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Nuclear Receptors (nuclear + receptor)
Kinds of Nuclear Receptors Terms modified by Nuclear Receptors Selected AbstractsTwo Key Proteins of the Vitamin D Endocrine System Come Into Crystal Clear Focus: Comparison of the X-ray Structures of the Nuclear Receptor for 1,,25(OH)2 Vitamin D3, the Plasma Vitamin D Binding Protein, and Their Ligands,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 5 2003Mathew T Mizwicki First page of article [source] The RNA coregulator SRA, its binding proteins and nuclear receptor signaling activityIUBMB LIFE, Issue 3 2008Shane M. Colley Abstract Nuclear receptor (NR) coregulators are key modulators of hormone signaling. Discovery of steroid receptor RNA activator (SRA), a coregulator that is active as a RNA, transformed thinking in the field of hormone action. The subsequent identification of SRA-binding coregulator proteins, including p68, SHARP and more recently SLIRP, has provided important insight into SRA's mechanism of action and potentially offers new opportunities to target NR signaling pathways for therapeutic gain. Here we outline advances in the field of NR coregulator biology, with a bias on recent progress in understanding SRA-protein interactions. © 2008 IUBMB IUBMB Life, 60(3): 159,164, 2008 [source] Nuclear receptors and drug disposition gene regulationJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 6 2005Rommel G. Tirona Abstract In this minireview, the role of various nuclear receptors and transcription factors in the expression of drug disposition genes is summarized. Specifically, the molecular aspects and functional impact of the aryl hydrocarbon receptor (AhR), nuclear factor-E2 p45-related factor 2 (Nrf2), hepatocyte nuclear factor 1, (HNF1,), constitutive androstane receptor (LAR), pregnane X receptor (PXR), farnesoid X receptor (FXR), peroxisome proliferator-activated receptor , (PPAR,), hepatocyte nuclear factor 4, (HNF4,), vitamin D receptor (VDR), liver receptor homolog 1 (LRH1), liver X receptor (LXR,), small heterodimer partner-1 (SHP-1), and glucocorticoid receptor (GR) on gene expression are detailed. Finally, we discuss some current topics and themes in nuclear receptor-mediated regulation of drug metabolizing enzymes and drug transporters. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:1169,1186, 2005 [source] Nuclear receptors of the enteric tract: guarding the frontierNUTRITION REVIEWS, Issue 2008Daniel R Schmidt In addition to its classical role in mineral homeostasis, the vitamin D receptor has been implicated in diverse physiologic and pathophysiologic processes including immunoregulation and cancer. Interestingly, the vitamin D receptor has been evolutionarily and functionally linked to a select group of nuclear receptors based on a common organism-wide tissue expression profile. These members of the nuclear receptor superfamily, which include the bile acid receptor, xenobiotic receptors, and several orphan nuclear receptors, comprise a transcriptional regulatory network that functions in nutrient uptake, xenobiotic metabolism, and mucosal protection. The major homeostatic functions of the enteric nuclear receptor network are the topic of this review. [source] Nuclear receptor NR5A2 is required for proper primitive streak morphogenesisDEVELOPMENTAL DYNAMICS, Issue 12 2006Cassandre Labelle-Dumais Abstract NR5A2, also known as liver receptor homologue 1 (LRH-1) and fetoprotein transcription factor (FTF), is an orphan nuclear receptor involved in the regulation of cholesterol metabolism and steroidogenesis in the adult. NR5A2 was also shown to be expressed during early mouse embryogenesis. Consistent with its early expression pattern, a targeted disruption of this gene leads to embryonic lethality around the gastrulation period. To characterize the embryonic phenotype resulting from NR5A2 loss of function, we undertook morphological and marker gene analyses and showed that NR5A2,/, embryos display growth retardation, epiblast disorganization, a mild embryonic,extraembryonic constriction, as well as abnormal thickening of the proximo-posterior epiblast. We demonstrated that, although initial specification of the anterior,posterior axis occurred in the absence of NR5A2, primitive streak formation was impaired and neither embryonic nor extraembryonic mesoderm was generated. Moreover, although the visceral endoderm does not show major morphological abnormalities in NR5A2,/, embryos, a decrease in the expression level of HNF4 and GATA4 was observed. Aggregation experiments demonstrated that, in the presence of wild-type tetraploid cells, NR5A2 mutant cells in the epiblast are capable of undergoing normal gastrulation. Therefore, our results suggest a requirement for NR5A2 in extraembryonic tissues and identify a novel role of this gene in proper primitive streak morphogenesis. Developmental Dynamics 235:3359,3369, 2006. © 2006 Wiley-Liss, Inc. [source] The mode of action of thiazolidinediones,DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue S2 2002Hans Hauner Abstract The thiazolidinediones (TZDs) or ,glitazones' are a new class of oral antidiabetic drugs that improve metabolic control in patients with type 2 diabetes through the improvement of insulin sensitivity. TZDs exert their antidiabetic effects through a mechanism that involves activation of the gamma isoform of the peroxisome proliferator-activated receptor (PPAR,), a nuclear receptor. TZD-induced activation of PPAR, alters the transcription of several genes involved in glucose and lipid metabolism and energy balance, including those that code for lipoprotein lipase, fatty acid transporter protein, adipocyte fatty acid binding protein, fatty acyl-CoA synthase, malic enzyme, glucokinase and the GLUT4 glucose transporter. TZDs reduce insulin resistance in adipose tissue, muscle and the liver. However, PPAR, is predominantly expressed in adipose tissue. It is possible that the effect of TZDs on insulin resistance in muscle and liver is promoted via endocrine signalling from adipocytes. Potential signalling factors include free fatty acids (FFA) (well-known mediators of insulin resistance linked to obesity) or adipocyte-derived tumour necrosis factor-, (TNF-,), which is overexpressed in obesity and insulin resistance. Although there are still many unknowns about the mechanism of action of TZDs in type 2 diabetes, it is clear that these agents have the potential to benefit the full ,insulin resistance syndrome' associated with the disease. Therefore, TZDs may also have potential benefits on the secondary complications of type 2 diabetes, such as cardiovascular disease. Copyright © 2002 John Wiley & Sons, Ltd. [source] Dose-dependent Induction of Cytochrome P450 (CYP) 3A4 and Activation of Pregnane X Receptor by TopiramateEPILEPSIA, Issue 12 2003Srikanth C. Nallani Summary:,Purpose: In clinical studies, topiramate (TPM) was shown to cause a dose-dependent increase in the clearance of ethinyl estradiol. We hypothesized that this interaction results from induction of hepatic cytochrome P450 (CYP) 3A4 by TPM. Accordingly, we investigated whether TPM induces CYP3A4 in primary human hepatocytes and activates the human pregnane X receptor (hPXR), a nuclear receptor that serves as a regulator of CYP3A4 transcription. Methods: Human hepatocytes were treated for 72 h with TPM (10, 25, 50, 100, 250, and 500 ,M) and known inducers, phenobarbital (PB; 2 mM), and rifampicin (10 ,M). The rate of testosterone 6,-hydroxylation by hepatocytes served as a marker for CYP3A4 activity. The CYP3A4-specific protein and mRNA levels were determined by using Western and Northern blot analyses, respectively. The hPXR activation was assessed with cell-based reporter gene assay. Results: Compared with controls, TPM (50,500 ,M),treated hepatocytes exhibited a considerable increase in the CYP3A4 activity (1. 6- to 8.2-fold), protein levels (4.6- to 17.3-fold), and mRNA levels (1.9- to 13.3-fold). Comparatively, rifampicin (10 ,M) effected 14.5-, 25.3-, and a 20.3-fold increase in CYP3A4 activity, immunoreactive protein levels, and mRNA levels, respectively. TPM (50,500 ,M) caused 1.3- to 3-fold activation of the hPXR, whereas rifampicin (10 ,M) caused a 6-fold activation. Conclusions: The observed induction of CYP3A4 by TPM, especially at the higher concentrations, provides a potential mechanistic explanation of the reported increase in the ethinyl estradiol clearance by TPM. It also is suggestive of other potential interactions when high-dose TPM therapy is used. [source] PRECLINICAL STUDY: FULL ARTICLE: Effects of fatty acid amide hydrolase inhibition on neuronal responses to nicotine, cocaine and morphine in the nucleus accumbens shell and ventral tegmental area: involvement of PPAR-, nuclear receptorsADDICTION BIOLOGY, Issue 3 2010Antonio Luchicchi ABSTRACT The endocannabinoid system regulates neurotransmission in brain regions relevant to neurobiological and behavioral actions of addicting drugs. We recently demonstrated that inhibition by URB597 of fatty acid amide hydrolase (FAAH), the main enzyme that degrades the endogenous cannabinoid N-acylethanolamine (NAE) anandamide and the endogenous non-cannabinoid NAEs oleoylethanolamide and palmitoylethanolamide, blocks nicotine-induced excitation of ventral tegmental area (VTA) dopamine (DA) neurons and DA release in the shell of the nucleus accumbens (ShNAc), as well as nicotine-induced drug self-administration, conditioned place preference and relapse in rats. Here, we studied whether effects of FAAH inhibition on nicotine-induced changes in activity of VTA DA neurons were specific for nicotine or extended to two drugs of abuse acting through different mechanisms, cocaine and morphine. We also evaluated whether FAAH inhibition affects nicotine-, cocaine- or morphine-induced actions in the ShNAc. Experiments involved single-unit electrophysiological recordings from DA neurons in the VTA and medium spiny neurons in the ShNAc in anesthetized rats. We found that URB597 blocked effects of nicotine and cocaine in the ShNAc through activation of both surface cannabinoid CB1-receptors and alpha-type peroxisome proliferator-activated nuclear receptor. URB597 did not alter the effects of either cocaine or morphine on VTA DA neurons. These results show that the blockade of nicotine-induced excitation of VTA DA neurons, which we previously described, is selective for nicotine and indicate novel mechanisms recruited to regulate the effects of addicting drugs within the ShNAc of the brain reward system. [source] Phenotypic and genetic analysis of the cerebellar mutant tmgc26, a new ENU-induced ROR-alpha alleleEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2010Douglas J. Swanson Abstract ROR-alpha is an orphan nuclear receptor, inactivation of which cell-autonomously blocks differentiation of cerebellar Purkinje cells with a secondary loss of granule neurons. As part of our ENU mutagenesis screen we isolated the recessive tmgc26 mouse mutant, characterized by early-onset progressive ataxia, cerebellar degeneration and juvenile lethality. Detailed analysis of the tmgc26,/, cerebella revealed Purkinje cell and granule cell abnormalities, and defects in molecular layer interneurons and radial glia. Chimera studies suggested a cell-autonomous effect of the tmgc26 mutation in Purkinje cells and molecular layer interneurons, and a non-cell-autonomous effect in granule cells. The mutation was mapped to a 13-Mb interval on chromosome 9, a region that contains the ROR-alpha gene. Sequencing of genomic DNA revealed a T-to-A transition in exon 5 of the ROR-alpha gene, resulting in a nonsense mutation C257X and severe truncation of the ROR-alpha protein. Together, our data identify new roles for ROR-alpha in molecular layer interneurons and radial glia development and suggest tmgc26 as a novel ROR-alpha allele that may be used to further delineate the molecular mechanisms of ROR-alpha action. [source] Sweat gland epithelial and myoepithelial cells are vitamin D targetsEXPERIMENTAL DERMATOLOGY, Issue 2 2007Nobuo Koike Abstract:, Nuclear receptor binding of 1,25(OH)2 -vitamin D3 (vitamin D) in skin keratinocytes of epidermis, hair sheaths and sebaceous glands was discovered through receptor microscopic autoradiography. Extended experiments with 3H-1,25(OH)2 -vitamin D3 and its analog 3H-oxacalcitriol (OCT) now demonstrate nuclear receptor binding in sweat gland epithelium of secretory coils and ducts as well as in myoepithelial cells, as studied in paws of nude mice after i.v. injection. The results suggest genomic regulation of cell proliferation and differentiation, as well as of secretory and excretory functions, indicating potential therapies for impaired secretion as in hypohidrosis of aged and diseased skin. [source] Role of ceramide kinase in peroxisome proliferator-activated receptor beta-induced cell survival of mouse keratinocytesFEBS JOURNAL, Issue 15 2008Kiyomi Tsuji Ceramide (Cer) is known to be a lipid mediator in apoptosis and to have an important role in cell fate, via control of intracellular Cer levels. Recently, ceramide kinase (CerK) was identified as an enzyme that converts Cer to ceramide 1-phosphate (C1P). We examined potential functions of CerK in the regulation of keratinocyte survival, and the possible involvement of peroxisome proliferator-activated receptor beta (PPAR,). PPAR, is known to be a nuclear receptor acting as a ligand-inducible transcription factor and has been implicated in the control of keratinocyte survival. In the mouse keratinocyte cell line SP1, serum starvation induced cell death and the accumulation of intracellular Cer, an apoptotic event. However, apoptosis was inhibited by activation of PPAR,. Interestingly, activation of PPAR, enhanced the mRNA expression of CerK and CerK activity. Furthermore, the cell survival effect of PPAR, was greatly diminished in keratinocytes isolated from CerK-null mice. Chromatin immunoprecipitation revealed that, in vivo, PPAR, binds to the CerK gene via a sequence located in the first intron. Electrophoretic mobility-shift assays confirmed that PPAR, associates with this sequence in vitro. These findings indicated that CerK gene expression was directly regulated by PPAR,. In conclusion, our results demonstrate that PPAR,-mediated upregulation of CerK gene expression is necessary for keratinocyte survival against serum starvation-induced apoptosis. [source] Association of a single nucleotide polymorphism in the steroid and xenobiotic receptor (SXR) gene (IVS1-579A/G) with bone mineral densityGERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 2 2007Tomohiko Urano Vitamin K2 plays an important role in the bone metabolism. The steroid and xenobiotic receptor (SXR) as a nuclear receptor activated by vitamin K2 as well as rifampicin could increase bone markers such as alkaline phosphatase in human osteoblastic cells. Thus, the SXR could mediate vitamin K2 signaling pathway in bone cells. Therefore, we analyzed expression of the SXR mRNA in human primary osteoblasts and chondrocytes. We also studied association of a single nucleotide polymorphism (SNP) in the SXR gene with bone mineral density (BMD). Expression levels of the SXR mRNA were analyzed during the culture course of human primary osteoblasts and chondrocytes. Association of a SNP in the SXR gene in intron 1 (IVS1-579A>G) with BMD was examined in 294 healthy postmenopausal Japanese women. The SXR mRNA increased at day 5 and then decreased at day 10 in human primary osteoblasts. Its mRNA gradually increased in human primary chondrocytes until day 10. As an association study of a SNP in the SXR gene (IVS1-579A/G), the subjects without the A allele (GG; n = 47) had significantly higher total BMD than the subjects bearing at least one A allele (AA + AG; n = 247) (Z score ± SD; 0.635 ± 1.031 versus 0.268 ± 1.061; P = 0.0298). The SXR mRNA was expressed and regulated in primary human osteoblasts and chondrocytes. A genetic variation at the SXR gene locus is associated with BMD, suggesting an involvement of the SXR gene in human bone metabolism. [source] A human phospholamban promoter polymorphism in dilated cardiomyopathy alters transcriptional regulation by glucocorticoids,HUMAN MUTATION, Issue 5 2008Kobra Haghighi Abstract Depressed calcium handling by the sarcoplasmic reticulum (SR) Ca-ATPase and its regulator phospholamban (PLN) is a key characteristic of human and experimental heart failure. Accumulating evidence indicates that increases in the relative levels of PLN to Ca-ATPase in failing hearts and resulting inhibition of Ca sequestration during diastole, impairs contractility. Here, we identified a genetic variant in the PLN promoter region, which increases its expression and may serve as a genetic modifier in dilated cardiomyopathy (DCM). The variant AF177763.1:g.203A>C (at position ,36,bp relative to the PLN transcriptional start site) was found only in the heterozygous form in 1 out of 296 normal subjects and in 22 out of 381 cardiomyopathy patients (heart failure at age of 18,44 years, ejection fraction=22±9%). In vitro analysis, using luciferase as a reporter gene in rat neonatal cardiomyocytes, indicated that the PLN-variant increased activity by 24% compared to the wild type. Furthermore, the g.203A>C substitution altered the specific sequence of the steroid receptor for the glucocorticoid nuclear receptor (GR)/transcription factor in the PLN promoter, resulting in enhanced binding to the mutated DNA site. These findings suggest that the g.203A>C genetic variant in the human PLN promoter may contribute to depressed contractility and accelerate functional deterioration in heart failure. Hum Mutat 29(5), 640,647, 2008. © 2008 Wiley-Liss, Inc. [source] The orphan nuclear receptor DAX1 is up-regulated by the EWS/FLI1 oncoprotein and is highly expressed in Ewing tumorsINTERNATIONAL JOURNAL OF CANCER, Issue 6 2006Marta Mendiola Abstract The Ewing family of tumors harbors chromosomal translocations that join the N-terminal region of the EWS gene with the C-terminal region of several transcription factors of the ETS family, mainly FLI1, resulting in chimeric transcription factors that play a pivotal role in the pathogenesis of Ewing tumors. To identify downstream targets of the EWS/FLI1 fusion protein, we established 293 cells expressing constitutively either the chimeric EWS/FLI1 or wild type FLI1 proteins and used cDNA arrays to identify genes differentially regulated by EWS/FLI1. DAX1 (NR0B1), an unusual orphan nuclear receptor involved in gonadal development, sex determination and steroidogenesis, showed a consistent up-regulation by EWS/FLI1 oncoprotein, but not by wild type FLI1. Specific induction of DAX1 by EWS/FLI1 was confirmed in two independent cell systems with inducible expression of EWS/FLI1. We also analyzed the expression of DAX1 in Ewing tumors and derived cell lines, as well as in other nonrelated small round cell tumors. DAX1 was expressed in all Ewing tumor specimens analyzed, and in seven out of eight Ewing tumor cell lines, but not in any neuroblastoma or embryonal rhabdomyosarcoma. Furthermore, silencing of EWS/FLI1 by RNA interference in a Ewing tumor cell line markedly reduced the levels of DAX1 mRNA and protein, confirming that DAX1 up-regulation is dependent upon EWS/FLI1 expression. The high levels of DAX1 found in Ewing tumors and its potent transcriptional repressor activity suggest that the oncogenic effect of EWS/FLI1 may be mediated, at least in part, by the up-regulation of DAX1 expression. © 2005 Wiley-Liss, Inc. [source] Association of the VDR Translation Start Site Polymorphism and Fracture Risk in Older Women,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 5 2007Susan P Moffett PhD Abstract We evaluated the association between the VDR translation start site polymorphism and osteoporotic phenotypes among 6698 older white women. Women with the C/C genotype had lower wrist BMD and an increased risk of wrist and all non-spine/low-trauma fractures. The high frequency of this variant confers a population attributable risk that is similar to several established risk factors for fracture. Introduction: The vitamin D receptor (VDR) is a nuclear receptor that regulates bone formation, bone resorption, and calcium homeostasis. A common C to T polymorphism in exon 2 of the VDR gene introduces a new translation start site and a protein that differs in length by three amino acids (T = 427aa, C = 424aa; rs10735810). Materials and Methods: We conducted genetic association analyses of this polymorphism, BMD, and fracture outcomes in a prospective cohort of 6698 white American women ,65 years of age. Incident fractures were confirmed by physician adjudication of radiology reports. There were 2532 incident nontraumatic/nonvertebral fractures during 13.6 yr of follow-up including 509 wrist and 703 hip fractures. Results: Women with the C/C genotype had somewhat lower distal radius BMD compared with those with the T/T genotype (CC = 0.358 g/cm2, CT = 0.361 g/cm2, TT = 0.369 g/cm2, p = 0.003). The C/C genotype was also associated with increased risk of non-spine, low traumatic fractures (HR: 1.18; 95% CI: 1.04, 1.33) and wrist fractures (HR: 1.33; 95% CI: 1.01, 1.75) compared with the T/T genotype in age-adjusted models. Further adjustments for distal radius BMD only slightly attenuated these associations. The VDR polymorphism was not associated with hip fracture. The population attributable risk (PAR) of the C/C genotype for incident fractures was 6.1%. The PAR for established risk factors for fracture were: low femoral neck BMD (PAR = 16.3%), maternal history of fracture (PAR = 5.1%), low body weight (PAR = 5.3%), corticosteroid use (PAR = 1.3%), and smoking (PAR = 1.6%). Similar PAR results were observed for wrist fractures. Conclusions: The common and potentially functional VDR translation start site polymorphism confers a modestly increased relative risk of fracture among older white women. However, the high frequency of this variant confers a population attributable risk that is similar to or greater than several established risk factors for fracture. [source] Th17 cells: The emerging reciprocal partner of regulatory T cells in the liverJOURNAL OF DIGESTIVE DISEASES, Issue 3 2010Li ZHAO T helper cells that produce interleukin-17 (IL-17) (Th17 cells) have recently been identified as the third distinct subset of effector T cells, the differentiation of which depends on specific transcription nuclear factor retinoic acid-related orphan nuclear receptor-,t. Emerging data have suggested that Th17 cells play an important role in innate immunity, adaptive immunity and autoimmunity. Interestingly, there is a reciprocal relationship between Th17 cells and regulatory T cells (Treg), not only in development, but also in their effector function. Transforming growth factor (TGF)-, induces Treg-specific transcription factor Forkhead box P3(FOXP3), while the addition of IL-6 to TGF-, inhibits the generation of Treg cells and induces Th17 cells. It is proposed that the fine balance between Th17 and Treg cells is crucial for maintenance of immune homeostasis. In addition to IL-6, other factors such as retinoic acid, rapamycin, or cytokines (e.g., IL-2 and IL-27) could dictate the balance between Th17 and Treg cells. Since Treg cells play an important role in hepatic immunity with overregulation in chronic viral hepatitis and hepatic carcinoma, and inadequate inhibition in autoimmune liver diseases, graft rejection and acute liver failure, it is reasonable to assume that Th17 cells may play a reciprocal role in these diseases. Thus, future research on the Treg/Th17 balance may provide an opportunity to illustrate the pathogenesis of hepatic inflammation and to explore new therapeutic targets for immune-related liver diseases. [source] Review article: nuclear receptors and liver disease , current understanding and new therapeutic implicationsALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 8 2009D. A. H. ELFAKI Aliment Pharmacol Ther,30, 816,825 Summary Background, The important role of nuclear receptors and their contribution to liver function in both physiological and pathological conditions has come to attention in recent years and has advanced our understanding of several liver diseases. These findings led to the introduction of targeting nuclear receptors as treatment strategies for various liver diseases. Aims, To review the new insights brought by the study of nuclear receptors to our understanding of the molecular basis of various liver diseases, and to summarize some of the recent studies that evaluated the efficacy of targeting nuclear receptor as a new approach in treating liver diseases. Methods, Review of articles, using PubMed and article references. Results, Nuclear receptor ligands in patients with liver diseases have been associated with a variety of toxicities. Some clinical results have not met the expectations predicted from animal experiments. Mechanistic explanations at the molecular level are needed for preventing toxicity and improving outcomes from nuclear receptor ligands. Conclusion, The use of various nuclear receptor ligands in liver diseases is a promising approach that can benefit many patients suffering from these devastating diseases. However, we are far from a full understanding of the molecular mechanisms by which these receptors work. [source] Enhancement of gene expression by a peptide p(CHWPR) produced by Bifidobacterium lactis BB-12MICROBIOLOGY AND IMMUNOLOGY, Issue 3 2008Takashi Mitsuma ABSTRACT Recently, probiotics, including Bifidobacterium, Lactobacillus, and Enterococcus, among other organisms, have been clinically applied for their enhancing effects on defense mechanisms. It is reported that gene expression in somatic cells can be activated by autoinducers, which are hormone-like molecules produced in a microbial QS system. In the present study, based on a hypothesis that a low-molecular substance related to the QS system is involved in the probiotics effects of Bifidobacterium, we intended to extract the low-molecular substance. As a result, we successfully isolated the peptide p(CHWPR), which was composed of five amino acids including Cys, His, Trp, Pro, and Arg, and found that the peptide was produced in the stationary phase of bacterial growth and that it could enhance the gene expression of oxalyl-CoA decarboxylase (Oxc). p(CHWPR) enhanced the gene expression of c-myc and interleukin (IL)-6 in an established cell line, HL-60. We demonstrated that p(CHWPR) penetrates the cell membrane and binds specifically to ROR,, which is a cytosolic nuclear receptor. This suggests that ROR, bound to p(CHWPR) would bind to promoter regions of the c-myc gene. Furthermore, we found that p(CHWPR) also bound to a transcriptional avtivation subunit, CRSP70; this suggests that p(CHWPR), ROR,, and CRSP70 in combination enhance transcription activity. [source] Evolution of our understanding of vitamin DNUTRITION REVIEWS, Issue 2008Hector F DeLuca The development of our understanding of the function of vitamin D from its discovery in the second and third decades of the 20th century to its hormonal activation of its nuclear receptor and to its present position of an important factor in public health has been traced. The key discoveries of the conversion of vitamin D to its hormonal form, its regulation, and the evolving picture of its molecular mechanism of action are presented. The recognition of its role beyond mineralization of the skeleton to its role in skin, the immune system, and its protective role in some forms of malignancy represent more recent developments. The evolution of derivatives of 1,,25-dihydroxyvitamin D3 as therapeutic agents suggests a richness of therapeutic potential. All of this nevertheless illustrates that much more remains to be discovered and applied to our armaments for preventing and treating disease. [source] A modified tandem affinity purification strategy identifies cofactors of the Drosophila nuclear receptor,dHNF4PROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 3 2006Ping Yang Abstract With the completion of numerous genome projects, new high-throughput methods are required to ascribe gene function and interactions. A method proven successful in yeast for protein interaction studies is tandem affinity purification (TAP) of native protein complexes followed by MS. Here, we show that TAP, using Protein,A and CBP tags, is not generally suitable for the purification and identification of proteins from tissues. A head-to-head comparison of tags shows that two others, FLAG and His, provide protein yields from Drosophila tissues that are an order of magnitude higher than Protein,A and CBP. FLAG-His purification worked sufficiently well so that two cofactors of the Drosophila nuclear receptor protein,dHNF4 could be purified from whole animals. These proteins, Hsc70 and Hsp83, are important chaperones and cofactors of other nuclear receptor proteins. However, this is the first time that they have been shown to interact with a non-steroid binding nuclear receptor. We show that the two proteins increase the ability of dHNF4 to bind DNA in,vitro and to function in,vivo. The tags and approaches developed here will help facilitate the routine purification of proteins from complex cells, tissues and whole organisms. [source] Androgen receptor corepressors: An overviewTHE PROSTATE, Issue 2 2005Liang Wang Androgens play pivotal roles in sex differentiation and development, in reproductive functions, and sexual behavior. The actions of androgens are mediated through the intracellular androgen receptor (AR), a member of the nuclear receptor (NR) superfamily, which regulates a wide range of target gene expression. Recent studies indicate that the proper transcriptional activity of AR is modulated by AR coregulators, including coactivators that can enhance AR transactivation and corepressors that can suppress AR transactivation. Here, we summarize the recent discoveries relating to AR corepressor function with the following different mechanisms: (1) corepressors that inhibit the DNA binding or nuclear translocation of AR; (2) corepressors that recruit histone deacetylases; (3) corepressors that interrupt the interaction between AR and its coactivators; (4) corepressors that interrupt the interaction between the N-terminus and C-terminus of AR; (5) corepressors that function as scaffolds for other AR coregulators; (6) corepressors that target the basal transcriptional machinery; (7) other mechanisms. The potential impact and future directions of AR corepressors are also discussed. © 2004 Wiley-Liss, Inc. [source] Gene Induction by Phenobarbital: An Update on an Old Question that Receives Key Novel Answers,BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 3 2001Laurent Corcos The drug is the representative of a myriad of lipophilic molecules able to evoke a pleiotropic response in the liver and also in prokaryotes and flies. A great deal of novel information has been obtained in recent years regarding the mechanism of cytochrome P450 (CYP) gene induction by phenobarbital. Most importantly, a nuclear orphan receptor, the constitutive androstane receptor has been identified as a primary determinant of the transcriptional activation of CYP genes in response to phenobarbital-like inducers in mammals. Another nuclear receptor, the pregnane X receptor can also mediate some of the phenobarbital response, but the functional overlap of the two inductive pathways is only partial. The response of mammalian CYP2B genes to phenobarbital was abolished in the liver of mice carrying a null allele of the constitutive androstane receptor gene, whereas that of CYP3A genes was lost in pregnane X receptor knock-out mice. [source] Vitamin D discovery outpaces FDA decision makingBIOESSAYS, Issue 2 2008Trevor G. Marshall The US FDA currently encourages the addition of vitamin D to milk and cereals, with the aim of reducing rickets in children and osteoporosis in adults. However, vitamin D not only regulates the expression of genes associated with calcium homeostasis, but also genes associated with cancers, autoimmune disease, and infection. It does this by controlling the activation of the vitamin D receptor (VDR), a type 1 nuclear receptor and DNA transcription factor. Molecular biology is rapidly coming to an understanding of the multiplicity of roles played by the VDR, but clinical medicine is having difficulty keeping up with the pace of change. For example, the FDA recently proposed a rule change that will encourage high levels of vitamin D to be added to even more foods, so that the manufacturers can claim those foods "reduce the risk of osteoporosis". The FDA docket does not review one single paper detailing the transcriptional activity of vitamin D, even though, on average, one new paper a day is being published on that topic. Nor do they review whether widespread supplementation with vitamin D, an immunomodulatory secosteroid, might predispose the population to immune dysfunction. This BioEssay explores how lifelong supplementation of the food chain with vitamin D might well be contributing to the current epidemics of obesity and chronic disease. BioEssays 30:173,182, 2008. © 2008 Wiley Periodicals, Inc. [source] Vitamin D and systemic cancer: is this relevant to malignant melanoma?BRITISH JOURNAL OF DERMATOLOGY, Issue 2 2002J.E. Osborne Summary 1,25-dihydroxyvitamin D3[1,25(OH)2D3] is a well-known potent regulator of cell growth and differentiation and there is recent evidence of an effect on cell death, tumour invasion and angiogenesis, which makes it a candidate agent for cancer regulation. The classical synthetic pathway of 1,25(OH)2D3 involves 25- and 1,-hydroxylation of vitamin D3, in the liver and kidney, respectively, of absorbed or skin-synthesized vitamin D3. There is recent focus on the importance in growth control of local metabolism of 1,25(OH)2D3, which is a function of local tissue synthetic hydroxylases and particularly the principal catabolizing enzyme, 24-hydroxylase. The classical signalling pathway of 1,25(OH)2D3 employs the vitamin D nuclear receptor (VDR), which is a transcription factor for 1,25(OH)2D3 target genes. Effects of this pathway include inhibition of cellular growth and invasion. Cytoplasmic signalling pathways are increasingly being recognized, which similarly may regulate growth and differentiation but also apoptosis. 1,25(OH)2D3 has a major inhibitory effect on the G1/S checkpoint of the cell cycle by upregulating the cyclin dependent kinase inhibitors p27 and p21, and by inhibiting cyclin D1. Indirect mechanisms include upregulation of transforming growth factor-, and downregulation of the epidermal growth factor receptor. 1,25(OH)2D3 may induce apoptosis either indirectly through effects on the insulin-like growth receptor and tumour necrosis factor-, or more directly via the Bcl-2 family system, the ceramide pathway, the death receptors (e.g. Fas) and the stress-activated protein kinase pathways (Jun N terminal kinase and p38). Inhibition of tumour invasion and metastasis potential has been demonstrated and mechanisms include inhibition of serine proteinases, metalloproteinases and angiogenesis. The lines of evidence for an effect of vitamin D3 in systemic cancer are the laboratory demonstration of relevant effects on cellular growth, differentiation, apoptosis, malignant cell invasion and metastasis; epidemiological findings of an association of the occurrence and outcome of cancers with derangements of vitamin D3/1,25(OH)2D3 and the association of functional polymorphisms of the VDR with the occurrence of certain cancers. In addition, vitamin D3 analogues are being developed as cancer chemotherapy agents. There is accumulating evidence that the vitamin D3/1,25(OH)2D3/VDR axis is similarly important in malignant melanoma (MM). MM cells express the VDR, and the antiproliferative and prodifferentiation effects of 1,25(OH)2D3 have been shown in cultured melanocytes, MM cells and MM xenografts. Recently, an inhibitory effect on the spread of MM cells has been demonstrated, low serum levels of 1,25(OH)2D3 have been reported in MM patients and the VDR polymorphisms have been shown to be associated with both the occurrence and outcome of MM. The relationship between solar irradiation and MM is more complex than for the systemic cancers. As in other cancers, there is evidence of a protective effect of vitamin D3 in MM, but ultraviolet radiation, which is a principal source of vitamin D3, is mutagenic. Further work is necessary on the influence of serum vitamin D3 levels on the occurrence and prognosis of MM, the effects of sun protection measures on serum vitamin D3 levels in temperate climates and epidemiological studies on geographical factors and skin type on the prognosis of MM. Meanwhile, it would seem mandatory to ensure an adequate vitamin D3 status if sun exposure were seriously curtailed, certainly in relation to carcinoma of breast, prostate and colon and probably also MM. [source] Differential expression of estrogen-related receptors , and , (ERR, and ERR,) and their clinical significance in human prostate cancerCANCER SCIENCE, Issue 3 2010Tetsuya Fujimura (Cancer Sci 2010; 101: 646,651) Estrogen-related receptor (ERR) is a nuclear receptor that modulates the estrogen-signaling pathway. Here, we investigated the expression of both ERR, and ERR, in human prostate tissues. Using original rabbit polyclonal anti-ERR, and anti-ERR, antibodies, the expression of ERR, and ERR, was evaluated by immunohistochemical analysis of cancerous lesions (n = 107) and benign foci (n = 92), obtained by radical prostatectomy. Stained slides were evaluated for the proportion of immunoreactive cells and their staining intensity. Total immunoreactivity scores (IR scores; range, 0,8) were calculated as the sum of the proportion and intensity scores. The relationship between the clinicopathological characteristics of the patients and the expression of the three ERRs (ERR,, ERR ,, and ERR ,) was evaluated. IR scores for ERR, and ERR, were significantly lower in cancerous lesions than that in benign foci (P < 0.0001, for both). Clinicopathological analyses revealed that the patients with low ERR, IR scores (,4) tended to show poor cancer-specific survival (P = 0.07). Then, we used data from our previous study (Fujimura T., Int J Cancer, 2007; 120: 2325,30). Patients with a high IR score for ERR, and a low score for ERR, showed significantly poorer cancer-specific survival than those with a low IR score for ERR, and a high score for ERR, (P = 0.0003). We demonstrated the differential expression of ERR, and ERR, in prostate tissue. The combined evaluation of the expression of ERR, and ERR, could be a significant prognostic factor for prostate cancer. [source] Silicon Analogues of the RXR-Selective Retinoid Agonist SR11237 (BMS649): Chemistry and BiologyCHEMMEDCHEM, Issue 7 2009W. Peter Lippert Abstract C/Si switch: Twofold sila-substitution (C/Si exchange) in the RXR-selective retinoids 4,a (SR11237) and 5,a leads to 4,b (disila-SR11237) and 5,b, respectively. Chemistry and biology of the C/Si pairs are reported. SR11237 (BMS649, 4,a) is a pan-RXR-selective retinoid agonist. Its silicon analogue, disila-SR11237 (4,b; twofold C/Si exchange), was prepared in a multistep synthesis by starting from 1,2-bis(ethynyldimethylsilyl)ethane. In addition, the related C/Si analogues 5,a and 5,b, with an indane (disila-indane) instead of a tetraline (disila-tetraline) skeleton, were synthesized. The C/Si pairs 4,a/4,b and 5,a/5,b were studied for their interaction with retinoid receptors and were demonstrated to be highly potent RXR-selective ("rexinoid") agonists. Interestingly, twofold C/Si exchange in the indane moiety of 5,a resulted in a 10-fold increase in biological activity of the corresponding silicon-containing rexinoid 5,b, possibly resulting from an increased receptor affinity or a divergent allosteric effect on co-regulator-binding surfaces. The crystal structures of the ternary complexes formed by 5,a and 5,b, respectively, with the ligand-binding domain of hRXR, and a peptide of the co-activator TIF2/GRIP1 revealed additional interactions of the disila analogue 5,b with the H7 and H11 residues, supporting the first option of increased binding affinity. This is the first demonstration of an increase in binding affinity of a ligand to a nuclear receptor by C/Si replacement, thereby adding this C/Si switch strategy to the repertoire of nuclear receptor ligand design. [source] PPAR, and metabolism: insights from the study of human genetic variantsCLINICAL ENDOCRINOLOGY, Issue 3 2003Mark Gurnell Summary Diabetes, obesity, atherosclerosis and cancer are the principal contributors to morbidity and mortality in Western society. Emerging evidence indicates that a nuclear receptor, the peroxisome proliferator-activated receptor , (PPAR,), plays a role in these pathological processes. Furthermore, modulation of receptor action in these diseases may be of therapeutic value, as exemplified by the recent introduction of the thiazolidinediones, a novel class of insulin-sensitizing agent for the treatment of type 2 diabetes mellitus. The availability of such high-affinity ligands has facilitated the study of signalling pathways through which PPAR, regulates metabolic processes; these analyses have been complemented by the study of human subjects harbouring (naturally occurring) mutations and polymorphisms within the receptor. The latter have provided unique genetic evidence for a link between PPAR, and mammalian glucose homeostasis, lipid metabolism and regulation of fat mass. This review highlights recent studies which have advanced our understanding of the pivotal role that this receptor plays in metabolism, with particular reference to the consequences of inherited variation in the human receptor gene. [source] Overview of retinoid metabolism and functionDEVELOPMENTAL NEUROBIOLOGY, Issue 7 2006Rune Blomhoff Abstract Retinoids (vitamin A) are crucial for most forms of life. In chordates, they have important roles in the developing nervous system and notochord and many other embryonic structures, as well as in maintenance of epithelial surfaces, immune competence, and reproduction. The ability of all- trans retinoic acid to regulate expression of several hundred genes through binding to nuclear transcription factors is believed to mediate most of these functions. The role of all- trans retinoic may extend beyond the regulation of gene transcription because a large number of noncoding RNAs also are regulated by retinoic acid. Additionally, extra-nuclear mechanisms of action of retinoids are also being identified. In organisms ranging from prokaryotes to humans, retinal is covalently linked to G protein-coupled transmembrane receptors called opsins. These receptors function as light-driven ion pumps, mediators of phototaxis, or photosensory pigments. In vertebrates phototransduction is initiated by a photochemical reaction where opsin-bound 11- cis -retinal is isomerized to all- trans -retinal. The photosensitive receptor is restored via the retinoid visual cycle. Multiple genes encoding components of this cycle have been identified and linked to many human retinal diseases. Central aspects of vitamin A absorption, enzymatic oxidation of all- trans retinol to all- trans retinal and all- trans retinoic acid, and esterification of all- trans retinol have been clarified. Furthermore, specific binding proteins are involved in several of these enzymatic processes as well as in delivery of all- trans retinoic acid to nuclear receptors. Thus, substantial progress has been made in our understanding of retinoid metabolism and function. This insight has improved our view of retinoids as critical molecules in vision, normal embryonic development, and in control of cellular growth, differentiation, and death throughout life. © 2006 Wiley Periodicals, Inc. J Neurobiol 66: 606,630, 2006 [source] Pomegranate flower: a unique traditional antidiabetic medicine with dual PPAR-,/-, activator propertiesDIABETES OBESITY & METABOLISM, Issue 1 2008Yuhao Li PPARs are transcription factors belonging to the superfamily of nuclear receptors. PPAR-, is involved in the regulation of fatty acid (FA) uptake and oxidation, inflammation and vascular function, while PPAR-, participates in FA uptake and storage, glucose homeostasis and inflammation. The PPARs are thus major regulators of lipid and glucose metabolism. Synthetic PPAR-, or PPAR-, agonists have been widely used in the treatment of dyslipidaemia, hyperglycaemia and their complications. However, they are associated with an incidence of adverse events. Given the favourable metabolic effects of both PPAR-, and PPAR-, activators, as well as their potential to modulate vascular disease, combined PPAR-,/-, activation has recently emerged as a promising concept, leading to the development of mixed PPAR-,/-, activators. However, some major side effects associated with the synthetic dual activators have been reported. It is unclear whether this is a specific effect of the particular synthetic compounds or a class effect. To date, a medication that may combine the beneficial metabolic effects of PPAR-, and PPAR-, activation with fewer undesirable side effects has not been successfully developed. Pomegranate plant parts are used traditionally for the treatment of various disorders. However, only pomegranate flower has been prescribed in Unani and Ayurvedic medicines for the treatment of diabetes. This review provides a new understanding of the dual PPAR-,/-, activator properties of pomegranate flower in the potential treatment of diabetes and its associated complications. [source] Insulin resistance , a common link between type 2 diabetes and cardiovascular diseaseDIABETES OBESITY & METABOLISM, Issue 3 2006Harold E. Lebovitz Evidence suggests that diabetes and cardiovascular disease (CVD) may share an underlying cause(s), a theory known as the ,common soil' hypothesis. Insulin resistance is central both to the progression from normal glucose tolerance to type 2 diabetes and to a constellation of cardiovascular risk factors known as the metabolic syndrome. These risk factors include visceral obesity and dyslipidaemia characterized by low levels of high-density lipoprotein cholesterol, hypertriglyceridaemia and raised small dense low-density lipoprotein particle levels. Changes in adipose tissue mass and metabolism may link insulin resistance and visceral obesity, a condition that is common in type 2 diabetes. Furthermore, weight reduction, increased physical activity, metformin and acarbose have been shown to reduce the development of type 2 diabetes in genetically predisposed subjects and may decrease the high cardiovascular risk of patients with diabetes. Some fatty acid derivatives can affect energy metabolism by activating peroxisome proliferator-activated receptors (PPARs), nuclear receptors that play a key role in energy homeostasis. These receptors represent an ideal therapeutic target for reducing cardiovascular risk, because they are involved in the regulation of both insulin action and lipid metabolism. In addition to lifestyle changes, PPAR, agonists such as thiazolidinediones are frequently beneficial and have been shown to ameliorate insulin resistance, while activation of PPAR, (e.g. by fibrates) can lead to improvements in free fatty acid oxidation and lipid profile, and a reduction in cardiovascular events. The development of agents with both PPAR, and PPAR, activity promises added benefits with amelioration of insulin resistance, delayed progression to and of type 2 diabetes and a reduction of CVD. [source] | |||||||||||||||||||||||||||||||||||||