Studying Nuclear Receptor Complexes in the Cellular Environment

2016 ◽  
pp. 79-104 ◽  
Author(s):  
Fred Schaufele
Keyword(s):  
Nuclear Receptor ◽  
Receptor Complexes ◽  
Cellular Environment

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 Corepressor CTBP2 Is a Coactivator of Retinoic Acid Receptor/Retinoid X Receptor in Retinoic Acid Signaling

2013 ◽  
Vol 33 (16) ◽  
pp. 3343-3353 ◽  
Author(s):  
Prashanth Kumar Bajpe ◽  
Guus J. J. E. Heynen ◽  
Lorenza Mittempergher ◽  
Wipawadee Grernrum ◽  
Iris A. de Rink ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Rna Interference ◽  
Nuclear Receptor ◽  
Transcriptional Control ◽  
Target Genes ◽  
Retinoic Acid Receptor ◽  
Retinoid X Receptor ◽  
Gene Promoters ◽  
Acid Receptor ◽  
Receptor Complexes

Retinoids play key roles in development, differentiation, and homeostasis through regulation of specific target genes by the retinoic acid receptor/retinoid X receptor (RAR/RXR) nuclear receptor complex. Corepressors and coactivators contribute to its transcriptional control by creating the appropriate chromatin environment, but the precise composition of these nuclear receptor complexes remains to be elucidated. Using an RNA interference-based genetic screen in mouse F9 cells, we identified the transcriptional corepressor CTBP2 (C-terminal binding protein 2) as a coactivator critically required for retinoic acid (RA)-induced transcription.CTBP2suppression by RNA interference confers resistance to RA-induced differentiation in diverse murine and human cells. Mechanistically, we find that CTBP2 associates with RAR/RXR at RA target gene promoters and is essential for their transactivation in response to RA. We show that CTBP2 is indispensable to create a chromatin environment conducive for RAR/RXR-mediated transcription by recruiting the histone acetyltransferase p300. Our data reveal an unexpected function of the corepressor CTBP2 as a coactivator for RAR/RXR in RA signaling.

Studies on the activation of the oestrogen receptor bound to the anti-oestrogens 4-hydroxytamoxifen and ICI 164,384 by using three monoclonal antibodies

1991 ◽  
Vol 7 (1) ◽  
pp. 9-19 ◽  
Author(s):  
N. Giambiagi ◽  
J. R. Pasqualini
Keyword(s):  
Monoclonal Antibodies ◽  
Guinea Pig ◽  
Nuclear Receptor ◽  
Structural Transformation ◽  
Oestrogen Receptor ◽  
The Other ◽  
Receptor Complex ◽  
Intact Cells ◽  
Receptor Dimerization ◽  
Receptor Complexes

ABSTRACT Three monoclonal antibodies, H222, H226 and D547, which provided evidence of the structural transformation and change in exposure of the functional domains of the oestrogen receptor from fetal guineapig uterus upon activation, were used to study the receptor bound to the anti-oestrogens 4-hydroxytamoxifen and ICI 164,384. No differences in the structure of non-activated 4-hydroxytamoxifen— and ICI 164,384—receptor complexes, as compared with the oestradiol—receptor complex, were detected by the three monoclonal antibodies. When heated at 28°C, both anti-oestrogen—receptor complexes became capable of binding the D547 antibody, which reacts selectively with the activated receptor; however, this binding was lower than that of the oestradiol-receptor complex. The interaction with the H226 antibody showed that anti-oestrogens can induce receptor dimerization, but to a lesser extent than oestradiol. In addition, both anti-oestrogen—receptor complexes can bind to DNA—cellulose and are retained in nuclei from intact cells at 28°C, but less efficiently than the oestradiol—receptor complex. On the other hand, the nuclear receptor seems to have a similar dimeric structure when bound to either anti-oestrogens or oestradiol, as detected by the three monoclonal antibodies. The data suggest that 4-hydroxytamoxifen and ICI 164,384 induce an impaired activation of the oestrogen receptor; this difference, although quantitative rather than qualitative, might be related to the partial agonistic action of these anti-oestrogens in the fetal guinea-pig uterus.

scholarly journals Molecular determinants of MED1 interaction with the DNA bound VDR–RXR heterodimer

2020 ◽  
Vol 48 (19) ◽  
pp. 11199-11213
Author(s):  
Anna Y Belorusova ◽  
Maxime Bourguet ◽  
Steve Hessmann ◽  
Sandra Chalhoub ◽  
Bruno Kieffer ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Transcriptional Activation ◽  
Retinoid X Receptor ◽  
Selective Recognition ◽  
Receptor Complexes ◽  
Binding Domains ◽  
Structural Details ◽  
Molecular Determinants ◽  
Binding Cleft ◽  
Dependent Interaction

Abstract The MED1 subunit of the Mediator complex is an essential coactivator of nuclear receptor-mediated transcriptional activation. While structural requirements for ligand-dependent binding of classical coactivator motifs of MED1 to numerous nuclear receptor ligand-binding domains have been fully elucidated, the recognition of the full-length or truncated coactivator by full nuclear receptor complexes remain unknown. Here we present structural details of the interaction between a large part of MED1 comprising its structured N-terminal and the flexible receptor-interacting domains and the mutual heterodimer of the vitamin D receptor (VDR) and the retinoid X receptor (RXR) bound to their cognate DNA response element. Using a combination of structural and biophysical methods we show that the ligand-dependent interaction between VDR and the second coactivator motif of MED1 is crucial for complex formation and we identify additional, previously unseen, interaction details. In particular, we identified RXR regions involved in the interaction with the structured N-terminal domain of MED1, as well as VDR regions outside the classical coactivator binding cleft affected by coactivator recruitment. These findings highlight important roles of each receptor within the heterodimer in selective recognition of MED1 and contribute to our understanding of the nuclear receptor-coregulator complexes.

NUCLEAR RECEPTOR FOR OESTROGEN IN THE BABOON ENDOMETRIUM: DETECTION, CHARACTERIZATION AND VARIATION IN ITS CONCENTRATION DURING THE MENSTRUAL CYCLE

1980 ◽  
Vol 84 (2) ◽  
pp. 273-280 ◽  
Author(s):  
DOMINIQUE MARTEL ◽  
CATHERINE MALET ◽  
MARIE-NOELLE MONIER ◽  
PIERRE DUBOUCH ◽  
ALEXANDRE PSYCHOYOS
Keyword(s):  
Menstrual Cycle ◽  
Nuclear Receptor ◽  
Oestrogen Receptor ◽  
Sucrose Gradient ◽  
Gradient Centrifugation ◽  
Sucrose Gradient Centrifugation ◽  
Physiological Conditions ◽  
Receptor Complexes ◽  
Receptor Concentration

The present paper describes studies conducted to detect and characterize the nuclear receptor for oestrogen in the baboon endometrium. Only 10% of the [3H]oestradiol nuclear receptor complexes were extracted with a 0·5 m-KCl solution. This solubilized receptor migrated as a 4·4S peak during 5–20% sucrose gradient centrifugation. The oestrogen receptor was not bound to oestrogen in the nuclei under normal physiological conditions. Using an unlabelled competitor addition technique with intact nuclei the variation in oestrogen-receptor concentration of baboon endometrium during the menstrual cycle was measured. This concentration increased slightly during the first week of the cycle, being maximal on day 7 before ovulation (2500 molecules/cell), then decreasing gradually, reaching the lowest level (300 molecules/cell) on day 5 after ovulation, where it remained until the end of the cycle.

scholarly journals The nuclear receptor NR4A1 is regulated by SUMO modification to induce autophagic cell death

2019 ◽  
Author(s):  
Gabriela Zárraga-Granados ◽  
Gabriel Muciño-Hernández ◽  
María R. Sánchez-Carbente ◽  
Wendy Villamizar-Gálvez ◽  
Ana Peñas-Rincón ◽  
...  
Keyword(s):  
Cell Death ◽  
Nuclear Receptor ◽  
Transcriptional Activity ◽  
Intracellular Localization ◽  
Neuronal Cell ◽  
Autophagic Cell Death ◽  
Receptor Protein ◽  
Protein Abundance ◽  
Ligand Interaction ◽  
Cellular Environment

AbstractNR4A is a nuclear receptor protein family whose members act as sensors of cellular environment and regulate multiple processes such as metabolism, proliferation, migration, apoptosis, and autophagy. Since the ligand binding domains of these receptors have no cavity for ligand interaction, their function is most likely regulated by protein abundance and post-translational modifications. In particular, NR4A1 is regulated by protein abundance, phosphorylation, and subcellular distribution (nuclear-cytoplasmic translocation), and acts both as a transcription factor and as a regulator of other interacting proteins. SUMOylation is a post-translational modification that can affect protein stability, transcriptional activity, alter protein-protein interactions and modify intracellular localization of target proteins. In the present study we evaluated the role of SUMOylation as a posttranslational modification that can regulate the activity of NR4A1 to induce autophagy-dependent cell death. We focused on a model potentially relevant for neuronal cell death and demonstrated that NR4A1 needs to be SUMOylated to induce autophagic cell death. We observed that a triple mutant in SUMOylation sites has reduced SUMOylation, increased transcriptional activity, altered intracellular distribution, and more importantly, its ability to induce autophagic cell death is impaired.Summary StatementThe modification of the nuclear receptor NR4A1 by SUMO regulates its transcriptional activity, intracellular localization and is required to induce autophagic cell death.

scholarly journals Acetylation in Nuclear Receptor Signaling and the Role of Sirtuins

2008 ◽  
Vol 22 (3) ◽  
pp. 539-545 ◽  
Author(s):  
Chenguang Wang ◽  
Michael J. Powell ◽  
Vladimir M. Popov ◽  
Richard G. Pestell
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Histone Deacetylases ◽  
Receptor Activity ◽  
Receptor Signaling ◽  
Therapeutic Implications ◽  
Proline Isomerization ◽  
Receptor Complexes ◽  
Nuclear Receptor Coregulators ◽  
Coregulatory Proteins

Abstract It has been known since the early 1970s that nuclear receptor complexes bind DNA in association with coregulatory proteins. Characterization of these nuclear receptor coregulators has revealed diverse enzymatic activities that temporally and spatially coordinate nuclear receptor activity within the context of local chromatin in response to diverse hormone signals. Chromatin-modifying proteins, which dictate the higher-order chromatin structure in which DNA is packaged, in turn orchestrate orderly recruitment of nuclear receptor complexes. Modifications of histones include acetylation, methylation, phosphorylation, ubiquitylation, sumoylation, ADP ribosylation, deimination, and proline isomerization. At this time, we understand how a subset of these modifications regulates nuclear receptor signaling. However, the effects, particularly of acetylation and demethylation, are profound. The finding that nuclear receptors are directly acetylated and that acetylation in turn directly regulates contact-independent growth has broad therapeutic implications. Studies over the past 7 yr have led to the understanding that nuclear receptor acetylation is a conserved function, regulating diverse nuclear receptor activity. Furthermore, we now know that acetylation of multiple and distinct substrates within nuclear receptor signaling pathways, form an acetylation signaling network from the cell surface to the nucleus. The finding that nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases, the sirtuins, are capable of deacetylating nuclear receptors provides a new level of complexity in the control of nuclear receptor activity in which local intracellular concentrations of NAD may regulate nuclear receptor physiology.

ALTERATIONS IN PROGESTERONE RECEPTORS IN THE RAT UTERUS BEARING AN INTRA-UTERINE DEVICE DURING THE OESTROUS CYCLE AND EARLY PREGNANCY

1980 ◽  
Vol 87 (3) ◽  
pp. 365-373 ◽  
Author(s):  
LESLIE MYATT ◽  
M. G. ELDER ◽  
LOUIS LIM
Keyword(s):  
Progesterone Receptor ◽  
Nuclear Receptor ◽  
Early Pregnancy ◽  
Dissociation Constants ◽  
Progesterone Receptors ◽  
Oestrous Cycle ◽  
Rat Uterus ◽  
Binding Characteristics ◽  
Receptor Complexes ◽  
And Control

The binding characteristics, content and intracellular distribution of cytosolic and nuclear progesterone receptors have been investigated, using [3H]progesterone as ligand, in the rat uterus bearing a unilateral intra-uterine device (IUD) during the oestrous cycle and from days 3 to 6 of pregnancy. The dissociation constants of nuclear and cytosolic progesterone–receptor complexes for IUD-containing and control uterine horns were similar. Cytosolic receptor concentrations in the IUD-containing uterus were always lower but changed in a manner similar to the control during the periods studied. Nuclear receptor concentrations in the control horn reflected changes in hormone levels during the oestrous cycle although concentrations measured were greater than previously reported. However, in IUD-containing uteri the pattern was completely reversed with minimal levels at pro-oestrus. Nuclear receptor concentrations were little different in both horns during early pregnancy. Total progesterone receptor synthesis determined between metoestrus and pro-oestrus in IUD-containing horns was significantly less than that of control horns. This correlated with the attenuated rise of nuclear oestrogen receptor levels previously observed between these times in IUD-containing uterine horns.

scholarly journals Molecular determinants of MED1 interaction with the DNA bound VDR-RXR heterodimer

2020 ◽  
Author(s):  
Anna Y. Belorusova ◽  
Maxime Bourguet ◽  
Steve Hessmann ◽  
Sandra Chalhoub ◽  
Bruno Kieffer ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Transcriptional Activation ◽  
Retinoid X Receptor ◽  
Selective Recognition ◽  
Receptor Complexes ◽  
Binding Domains ◽  
Structural Details ◽  
Molecular Determinants ◽  
Binding Cleft ◽  
Dependent Interaction

AbstractThe MED1 subunit of the Mediator complex is an essential coactivator of nuclear receptor-mediated transcriptional activation. While structural requirements for ligand-dependent binding of classical coactivator motifs of MED1 to numerous nuclear receptor ligand-binding domains have been fully elucidated, the recognition of the full-length or truncated coactivator by full nuclear receptor complexes remain unknown. Here we present structural details of the interaction between a large part of MED1 comprising its structured N-terminal and the flexible receptor-interacting domains and the mutual heterodimer of the vitamin D receptor (VDR) and the retinoid X receptor (RXR) bound to their cognate DNA response element. Using a combination of structural and biophysical methods we show that the ligand-dependent interaction between VDR and the second coactivator motif of MED1 is crucial for complex formation and we identify additional, previously unseen, interaction details. In particular, we identified RXR regions involved in the interaction with structured N-terminal domain of MED1, as well as VDR regions outside the classical coactivator binding cleft affected by coactivator recruitment. These findings highlight important roles of each receptor within the heterodimer in selective recognition of MED1 and contribute to our understanding of the nuclear receptor-coregulator complexes.

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