scholarly journals Developmental changes in the content of oestrogen receptors in the hypothalamus of the female rat

1979 ◽  
Vol 184 (2) ◽  
pp. 465-468 ◽  
Author(s):  
J O White ◽  
C Hall ◽  
L Lim
Keyword(s):  
Nuclear Receptors ◽  
Early Development ◽  
Nuclear Receptor ◽  
Sexual Differentiation ◽  
Fold Increase ◽  
Developmental Changes ◽  
Female Rat ◽  
Oestrogen Receptors

Hypothalamic cytosol and nuclear oestrogen receptors are present at birth. A 2-fold increase in cytoplasmic receptor content occurs by the second week, whereas the first significant and equivalent increase in nuclear receptor occurs in the fourth week. The latter reflects reported increases in oestradiol availability thought to lead to complete feminine sexual differentiation. The presence of nuclear receptors in the newborn suggests a requirement for oestrogenic stimulation in early development.

scholarly journals Unoccupied nuclear oestrogen receptors in the female rat hypothalamus. Increases on oestrogen administration

1980 ◽  
Vol 190 (3) ◽  
pp. 833-837 ◽  
Author(s):  
J O White ◽  
L Lim
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Female Rat ◽  
Oestrogen Receptors ◽  
Rat Hypothalamus ◽  
Active Elements

A major proportion of the hypothalamic nuclear oestrogen receptors were available for complexing with radioactive oestradiol in vitro at 4 degrees C and were apparently unoccupied . At 6 h after oestradiol administration the content of unoccupied nuclear receptors had increased 2.5-fold and represented 71% of the total nuclear receptor content. These results suggest that unoccupied receptors may be active elements in the ‘long-term’ receptor population of the hypothalamus. Androgenized females had lower contents of these receptors.

scholarly journals Nucleo-cytoplasmic relationships of oestrogen receptors in rat liver during the oestrous cycle and in response to administered natural and synthetic oestrogen

1980 ◽  
Vol 190 (1) ◽  
pp. 17-25 ◽  
Author(s):  
W Marr ◽  
J O White ◽  
M G Elder ◽  
L Lim
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Rat Liver ◽  
Fold Increase ◽  
Oestrous Cycle ◽  
Physiological Changes ◽  
Oestrogen Receptors ◽  
High Affinity ◽  
Cyclic Changes ◽  
Similar Affinity

Oestrogen receptors were measured in the cytosolic and purified nuclear fractions of rat liver. Both cytosolic and nuclear receptors bind oestrogen with high affinity (Kd = 1.47 and 2.28 nM respectively) and specificity similar to that of receptors in order oestrogen-target tissues such as the uterus. During the 4-day oestrous cycle the receptor content and distribution between cytosol and nucleus did not vary; in particular, the content of nuclear receptor did not appear to fluctuate in concert with known cyclic changes in the concentration of plasma oestrogen. Injection of 50 micrograms of oestradiol-17 beta or 10 micrograms of ethynyloestradiol resulted in a 4–6-fold increase in the nuclear receptor content, with a concomitant decrease in the unoccupied-receptor content of cytosol 1 h after injection. The nuclear receptors present after injection bind oestrogens with similar affinity (Kd = 2.78 nM) and specificity to receptors present in uninjected animals. The administration of lower doses of either oestrogen was less effective in producing increases in nuclear receptor content. Hence there is apparently substantial translocation of receptor to the nucleus in response to hyperphysiological doses of oestrogen, but not to the physiological changes in plasma oestrogen concentrations during the oestrous cycle. The response to exogenous oestrogens is discussed in relation to the clinical use of synthetic oestrogens and progestogens.

scholarly journals Unoccupied binding sites for oestrogen in nuclei of a breast tumour cell line (MCF-7)

1981 ◽  
Vol 200 (3) ◽  
pp. 515-520 ◽  
Author(s):  
A Geier ◽  
M Haimsohn ◽  
Z Malik ◽  
B Lunenfeld
Keyword(s):  
Nuclear Receptor ◽  
Fold Increase ◽  
Breast Tumour ◽  
Considerable Change ◽  
Tumour Cell Line ◽  
Nuclear Fraction ◽  
Oestrogen Receptors ◽  
Triton X ◽  
Mcf 7 ◽  
In Cells

1. A method to measure both occupied and unoccupied oestrogen receptors directly in the crude nuclear fraction of the MCF-7 cells was developed. The receptors had high affinity for oestradiol (Kd approx. 0.7 nM) and binding specificity characteristics of oestrogen receptors. 2. A substantial amount of the unoccupied receptors were found in the crude nuclear fraction. 3. Several experiments excluded the possibility that the unoccupied nuclear receptor might be a cytoplasmic contaminant. (a) Multiple extractions with Tris buffer released about 75% of the total receptor content, leaving the rest unextractable in the crude nuclear fraction. (b) Nuclei purified by centrifugation through 1.8M-sucrose and treatment with 0.7% Triton X-100, or by centrifugation through 50% glycerol with 0.1% Triton X-100 contained similar amounts of unoccupied receptors to that found in the crude nuclear fraction. (c) In cells cultured during 5 days after preconfluency a 3-fold increase in the amount of unoccupied cytoplasmic receptors occurred, whereas the amount of unoccupied nuclear receptors did not change significantly and conversely in cells exposed to increasing concentrations of oestradiol the unoccupied cytoplasmic receptor was continuously depleted but no considerable change in the unoccupied nuclear receptor was found.

Nuclear receptors in disease: the oestrogen receptors

2004 ◽  
Vol 40 ◽  
pp. 157-167 ◽  
Author(s):  
Maria Nilsson ◽  
Karin Dahlman-Wright ◽  
Jan-Åke Gustafsson
Keyword(s):  
Nuclear Receptors ◽  
Target Genes ◽  
Receptor Subtype ◽  
Target Tissue ◽  
Oestrogen Receptors ◽  
Nucleotide Polymorphisms ◽  
Cell Type ◽  
Single Nucleotide ◽  
Beneficial Effects ◽  
The Family

For several decades, it has been known that oestrogens are essential for human health. The discovery that there are two oestrogen receptors (ERs), ERalpha and ERbeta, has facilitated our understanding of how the hormone exerts its physiological effects. The ERs belong to the family of ligand-activated nuclear receptors, which act by modulating the expression of target genes. Studies of ER-knockout (ERKO) mice have been instrumental in defining the relevance of a given receptor subtype in a certain tissue. Phenotypes displayed by ERKO mice suggest diseases in which dysfunctional ERs might be involved in aetiology and pathology. Association between single-nucleotide polymorphisms (SNPs) in ER genes and disease have been demonstrated in several cases. Selective ER modulators (SERMs), which are selective with regard to their effects in a certain cell type, already exist. Since oestrogen has effects in many tissues, the goal with a SERM is to provide beneficial effects in one target tissue while avoiding side effects in others. Refined SERMs will, in the future, provide improved therapeutic strategies for existing and novel indications.

scholarly journals Characterization of Receptor Interaction and Transcriptional Repression by the Corepressor SMRT

1997 ◽  
Vol 11 (13) ◽  
pp. 2025-2037 ◽  
Author(s):  
Hui Li ◽  
Christopher Leo ◽  
Daniel J. Schroen ◽  
J. Don Chen
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Transcriptional Repression ◽  
Thyroid Hormone Receptor ◽  
Receptor Interaction ◽  
Basal Transcription ◽  
Protein Protein Interaction ◽  
Stable Association ◽  
Interacting Surfaces ◽  
Transcriptional Corepressors

Abstract SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) and N-CoR (nuclear receptor corepressor) are two related transcriptional corepressors that contain separable domains capable of interacting with unliganded nuclear receptors and repressing basal transcription. To decipher the mechanisms of receptor interaction and transcriptional repression by SMRT/N-CoR, we have characterized protein-protein interacting surfaces between SMRT and nuclear receptors and defined transcriptional repression domains of both SMRT and N-CoR. Deletional analysis reveals two individual nuclear receptor domains necessary for stable association with SMRT and a C-terminal helix essential for corepressor dissociation. Coordinately, two SMRT domains are found to interact independently with the receptors. Functional analysis reveals that SMRT contains two distinct repression domains, and the corresponding regions in N-CoR also repress basal transcription. Both repression domains in SMRT and N-CoR interact weakly with mSin3A, which in turn associates with a histone deacetylase HDAC1 in a mammalian two-hybrid assay. Far-Western analysis demonstrates a direct protein-protein interaction between two N-CoR repression domains with mSin3A. Finally we demonstrate that overexpression of full-length SMRT further represses basal transcription from natural promoters. Together, these results support a role of SMRT/N-CoR in corepression through the utilization of multiple mechanisms for receptor interactions and transcriptional repression.

scholarly journals Inactivation of the Nuclear Receptor Coactivator RAP250 in Mice Results in Placental Vascular Dysfunction

2003 ◽  
Vol 23 (4) ◽  
pp. 1260-1268 ◽  
Author(s):  
Per Antonson ◽  
Gertrud U. Schuster ◽  
Ling Wang ◽  
Björn Rozell ◽  
Elin Holter ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Blood Circulation ◽  
Transcriptional Activity ◽  
Vascular Dysfunction ◽  
Diverse Group ◽  
Placental Development ◽  
Nuclear Receptor Coactivator ◽  
The Past ◽  
Placental Blood

ABSTRACT Coactivators constitute a diverse group of proteins that are essential for optimal transcriptional activity of nuclear receptors. In the past few years many coactivators have been identified but it is still unclear whether these proteins interact indiscriminately with all nuclear receptors and whether there is some redundancy in their functions. We have previously cloned and characterized RAP250 (ASC-2/PRIP/TRBP/NRC), an LXXLL-containing coactivator for nuclear receptors. In order to study its biological role, Rap250 null mice were generated by gene targeting. Here we show that genetic disruption of Rap250 results in embryonic lethality at embryonic day (E) 13.5. Histological examination of placentas revealed a dramatically reduced spongiotrophoblast layer, a collapse of blood vessels in the region bordering the spongiotrophoblast, and labyrinthine layers in placentas from Rap250−/− embryos. These findings suggest that the lethality of Rap250−/− embryos is the result of obstructed placental blood circulation. Moreover, the transcriptional activity of PPARγ is reduced in fibroblasts derived from Rap250−/− embryos, suggesting that RAP250 is an essential coactivator for this nuclear receptor in the placenta. Our results demonstrate that RAP250 is necessary for placental development and thus essential for embryonic development.

scholarly journals Type 1 Nuclear Receptor Activity in Breast Cancer: Translating Preclinical Insights to the Clinic

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4972
Author(s):  
Sanjeev Kumar ◽  
Allegra Freelander ◽  
Elgene Lim
Keyword(s):  
Breast Cancer ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Patient Outcomes ◽  
Estrogen Receptor Α ◽  
Receptor Activity ◽  
Breast Cancers ◽  
Cancer Subtypes ◽  
Major Breast

The nuclear receptor (NR) family of transcription factors is intimately associated with the development, progression and treatment of breast cancer. They are used diagnostically and prognostically, and crosstalk between nuclear receptor pathways and growth factor signalling has been demonstrated in all major subtypes of breast cancer. The majority of breast cancers are driven by estrogen receptor α (ER), and anti-estrogenic therapies remain the backbone of treatment, leading to clinically impactful improvements in patient outcomes. This serves as a blueprint for the development of therapies targeting other nuclear receptors. More recently, pivotal findings into modulating the progesterone (PR) and androgen receptors (AR), with accompanying mechanistic insights into NR crosstalk and interactions with other proliferative pathways, have led to clinical trials in all of the major breast cancer subtypes. A growing body of evidence now supports targeting other Type 1 nuclear receptors such as the glucocorticoid receptor (GR), as well as Type 2 NRs such as the vitamin D receptor (VDR). Here, we reviewed the existing preclinical insights into nuclear receptor activity in breast cancer, with a focus on Type 1 NRs. We also discussed the potential to translate these findings into improving patient outcomes.

scholarly journals WOMEN IN CANCER THEMATIC REVIEW: New roles for nuclear receptors in prostate cancer

2016 ◽  
Vol 23 (11) ◽  
pp. T85-T108 ◽  
Author(s):  
Damien A Leach ◽  
Sue M Powell ◽  
Charlotte L Bevan
Keyword(s):  
Prostate Cancer ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Current Knowledge ◽  
Transcriptional Responses ◽  
Number Variation ◽  
Genomic Studies ◽  
Life Threatening ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

Prostate cancer has, for decades, been treated by inhibiting androgen signalling. This is effective in the majority of patients, but inevitably resistance develops and patients progress to life-threatening metastatic disease – hence the quest for new effective therapies for ‘castrate-resistant’ prostate cancer (CRPC). Studies into what pathways can drive tumour recurrence under these conditions has identified several other nuclear receptor signalling pathways as potential drivers or modulators of CRPC.The nuclear receptors constitute a large (48 members) superfamily of transcription factors sharing a common modular functional structure. Many of them are activated by the binding of small lipophilic molecules, making them potentially druggable. Even those for which no ligand exists or has yet been identified may be tractable to activity modulation by small molecules. Moreover, genomic studies have shown that in models of CRPC, other nuclear receptors can potentially drive similar transcriptional responses to the androgen receptor, while analysis of expression and sequencing databases shows disproportionately high mutation and copy number variation rates among the superfamily. Hence, the nuclear receptor superfamily is of intense interest in the drive to understand how prostate cancer recurs and how we may best treat such recurrent disease. This review aims to provide a snapshot of the current knowledge of the roles of different nuclear receptors in prostate cancer – a rapidly evolving field of research.

scholarly journals Nuclear receptor phosphorylation in xenobiotic signal transduction

2020 ◽  
Vol 295 (45) ◽  
pp. 15210-15225 ◽  
Author(s):  
Masahiko Negishi ◽  
Kaoru Kobayashi ◽  
Tsutomu Sakuma ◽  
Tatsuya Sueyoshi
Keyword(s):  
Dna Binding ◽  
Cell Signaling ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Pregnane X Receptor ◽  
Receptor Activation ◽  
Binding Domain ◽  
Activation Mechanism ◽  
Dna Binding Domain ◽  
Phosphorylation Motif

Nuclear pregnane X receptor (PXR, NR1I2) and constitutive active/androstane receptor (CAR, NR1I3) are nuclear receptors characterized in 1998 by their capability to respond to xenobiotics and activate cytochrome P450 (CYP) genes. An anti-epileptic drug, phenobarbital (PB), activates CAR and its target CYP2B genes, whereas PXR is activated by drugs such as rifampicin and statins for the CYP3A genes. Inevitably, both nuclear receptors have been investigated as ligand-activated nuclear receptors by identifying and characterizing xenobiotics and therapeutics that directly bind CAR and/or PXR to activate them. However, PB, which does not bind CAR directly, presented an alternative research avenue for an indirect ligand-mediated nuclear receptor activation mechanism: phosphorylation-mediated signal regulation. This review summarizes phosphorylation-based mechanisms utilized by xenobiotics to elicit cell signaling. First, the review presents how PB activates CAR (and other nuclear receptors) through a conserved phosphorylation motif located between two zinc fingers within its DNA-binding domain. PB-regulated phosphorylation at this motif enables nuclear receptors to form communication networks, integrating their functions. Next, the review discusses xenobiotic-induced PXR activation in the absence of the conserved DNA-binding domain phosphorylation motif. In this case, phosphorylation occurs at a motif located within the ligand-binding domain to transduce cell signaling that regulates hepatic energy metabolism. Finally, the review delves into the implications of xenobiotic-induced signaling through phosphorylation in disease development and progression.

Sign in / Sign up

Export Citation Format

Share Document