whereas the coactivator function was intact. This finding suggests that the AS phenotype results from a defect in the ubiquitin-proteosome protein degradation pathway.

scholarly journals Molecular cloning and characterization of thyroid hormone receptors in teleost fish

2001 ◽  
Vol 26 (1) ◽  
pp. 51-65 ◽  
Author(s):  
O Marchand ◽  
R Safi ◽  
H Escriva ◽  
E Van Rompaey ◽  
P Prunet ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Teleost Fish ◽  
Hormone Receptor ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Nuclear Hormone Receptor ◽  
Hormone Response Elements ◽  
Reverse Transcription Pcr ◽  
Wide Range

Thyroid hormones are pleiotropic factors important for many developmental and physiological functions in vertebrates. Their effects are mediated by two specific receptors (TRalpha and TRbeta) which are members of the nuclear hormone receptor superfamily. To clarify the function of these receptors, our laboratory has started a comparative study of their role in teleost fish. This type of approach has been hampered by the isolation of specific clones for each fish species studied. In this report, we describe an efficient reverse transcription/PCR procedure that allows the isolation of large fragments corresponding to TRalpha and TRbeta of a wide range of teleost fish. Phylogenetic analysis of these receptors revealed a placement consistent with their origin, sequences from teleost fish being clearly monophyletic for both TRalpha and TRbeta. Interestingly, this approach allowed us to isolate (from tilapia and salmon) several new TRalpha or TRbeta isoforms resulting from alternative splicing. These isoforms correspond to expressed transcripts and thus may have an important physiological function. In addition, we isolated a cDNA encoding TRbeta in the Atlantic salmon (Salmo salar) encoding a functional thyroid hormone receptor which binds specific thyroid hormone response elements and regulates transcription in response to thyroid hormones.

scholarly journals Conserved nuclear receptors controlling a novel trait target fast-evolving genes expressed in a single cell

2019 ◽  
Author(s):  
Bogdan Sieriebriennikov ◽  
Shuai Sun ◽  
James W. Lightfoot ◽  
Hanh Witte ◽  
Eduardo Moreno ◽  
...  
Keyword(s):  
Hormone Receptor ◽  
Developmental Plasticity ◽  
Genetic Basis ◽  
Target Genes ◽  
Gland Cell ◽  
Nuclear Hormone Receptor ◽  
Wild Type ◽  
Phenotypic Effect ◽  
Pharyngeal Gland ◽  
Gene Regulatory

AbstractEnvironment shapes development through a phenomenon called developmental plasticity. Deciphering its genetic basis has implications for understanding evolution and adaptation to novel environments, yet molecular studies are scarce. Here, we expanded the gene regulatory network controlling predatory vs. non-predatory morphology in the nematode Pristionchus pacificus. First, we isolated a mutant in the nuclear hormone receptor nhr-1 with a previously unseen phenotypic effect. It disrupts mouth-form determination and results in animals combining features of both wild-type morphs. Further, we identified common targets of NHR-1 and the previously identified nuclear hormone receptor NHR-40 through transcriptomics. Unlike their highly conserved regulators, the target genes have no orthologs in Caenorhabditis elegans and likely result from lineage-specific expansions. An array of transcriptional reporters revealed co-expression of all tested targets in the same pharyngeal gland cell. The morphological remodeling of this cell accompanied the evolution of teeth and predation, linking rapid gene turnover with morphological innovations.

scholarly journals Alien, a Highly Conserved Protein with Characteristics of a Corepressor for Members of the Nuclear Hormone Receptor Superfamily

1999 ◽  
Vol 19 (5) ◽  
pp. 3383-3394 ◽  
Author(s):  
Uwe Dressel ◽  
Dorit Thormeyer ◽  
Boran Altincicek ◽  
Achim Paululat ◽  
Martin Eggert ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Retinoic Acid Receptor ◽  
Specific Interaction ◽  
Gene Activation ◽  
Nuclear Hormone Receptor ◽  
Nuclear Hormone Receptors ◽  
Reporter Assays

ABSTRACT Some members of nuclear hormone receptors, such as the thyroid hormone receptor (TR), silence gene expression in the absence of the hormone. Corepressors, which bind to the receptor’s silencing domain, are involved in this repression. Hormone binding leads to dissociation of corepressors and binding of coactivators, which in turn mediate gene activation. Here, we describe the characteristics of Alien, a novel corepressor. Alien interacts with TR only in the absence of hormone. Addition of thyroid hormone leads to dissociation of Alien from the receptor, as shown by the yeast two-hybrid system, glutathioneS-transferase pull-down, and coimmunoprecipitation experiments. Reporter assays indicate that Alien increases receptor-mediated silencing and that it harbors an autonomous silencing function. Immune staining shows that Alien is localized in the cell nucleus. Alien is a highly conserved protein showing 90% identity between human and Drosophila. Drosophila Alien shows similar activities in that it interacts in a hormone-sensitive manner with TR and harbors an autonomous silencing function. Specific interaction of Alien is seen with Drosophila nuclear hormone receptors, such as the ecdysone receptor and Seven-up, the Drosophila homologue of COUP-TF1, but not with retinoic acid receptor, RXR/USP, DHR 3, DHR 38, DHR 78, or DHR 96. These properties, taken together, show that Alien has the characteristics of a corepressor. Thus, Alien represents a member of a novel class of corepressors specific for selected members of the nuclear hormone receptor superfamily.

scholarly journals Determinants of CoRNR-Dependent Repression Complex Assembly on Nuclear Hormone Receptors

2001 ◽  
Vol 21 (5) ◽  
pp. 1747-1758 ◽  
Author(s):  
Xiao Hu ◽  
Yun Li ◽  
Mitchell A. Lazar
Keyword(s):  
Retinoic Acid ◽  
Hormone Receptor ◽  
Hormone Receptors ◽  
Retinoic Acid Receptor ◽  
Nuclear Hormone Receptor ◽  
Nuclear Hormone Receptors ◽  
Complex Assembly ◽  
Acid Receptor ◽  
Repression Complex ◽  
The Individual

ABSTRACT Ligand-dependent exchange of coactivators and corepressors is the fundamental regulator of nuclear hormone receptor (NHR) function. The interaction surfaces of coactivators and corepressors are similar but distinct enough to allow the ligand to function as a switch. Multiple NHRs share features that allow corepressor binding, and each of two distinct corepressors (N-CoR and SMRT) contains two similar CoRNR motifs that interact with NHRs. Here we report that the specificity of corepressor-NHR interaction is determined by the individual NHR interacting with specific CoRNR boxes within a preferred corepressor. First, receptors have distinct preferences for CoRNR1 versus CoRNR2. For example, the retinoic acid receptor binds CoRNR1, while RXR interacts almost exclusively with CoRNR2. Second, the NHR preference for N-CoR or SMRT is due to differences in CoRNR1 but not CoRNR2. Moreover, within a single corepressor, affinity for different NHRs is determined by distinct regions flanking CoRNR1. The highly specific determinants of NHR-corepressor interaction and preference suggest that repression is regulated by the permissibility of selected receptor-CoRNR-corepressor combinations. Interestingly, different NHR surfaces contribute to binding of CoRNR1 and CoRNR2, suggesting a model to explain corepressor binding to NHR heterodimers.

scholarly journals A nuclear hormone receptor corepressor mediates transcriptional silencing by receptors with distinct repression domains.

1996 ◽  
Vol 16 (10) ◽  
pp. 5458-5465 ◽  
Author(s):  
I Zamir ◽  
H P Harding ◽  
G B Atkins ◽  
A Hörlein ◽  
C K Glass ◽  
...  
Keyword(s):  
Amino Acid ◽  
Nuclear Receptors ◽  
Hormone Receptor ◽  
Transcriptional Repression ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Nuclear Hormone Receptor ◽  
Amino Acid Sequences ◽  
Orphan Receptor ◽  
Primary Amino

Ligand-independent transcriptional repression is an important function of nuclear hormone receptors. An interaction screen with the repression domain of the orphan receptor RevErb identified N-CoR, the corepressor for thyroid hormone receptor (TR) and retinoic acid receptor (RAR). N-CoR is likely to be a bona fide transcriptional corepressor for RevErb because (i) RevErb interacts with endogenous N-CoR, (ii) ectopic N-CoR potentiates RevErb-mediated repression, and (iii) transcriptional repression by RevErb correlates with its ability to bind N-CoR. Remarkably, a region homologous to the CoR box which is necessary for TR and RAR to interact with N-CoR is not required for RevErb. Rather, two short regions of RevErb separated by approximately 200 amino acids are required for interaction with N-CoR. The primary amino acid sequence of the N-terminal region of RevErb essential for N-CoR interaction is not homologous to that of TR or RAR, whereas similarities exist among the C-terminal domains of the receptors. N-CoR contains two adjacent but distinct interaction domains, one of which binds tightly to both RevErb and TR whereas the other binds more weakly and differentially interacts with the nuclear receptors. These results indicate that multiple nuclear receptors, utilizing different primary amino acid sequences, repress transcription by interacting with N-CoR.

scholarly journals Differential Inhibition of Nuclear Hormone Receptor-Dependent Hepatitis B Virus Replication by the Small Heterodimer Partner

2008 ◽  
Vol 82 (8) ◽  
pp. 3814-3821 ◽  
Author(s):  
Claudia E. Oropeza ◽  
Lie Li ◽  
Alan McLachlan
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hormone Receptor ◽  
Rna Synthesis ◽  
Hormone Receptors ◽  
Nuclear Hormone Receptor ◽  
Nuclear Hormone Receptors ◽  
Hbv Replication ◽  
Small Heterodimer Partner ◽  
B Virus

ABSTRACT The nuclear hormone receptors hepatocyte nuclear factor 4 (HNF4) and retinoid X receptor α (RXRα) plus peroxisome proliferator-activated receptor α (PPARα) heterodimer support hepatitis B virus (HBV) pregenomic RNA synthesis and viral replication in nonhepatoma cells. Small heterodimer partner (SHP), an orphan nuclear hormone receptor lacking a DNA binding domain, inhibits nuclear hormone receptor-mediated viral transcription and replication. The inhibition of HBV replication by SHP is dependent on the presence of nuclear hormone receptors. HBV replication that is dependent on HNF4 is considerably more sensitive to SHP-mediated inhibition than RXRα/PPARα-directed viral biosynthesis. SHP inhibition of HBV biosynthesis in HepG2 cells suggests that multiple nuclear hormone receptors mediate viral replication in this human hepatoma cell line. These observations suggest that the physiological regulation of HBV biosynthesis by SHP in the liver will depend on both the level of SHP expression and the relative contribution of HNF4 and RXRα/PPARα, plus potentially additional nuclear hormone receptors, to HBV RNA synthesis and replication.

scholarly journals RORα Augments Thyroid Hormone Receptor-Mediated Transcriptional Activation*

Endocrinology ◽  
1999 ◽  
Vol 140 (3) ◽  
pp. 1356-1364 ◽  
Author(s):  
Noriyuki Koibuchi ◽  
Ying Liu ◽  
Harumi Fukuda ◽  
Akira Takeshita ◽  
Paul M. Yen ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Transcriptional Activation ◽  
Hormone Receptor ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Critical Role ◽  
Nuclear Hormone Receptor ◽  
Dominant Negative ◽  
Mobility Shift ◽  
Response Element

Abstract This study is designed to clarify the role of an orphan nuclear hormone receptor, RORα, on thyroid hormone (TH) receptor (TR)-mediated transcription on a TH-response element (TRE). A transient transfection study using various TREs [i.e., F2 (chick lysozyme TRE), DR4 (direct repeat), and palindrome TRE] and TR and RORα1 was performed. When RORα1 and TR were cotransfected into CV1 cells, RORα1 enhanced the transactivation by liganded-TR on all TREs tested without an effect on basal repression by unliganded TR. By electrophoretic mobility shift assay, on the other hand, although RORα bound to all TREs tested as a monomer, no (or weak) TR and RORα1 heterodimer formation was observed on various TREs except when a putative ROR-response element was present. The transactivation by RORα1 on a ROR-response element, which does not contain a TRE, was not enhanced by TR. The effect of RORα1 on the TREs is unique, because, whereas other nuclear hormone receptors (such as vitamin D receptor) may competitively bind to TRE to exert dominant negative function, RORα1 augmented TR action. These results indicate that RORα1 may modify the effect of liganded TR on TH-responsive genes. Because TR and RORα are coexpressed in cerebellar Purkinje cells, and perinatal hypothyroid animals and RORα-disrupted animals show similar abnormalities of this cell type, cross-talk between these two receptors may play a critical role in Purkinje cell differentiation.

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