scholarly journals Nutrition–hormone receptor–gene interactions: implications for development and disease

2001 ◽  
Vol 60 (1) ◽  
pp. 63-72 ◽  
Author(s):  
M. J. Dauncey ◽  
P. White ◽  
K. A. Burton ◽  
M. Katsumata
Keyword(s):  
Nuclear Receptors ◽  
Gene Transcription ◽  
Hormone Receptors ◽  
Receptor Gene ◽  
Phenotypic Expression ◽  
Nutrient Utilization ◽  
Human Populations ◽  
Myosin Isoforms ◽  
Energy Status ◽  
Stage Of Development

Nutrition profoundly alters the phenotypic expression of a given genotype, particularly during fetal and postnatal development. Many hormones act as nutritional signals and their receptors play a key role in mediating the effects of nutrition on numerous genes involved in differentiation, growth and metabolism. Polypeptide hormones act on membrane-bound receptors to trigger gene transcription via complex intracellular signalling pathways. By contrast, nuclear receptors for lipid-soluble molecules such as glucocorticoids (GC) and thyroid hormones (TH) directly regulate transcription via DNA binding and chromatin remodelling. Nuclear hormone receptors are members of a large superfamily of transcriptional regulators with the ability to activate or repress many genes involved in development and disease. Nutrition influences not only hormone synthesis and metabolism but also hormone receptors, and regulation is mediated either by specific nutrients or by energy status. Recent studies on the role of early environment on development have implicated GC and their receptors in the programming of adult disease. Intrauterine growth restriction and postnatal undernutrition also induce striking differences in TH-receptor isoforms in functionally-distinct muscles, with critical implications for gene transcription of myosin isoforms, glucose transporters, uncoupling proteins and cation pumps. Such findings highlight a mechanism by which nutritional status can influence normal development, and modify nutrient utilization, thermogenesis, peripheral sensitivity to insulin and optimal cardiac function. Diet and stage of development will also influence the transcriptional activity of drugs acting as ligands for nuclear receptors. Potential interactions between nuclear receptors, including those for retinoic acid and vitamin D, should not be overlooked in intervention programmes using I or vitamin A supplementation of young and adult human populations.

scholarly journals Minireview: Genomics Versus Orphan Nuclear Receptors—A Half-Time Report

2002 ◽  
Vol 16 (6) ◽  
pp. 1135-1144
Author(s):  
Timothy M. Willson ◽  
John T. Moore
Keyword(s):  
Nuclear Receptors ◽  
Drug Targets ◽  
Hormone Receptors ◽  
Receptor Gene ◽  
Orphan Nuclear Receptors ◽  
Orphan Receptors ◽  
Genomic Technologies ◽  
Full Complement ◽  
And Function ◽  
The Impact

Abstract Following the successful cloning of the orphan nuclear receptors during the 1990s we entered the 21st century with knowledge of the full complement of human nuclear receptors. Many of these proteins are ligand-activated transcription factors that act as the cognate receptors for steroid, retinoid, and thyroid hormones. In addition to these well characterized endocrine hormone receptors, there are a large number of orphan receptors of which less is known about the nature and function of their ligands. The task of deciphering the physiological function of these orphan receptors has been aided by a new generation of genomic technologies. Through application of chemical, structural, and functional genomics, several orphan nuclear receptors have emerged as pharmaceutical drug targets for the treatment of important human diseases. The significant progress that has been made in the functional analysis of more than half of the nuclear receptor gene family provides an opportunity to review the impact of genomics in this endeavor.

Activator protein-1 is necessary for angiotensin-II stimulation of human adrenocorticotropin receptor gene transcription

2001 ◽  
Vol 268 (6) ◽  
pp. 1802-1810
Author(s):  
Danielle Naville ◽  
Estelle Bordet ◽  
Marie-Claude Berthelon ◽  
Philippe Durand ◽  
Martine Begeot
Keyword(s):  
Angiotensin Ii ◽  
Gene Transcription ◽  
Receptor Gene ◽  
Activator Protein 1 ◽  
Activator Protein ◽  
Stimulation Of

Effects of thyroid hormone receptor gene disruption on myosin isoform expression in mouse skeletal muscles

2000 ◽  
Vol 278 (6) ◽  
pp. R1545-R1554 ◽  
Author(s):  
Fushun Yu ◽  
Sten Göthe ◽  
Lilian Wikström ◽  
Douglas Forrest ◽  
Björn Vennström ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Receptor Gene ◽  
Type I ◽  
Variable Response ◽  
Slow Type ◽  
Isoform Expression ◽  
Edl Muscle ◽  
Deficient Mice

Skeletal muscle is known to be a target for the active metabolite of thyroid hormone, i.e., 3,5,3′-triiodothyronine (T3). T3 acts by repressing or activating genes coding for different myosin heavy chain (MHC) isoforms via T3 receptors (TRs). The diverse function of T3 is presumed to be mediated by TR-α1 and TR-β, but the function of specific TRs in regulating MHC isoform expression has remained undefined. In this study, TR-deficient mice were used to expand our knowledge of the mechanisms by which T3 regulates the expression of specific MHC isoforms via distinct TRs. In fast-twitch extensor digitorum longus (EDL) muscle, TR-α1-, TR-β-, or TR-α1β-deficient mice showed a small but statistically significant decrease ( P < 0.05) of type IIB MHC content and an increased number of type I fibers. In the slow-twitch soleus, the β/slow MHC (type I) isoform was significantly ( P < 0.001) upregulated in the TR-deficient mice, but this effect was highly dependent on the type of receptor deleted. The lack of TR-β had no significant effect on the expression of MHC isoforms. An increase ( P < 0.05) of type I MHC was observed in the TR-α1-deficient muscle. A dramatic overexpression ( P < 0.001) of the slow type I MHC and a corresponding downregulation of the fast type IIA MHC ( P < 0.001) was observed in TR-α1β-deficient mice. The muscle- and fiber-specific differences in MHC isoform expression in the TR-α1β-deficient mice resembled the MHC isoform transitions reported in hypothyroid animals, i.e., a mild MHC transition in the EDL, a dramatic but not complete upregulation of the β/slow MHC isoform in the soleus, and a variable response to TR deficiency in different soleus muscle fibers. Thus the consequences on muscle are similar in the absence of thyroid hormone or absence of thyroid hormone receptors, indicating that TR-α1 and TR-β together mediate the known actions of T3. However, it remains unknown how thyroid hormone exerts muscle- and muscle fiber-specific effects in its action. Finally, although developmental MHC transitions were not studied specifically in this study, the absence of embryonic and fetal MHC isoforms in the TR-deficient mice indicates that ultimately the transition to the adult MHC isoforms is not solely mediated by TRs.

scholarly journals Expression Profiling of Nuclear Receptors in the NCI60 Cancer Cell Panel Reveals Receptor-Drug and Receptor-Gene Interactions

2010 ◽  
Vol 24 (6) ◽  
pp. 1287-1296 ◽  
Author(s):  
Susan Holbeck ◽  
Jianjun Chang ◽  
Anne M. Best ◽  
Angie L. Bookout ◽  
David J. Mangelsdorf ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Cell Lines ◽  
Nuclear Receptors ◽  
Cancer Cell ◽  
Expression Profiling ◽  
Expression Profiles ◽  
Receptor Gene ◽  
Receptor Expression ◽  
Cancer Drug ◽  
Mrna Levels

Abstract We profiled the expression of the 48 human nuclear receptors (NRs) by quantitative RT-PCR in 51 human cancer cell lines of the NCI60 collection derived from nine different tissues. NR mRNA expression accurately classified melanoma, colon, and renal cancers, whereas lung, breast, prostate, central nervous system, and leukemia cell lines exhibited heterogeneous receptor expression. Importantly, receptor mRNA levels faithfully predicted the growth-inhibitory qualities of receptor ligands in nonendocrine tumors. Correlation analysis using NR expression profiles and drug response information across the cell line panel uncovered a number of new potential receptor-drug interactions, suggesting that in these cases, individual receptor levels may predict response to chemotherapeutic interventions. Similarly, by cross-comparing receptor levels within our expression dataset and relating these profiles to existing microarray gene expression data, we defined interactions among receptors and between receptors and other genes that can now be mechanistically queried. This work supports the strategy of using NR expression profiling to classify various types of cancer, define NR-drug interactions and receptor-gene networks, predict cancer-drug sensitivity, and identify druggable targets that may be pharmacologically manipulated for potential therapeutic intervention.

Abstract 191: Transcriptional Regulation of Renin by Nuclear Receptors Co-regulated With Renin

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Ko-Ting Lu ◽  
Eric T Weatherford ◽  
Pimonrat Ketsawatsomkron ◽  
Justin L Grobe ◽  
Curt D Sigmund
Keyword(s):  
Gene Expression ◽  
Nuclear Receptors ◽  
Estrogen Receptor Alpha ◽  
Hormone Receptors ◽  
Cell Types ◽  
Negative Control ◽  
Sirna Duplex ◽  
Expression Of Genes ◽  
Renin Gene ◽  
Genes Encoding

Expression of the renin gene is required to maintain normal morphological and physiological identity of renal juxtaglomerular (JG) cells, yet the mechanisms regulating renin gene transcription remain elusive. We re-examined data from Brunskill et. al (JASN 22:2213, 2011), investigating genome-wide gene expression in JG and other renal cell types. Based on our previous data implicating nuclear receptors (RAR, RXR, VDR, PPARG, Nr2f2 and Nr2f6) in the regulation of mouse and human renin gene expression, we focused our analysis on the expression of genes encoding the 48 nuclear hormone receptors and their co-regulation with renin. Several nuclear receptors have an expression pattern emulating that of renin, that is, they were similarly enriched in JG cells but not in other cell types. These include Esr1, Nr1h4, Ppara, VDR, Nr1i2, Ppard, Hnf4g, Nr1h3, Thrb, Hnf4a, Esrrg, Nr4a3, Nr3c2, and Ar. We tested the hypothesis that a nuclear receptor that is co-regulated with renin may participate in renin gene regulation. To accomplish this, endogenous renin expression was evaluated in renin-expressing As4.1 cells after siRNA-mediated knock down of selected nuclear receptors. Each experiment included a negative control siRNA duplex (NC) that does not target any known genes. By way of example, siRNA-mediated inhibition of estrogen receptor alpha (Esr1) by 70-80% resulted in a 2-fold decrease in renin mRNA (fold change ± SEM: siEsr1: 0.4±0.2, p<0.001 vs NC). Similar results were obtained with a different siRNA targeting Esr1. Interestingly, loss of Esr1 also caused up-regulation of vitamin D receptor (VDR, 2.8±0.7 fold, p<0.001 vs NC) and Nr2f6 (2.0±0.2 fold, p<0.05 vs NC), both of which are known to be negative regulators of renin. Similarly, both renin (0.1±0.02, p<0.001 vs untreated) and Esr1 (0.3±0.1, p<0.05 vs untreated) mRNA were reduced in the kidney from mice treated with deoxycorticosterone acetate (50mg) and receiving 0.15 M NaCl in drinking water for 21 days (DOCA-salt). These data suggest Esr1 may regulate renin expression. Studies are in progress to assess if Esr1 stimulates renin expression on its own or acts by affecting the level of other nuclear receptors; and to determine if other co-regulated nuclear receptors also regulate expression of the renin gene.

Spatial- and temporal-restricted pattern for amelogenin gene expression during mouse molar tooth organogenesis

Development ◽  
1988 ◽  
Vol 104 (1) ◽  
pp. 77-85 ◽  
Author(s):  
M.L. Snead ◽  
W. Luo ◽  
E.C. Lau ◽  
H.C. Slavkin
Keyword(s):  
Gene Expression ◽  
In Situ Hybridization ◽  
Gene Transcription ◽  
Developmental Stages ◽  
Three Dimensional ◽  
Molar Tooth ◽  
Specific Expression ◽  
Amelogenin Gene ◽  
Stage Of Development

Position- and time-restricted amelogenin gene transcription was analysed in developing tooth organs using in situ hybridization with asymmetric complementary RNA probes produced from a cDNA specific to the mouse 26 × 10(3) Mr amelogenin. In situ analysis was performed on developmentally staged fetal and neonatal mouse mandibular first (M1) and maxillary first (M1) molar tooth organs using serial sections and three-dimensional reconstruction. Amelogenin mRNA was first detected in a cluster of ameloblasts along one cusp of the M1 molar at the newborn stage of development. In subsequent developmental stages, amelogenin transcripts were detected within foci of ameloblasts lining each of the five cusps comprising the molar crown form. The number of amelogenin transcripts appeared to be position-dependent, being more abundant on one cusp surface while reduced along the opposite surface. Amelogenin gene transcription was found to be bilaterally symmetric between the developing right and left M1 molars, and complementary between the M1 and M1 developing molars; indicating position-restricted gene expression resulting in organ stereoisomerism. The application of in situ hybridization to forming tooth organ geometry provides a novel strategy to define epithelial-mesenchymal signal(s) which are believed to be responsible for organ morphogenesis, as well as for temporal- and spatial-restricted tissue-specific expression of enamel extracellular matrix.

Mechanisms of Hormone Action

2011 ◽  
Author(s):  
Stephen R. Hammes ◽  
Carole R. Mendelson
Keyword(s):  
Signal Transduction ◽  
Plasma Membrane ◽  
Nuclear Receptors ◽  
Plasma Membranes ◽  
Hormone Receptors ◽  
Membrane Receptors ◽  
Endocrine Disorders ◽  
Messenger Rnas ◽  
Dihydroxyvitamin D3 ◽  
Transduction Mechanisms

The capacity of a cell to respond to a particular hormone depends on the presence of cellular receptors specific for that hormone. After binding hormone, the receptor is biochemically and structurally altered, resulting in its activation; the activated receptor then mediates all of the actions of the hormone on the cell. The steroid and thyroid hormones as well as retinoids and 1,25-dihydroxyvitamin D3 diffuse freely through the lipophilic plasma membrane of the cell and interact with receptors that are primarily within the nucleus. On activation, the receptors alter the transcription of specific genes, resulting in changes in the levels of specific messenger RNAs (mRNAs), which are in turn translated into proteins. Hormones that are water soluble, such as the peptide and polypeptide hormones, catecholamines, and other neurotransmitters, as well as the relatively hydrophobic prostaglandins, interact with receptors in the plasma membrane. After hormone binding, the activated membrane receptors initiate signal transduction cascades that result in changes in enzyme activities and alterations in gene expression. In this chapter, the properties of various classes of receptors that are localized within the plasma membranes of target cells and the signal transduction mechanisms that mediate interactions with their ligands will first be addressed. This will be followed by consideration of the structural properties of the nuclear hormone receptors, the events that result in their activation, and the mechanisms whereby the activated nuclear receptors alter the expression of specific genes. Finally, a number of endocrine disorders that are caused by alterations in the number and/or function of plasma membranes and nuclear receptors will be reviewed. The function of a receptor is to recognize a particular hormone among all the molecules in the environment of the cell at a given time and, after binding the hormone, to transmit a signal that ultimately results in a biological response. Hormones are normally present in the circulation in extremely low concentrations, ranging from 10 –9 to 10 –11 M.

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