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1

Cloning and differential tissue-specific expression of three mouse beta chemokine receptor-like genes, including the gene for a functional macrophage inflammatory protein-1 alpha receptor.  

PubMed

Macrophage inflammatory protein-1 alpha (MIP-1 alpha) and RANTES, members of the beta chemokine family of leukocyte chemoattractants, bind to a common seven-transmembrane-domain human receptor. We have now cloned three related mouse genes: one for a selective MIP-1 alpha receptor (MIP-1 alpha R) and two for orphan receptors provisionally designated MIP-1 alpha receptor-like 1 and 2 (MIP-1 alpha RL1 and 2). Their deduced sequences are 80, 62, and 63% identical to the human MIP-1 alpha/RANTES receptor, respectively. K562 cells stably transfected with MIP-1 alpha R specifically bound 125I-human MIP-1 alpha and 125I-human RANTES with high affinity. The rank order of beta chemokine competition for 125I-human MIP-1 alpha binding was human MIP-1 alpha > mouse MIP-1 alpha approximately RANTES approximately MIP-1 beta > MCP-1. However, human RANTES was approximately 100-fold less potent as a calcium-mobilizing agonist for MIP-1 alpha R than either human or mouse MIP-1 alpha, which matched the selectively of mouse leukocytes for calcium mobilization by MIP-1 alpha and RANTES. No other beta or alpha chemokines tested were agonists for MIP-1 alpha R. RNA for all three genes was detected in mouse leukocytes, but unique patterns of expression were identified in solid organs: MIP-1 alpha R, heart, spleen, and lung; MIP-1 alpha RL1, skeletal muscle; and MIP-1 alpha RL2, spleen and liver. These data identify potentially important new targets for beta chemokine action in the mouse. PMID:7542241

Gao, J L; Murphy, P M

1995-07-21

2

Cooperative transcriptional activation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 genes by nuclear receptors including Liver-X-Receptor.  

PubMed

The ATP-binding cassette transporters ABCG5 and ABCG8 form heterodimers that limit absorption of dietary sterols in the intestine and promote cholesterol elimination from the body through hepatobiliary secretion. To identify cis-regulatory elements of the two genes, we have cloned and analyzed twenty-three evolutionary conserved region (ECR) fragments using the CMV-luciferase reporter system in HepG2 cells. Two ECRs were found to be responsive to the Liver-X-Receptor (LXR). Through elaborate deletion studies, regions containing putative LXREs were identified and the binding of LXR? was demonstrated by EMSA and ChIP assay. When the LXREs were inserted upstream of the intergenic promoter, synergistic activation by LXR?/RXR? in combination with GATA4, HNF4?, and LRH-1, which had been shown to bind to the intergenic region, was observed. In conclusion, we have identified two LXREs in ABCG5/ABCG8 genes for the first time and propose that these LXREs, especially in the ECR20, play major roles in regulating these genes. PMID:23790976

Back, Su Sun; Kim, Jinsu; Choi, Daehyung; Lee, Eui Sup; Choi, Soo Young; Han, Kyuhyung

2013-06-01

3

Melatonin receptor genes in vertebrates.  

PubMed

Melatonin receptors are members of the G protein-coupled receptor (GPCR) family. Three genes for melatonin receptors have been cloned. The MT1 (or Mel1a or MTNR1A) and MT2 (or Mel1b or MTNR1B) receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype, Mel1c (or MTNR1C), has been identified in fish, amphibians and birds. Another melatonin related orphan receptor, GPR50, which does not bind melatonin, is found exclusively in mammals. The hormone melatonin is secreted primarily by the pineal gland, with highest levels occurring during the dark period of a circadian cycle. This hormone acts systemically in numerous organs. In the brain, it is involved in the regulation of various neural and endocrine processes, and it readjusts the circadian pacemaker, the suprachiasmatic nucleus. This article reviews recent studies of gene organization, expression, evolution and mutations of melatonin receptor genes of vertebrates. Gene polymorphisms reveal that numerous mutations are associated with diseases and disorders. The phylogenetic analysis of receptor genes indicates that GPR50 is an outgroup to all other melatonin receptor sequences. GPR50 may have separated from a melatonin receptor ancestor before the split between MTNR1C and the MTNR1A/B ancestor. PMID:23712359

Li, Di Yan; Smith, David Glenn; Hardeland, Rüdiger; Yang, Ming Yao; Xu, Huai Liang; Zhang, Long; Yin, Hua Dong; Zhu, Qing

2013-01-01

4

Concordance between isolated cleft palate in mice and alterations within a region including the gene encoding the [beta][sub 3] subunit of the type A [gamma]-aminobutyric acid receptor  

SciTech Connect

Genetic and molecular analyses of a number of radiation-induced deletion mutations of the pink-eyed dilution (p) locus in mouse chromosome 7 have identified a specific interval on the genetic map associated with a neonatally lethal mutation that results in cleft palate. This interval, closely linked and distal to p, and bracketed by the genes encoding the [alpha][sub 5] and [beta][sub 3] subunits of the type A [gamma]-aminobutyric acid receptor (Gabra5 and Gabrb3, respectively), contains a gene(s) (cp1; cleft palate 1) necessary for normal palate development. The cp1 interval extends from the distal breakpoint of the prenatally lethal p[sup 83FBFo] deletion to the Gabrb3 locus. Among 20 p deletions tested, there was complete concordance between alterations at the Gabrb3 transcription unit and inability to complement the cleft-palate defect. These mapping data, along with previously described in vivo and in vitro teratological effects of [gamma]-aminobutyric acid or its agonists on palate development, suggest the possibility that a particular type A [gamma]-aminobutyric acid receptor that includes the [beta][sub 3] subunit may be necessary for normal palate development. The placement of the cp1 gene within a defined segment of the larger D15S12h (p)-D15S9h-1 interval in the mouse suggests that the highly homologous region of the human genome, 15q11-q13, be evaluated for a role(s) in human fetal facial development. 29 refs., 4 figs., 1 tab.

Culiat, C.T.; Stubbs, L.; Nicholls, R.D.; Montgomery, C.S.; Russell, L.B.; Johnson, D.K. (Oak Ridge National Lab., TN (United States)); Rinchik, E.M. (Oak Ridge National Lab., TN (United States) Univ. of Florida, Gainesville (United States))

1993-06-01

5

Antigen receptor gene rearrangement.  

PubMed

Two specialized forms of site-directed double-strand (ds) DNA breakage and rejoining are part of the physiologic program of lymphocytes. One is recombination of the V, D and J gene sequences, termed V(D)J recombination, occurring during early B- and T-cell development, and the other is class-switch recombination occurring exclusively in mature B cells. For V(D)J recombination significant progress has been made recently elucidating the biochemistry of the reaction. In particular our understanding of how DNA ds breaks are both generated and rejoined has increased. For class-switch recombination no definitive information is known about the nucleases required for making the ds breaks, but recent evidence suggests that the joining phase shares activities also required for V(D)J recombination and general DNA ds break repair. PMID:9602306

Grawunder, U; West, R B; Lieber, M R

1998-04-01

6

The androgen receptor gene mutations database.  

PubMed Central

The androgen receptor gene mutations database is a comprehensive listing of mutations published in journals and meetings proceedings. The majority of mutations are point mutations identified in patients with androgen insensitivity syndrome. Information is included regarding the phenotype, the nature and location of the mutations, as well as the effects of the mutations on the androgen binding activity of the receptor. The current version of the database contains 149 entries, of which 114 are unique mutations. The database is available from EMBL (NetServ@EMBL-Heidelberg.DE) or as a Macintosh Filemaker file (mc33001@musica.mcgill.ca).

Patterson, M N; Hughes, I A; Gottlieb, B; Pinsky, L

1994-01-01

7

PPAR ? agonist GW0742 interacts weakly with multiple nuclear receptors including the vitamin D receptor  

PubMed Central

A high throughput screening campaign was conducted to identify small molecules with the ability to inhibit the interaction between the vitamin D receptor (VDR) and steroid receptor coactivator 2. These inhibitors represent novel molecular probes to modulate gene regulation mediated by VDR. The peroxisome proliferator-activated receptor ? (PPAR?) agonist GW0742 was among the identified VDR-coactivator inhibitors and has been characterized herein as a pan nuclear receptor antagonist at concentrations higher than 12.1 µM. The highest antagonist activity for GW0742 was found for VDR and the androgen receptor (AR). Surprisingly, GW0742 behaved as PPAR agonist/antagonist activating transcription at lower concentration and inhibiting this effect at higher concentrations. A unique spectroscopic property of GW0742 was identified as well. In the presence of rhodamine-derived molecules, GW0742+ increased fluorescence intensity and fluorescence polarization at an excitation wavelength of 595 nm and emission wavelength of 615 nm in a dose dependent manner. The GW0742-inhibited NR-coactivator binding resulted in a reduced expression of five different NR target genes in LNCaP cells in the presence of agonist. Especially VDR target genes CYP24A1, IGFBP-3 and TRPV6 were negatively regulated by GW0742. GW0742 is the first VDR ligand inhibitor lacking the secosteroid structure of VDR ligand antagonists. Nevertheless, the VDR-meditated downstream process of cell differentiation was antagonized by GW0742 in HL-60 cells that were pretreated with the endogenous VDR agonist 1,25-dihydroxyvitamin D3.

Nandhikonda, Premchendar; Yasgar, Adam; Baranowski, Athena M.; Sidhu, Preetpal S.; McCallum, Megan M.; Pawlak, Alan J.; Teske, Kelly; Feleke, Belaynesh; Yuan, Nina Y.; Kevin, Chinedum; Bikle, Daniel D.; Ayers, Steven D.; Webb, Paul; Rai, Ganesha; Simeonov, Anton; Jadhav, Ajit; Maloney, David; Arnold, Leggy A.

2013-01-01

8

Regulating antigen-receptor gene assembly  

Microsoft Academic Search

The genes encoding antigen receptors are unique because of their high diversity and their assembly in developing lymphocytes from gene segments through a series of site-specific DNA recombination reactions known as V(D)J rearrangement. This review focuses on our understanding of how recombination of immunoglobulin and T-cell receptor gene segments is tightly regulated despite being catalysed by a common lymphoid recombinase,

Mark S. Schlissel

2003-01-01

9

Promoter architecture of mouse olfactory receptor genes.  

PubMed

Odorous chemicals are detected by the mouse main olfactory epithelium (MOE) by about 1100 types of olfactory receptors (OR) expressed by olfactory sensory neurons (OSNs). Each mature OSN is thought to express only one allele of a single OR gene. Major impediments to understand the transcriptional control of OR gene expression are the lack of a proper characterization of OR transcription start sites (TSSs) and promoters, and of regulatory transcripts at OR loci. We have applied the nanoCAGE technology to profile the transcriptome and the active promoters in the MOE. nanoCAGE analysis revealed the map and architecture of promoters for 87.5% of the mouse OR genes, as well as the expression of many novel noncoding RNAs including antisense transcripts. We identified candidate transcription factors for OR gene expression and among them confirmed by chromatin immunoprecipitation the binding of TBP, EBF1 (OLF1), and MEF2A to OR promoters. Finally, we showed that a short genomic fragment flanking the major TSS of the OR gene Olfr160 (M72) can drive OSN-specific expression in transgenic mice. PMID:22194471

Plessy, Charles; Pascarella, Giovanni; Bertin, Nicolas; Akalin, Altuna; Carrieri, Claudia; Vassalli, Anne; Lazarevic, Dejan; Severin, Jessica; Vlachouli, Christina; Simone, Roberto; Faulkner, Geoffrey J; Kawai, Jun; Daub, Carsten O; Zucchelli, Silvia; Hayashizaki, Yoshihide; Mombaerts, Peter; Lenhard, Boris; Gustincich, Stefano; Carninci, Piero

2012-03-01

10

Singular expression of olfactory receptor genes.  

PubMed

Understanding the mechanisms of monogenic and monoallelic transcription of the large repertoire of olfactory receptor genes represents a challenging task. A picture is now emerging in which odorant receptor choice and stabilization involve an escape from silencing followed by the activation of an unconventional feedback loop. PMID:24120129

Rodriguez, Ivan

2013-10-10

11

Expression of plasma membrane receptor genes during megakaryocyte development  

PubMed Central

Megakaryocyte (MK) development is critically informed by plasma membrane-localized receptors that integrate a multiplicity of environmental cues. Given that the current understanding about receptors and ligands involved in megakaryocytopoiesis is based on single targets, we performed a genome-wide search to identify a plasma membrane receptome for developing MKs. We identified 40 transmembrane receptor genes as being upregulated during MK development. Seven of the 40 receptor-associated genes were selected to validate the dataset. These genes included: interleukin-9 receptor (IL9R), transforming growth factor, ? receptor II (TGFBR2), interleukin-4 receptor (IL4R), colony stimulating factor-2 receptor-beta (CSFR2B), adiponectin receptor (ADIPOR2), thrombin receptor (F2R), and interleukin-21 receptor (IL21R). RNA and protein analyses confirmed their expression in primary human MKs. Matched ligands to IL9R, TGFBR2, IL4R, CSFR2B, and ADIPOR2 affected megakaryocytopoiesis. IL9 was unique in its ability to increase the number of MKs formed. In contrast, MK colony formation was inhibited by adiponectin, TGF-?, IL4, and GM-CSF. The thrombin-F2R axis affected platelet function, but not MK development, while IL21 had no apparent detectable effects. ADP-induced platelet aggregation was suppressed by IL9, TGF-?, IL4, and adiponectin. Overall, six of seven of the plasma membrane receptors were confirmed to have functional roles in MK and platelet biology. Also, results show for the first time that adiponectin plays a regulatory role in MK development. Together these data support a strong likelihood that the 40 transmembrane genes identified as being upregulated during MK development will be an important resource to the research community for deciphering the complex repertoire of environmental cues regulating megakaryocytopoiesis and/or platelet function.

Sun, Sijie; Wang, Wenjing; Latchman, Yvette; Gao, Dayong; Aronow, Bruce

2013-01-01

12

Dynamics of nuclear receptor target gene regulation  

PubMed Central

Ligand-regulated nuclear receptors, such as estrogen receptors, glucocorticoid receptor, vitamin D receptor, and peroxisome proliferator-activated receptors, belong to the most widely studied and best understood transcription factors. Therefore, the dynamic nature of transcriptional regulation was observed first with different members of the nuclear receptor superfamily, but is now also extended to other transcription factors, such as nuclear factor ?B. Dynamic and in part cyclical processes were observed on the level of translocation into the nucleus, association with genomic binding sites, exchange of co-regulators and chromatin modifiers, occurrence of chromatin marks, and activities of RNA polymerase II resulting in mRNA synthesis. In this review, we summarize recent findings on the dynamic regulation of nuclear receptor target genes in the chromatin context.

Seuter, Sabine

2010-01-01

13

Chromosomal localization of prostanoid receptor genes  

SciTech Connect

Prostanoids such as prostaglandins (PGs) and thromboxane (TXA{sub 2}) are a family of oxygenated metabolites of arachidonic acid. They produce a wide variety of physiological and pathophysiological effects mediated through specific cell surface receptors. Recent cDNA cloning of the prostaglandins and thromboxane receptors indicates that they are a unique family of receptors within the superfamily of G-protein-coupled receptors. Not only are all the prostanoids (PGE{sub 2}, PGF{sub 2{alpha}}, PGI{sub 2}, PGD{sub 2} and TXA{sub 2}) structurally related, but their receptors also show significant (26-47%) amino acid sequence identity. To investigate the evolutionary relationship between the various prostanoid receptors and their involvement in a number of pathophysiological conditions, we have mapped these loci in the human genome. The PGE{sub 2} receptor subtypes Ep{sub 1}, EP{sub 2}, EP{sub 3}, the PGF{sub 2{alpha}} receptor (FP), the PGI{sub 2} receptor (IP) and the TXA{sub 2} receptor (Tbxa2r) were sublocalized by in situ hybridization. EP{sub 1},IP and Tbxa2r were mapped to chromosome 19 at 19p13.1, 19q13.3 and 19p13.3, respectively. EP{sub 3} and FP mapped to 1p13.2 and 1p13.1, respectively. EP{sub 2} mapped to 5p13.1. Mapping the genomic loci of the prostanoid receptor family genes should expand our understanding of the evolution of G-protein-coupled receptor family genes and advance our investigation of the involvement of these genes in various pathophysiological conditions.

Adam, M.A.; Abramovitz, M.; Anderson, L.L. [Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec (Canada)] [and others

1994-09-01

14

Molecular cloning of a fish gene encoding a novel seven-transmembrane receptor related distantly to catecholamine, histamine, and serotonin receptors.  

PubMed

A genomic DNA fragment encoding a G protein-coupled seven-transmembrane receptor was isolated from Medaka fish, Oryzias latipes. The encoded protein is similar in sequence to other receptors including catecholamine, histamine and serotonin receptors. However, the similarity is much lower than those among members of these receptor subfamilies, thus suggesting this seven-transmembrane receptor to be an orphan receptor whose ligand has not yet been identified. Genomic Southern blot analysis suggested that the fish genome contains additional receptor genes related to the isolated gene, indicating that this novel receptor, possibly with its related receptors, might constitute a novel subfamily of the seven-transmembrane receptor superfamily. PMID:7756357

Yasuoka, A; Abe, K; Saigo, K; Arai, S; Emori, Y

1995-05-01

15

Widespread ectopic expression of olfactory receptor genes  

Microsoft Academic Search

BACKGROUND: Olfactory receptors (ORs) are the largest gene family in the human genome. Although they are expected to be expressed specifically in olfactory tissues, some ectopic expression has been reported, with special emphasis on sperm and testis. The present study systematically explores the expression patterns of OR genes in a large number of tissues and assesses the potential functional implication

Ester Feldmesser; Tsviya Olender; Miriam Khen; Itai Yanai; Ron Ophir; Doron Lancet

2006-01-01

16

Adaptive Evolution of G-Protein Coupled Receptor Genes  

Microsoft Academic Search

The phylogeny and patterns of nucleotide substitutions in the visual pigment genes, adrenergic receptor genes, muscarinic receptor genes, and in the human mas on- cogene were studied by comparing their DNA sequences. The evolutionary tree obtained shows that the visual pigment genes and mas oncogene form one cluster and that the receptor genes form another. In the evolution of rhodopsin

Shozo Yokoyama; Keith E. Isenberg; Alan F. Wright

17

Identification of an Orphan Receptor Gene as a Type 1 Calcitonin Gene-Related Peptide Receptor  

Microsoft Academic Search

Calcitonin gene-related peptide (CGRP) is a 37 residue neuropeptide that is distantly related to adrenomedullin, We have recently reported the cloning and expression of an adrenomedullin receptor which is ? 30% homologous to the canine orphan receptor RDC-1. Therefore we tested the hypothesis that RDC-1 was a CGRP receptor. The RDC-1 gene was expressed in COS-7 cells and showed a

S. Kapas; A. J. L. Clark

1995-01-01

18

Estrogen receptor genes variations and breast cancer risk in Iran  

PubMed Central

Evidence suggests that alterations in estrogen signaling pathways, including estrogen receptor ? (ER-?) and estrogen receptor ? (ER-?) occur during breast cancer development. ER-? and ER-? genes polymorphisms have been found to be associated with breast cancer and clinical features of the disease in the western countries. In the current study, we evaluated the hypothesis that certain sequence variants of the ER-? and ER-? genes are associated with an additively increased risk for breast cancer in Iranian women breast cancer patients. The genes were scanned in 150 Iranian patients with newly diagnosed invasive breast tumors and in healthy control individuals by PCR single-strand conformation polymorphism (SSCP) method. Three single nucleotide polymorphisms (SNPs) in codon10 (TCT?TCC), codon 352 (CCG?CCC) and codon 594 (ACG?ACA) in ER-? gene and one SNP codon 392 (CTC?CTG) in ER-? were revealed have additive effects in developing breast cancer and LN metastases. Also, SNP in codon 392 of estrogen receptor-? gene is more effective (threefold) than those SNPs in codons 10, 325, 594 of estrogen receptor-? gene in developing LN metastases in breast cancer patients. SNPs in estrogen receptor ? and ? have additive effects in increasing risk for developing breast cancer with LN metastases among Iranian women breast cancer patients.

Abbasi, Sakineh; Nouri, Mehrnaz; Azimi, Cyrus

2012-01-01

19

Antigen-receptor genes of the agnathan lamprey are assembled by a process involving copy choice  

Microsoft Academic Search

Jawless vertebrates have acquired immunity but do not have immunoglobulin-type antigen receptors. Variable lymphocyte receptors (VLRs) have been identified in lamprey that consist of multiple leucine-rich repeat (LRR) modules. An active VLR gene is generated by the assembly of a series of variable gene segments, including many that encode LRRs. Stepwise assembly of the gene segments seems to occur by

Natsuko Kishishita; Kazumichi Shimizu; Satoshi Hirose; Masato Miyoshi; Junnya Nezu; Toshinobu Nishimura; Hirofumi Nishizumi; Yoshimasa Takahashi; Shu-ichi Hashimoto; Masaki Takeuchi; Atsushi Miyajima; Toshitada Takemori; Anthony J Otsuka; Hitoshi Sakano; Fumikiyo Nagawa

2006-01-01

20

Structure of the human histamine H1 receptor gene.  

PubMed Central

Histamine H1 receptor expression has been reported to change in disorders such as allergic rhinitis, autoimmune myocarditis, rheumatoid arthritis and atherosclerosis. Here we report the isolation and characterization of genomic clones containing the 5' flanking (regulatory) region of the human histamine H1 receptor gene. An intron of approx. 5.8 kb was identified in the 5' untranslated region, which suggests that an entire subfamily of G-protein-coupled receptors may contain an intron immediately upstream of the start codon. The transcription initiation site was mapped by 5' rapid amplification of cDNA ends to a region 6.2 kb upstream of the start codon. Immediately upstream of the transcription start site a fragment of 1.85 kb was identified that showed promoter activity when placed upstream of a luciferase reporter gene and transiently transfected into cells expressing the histamine H1 receptor. The promoter sequence shares a number of characteristics with the promoter sequences of other G-protein-coupled receptor encoding genes, including binding sites for several transcription factors, and the absence of TATA and CAAT sequences at the appropriate locations. The promoter sequence described here differs from that reported previously [Fukui, Fujimoto, Mizuguchi, Sakamoto, Horio, Takai, Yamada and Ito (1994) Biochem. Biophys. Res. Commun. 201, 894-901] because the reported genomic clone was chimaeric. Furthermore our study provides evidence that the 3' untranslated region of the H1 receptor mRNA is much longer than previously accepted. Together, these findings provide a complete view of the structure of the human histamine H1 receptor gene. Both the coding region of the H1 receptor gene and its promoter region were independently mapped to chromosome 3p25.

De Backer, M D; Loonen, I; Verhasselt, P; Neefs, J M; Luyten, W H

1998-01-01

21

Reciprocal activation of Xenobiotic response genes by nuclear receptors SXR\\/PXR and CAR  

Microsoft Academic Search

The cytochrome P450 (CYP) gene products such as CYP3A and CYP2B are essential for the metabolism of steroid hormones and xenochemicals including prescription drugs. Nuclear receptor SXR\\/PXR (steroid and xenobiotic receptor\\/pregnenolone X receptor) has been shown both biochemically and genetically to activate CYP3A genes, while similar studies have established constitutive androstane receptor (CAR) as a CYP2B regulator. The response elements

Wen Xie; Joyce L. Barwick; Cynthia M. Simon; Alexis M. Pierce; Stephen Safe; Bruce Blumberg; Philip S. Guzelian; Ronald M. Evans

2000-01-01

22

Isolation of a Novel Receptor cDNA Establishes the Existence of Two PDGF Receptor Genes  

Microsoft Academic Search

A genomic sequence and cloned complementary DNA has been identified for a novel receptor-like gene of the PDGF receptor\\/CSF1 receptor subfamily (platelet-derived growth factor receptor\\/colony-stimulating factor type 1 receptor). The gene recognized a 6.4-kilobase transcript that was coexpressed in normal human tissues with the 5.3-kilobase PDGF receptor messenger RNA. Introduction of complementary DNA of the novel gene into COS-1 cells

Toshimitsu Matsui; Mohammad Heidaran; Toru Miki; Nicholas Popescu; William La Rochelle; Matthias Kraus; Jacalyn Pierce; Stuart Aaronson

1989-01-01

23

Genes involved in Drosophila glutamate receptor expression and localization  

PubMed Central

Background A clear picture of the mechanisms controlling glutamate receptor expression, localization, and stability remains elusive, possibly due to an incomplete understanding of the proteins involved. We screened transposon mutants generated by the ongoing Drosophila Gene Disruption Project in an effort to identify the different types of genes required for glutamate receptor cluster development. Results To enrich for non-silent insertions with severe disruptions in glutamate receptor clustering, we identified and focused on homozygous lethal mutants in a collection of 2185 BG and KG transposon mutants generated by the BDGP Gene Disruption Project. 202 lethal mutant lines were individually dissected to expose glutamatergic neuromuscular junctions, stained using antibodies that recognize neuronal membrane and the glutamate receptor subunit GluRIIA, and viewed using laser-scanning confocal microscopy. We identified 57 mutants with qualitative differences in GluRIIA expression and/or localization. 84% of mutants showed loss of receptors and/or clusters; 16% of mutants showed an increase in receptors. Insertion loci encode a variety of protein types, including cytoskeleton proteins and regulators, kinases, phosphatases, ubiquitin ligases, mucins, cell adhesion proteins, transporters, proteins controlling gene expression and protein translation, and proteins of unknown/novel function. Expression pattern analyses and complementation tests, however, suggest that any single mutant – even if a mutant gene is uniquely tagged – must be interpreted with caution until the mutation is validated genetically and phenotypically. Conclusion Our study identified 57 transposon mutants with qualitative differences in glutamate receptor expression and localization. Despite transposon tagging of every insertion locus, extensive validation is needed before one can have confidence in the role of any individual gene. Alternatively, one can focus on the types of genes identified, rather than the identities of individual genes. This genomic approach, which circumvents many technical caveats in favor of a wider perspective, suggests that glutamate receptor cluster formation involves many cellular processes, including: 1) cell adhesion and signaling, 2) extensive and relatively specific regulation of gene expression and RNA, 3) the actin and microtubule cytoskeletons, and 4) many novel/unexplored processes, such as those involving mucin/polycystin-like proteins and proteins of unknown function.

Liebl, Faith LW; Featherstone, David E

2005-01-01

24

Human low-density lipoprotein receptor gene and its regulation  

Microsoft Academic Search

The low-density lipoprotein (LDL) receptor is a transmembrane glycoprotein that mediates the binding and endocytosis of lipoproteins containing apolipoprotein B and E, especially the cholesterol-rich LDL. Mutations in the LDL receptor gene can produce dysfunctional LDL receptors and cause familial hypercholesterolemia. The expression of the LDL receptor gene is under an intriguing regulation by sterol and nonsterol mediators either at

Wei-Jia Kong; Jingwen Liu; Jian-Dong Jiang

2006-01-01

25

Quantitative set analysis for gene expression: a method to quantify gene set differential expression including gene-gene correlations  

PubMed Central

Enrichment analysis of gene sets is a popular approach that provides a functional interpretation of genome-wide expression data. Existing tests are affected by inter-gene correlations, resulting in a high Type I error. The most widely used test, Gene Set Enrichment Analysis, relies on computationally intensive permutations of sample labels to generate a null distribution that preserves gene–gene correlations. A more recent approach, CAMERA, attempts to correct for these correlations by estimating a variance inflation factor directly from the data. Although these methods generate P-values for detecting gene set activity, they are unable to produce confidence intervals or allow for post hoc comparisons. We have developed a new computational framework for Quantitative Set Analysis of Gene Expression (QuSAGE). QuSAGE accounts for inter-gene correlations, improves the estimation of the variance inflation factor and, rather than evaluating the deviation from a null hypothesis with a P-value, it quantifies gene-set activity with a complete probability density function. From this probability density function, P-values and confidence intervals can be extracted and post hoc analysis can be carried out while maintaining statistical traceability. Compared with Gene Set Enrichment Analysis and CAMERA, QuSAGE exhibits better sensitivity and specificity on real data profiling the response to interferon therapy (in chronic Hepatitis C virus patients) and Influenza A virus infection. QuSAGE is available as an R package, which includes the core functions for the method as well as functions to plot and visualize the results.

Yaari, Gur; Bolen, Christopher R.; Thakar, Juilee; Kleinstein, Steven H.

2013-01-01

26

Thyroid Hormone Receptor Genes of Neotenic Amphibians  

Microsoft Academic Search

.   Since thyroid hormones play a pivotal role in amphibian metamorphosis we used PCR to amplify DNA fragments corresponding\\u000a to a portion of the ligand-binding domain of the thyroid hormone receptor (TR) genes in several neotenic amphibians: the obligatory\\u000a neotenic members of the family Proteidea the mudpuppy Necturus maculosus and Proteus anguinus as well as two members of the facultative

Rachid Safi; Agnès Begue; Catherine Hänni; Dominique Stehelin; Jamshed R. Tata; Vincent Laudet

1997-01-01

27

Skeletal muscle denervation activates acetylcholine receptor genes  

PubMed Central

Transcriptional activity of acetylcholine receptor subunit genes was investigated in innervated and denervated chick skeletal muscle. The sciatic nerve of 3-d-old White Leghorn chicks was sectioned unilaterally; after various intervals, nuclei were isolated from operated and sham-operated animals, and run-on assays performed. Nuclei were incubated with 32P-UTP, and total RNA was extracted and hybridized onto filters containing an excess of subunit-specific DNA. Specific transcripts were detected by autoradiography and quantitated densitometrically. A sharp increase in transcriptional activity was observed to begin approximately 1/2 d after the operation and peak 1 d later when transcriptional rates reached approximately seven-, six-, and fivefold control levels for the alpha-, delta-, and gamma-subunit genes, respectively. The specificity of the effect was ascertained by normalization to total RNA synthesis and by the demonstration that several nonreceptor genes respond differently to denervation. These results suggest that a denervation signal reaches the genome to induce receptor expression. In addition, since the increase in mRNA levels significantly exceeds what can be accounted for by increased gene activity, posttranscriptional effects are suggested.

1989-01-01

28

Social dominance regulates androgen and estrogen receptor gene expression  

Microsoft Academic Search

In Astatotilapia burtoni, dominant males have higher levels of sex steroid hormones than subordinate males. Because of the complex regulatory interactions between steroid hormones and receptors, we asked whether dominance is also associated with variation in sex steroid receptor gene expression. Using quantitative PCR, we compared the expression of specific subtypes of androgen (AR) and estrogen (ER) receptor genes between

Sabrina S. Burmeister; Vinita Kailasanath; Russell D. Fernald

2007-01-01

29

Polymorphisms of the glucocorticoid receptor gene in Graves ophthalmopathy  

Microsoft Academic Search

Background\\/aims:Glucocorticoids have an important role in the regulation of the immune system, and alterations in glucocorticoid signaling may have an impact on the pathophysiology of autoimmune and inflammatory disorders. Because polymorphisms of the glucocorticoid receptor (GR) gene, including the N363S, ER22\\/23EK, A3669G and BclI variants were found to influence glucocorticoid signalling, we examined whether these polymorphisms could be associated with

B Boyle; K Korányi; A Patocs; I Liko; A Szappanos; R Bertalan; K Racz; C Balazs

2008-01-01

30

Gene Specific Actions of Thyroid Hormone Receptor Subtypes  

PubMed Central

There are two homologous thyroid hormone (TH) receptors (TRs ? and ?), which are members of the nuclear hormone receptor (NR) family. While TRs regulate different processes in vivo and other highly related NRs regulate distinct gene sets, initial studies of TR action revealed near complete overlaps in their actions at the level of individual genes. Here, we assessed the extent that TR? and TR? differ in target gene regulation by comparing effects of equal levels of stably expressed exogenous TRs +/? T3 in two cell backgrounds (HepG2 and HeLa). We find that hundreds of genes respond to T3 or to unliganded TRs in both cell types, but were not able to detect verifiable examples of completely TR subtype-specific gene regulation. TR actions are, however, far from identical and we detect TR subtype-specific effects on global T3 response kinetics in HepG2 cells and many examples of TR subtype specificity at the level of individual genes, including effects on magnitude of response to TR +/? T3, TR regulation patterns and T3 dose response. Cycloheximide (CHX) treatment confirms that at least some differential effects involve verifiable direct TR target genes. TR subtype/gene-specific effects emerge in the context of widespread variation in target gene response and we suggest that gene-selective effects on mechanism of TR action highlight differences in TR subtype function that emerge in the environment of specific genes. We propose that differential TR actions could influence physiologic and pharmacologic responses to THs and selective TR modulators (STRMs).

Yuan, Chaoshen; Su, Jing; Arumanayagam, AnithaChristy S.; Firouzbakht, Sharareh; Cantu Pompa, Jaime J.; Reynolds, Frances Denoto; Zhou, Xiabo; Cvoro, Aleksandra; Webb, Paul

2013-01-01

31

Ghrelin axis genes, peptides and receptors: recent findings and future challenges.  

PubMed

The ghrelin axis consists of the gene products of the ghrelin gene (GHRL), and their receptors, including the classical ghrelin receptor GHSR. While it is well-known that the ghrelin gene encodes the 28 amino acid ghrelin peptide hormone, it is now also clear that the locus encodes a range of other bioactive molecules, including novel peptides and non-coding RNAs. For many of these molecules, the physiological functions and cognate receptor(s) remain to be determined. Emerging research techniques, including proteogenomics, are likely to reveal further ghrelin axis-derived molecules. Studies of the role of ghrelin axis genes, peptides and receptors, therefore, promises to be a fruitful area of basic and clinical research in years to come. PMID:21616122

Seim, Inge; Josh, Peter; Cunningham, Peter; Herington, Adrian; Chopin, Lisa

2011-06-20

32

Widespread ectopic expression of olfactory receptor genes  

PubMed Central

Background Olfactory receptors (ORs) are the largest gene family in the human genome. Although they are expected to be expressed specifically in olfactory tissues, some ectopic expression has been reported, with special emphasis on sperm and testis. The present study systematically explores the expression patterns of OR genes in a large number of tissues and assesses the potential functional implication of such ectopic expression. Results We analyzed the expression of hundreds of human and mouse OR transcripts, via EST and microarray data, in several dozens of human and mouse tissues. Different tissues had specific, relatively small OR gene subsets which had particularly high expression levels. In testis, average expression was not particularly high, and very few highly expressed genes were found, none corresponding to ORs previously implicated in sperm chemotaxis. Higher expression levels were more common for genes with a non-OR genomic neighbor. Importantly, no correlation in expression levels was detected for human-mouse orthologous pairs. Also, no significant difference in expression levels was seen between intact and pseudogenized ORs, except for the pseudogenes of subfamily 7E which has undergone a human-specific expansion. Conclusion The OR superfamily as a whole, show widespread, locus-dependent and heterogeneous expression, in agreement with a neutral or near neutral evolutionary model for transcription control. These results cannot reject the possibility that small OR subsets might play functional roles in different tissues, however considerable care should be exerted when offering a functional interpretation for ectopic OR expression based only on transcription information.

Feldmesser, Ester; Olender, Tsviya; Khen, Miriam; Yanai, Itai; Ophir, Ron; Lancet, Doron

2006-01-01

33

Human specific loss of olfactory receptor genes  

PubMed Central

Olfactory receptor (OR) genes constitute the basis for the sense of smell and are encoded by the largest mammalian gene superfamily of >1,000 genes. In humans, >60% of these are pseudogenes. In contrast, the mouse OR repertoire, although of roughly equal size, contains only ?20% pseudogenes. We asked whether the high fraction of nonfunctional OR genes is specific to humans or is a common feature of all primates. To this end, we have compared the sequences of 50 human OR coding regions, regardless of their functional annotations, to those of their putative orthologs in chimpanzees, gorillas, orangutans, and rhesus macaques. We found that humans have accumulated mutations that disrupt OR coding regions roughly 4-fold faster than any other species sampled. As a consequence, the fraction of OR pseudogenes in humans is almost twice as high as in the non-human primates, suggesting a human-specific process of OR gene disruption, likely due to a reduced chemosensory dependence relative to apes.

Gilad, Yoav; Man, Orna; Paabo, Svante; Lancet, Doron

2003-01-01

34

Identification of a family of muscarinic acetylcholine receptor genes  

SciTech Connect

Complementary DNAs for three different muscarinic acetylcholine receptors were isolated from a rat cerebral cortex library, and the cloned receptors were expressed in mammalian cells. Analysis of human and rat genomic clones indicates that there are at least four functional muscarinic receptor genes and that these genes lack introns in the coding sequence. This gene family provides a new basis for evaluating the diversity of muscarinic mechanisms in the nervous system.

Bonner, T.I.; Buckley, N.J.; Young, A.C.; Brann, M.R.

1987-07-31

35

Neurotensin Receptor 1 Gene (NTSR1) Polymorphism Is Associated with Working Memory  

Microsoft Academic Search

BackgroundRecent molecular genetics studies showed significant associations between dopamine-related genes (including genes for dopamine receptors, transporters, and degradation) and working memory, but little is known about the role of genes for dopamine modulation, such as those related to neurotensin (NT), in working memory. A recent animal study has suggested that NT antagonist administration impaired working memory in a learning task.

Jin Li; Chuansheng Chen; Chunhui Chen; Qinghua He; He Li; Jun Li; Robert K. Moyzis; Gui Xue; Qi Dong

2011-01-01

36

Vitamin D Receptor Gene Polymorphism Is Associated with Graves' Disease in the Japanese Population  

Microsoft Academic Search

Susceptibility to Graves' disease (GD), which is determined by environmental and genetic factors, is conferred by genes in the human leukocyte antigen (HLA) and genes unlinked to HLA, including the CTLA-4 gene. We recently described the association of GD with the vitamin D receptor (VDR) exon 2 initiation codon (VDR-FokI) poly- morphism. An association of some VDR genotypes with osteoporosis,

YOSHIYUKI BAN; MATSUO TANIYAMA; YOSHIO BAN

2010-01-01

37

Human chromosome 11 DNA sequence and analysis including novel gene identification  

Microsoft Academic Search

Chromosome 11, although average in size, is one of the most gene- and disease-rich chromosomes in the human genome. Initial gene annotation indicates an average gene density of 11.6 genes per megabase, including 1,524 protein-coding genes, some of which were identified using novel methods, and 765 pseudogenes. One-quarter of the protein-coding genes shows overlap with other genes. Of the 856

Hideki Noguchi; Yasushi Totoki; Atsushi Toyoda; Yoko Kuroki; Ken Dewar; Christine Lloyd; Takehiko Itoh; Tadayuki Takeda; Dae-Won Kim; Xinwei She; Karen F. Barlow; Toby Bloom; Elspeth Bruford; Jean L. Chang; Christina A. Cuomo; Evan Eichler; Michael G. FitzGerald; David B. Jaffe; Kurt LaButti; Robert Nicol; Hong-Seog Park; Christopher Seaman; Carrie Sougnez; Xiaoping Yang; Andrew R. Zimmer; Michael C. Zody; Bruce W. Birren; Chad Nusbaum; Asao Fujiyama; Masahira Hattori; Jane Rogers; Eric S. Lander; Todd D. Taylor; Yoshiyuki Sakaki

2006-01-01

38

Comparison of the canine and human olfactory receptor gene repertoires  

PubMed Central

Background Olfactory receptors (ORs), the first dedicated molecules with which odorants physically interact to arouse an olfactory sensation, constitute the largest gene family in vertebrates, including around 900 genes in human and 1,500 in the mouse. Whereas dogs, like many other mammals, have a much keener olfactory potential than humans, only 21 canine OR genes have been described to date. Results In this study, 817 novel canine OR sequences were identified, and 640 have been characterized. Of the 661 characterized OR sequences, representing half of the canine repertoire, 18% are predicted to be pseudogenes, compared with 63% in human and 20% in mouse. Phylogenetic analysis of 403 canine OR sequences identified 51 families, and radiation-hybrid mapping of 562 showed that they are distributed on 24 dog chromosomes, in 37 distinct regions. Most of these regions constitute clusters of 2 to 124 closely linked genes. The two largest clusters (124 and 109 OR genes) are located on canine chromosomes 18 and 21. They are orthologous to human clusters located on human chromosomes 11q11-q13 and HSA11p15, containing 174 and 115 ORs respectively. Conclusions This study shows a strongly conserved genomic distribution of OR genes between dog and human, suggesting that OR genes evolved from a common mammalian ancestral repertoire by successive duplications. In addition, the dog repertoire appears to have expanded relative to that of humans, leading to the emergence of specific canine OR genes.

Quignon, Pascale; Kirkness, Ewen; Cadieu, Edouard; Touleimat, Nizar; Guyon, Richard; Renier, Corinne; Hitte, Christophe; Andre, Catherine; Fraser, Claire; Galibert, Francis

2003-01-01

39

GPR48 Increases Mineralocorticoid Receptor Gene Expression  

PubMed Central

Aldosterone and the mineralocorticoid receptor (MR) are critical to the maintenance of electrolyte and BP homeostasis. Mutations in the MR cause aldosterone resistance known as pseudohypoaldosteronism type 1 (PHA1); however, some cases consistent with PHA1 do not exhibit known gene mutations, suggesting the possibility of alternative genetic variants. We observed that G protein–coupled receptor 48 (Gpr48/Lgr4) hypomorphic mutant (Gpr48m/m) mice had hyperkalemia and increased water loss and salt excretion despite elevated plasma aldosterone levels, suggesting aldosterone resistance. When we challenged the mice with a low-sodium diet, these features became more obvious; the mice also developed hyponatremia and increased renin expression and activity, resembling a mild state of PHA1. There was marked renal downregulation of MR and its downstream targets (e.g., the ?-subunit of the amiloride-sensitive epithelial sodium channel), which could provide a mechanism for the aldosterone resistance. We identified a noncanonical cAMP-responsive element located in the MR promoter and demonstrated that GPR48 upregulates MR expression via the cAMP/protein kinase A pathway in vitro. Taken together, our data demonstrate that GPR48 enhances aldosterone responsiveness by activating MR expression, suggesting that GPR48 contributes to homeostasis of electrolytes and BP and may be a candidate gene for PHA1.

Wang, Jiqiu; Li, Xiaoying; Ke, Yingying; Lu, Yan; Wang, Feng; Fan, Nengguang; Sun, Haiyan; Zhang, Huijie; Liu, Ruixin; Yang, Jun; Ye, Lei; Liu, Mingyao

2012-01-01

40

Mechanisms of odor receptor gene choice in Drosophila  

PubMed Central

SUMMARY A remarkable problem in neurobiology is how olfactory receptor neurons (ORNs) select, from among a large odor receptor repertoire, which receptors to express. We use computational algorithms and mutational analysis to define positive and negative regulatory elements that are required for selection of odor receptor (Or) genes in the proper olfactory organ of Drosophila, and we identify an element that is essential for selection in one ORN class. Two odor receptors are coexpressed by virtue of the alternative splicing of a single gene, and we identify dicistronic mRNAs that each encode two receptors. Systematic analysis reveals no evidence for negative feedback regulation, but provides evidence that the choices made by neighboring ORNs of a sensillum are coordinated via the asymmetric segregation of regulatory factors from a common progenitor. We show that receptor gene choice in Drosophila also depends on a combinatorial code of transcription factors to generate the receptor-to-neuron map.

Ray, Anandasankar; van der Goes van Naters, Wynand; Shiraiwa, Takashi; Carlson, John R.

2007-01-01

41

Somatic mutations of TRAIL-receptor 1 and TRAIL-receptor 2 genes in non-Hodgkin's lymphoma  

Microsoft Academic Search

Tumor necrosis factor-related apoptosis-inducing ligand-receptor 1 (TRAIL-R1) and tumor necrosis factor-related apoptosis-inducing ligand-receptor 2 (TRAIL-R2) are cell-surface receptors involved in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell-death signaling. TRAIL-R1 and TRAIL-R2 genes have recently been mapped to chromosome 8p21-22, which is a frequent site of allelic deletions in many types of human tumors, including non-Hodgkin's lymphoma (NHL). Because TRAIL\\/TRAIL receptor

Sug Hyung Lee; Min Sun Shin; Hong Sug Kim; Hun Kyung Lee; Won Sang Park; Su Young Kim; Jong Heun Lee; Seo Young Han; Jik Young Park; Ro Ra Oh; Chang Suk Kang; Kyung Mee Kim; Ja June Jang; Suk Woo Nam; Jung Young Lee; Nam Jin Yoo

2001-01-01

42

Analysis of antigen receptor genes in Hodgkin's disease.  

PubMed Central

AIM--To analyse the configuration of the antigen receptor genes in Hodgkin's disease. METHODS--DNA extracted from 45 samples of Hodgkin's disease was analysed using Southern blotting and DNA hybridisation, using probes to the joining region of the immunoglobulin heavy chain gene, the constant region of kappa immunoglobulin light chain gene, and the constant region of the beta chain of the T cell receptor gene. RESULTS--A single case of nodular sclerosing disease showed clonal rearrangement of the immunoglobulin heavy and light chain genes, all other samples having germline immunoglobulin genes. The nature of the clonal population in the diseased tissue is uncertain, because the intensity of the rearranged bands did not correlate with the percentage of Reed-Sternberg cells present. The T cell receptor genes were in germline configuration in all the samples. CONCLUSIONS--Antigen receptor gene rearrangement is a rare finding in unselected cases of Hodgkin's disease. Images

Angel, C A; Pringle, J H; Naylor, J; West, K P; Lauder, I

1993-01-01

43

The rpoN gene product of Pseudomonas aeruginosa is required for expression of diverse genes, including the flagellin gene.  

PubMed Central

The product of the rpoN gene is an alternative sigma factor of RNA polymerase which is required for transcription of a number of genes in members of the family Enterobacteriaceae, including those that specify enzymes of nitrogen assimilation, amino acid uptake, and degradation of a variety of organic molecules. We have previously shown that transcription of the pilin gene of Pseudomonas aeruginosa also requires RpoN (K. S. Ishimoto and S. Lory, Proc. Natl. Acad. Sci. USA 86:1954-1957, 1989) and have undertaken a more extensive survey of genes under RpoN control. Strains of P. aeruginosa that carry an insertionally inactivated rpoN gene were constructed and shown to be nonmotile because of the inability of these mutants to synthesize flagellin. The mutation in rpoN had no effect on expression of extracellular polypeptides, outer membrane proteins, and the alginate capsule. However, the rpoN mutants were glutamine auxotrophs and were defective in glutamine synthetase, indicating defects in nitrogen assimilation. In addition, the P. aeruginosa rpoN mutants were defective in urease activity. These findings indicate that the sigma factor encoded by the rpoN gene is used by P. aeruginosa for transcription of a diverse set of genes that specify biosynthetic enzymes, degradative enzymes, and surface components. These rpoN-controlled genes include pili and flagella which are required for full virulence of the organism. Images FIG. 1 FIG. 2

Totten, P A; Lara, J C; Lory, S

1990-01-01

44

Human Diversity in Killer Cell Inhibitory Receptor Genes  

Microsoft Academic Search

The presence and expression of killer inhibitory receptor (KIR) and CD94:NKG2 genes from 68 donors were analyzed using molecular typing techniques. The genes encoding CD94:NKG2 receptors were present in each person, but KIR gene possession varied. Most individuals expressed inhibitory KIR for the three well-defined HLA-B and -C ligands, but noninhibitory KIR genes were more variable. Twenty different KIR phenotypes

Markus Uhrberg; Nicholas M Valiante; Benny P Shum; Heather G Shilling; Kristin Lienert-Weidenbach; Brian Corliss; Dolly Tyan; Lewis L Lanier; Peter Parham

1997-01-01

45

An epigenetic trap involved in olfactory receptor gene choice.  

PubMed

Reporting recently in Cell, Lyons et al. (2013) reveal key roles for transient LSD1 histone demethylase activity in activation of a single olfactory receptor allele and suppression of the rest of the olfactory receptor gene family, thereby locking in the expression of a single olfactory receptor per sensory neuron. PMID:23906063

Reinsborough, Calder; Chess, Andrew

2013-07-29

46

Interaction effects between estrogen receptor a gene, vitamin D receptor gene, age, and sex on bone mineral density in Chinese  

Microsoft Academic Search

We evaluated the interaction effects between the estrogen receptor a gene (ER-a), vitamin D receptor gene (VDR), age and sex on bone mineral density (BMD) in a sample of 340 unrelated males and 297 unrelated females from 401 Chinese nuclear families. Polymorphisms of PvuII and XbaI in the ER-a gene and ApaI in the VDR gene were detected by RFLP,

Jirong Long; Pengyuan Liu; Yuanyuan Zhang; Hui Shen; Yongjun Liu; Volodymyr Dvornyk; Hong-Wen Deng

2003-01-01

47

Anti-NMDA-receptor encephalitis in a 3 year old patient with chromosome 6p21.32 microdeletion including the HLA cluster  

PubMed Central

Anti-NMDA-receptor encephalitis was initially described as a paraneoplastic disorder in young women with ovarian teratoma. We report on a 3-year-old boy who developed anti-NMDA-receptor encephalitis one month after a respiratory infection. Moreover, array-comparative genomic hybridization in this patient revealed an inherited microdeletion in chromosomeband 6p21.32, including the HLA-DPB1 and HLA-DPB2 genes. The clinical relevance of this microdeletion is discussed.

Verhelst, Helene; Verloo, Patrick; Dhondt, Karlien; De Paepe, Boel; Menten, Bjorn; Dalmau, Josep; Van Coster, Rudy

2011-01-01

48

Melanocortin receptor genes in the chicken--tissue distributions.  

PubMed

Two receptor genes belonging to the melanocortin receptor (MC-R) family were isolated in the chicken, the CMC4 and CMC5, each of which is a chicken homologue of the mammalian MC4-R and MC5-R, respectively. The CMC4 encodes a 331 amino acid protein, sharing 86. 4-88.1% identity with mammalian analogs, and the CMC5 encodes a 325 amino acid protein, which is 72.3-79.1% identical to mammalian counterparts. Both genes contain no intron in their coding regions and exist in the chicken genome as single copy genes. Reverse transcription-PCR analysis revealed that the CMC4 mRNA is expressed in a wide variety of peripheral tissues, including the adrenal, gonads, spleen, and adipose tissues, as well as in the brain, where mammalian counterparts are exclusively expressed in the brain, indicating that the regulation of MC4-R gene expression differs between mammals and chickens. The CMC5 mRNA, on the other hand, is expressed in the liver, gonads, adrenal, kidney, brain, and adipose tissues as well as in the uropygial gland. These findings raise the possibility that melanocortins affect a variety of functions both in the brain and in the peripheral tissues of the chicken. PMID:9784305

Takeuchi, S; Takahashi, S

1998-11-01

49

Structural organization and chromosomal assignment of the human prostacyclin receptor gene  

SciTech Connect

Prostacyclin receptor is a member of the prostanoid receptor family in the G protein-coupled receptor superfamily with seven transmembrane domains. The authors report here the isolation and structural organization of the human prostacyclin receptor gene. Southern blot analysis demonstrated a single copy of the human prostacyclin receptor gene in the human genome. The human prostacyclin receptor gene spanned approximately 7.0 kb and was composed of three exons separated by two introns. The first intron occurred in the 5`-untranslated region, 13 bp upstream to the ATG start codon. The second intron was located at the end of the sixth transmembrane domain, thereby separating it from the downstream coding region and the 3`-untranslated region. By primer extension analysis, the transcription initiation sites were mapped 870-872 bp upstream to the ATG start codon. The 1.2-kb human prostacyclin receptor 5`-flanking region lacked conventional TATA and CCAAT boxes, but it contained several cis-acting regulatory elements including an inverted CCAAT box (Y box) and two copies of SP-1 binding sites. Using human-rodent somatic hybrid cell DNA, the human prostacyclin receptor gene was assigned to human chromosome 19. The present study helps establish the genetic basis for prostacyclin receptor research and provides further insight into the molecular mechanisms underlying the prostanoid receptor family. 38 refs., 6 figs.

Ogawa, Yoshihiro; Tanaka, Issei; Inoue, Miho [Kyoto Univ. Faculty of Medicine (Japan)] [and others] [Kyoto Univ. Faculty of Medicine (Japan); and others

1995-05-01

50

Effect of glucocorticoid receptor gene polymorphisms on asthma phenotypes.  

PubMed

The clinical presentation of asthma results from complex gene-gene and gene-environment interactions. The natural variability of the DNA sequence within the NR3C1 gene affects the activity of glucocorticoid receptors (GCRs). The NR3C1 gene is localized on chromosome 5q31-q32. The gene coding for the GCR comprises nine exons. The structural domains of the GCR determine the biological functions of the functional domains. The observed resistance to glucocorticosteroids and the normal metabolic profile of Tth111I single nucleotide polymorphism (SNP) carriers is due to the ER22/23EK polymorphism that is present in them. BclI polymorphism significantly affects the process of alternative NR3C1 gene splicing and within that mechanism increases the sensitivity to glucocorticoids (GCs). A total of 451 subjects were enrolled in the present study, including 235 qualified to the group of bronchial asthma patients. A group of 216 healthy participants with no history of asthma or atopic conditions was qualified for the study. Genotyping was accomplished using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and PCR-high resolution melting (HRM) methods. No statistically significant differences were observed in the frequency of Tth111I, BclI and ER22/23EK polymorphisms of the NR3C1 gene when comparing mild, moderate and severe asthma vs. the control group. Investigative analyses demonstrated statistically significant correlations for alleles and genotypes of Tth111I polymorphism of the NR3C1 gene between healthy subjects and patients with severe asthma characterized by a control profile corresponding to an Asthma Control Test (ACT)™ score ?20. It was established that only the Tth111I polymorphism of the NR3C1 gene plays an important role in the pathogenesis of chronic bronchitis leading to the development of asthma with both allergic and non-allergic etiology. PMID:23407653

Panek, Micha?; Pietras, Tadeusz; Fabijan, Artur; Mi?anowski, Maciej; Wieteska, Lukasz; Górski, Pawe?; Kuna, Piotr; Szemraj, Janusz

2013-02-01

51

Effect of glucocorticoid receptor gene polymorphisms on asthma phenotypes  

PubMed Central

The clinical presentation of asthma results from complex gene-gene and gene-environment interactions. The natural variability of the DNA sequence within the NR3C1 gene affects the activity of glucocorticoid receptors (GCRs). The NR3C1 gene is localized on chromosome 5q31–q32. The gene coding for the GCR comprises nine exons. The structural domains of the GCR determine the biological functions of the functional domains. The observed resistance to glucocorticosteroids and the normal metabolic profile of Tth111I single nucleotide polymorphism (SNP) carriers is due to the ER22/23EK polymorphism that is present in them. BclI polymorphism significantly affects the process of alternative NR3C1 gene splicing and within that mechanism increases the sensitivity to glucocorticoids (GCs). A total of 451 subjects were enrolled in the present study, including 235 qualified to the group of bronchial asthma patients. A group of 216 healthy participants with no history of asthma or atopic conditions was qualified for the study. Genotyping was accomplished using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and PCR-high resolution melting (HRM) methods. No statistically significant differences were observed in the frequency of Tth111I, BclI and ER22/23EK polymorphisms of the NR3C1 gene when comparing mild, moderate and severe asthma vs. the control group. Investigative analyses demonstrated statistically significant correlations for alleles and genotypes of Tth111I polymorphism of the NR3C1 gene between healthy subjects and patients with severe asthma characterized by a control profile corresponding to an Asthma Control Test (ACT)™ score ?20. It was established that only the Tth111I polymorphism of the NR3C1 gene plays an important role in the pathogenesis of chronic bronchitis leading to the development of asthma with both allergic and non-allergic etiology.

PANEK, MICHAL; PIETRAS, TADEUSZ; FABIJAN, ARTUR; MILANOWSKI, MACIEJ; WIETESKA, LUKASZ; GORSKI, PAWEL; KUNA, PIOTR; SZEMRAJ, JANUSZ

2013-01-01

52

Corticosteroid receptors in the brain: gene targeting studies.  

PubMed

Corticosteroids are released by the adrenal cortex with a diurnal rhythm and in response to stressful environmental changes. They not only act on peripheral organs, but also regulate brain physiology, thereby affecting mental processes like emotion and cognition. Here, we discuss the role of the two known corticosteroid receptors--glucocorticoid receptor (GR) and mineralocorticoid receptor (MR)--in the brain by summarizing the results obtained with various genetically modified mouse lines. In these lines, either the GR or the MR gene has been targeted or GR protein levels have been upregulated or downregulated. Analysis of the different lines confirms the importance of GR in the regulation of the hypothalamic pituitary adrenal (HPA) axis because interference with GR activity activates the HPA axis, whereas increased GR protein levels inhibit HPA axis activity. Genetic downregulation of GR protein levels and inactivation of the GR gene in the brain reduce anxiety-related behavior, which reveals a central role of GR in emotional behavior. Both HPA axis activity and anxiety are modulated by corticotropin releasing hormone (CRH); therefore, we include in the discussion results obtained with genetically modified CRH or CRH receptor mice. We further address the important role of corticosteroid receptors for hippocampal function and integrity. Cellular properties of CA1 neurons are changed, and hippocampal-dependent explicit memory is affected in GR mutant animals. Comparing MR and GR mutant animals suggests the requirement of MR but not GR for dentate gyrus granule cell maintenance. Because an imbalance in glucocorticoid levels is associated with cognitive impairments and mental disorders, the described mouse lines will aid in understanding the mechanisms involved in the pathology of these disorders. PMID:11827739

Kellendonk, Christoph; Gass, Peter; Kretz, Oliver; Schütz, Günther; Tronche, François

2002-01-01

53

Characterisation of the legume SERK-NIK gene superfamily including splice variants: Implications for development and defence  

PubMed Central

Background SOMATIC EMBRYOGENESIS RECEPTOR-LIKE KINASE (SERK) genes are part of the regulation of diverse signalling events in plants. Current evidence shows SERK proteins function both in developmental and defence signalling pathways, which occur in response to both peptide and steroid ligands. SERKs are generally present as small gene families in plants, with five SERK genes in Arabidopsis. Knowledge gained primarily through work on Arabidopsis SERKs indicates that these proteins probably interact with a wide range of other receptor kinases and form a fundamental part of many essential signalling pathways. The SERK1 gene of the model legume, Medicago truncatula functions in somatic and zygotic embryogenesis, and during many phases of plant development, including nodule and lateral root formation. However, other SERK genes in M. truncatula and other legumes are largely unidentified and their functions unknown. Results To aid the understanding of signalling pathways in M. truncatula, we have identified and annotated the SERK genes in this species. Using degenerate PCR and database mining, eight more SERK-like genes have been identified and these have been shown to be expressed. The amplification and sequencing of several different PCR products from one of these genes is consistent with the presence of splice variants. Four of the eight additional genes identified are upregulated in cultured leaf tissue grown on embryogenic medium. The sequence information obtained from M. truncatula was used to identify SERK family genes in the recently sequenced soybean (Glycine max) genome. Conclusions A total of nine SERK or SERK-like genes have been identified in M. truncatula and potentially 17 in soybean. Five M. truncatula SERK genes arose from duplication events not evident in soybean and Lotus. The presence of splice variants has not been previously reported in a SERK gene. Upregulation of four newly identified SERK genes (in addition to the previously described MtSERK1) in embryogenic tissue cultures suggests these genes also play a role in the process of somatic embryogenesis. The phylogenetic relationship of members of the SERK gene family to closely related genes, and to development and defence function is discussed.

2011-01-01

54

Cloning and Expression of the Moraxella catarrhalis Lactoferrin Receptor Genes  

Microsoft Academic Search

The lactoferrin receptor genes from two strains of Moraxella catarrhalis have been cloned and sequenced. The lfr genes are arranged as lbpB followed by lbpA, a gene arrangement found in lactoferrin and transferrin receptor operons from several bacterial species. In addition, a third open reading frame, orf3, is located one nucleotide downstream of lbpA. The deduced lactoferrin binding protein A

RUN-PAN DU; QIJUN WANG; YAN-PING YANG; ANTHONY B. SCHRYVERS; PELE CHONG; MICHEL H. KLEIN; SHEENA M. LOOSMORE

1998-01-01

55

Androgen Activation of the Folate Receptor ? Gene through Partial Tethering of the Androgen Receptor by C/EBP??  

PubMed Central

The folate receptor ? (FR?) is critical for normal embryonic and fetal development. The receptor has a relatively narrow tissue specificity which includes the visceral endoderm and the placenta and mediates delivery of folate, inadequacy of which results in termination of pregnancy or developmental defects. We have previously reported that the FR? gene is negatively and directly regulated by estrogen and positively but indirectly by progesterone and glucocorticoid. To further investigate hormonal control of this gene and in view of the growing evidence for the importance of the androgen receptor (AR) in endometrial and placental functions, we examined the response of the FR? gene to androgen. Here we demonstrate that the FR? gene is directly activated by androgen. The P4 promoter of the FR? gene is the target of hormone-dependent activation by the androgen receptor (AR) in a manner that is co-activator-dependent. The site of functional association of AR in the FR? gene maps to a 35bp region occurring ~1500bp upstream of the target promoter. The functional elements within this region are an androgen response element (ARE) half-site and a non-canonical C/EBP element that cooperate to recruit AR in a manner that is dependent on the DNA-bound C/EBP?. Since the placenta is rich in C/EBP?, the findings underscore the multiplicity of mechanisms by which the FR? gene is under the exquisite control of steroid hormones.

Sivakumaran, Suneethi; Zhang, Juan; Kelley, Karen M.M.; Gonit, Mesfin; Hao, Hong; Ratnam, Manohar

2010-01-01

56

Regulation of cytochrome P450 (CYP) genes by nuclear receptors.  

PubMed Central

Members of the nuclear-receptor superfamily mediate crucial physiological functions by regulating the synthesis of their target genes. Nuclear receptors are usually activated by ligand binding. Cytochrome P450 (CYP) isoforms often catalyse both formation and degradation of these ligands. CYPs also metabolize many exogenous compounds, some of which may act as activators of nuclear receptors and disruptors of endocrine and cellular homoeostasis. This review summarizes recent findings that indicate that major classes of CYP genes are selectively regulated by certain ligand-activated nuclear receptors, thus creating tightly controlled networks.

Honkakoski, P; Negishi, M

2000-01-01

57

Identification of chemosensory receptor genes from vertebrate genomes.  

PubMed

Chemical senses are essential for the survival of animals. In vertebrates, mainly three different types of receptors, olfactory receptors (ORs), vomeronasal receptors type 1 (V1Rs), and vomeronasal receptors type 2 (V2Rs), are responsible for the detection of chemicals in the environment. Mouse or rat genomes contain >1,000 OR genes, forming the largest multigene family in vertebrates, and have >100 V1R and V2R genes as well. Recent advancement in genome sequencing enabled us to computationally identify nearly complete repertories of OR, V1R, and V2R genes from various organisms, revealing that the numbers of these genes are highly variable among different organisms depending on each species' living environment. Here I would explain bioinformatic methods to identify the entire repertoires of OR, V1R, and V2R genes from vertebrate genome sequences. PMID:24014356

Niimura, Yoshihito

2013-01-01

58

An autoregulatory loop controlling orphan nuclear receptor DAX-1 gene expression by orphan nuclear receptor ERRg  

Microsoft Academic Search

The estrogen receptor-related receptor gamma (ERRg\\/ERR3\\/NR3B3) is a member of the nuclear receptor superfamily that activates transcription in the absence of ligand. However, the detailed mechan- ism of gene regulation by ERRg is not fully under- stood. In this study we have found that the orphan nuclear receptor ERRg activates the DAX-1 promoter, which, in turn, represses transactivation by ERRg.

Yun-Yong Park; Seung-Won Ahn; Hye-Jin Kim; Jin-Man Kim; In-Kyu Lee; Heonjoong Kang; Hueng-Sik Choi

59

Amplification and Expression of the Epidermal Growth Factor Receptor Gene in Human Glioma Xenografts1  

Microsoft Academic Search

Xenografts from eight malignant human gliomas were established in athymic mice and were used to study amplification and expression of the epidermal growth factor receptor (EGFR) gene. Tissue identity between biopsy and xenografts was confirmed by karyotypic profiles, which showed that each glioma xenograft retained structural abnormalities, including double minute chromosomes, present in the parent glioma. EGFR gene amplification was

Peter A. Humphrey; Albert J. Wong; Bert Vogelstein; Henry S. Friedman; Mark H. Werner; Dareil D. Bigner; Sandra H. Bigner

60

First evidence for functional vomeronasal 2 receptor genes in primates  

PubMed Central

Two classes of vomeronasal receptor genes, V1R and V2R, occur in vertebrates. Whereas, V1R loci are found in a wide variety of mammals, including primates, intact V2R genes have thus far only been described in rodents and marsupials. In primates, the V2R repertoire has been considered degenerate. Here, we identify for the first time two intact V2R loci in a strepsirrhine primate, the grey mouse lemur (Microcebus murinus), and demonstrate their expression in the vomeronasal organ. Putatively functional orthologues are present in two other strepsirrhines, whereas, both loci are pseudogenes in a range of anthropoid species. The functional significance of the loci is unknown, but positive selection on one of them is consistent with an adaptive role in pheromone detection. Finally, conservation of V2R loci in strepsirrhines is notable, given their high diversity and role in MUP and MHC detection in rodents.

Hohenbrink, Philipp; Mundy, Nicholas I.; Zimmermann, Elke; Radespiel, Ute

2013-01-01

61

First evidence for functional vomeronasal 2 receptor genes in primates.  

PubMed

Two classes of vomeronasal receptor genes, V1R and V2R, occur in vertebrates. Whereas, V1R loci are found in a wide variety of mammals, including primates, intact V2R genes have thus far only been described in rodents and marsupials. In primates, the V2R repertoire has been considered degenerate. Here, we identify for the first time two intact V2R loci in a strepsirrhine primate, the grey mouse lemur (Microcebus murinus), and demonstrate their expression in the vomeronasal organ. Putatively functional orthologues are present in two other strepsirrhines, whereas, both loci are pseudogenes in a range of anthropoid species. The functional significance of the loci is unknown, but positive selection on one of them is consistent with an adaptive role in pheromone detection. Finally, conservation of V2R loci in strepsirrhines is notable, given their high diversity and role in MUP and MHC detection in rodents. PMID:23269843

Hohenbrink, Philipp; Mundy, Nicholas I; Zimmermann, Elke; Radespiel, Ute

2013-02-23

62

Novel alleles of the chemokine-receptor gene CCR5.  

PubMed Central

The CCR5 gene encodes a cell-surface chemokine-receptor molecule that serves as a coreceptor for macrophage-tropic strains of HIV-1. Mutations in this gene may alter expression or function of the protein product, thereby altering chemokine binding/signaling or HIV-1 infection of cells that normally express CCR5 protein. Indeed, homozygotes for a 32-bp deletion allele of CCR5 (CCR5-delta 32), which causes a frameshift at amino acid 185, are relatively resistant to HIV-1 infection. Here we report the identification of 16 additional mutations in the coding region of the CCR5 gene, all but 3 of which are codon altering or "nonsynonymous." Most mutations were rare (found only once or twice in the sample); five were detected exclusively among African Americans, whereas eight were observed only in Caucasians. The mutations included 11 codon-altering nonsynonymous variants, one trinucleotide deletion, one chain-termination mutant, and three synonymous mutations. The high predominance of codon-altering alleles among CCR5 mutants (14/17 [81%], including CCR5-delta 32) is consistent with an adaptive accumulation of function-altering alleles for this gene, perhaps as a consequence of historic selective pressures.

Carrington, M; Kissner, T; Gerrard, B; Ivanov, S; O'Brien, S J; Dean, M

1997-01-01

63

Profiling of olfactory receptor gene expression in whole human olfactory mucosa.  

PubMed

Olfactory perception is mediated by a large array of olfactory receptor genes. The human genome contains 851 olfactory receptor gene loci. More than 50% of the loci are annotated as nonfunctional due to frame-disrupting mutations. Furthermore haplotypic missense alleles can be nonfunctional resulting from substitution of key amino acids governing protein folding or interactions with signal transduction components. Beyond their role in odor recognition, functional olfactory receptors are also required for a proper targeting of olfactory neuron axons to their corresponding glomeruli in the olfactory bulb. Therefore, we anticipate that profiling of olfactory receptor gene expression in whole human olfactory mucosa and analysis in the human population of their expression should provide an opportunity to select the frequently expressed and potentially functional olfactory receptors in view of a systematic deorphanization. To address this issue, we designed a TaqMan Low Density Array (Applied Biosystems), containing probes for 356 predicted human olfactory receptor loci to investigate their expression in whole human olfactory mucosa tissues from 26 individuals (13 women, 13 men; aged from 39 to 81 years, with an average of 67±11 years for women and 63±12 years for men). Total RNA isolation, DNase treatment, RNA integrity evaluation and reverse transcription were performed for these 26 samples. Then 384 targeted genes (including endogenous control genes and reference genes specifically expressed in olfactory epithelium for normalization purpose) were analyzed using the same real-time reverse transcription PCR platform. On average, the expression of 273 human olfactory receptor genes was observed in the 26 selected whole human olfactory mucosa analyzed, of which 90 were expressed in all 26 individuals. Most of the olfactory receptors deorphanized to date on the basis of sensitivity to known odorant molecules, which are described in the literature, were found in the expressed olfactory receptors gene set. PMID:24800820

Verbeurgt, Christophe; Wilkin, Françoise; Tarabichi, Maxime; Gregoire, Françoise; Dumont, Jacques E; Chatelain, Pierre

2014-01-01

64

Profiling of Olfactory Receptor Gene Expression in Whole Human Olfactory Mucosa  

PubMed Central

Olfactory perception is mediated by a large array of olfactory receptor genes. The human genome contains 851 olfactory receptor gene loci. More than 50% of the loci are annotated as nonfunctional due to frame-disrupting mutations. Furthermore haplotypic missense alleles can be nonfunctional resulting from substitution of key amino acids governing protein folding or interactions with signal transduction components. Beyond their role in odor recognition, functional olfactory receptors are also required for a proper targeting of olfactory neuron axons to their corresponding glomeruli in the olfactory bulb. Therefore, we anticipate that profiling of olfactory receptor gene expression in whole human olfactory mucosa and analysis in the human population of their expression should provide an opportunity to select the frequently expressed and potentially functional olfactory receptors in view of a systematic deorphanization. To address this issue, we designed a TaqMan Low Density Array (Applied Biosystems), containing probes for 356 predicted human olfactory receptor loci to investigate their expression in whole human olfactory mucosa tissues from 26 individuals (13 women, 13 men; aged from 39 to 81 years, with an average of 67±11 years for women and 63±12 years for men). Total RNA isolation, DNase treatment, RNA integrity evaluation and reverse transcription were performed for these 26 samples. Then 384 targeted genes (including endogenous control genes and reference genes specifically expressed in olfactory epithelium for normalization purpose) were analyzed using the same real-time reverse transcription PCR platform. On average, the expression of 273 human olfactory receptor genes was observed in the 26 selected whole human olfactory mucosa analyzed, of which 90 were expressed in all 26 individuals. Most of the olfactory receptors deorphanized to date on the basis of sensitivity to known odorant molecules, which are described in the literature, were found in the expressed olfactory receptors gene set.

Tarabichi, Maxime; Gregoire, Francoise; Dumont, Jacques E.; Chatelain, Pierre

2014-01-01

65

Adenovirus receptors and their implications in gene delivery  

PubMed Central

Adenoviruses (Ads) have gained popularity as gene delivery vectors for therapeutic and prophylactic applications. Ad entry into host cells involves specific interactions between cell surface receptors and viral capsid proteins. Several cell surface molecules have been identified as receptors for Ad attachment and entry. Tissue tropism of Ad vectors is greatly influenced by their receptor usage. A variety of strategies have been investigated to modify Ad vector tropism by manipulating the receptor-interacting moieties. Many such strategies are aimed at targeting and/or detargeting of Ad vectors. In this review, we discuss the various cell surface molecules that are implicated as receptors for virus attachment and internalization. Special emphasis is given to Ad types that are utilized as gene delivery vectors. Various strategies to modify Ad tropism using the knowledge of Ad receptors are also discussed.

Sharma, Anurag; Li, Xiaoxin; Bangari, Dinesh S.; Mittal, Suresh K.

2010-01-01

66

Dopamine receptor gene expression by enkephalin neurons in rat forebrain  

Microsoft Academic Search

In situ hybridization experiments were performed with brain sections from normal, control and haloperidol-treated rats to identify and map the cells expressing the D2 dopamine receptor gene. D2 receptor mRNA was detected with radioactive or biotinylated oligonucleotide probes. D2 receptor mRNA was present in glandular cells of the pituitary intermediate lobe and in neurons of the substantia nigra, ventral tegmental

C. Le Moine; E. Normand; A. F. Guitteny; B. Fouque; R. Teoule; B. Bloch

1990-01-01

67

Vitamin E activates gene expression via the pregnane X receptor  

Microsoft Academic Search

Tocopherols and tocotrienols are metabolized by side chain degradation via initial ?-oxidation and subsequent ?-oxidation. ?-Oxidation is performed by cytochrome P450 (CYP) enzymes which are often regulated by their substrates themselves. Results presented here show that all forms of Vitamin E are able to activate gene expression via the pregnane X receptor (PXR), a nuclear receptor regulating a variety of

Nico Landes; Paul Pfluger; Dirk Kluth; Marc Birringer; Ralph Rühl; Gaby-Fleur Böl; Hansruedi Glatt; Regina Brigelius-Flohé

2003-01-01

68

Mechanisms of induction of adenosine receptor genes and its functional significance  

PubMed Central

Adenosine is a metabolite generated and released from cells, particularly under injury or stress. It elicits protective or damaging responses via signaling through the adenosine receptors, including the adenylyl cyclase inhibitory A1, and A3, and the adenylyl cyclase stimulatory A2A and A2B. Multiple adenosine receptor types, including stimulatory and inhibitory, can be found in the same cell, suggesting that a careful balance of adenosine receptor expression in a particular cell is necessary for a specific adenosine-induced response. This balance could be controlled by differential expression of the adenosine receptor genes under different stimuli. Here, we have reviewed an array of studies that have characterized basal or induced expression of the adenosine receptors and common as well as distinct mechanisms of effect, in hopes that ongoing studies on this topic will further elucidate detailed mechanisms of adenosine receptor regulation, leading to potential therapeutic applications.

St. Hilaire, Cynthia; Carroll, Shannon H.; Chen, Hongjie; Ravid, Katya

2012-01-01

69

Expression of serine\\/threonine kinase receptors including the bone morphogenetic factor type II receptor in the developing and adult rat brain  

Microsoft Academic Search

The expression patterns of serine\\/threonine kinase receptors in the central nervous system of the developing and adult rat were studied by in situ hybridization. The recently cloned bone morphogenetic factor receptor type II (BMPR-II) was compared with the ActR-II and several type I receptors including ActR-I, ActR-IB, BMPR-IA, BMPR-IB and T#R-I. We found that these receptors are spatially and temporally

Stine Söderström; Henrik Bengtsson; Ted Ebendal

1996-01-01

70

Regulation of the Oct-4 gene by nuclear receptors.  

PubMed

To unravel the network of transcription factors established during development it is important to understand how genes specifically expressed during embryogenesis are regulated. Oct-4 is a transcription factor whose expression is associated with an undifferentiated cell phenotype in the early mouse embryo and is downregulated when such cells differentiate. An enhancer in the upstream region of Oct-4 has previously been reported as being sufficient to mediate the cell-type specific expression and RA-dependent down-regulation in EC cells, although the enhancer contains no retinoic acid receptor (RAR) binding sites. Here we report the identification of promoter elements important for the regulation of the Oct-4 gene in EC cells. A region of the proximal Oct-4 promoter contains an overlapping set of regulatory elements including a high affinity binding site for Sp1 and three direct repeats of an AGGTCA-like sequence with either +1 or 0 spacing. Binding and transient transfection assays reveal that Oct-4 is subject to negative regulation by different members of the steroid-thyroid hormone receptor superfamily. Specifically, important roles for ARP-1 and RAR in Oct-4 expression are indicated. PMID:8152920

Sylvester, I; Schöler, H R

1994-03-25

71

Characterization of a dwarf gene in Brassica rapa , including the identification of a candidate gene  

Microsoft Academic Search

Dwarf genes have been valuable for improving harvestable yield of several crop plants and may be useful in oilseed Brassica. We evaluated a dwarf gene, dwf2, from Brassica rapa in order to determine its phenotypic effects and genetic characteristics. The dwf2 mutant was insensitive to exogenous GA 3 for both plant height and flowering time, suggesting that it is not

A. Muangprom; T. C. Osborn

2004-01-01

72

An intronless gene encoding a potential member of the family of receptors coupled to guanine nucleotide regulatory proteins  

Microsoft Academic Search

Plasma membrane receptors for hormones, drugs, neurotransmit-ters and sensory stimuli are coupled to guanine nucleotide regulatory proteins. Recent cloning of the genes and\\/or cDNAs for several of these receptors including the visual pigment rhodopsin1, the adenylate-cyclase stimulatory beta-adrenergic receptor2-4 and two subtypes of muscarinic cholinergic receptors5,6 has suggested that these are homologous proteins with several conserved structural and functional features.

Brian K. Kobilka; Thomas Frielle; Sheila Collins; Theresa Yang-Feng; Tong Sun Kobilka; Uta Francke; Robert J. Lefkowitz; Marc G. Caron

1987-01-01

73

Selective effects of ligands on vitamin D3 receptor- and retinoid X receptor-mediated gene activation in vivo.  

PubMed Central

Steroid/nuclear hormone receptors are ligand-regulated transcription f factors that play key roles in cell regulation, differentiation, and oncogenesis. Many nuclear receptors, including the human 1,25-dihydroxyvitamin D3 receptor (VDR), bind cooperatively to DNA either as homodimers or as heterodimers with the 9-cis retinoic acid (RA) receptor (retinoid X-receptor [RXR]). We have previously reported that the ligands for VDR and RXR can differentially modulate the affinity of the receptors' interaction with DNA in vitro, primarily by modulating the dimerization status of these receptors. These experiments suggested a complex interaction between VDR and RXR and their respective ligands on inducible target genes in vivo. To examine these effects in cells, we used a transient-transfection strategy whereby we simultaneously introduced two different reporter plasmids that are selectively inducible by each ligand. Although VDR can bind as a homodimer to the osteopontin gene vitamin D response element, we find that a RXR-VDR heterodimer must be the transactivating species from the element in vivo, since RXR enhances and 9-cis RA and other RXR-specific ligands attenuate this induction. Conversely, when VDR is overexpressed, vitamin D3 attenuates 9-cis RA induction from an RXR-responsive element. These effects, however, appear to be very sensitive to both the relative ratios of the two receptors and their respective target elements. Functional RXR-VDR complexes are strictly dependent on the DNA-binding polarity. Chimeric versions of VDR and RXR were also constructed to examine the putative activities of homodimeric receptors; a VDR chimera can transactivate in the absence of RXR, demonstrating that VDR has intrinsic transactivation properties. Taken together, these results establish a complex, sensitive cross talk in vivo between two ligands and their receptors that signal through two distinct endocrine pathways.

Lemon, B D; Freedman, L P

1996-01-01

74

Cloning of the Human Erythropoietin Receptor Gene  

Microsoft Academic Search

RYTHROPOIETIN (Epo) is manufactured in the E kidney and stimulates the proliferation and differenti- ation of erythroid cells.' This 34,000 d glycoprotein is believed to be the primary regulator of erythropoiesis. The action of Epo is initiated by its binding to a specific cell surface receptor followed by receptor-mediated endocyto- sis.' However, the molecular details regarding the manner in which

Constance Tom Noguchi; Kyung S. Bae; Kyung Chin; Yuko Wada; Alan N. Schechter; W. David Hankins

1991-01-01

75

Paternal Uniparental Isodisomy of Chromosome 6 Causing a Complex Syndrome Including Complete IFN-? Receptor 1 Deficiency  

PubMed Central

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency associated with clinical disease caused by weakly virulent mycobacterial species. Interferon gamma receptor 1 (IFN-?R1) deficiency is a genetic etiology of MSMD. We describe the clinical and genetic features of a seven-year-old Italian boy suffering from MSMD associated with a complex phenotype, including neonatal hyperglycemia, neuromuscular disease, and dysmorphic features. The child also developed necrotizing pneumonia caused by Rhodococcus equi. The child is homozygous for a nonsense mutation in exon 3 of IFNGR1 as a result of paternal uniparental disomy (UPD) of the entire chromosome 6. This is the first reported case of uniparental disomy resulting in a complex phenotype including MSMD.

Prando, Carolina; Boisson-Dupuis, Stephanie; Grant, Audrey; Kong, Xiao-Fei; Bustamante, Jacinta; Feinberg, Jacqueline; Chapgier, Ariane; Rose, Yoann; Janniere, Lucile; Rizzardi, Elena; Zhang, Qiuping; Shanahan, Catherine M; Viollet, Louis; Lyonnet, Stanislas; Abel, Laurent; Ruga, Ezia Maria; Casanova, Jean-Laurent

2010-01-01

76

Relationship between polymorphism of insulin receptor gene, and adiponectin gene with PCOS  

PubMed Central

Background: Polycystic ovary syndrome (PCOS) is a complex disease having both genetic and environmental components and candidate genes on obesity and insulin metabolism have been hypothesized to be involved in its etiology. Objective: We examined the possible association of adiponectin and insulin receptor gene polymorphisms with PCOS. Materials and Methods: A total of 186 women with PCOS using NIH criteria and 156 healthy women were recruited. Their samples were genotyped for the polymorphism in exon 17 and 8 of the insulin receptor gene or exon and intron 2 of the adiponectin gene. Results: The distributions of genotypes and alleles of both polymorphisms were not different in women with PCOS and controls. There was no significant differences on the anthropometric and hormonal profiles of various adiponectin and insulin receptor genes polymorphisms among both groups. Conclusion: Adiponectin and insulin receptor gene polymorphisms are not associated with PCOS in a sample of Iranian population.

Ramezani Tehrani, Fahimeh; Daneshpour, Maryam; Hashemi, Somayeh; Zarkesh, Maryam; Azizi, Feridoun

2013-01-01

77

Androgen Receptor Gene Alterations in Finnish Male Breast Cancer  

Microsoft Academic Search

Mutations in the androgen receptor (AR) gene have been suggested to predispose to male breast cancer (MBC). Studies on MBC patients have not been based on the mutation screening of the entire coding region of the AR and the number of subjects has been small. Therefore, some AR gene alterations may have remained undetected. In the present study, we have

Kirsi Syrjäkoski; Eija-R. Hyytinen; Tuula Kuukasjärvi; Anssi Auvinen; Olli-P. Kallioniemi; Tommi Kainu; Pasi A. Koivisto

2003-01-01

78

Farnesoid X receptor represses hepatic lipase gene expression  

Microsoft Academic Search

The farnesoid X receptor (FXR) is a nuclear re- ceptor that regulates gene expression in response to bile ac- ids (BAs). FXR plays a central role in BA, cholesterol, and lipoprotein metabolism. Here, we identify HL, an enzyme involved in the metabolism of remnant and high density lipoproteins, as a novel FXR-regulated gene. The natural FXR ligand, chenodeoxycholic acid (CDCA),

Audrey Sirvent; Adrie J. M. Verhoeven; Hans Jansen; Vladimir Kosykh; Raphaël J. Darteil; Dean W. Hum; Jean-Charles Fruchart; Bart Staels

2004-01-01

79

Dopamine D4 Receptor Gene: Novelty or Nonsense?  

Microsoft Academic Search

Although the role of genetics in personality has been studied extensively at a phenomenological level, only lately has the investigation of specific genes been performed. Recent reports suggest that DNA variants of the dopamine D4 receptor gene (DRD4) are associated with the personality trait of novelty seeking; however, others fail to replicate this finding. Such conflicting results suggest either a

Andrew D Paterson; Glen A Sunohara; James L Kennedy

1999-01-01

80

Identification of a null mutation in the human dopamine D4 receptor gene  

SciTech Connect

Dopamine receptors belong to the family of G protein-coupled receptors. Five different dopamine receptor genes have thus far been identified. These receptors are classified into two main subfamilies: D1, which includes the D1 and D5 receptors, and D2, which includes the D2, D3, and D4 receptors. The dopamine D4 receptor is of great interest for research into neuropsychiatric disorders and psychopharmacology in light of the fact that it binds the antipsychotic medication clozapine with higher affinity than does any other dopamine receptor. In addition, among the dopamine receptors, the D4 receptor shows a uniquely high degree of genetic variation in the human population. We identified a new 13 bp deletion in exon 1 of the D4 gene. This frameshift creates a terminator codon at amino acid position 98. mRNA isolated from brain tissue of two heterozygous persons showed both alleles to be expressed. The deletion occurs with a frequency of 2% in the German population. One person was identified to be homozygous for the deletion. Interestingly, he has a normal intelligence and did not exhibit a major psychiatric disorder as defined by DSM III-R. The 13 bp deletion is the first mutation resulting in premature translation termination reported for a dopamine receptor gene so far. This mutation is a good candidate to test for potential effects on disease and/or individual response to pharmacotherapy. Association studies in patients with various psychiatric illnesses and differences in response to clozapine are underway.

Noethen, M.M.; Cichon, S. [Univ. of Bonn (Georgia); Hebebrand, J. [Univ. of Marburg (Georgia)] [and others

1994-09-01

81

Role of folate receptor genes in reproduction and related cancers.  

PubMed

The expression patterns of folate receptor (FR) isoforms, alpha and beta, in normal and malignant male and female reproductive tissues is described. The significance of the receptor in reproductive and developmental physiology is discussed. The potential value of the receptor expressed in malignant tissues including ovarian and endometrial cancers as a diagnostic marker and a therapeutic target is reviewed. Finally, the various transcriptional and post-transcriptional mechanisms that govern the tissue/tumor-specificity of the receptor and its regulation by folate and steroid receptor ligands are described; the potential value of this knowledge in developing better methods for the early detection and treatment of certain cancers is discussed. PMID:16146749

Elnakat, Hala; Ratnam, Manohar

2006-01-01

82

Melanocortin 3 receptor gene and melanocortin 4 receptor gene mutations: the Asian Perspective.  

PubMed

Melanocortin 4 receptor (MC4R) deficiency resulting from disruption of one or both MC4R alleles represents the commonest monogenic form of human obesity to date. Human MC4R deficiency was reported to affect 4 and 5.8% of severely obese French and British populations respectively. However, studies elsewhere reported low incidence of MC4R mutations in their obese populations. The significance of MC4R mutations in Asian obese populations has not been adequately examined, though small studies in Japan, China, and Singapore reported few or no pathogenic mutations, suggesting a low prevalence in this part of the world. There were also few common mutations described across populations, suggesting a relative lack of founder effect. The pathogenic role of melanocortin 3 receptor gene (MC3R) mutations in human obesity is not as well described and accepted as MC4R mutations, though it is gradually gaining ground. Two common single nucleotide polymorphisms Thr6Lys and Val81Ile within the coding region were associated with higher body fat and leptin levels in obese children, supported by impaired signaling activity in vitro. There were also reports of missense mutations enriched in obese populations. While MC3R mutations are unlikely to result in an autosomal dominant form of monogenic obesity given the lack of strong co-segregation in family studies, the studies so far provided evidence that MC3R can be one of the genes which contributes to increased adiposity, and exert an effect on the human phenotype. PMID:23280863

Lee, Yung Seng

2012-12-01

83

Genetic Amplification of the VEGF Pathway Genes Including VEGFA in Human Osteosarcoma  

PubMed Central

Background Osteosarcoma is the most common primary tumor of bone. It is a highly vascular and extremely destructive malignancy mainly affecting children and young adults. We performed microarray-based comparative genomic hybridization (aCGH) and carried out pathway analysis to gain a systemic view on the pathway alterations of the genetically altered genes. Methods Recurrent amplified and deleted genes detected by aCGH were subjected to the Kyoto Encyclopedia of Genes and Genomes (KEEG) pathway analysis to identify the altered pathways. Among enriched pathways, vascular endothelial growth factor (VEGF) pathway genes were collectively amplified and the alterations of this pathway were validated by fluorescence in situ hybridization (FISH) and immunohistochemistry in 58 formalin-fixed and paraffin-embedded osteosarcoma archival tissues with clinical follow-up information. Results the pathway enrichment analyses of the aCGH data revealed that VEGF pathway genes, including vascular endothelial growth factor A(VEGFA) gene itself, were significantly amplified in osteosarcoma. Genetic amplification of the VEGFA gene, both focally and in larger fragment, was validated by FISH. Notably, amplification of VEGFA gene and elevated expression of the VEGFA protein were significantly associated with microvascular density (MVD) and adverse tumor-free survival in osteosarcoma. Conclusions We reported for the first time that VEGF pathway genes including VEGFA gene are amplified in osteosarcoma. Amplification of the VEGFA gene is not only an important mechanism for elevated VEGFA protein expression, but also a poor prognostic factor for tumor-free survival. Combined classification of VEGFA gene amplification and positive VEGFA protein expression might provide more accurate patient stratification method for selection of anti-VEGF therapy for osteosarcoma.

Yang, Jilong; Yang, Da; Sun, Yan; Sun, Baocun; Wang, Guowen; Trent, Jonathan; Araujo, Dejka; Chen, Kexin; Zhang, Wei

2012-01-01

84

Odorant receptor genes are expressed in olfactory neuroblastoma.  

PubMed

Olfactory neuroblastoma (ONB) is a malignant tumor found in the human nasal cavity. These tumors are rare and poorly characterized at the molecular level. In this study, we asked whether olfactory-specific genes are expressed in ONBs by using reverse-transcriptase-polymerase chain reaction. We found that the olfactory marker protein and the RIC-8B genes, which are specifically expressed in mature olfactory neurons, are expressed in ONBs. Importantly, we also found that ONBs express a large variety of odorant receptor genes, representative of different odorant receptor gene subfamilies. Our results show that the ONBs express genes that are normally expressed in mature olfactory neurons and indicate that they are derived from progenitor or immature cells in the olfactory epithelium and not from a clonal expansion of a single or few mature olfactory neurons. PMID:24065686

Gonzalez-Kristeller, D C; Gutiyama, L M; Campos, A H; Soares, F A; Brentani, H; Malnic, B

2013-01-01

85

Diagnosis of canine lymphoid neoplasia using clonal rearrangements of antigen receptor genes.  

PubMed

Although the diagnosis of canine leukemia and lymphoma in advanced stages is usually uncomplicated, some presentations of the disease can be a diagnostic challenge. In certain situations, lymphoma and leukemia can be difficult to distinguish from a benign reactive proliferation of lymphocytes. Because clonality is the hallmark of malignancy, we have developed an assay that uses the polymerase chain reaction to amplify the variable regions of immunoglobulin genes and T-cell receptor genes to detect the presence of a clonal lymphocyte population. The assay detected clonally rearranged antigen receptor genes in 91% of the 77 dogs with lymphoid malignancy. Of the 24 dogs tested, that were either healthy or had clearly defined conditions not related to lymphoid malignancy, a clonally rearranged antigen receptor gene was found in one (a dog with Ehrlichia canis infection). Gene rearrangement was appropriate for the immunophenotype (immunoglobulin gene rearrangement in B-cell leukemias and T-cell receptor gene rearrangement in T-cell leukemias). Dilution analysis showed that the clonal rearrangement could be detected when 0.1-10% of the DNA was derived from neoplastic cells, depending on the source tissue. Potential applications of this assay include the diagnosis of lymphoma or leukemia in biopsy samples, cavity fluids, fine needle aspirates, bone marrow and peripheral blood; the determination of lineage (B or T cell); staging of lymphoma; and detection of residual disease after chemotherapy. PMID:12627711

Burnett, R C; Vernau, W; Modiano, J F; Olver, C S; Moore, P F; Avery, A C

2003-01-01

86

Integrated olfactory receptor and microarray gene expression databases  

PubMed Central

Background Gene expression patterns of olfactory receptors (ORs) are an important component of the signal encoding mechanism in the olfactory system since they determine the interactions between odorant ligands and sensory neurons. We have developed the Olfactory Receptor Microarray Database (ORMD) to house OR gene expression data. ORMD is integrated with the Olfactory Receptor Database (ORDB), which is a key repository of OR gene information. Both databases aim to aid experimental research related to olfaction. Description ORMD is a Web-accessible database that provides a secure data repository for OR microarray experiments. It contains both publicly available and private data; accessing the latter requires authenticated login. The ORMD is designed to allow users to not only deposit gene expression data but also manage their projects/experiments. For example, contributors can choose whether to make their datasets public. For each experiment, users can download the raw data files and view and export the gene expression data. For each OR gene being probed in a microarray experiment, a hyperlink to that gene in ORDB provides access to genomic and proteomic information related to the corresponding olfactory receptor. Individual ORs archived in ORDB are also linked to ORMD, allowing users access to the related microarray gene expression data. Conclusion ORMD serves as a data repository and project management system. It facilitates the study of microarray experiments of gene expression in the olfactory system. In conjunction with ORDB, ORMD integrates gene expression data with the genomic and functional data of ORs, and is thus a useful resource for both olfactory researchers and the public.

Liu, Nian; Crasto, Chiquito J; Ma, Minghong

2007-01-01

87

A 1-adenosine receptor gene expression in fetal rat brain  

Microsoft Academic Search

Adenosine influences neurotransmitter release, neuronal excitability, and firing rate, through A1-adenosine receptors (A1-R). Caffeine and related methylxanthines are adenosine receptor antagonists. Exposure of developing rodents to caffeine is associated with subtle, long-term changes in neurochemistry and behavior. The developmental appearance of A1-R gene expression was examined in rats by in situ hybridization. On gestational day (GD) 10, A1-R mRNA was

1996-01-01

88

Efficient Bayesian approach for multilocus association mapping including gene-gene interactions  

PubMed Central

Background Since the introduction of large-scale genotyping methods that can be utilized in genome-wide association (GWA) studies for deciphering complex diseases, statistical genetics has been posed with a tremendous challenge of how to most appropriately analyze such data. A plethora of advanced model-based methods for genetic mapping of traits has been available for more than 10 years in animal and plant breeding. However, most such methods are computationally intractable in the context of genome-wide studies. Therefore, it is hardly surprising that GWA analyses have in practice been dominated by simple statistical tests concerned with a single marker locus at a time, while the more advanced approaches have appeared only relatively recently in the biomedical and statistical literature. Results We introduce a novel Bayesian modeling framework for association mapping which enables the detection of multiple loci and their interactions that influence a dichotomous phenotype of interest. The method is shown to perform well in a simulation study when compared to widely used standard alternatives and its computational complexity is typically considerably smaller than that of a maximum likelihood based approach. We also discuss in detail the sensitivity of the Bayesian inferences with respect to the choice of prior distributions in the GWA context. Conclusions Our results show that the Bayesian model averaging approach which explicitly considers gene-gene interactions may improve the detection of disease associated genetic markers in two respects: first, by providing better estimates of the locations of the causal loci; second, by reducing the number of false positives. The benefits are most apparent when the interacting genes exhibit no main effects. However, our findings also illustrate that such an approach is somewhat sensitive to the prior distribution assigned on the model structure.

2010-01-01

89

Evolution of olfactory receptor genes in the human genome  

PubMed Central

Olfactory receptor (OR) genes form the largest known multigene family in the human genome. To obtain some insight into their evolutionary history, we have identified the complete set of OR genes and their chromosomal locations from the latest human genome sequences. We detected 388 potentially functional genes that have intact ORFs and 414 apparent pseudogenes. The number and the fraction (48%) of functional genes are considerably larger than the ones previously reported. The human OR genes can clearly be divided into class I and class II genes, as was previously noted. Our phylogenetic analysis has shown that the class II OR genes can further be classified into 19 phylogenetic clades supported by high bootstrap values. We have also found that there are many tandem arrays of OR genes that are phylogenetically closely related. These genes appear to have been generated by tandem gene duplication. However, the relationships between genomic clusters and phylogenetic clades are very complicated. There are a substantial number of cases in which the genes in the same phylogenetic clade are located on different chromosomal regions. In addition, OR genes belonging to distantly related phylogenetic clades are sometimes located very closely in a chromosomal region and form a tight genomic cluster. These observations can be explained by the assumption that several chromosomal rearrangements have occurred at the regions of OR gene clusters and the OR genes contained in different genomic clusters are shuffled.

Niimura, Yoshihito; Nei, Masatoshi

2003-01-01

90

Sulfotransferase genes: Regulation by nuclear receptors in response to xeno/endo-biotics  

PubMed Central

Pregnane X receptor (PXR) and constitutive active/androstane receptor (CAR), members of the nuclear receptor superfamily, are two major xeno-sensing transcription factors. They can be activated by a broad range of lipophilic xenobiotics including therapeutics drugs. In addition to xenobiotics, endogenous compounds such as steroid hormones and bile acids can also activate PXR and/or CAR. These nuclear receptors regulate genes that encode enzymes and transporters that metabolize and excrete both xenobiotics and endobiotics. Sulfotransferases (SULTs) are a group of these enzymes and sulfate xenobiotics for detoxification. In general, inactivation by sulfation constitutes the mechanism to maintain homeostasis of endobiotics. Thus, deciphering the molecular mechanism by which PXR and CAR regulate SULT genes is critical for understanding the roles of SULTs in the alterations of physiological and pathophysiological processes caused by drug treatment or environmental exposures.

Kodama, Susumu; Negishi, Masahiko

2014-01-01

91

Odorant and pheromone receptor gene regulation in vertebrates.  

PubMed

The largest mammalian gene family codes for odorant receptors and is exclusively devoted to the perception of the outside world. Its expression is very peculiar, since olfactory sensory neurons are only allowed to express a single of its numerous members, from a single parental allele. How this is achieved is unknown, but recent work points to multiple regulatory mechanisms, possibly shared by pheromone receptor genes, acting at (a) a general level, via the expression of the chemoreceptor itself and (b) a more restricted level, defined by activator elements. PMID:17709237

Rodriguez, Ivan

2007-10-01

92

Nutrition-hormone receptor-gene interactions: implications for development and disease.  

PubMed

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 PMID:11310425

Dauncey, M J; White, P; Burton, K A; Katsumata, M

2001-02-01

93

Natural killer cell receptor genes in the family Equidae: not only Ly49.  

PubMed

Natural killer (NK) cells have important functions in immunity. NK recognition in mammals can be mediated through killer cell immunoglobulin-like receptors (KIR) and/or killer cell lectin-like Ly49 receptors. Genes encoding highly variable NK cell receptors (NKR) represent rapidly evolving genomic regions. No single conservative model of NKR genes was observed in mammals. Single-copy low polymorphic NKR genes present in one mammalian species may expand into highly polymorphic multigene families in other species. In contrast to other non-rodent mammals, multiple Ly49-like genes appear to exist in the horse, while no functional KIR genes were observed in this species. In this study, Ly49 and KIR were sought and their evolution was characterized in the entire family Equidae. Genomic sequences retrieved showed the presence of at least five highly conserved polymorphic Ly49 genes in horses, asses and zebras. These findings confirmed that the expansion of Ly49 occurred in the entire family. Several KIR-like sequences were also identified in the genome of Equids. Besides a previously identified non-functional KIR-Immunoglobulin-like transcript fusion gene (KIR-ILTA) and two putative pseudogenes, a KIR3DL-like sequence was analyzed. In contrast to previous observations made in the horse, the KIR3DL sequence, genomic organization and mRNA expression suggest that all Equids might produce a functional KIR receptor protein molecule with a single non-mutated immune tyrosine-based inhibition motif (ITIM) domain. No evidence for positive selection in the KIR3DL gene was found. Phylogenetic analysis including rhinoceros and tapir genomic DNA and deduced amino acid KIR-related sequences showed differences between families and even between species within the order Perissodactyla. The results suggest that the order Perissodactyla and its family Equidae with expanded Ly49 genes and with a potentially functional KIR gene may represent an interesting model for evolutionary biology of NKR genes. PMID:23724088

Futas, Jan; Horin, Petr

2013-01-01

94

Natural Killer Cell Receptor Genes in the Family Equidae: Not only Ly49  

PubMed Central

Natural killer (NK) cells have important functions in immunity. NK recognition in mammals can be mediated through killer cell immunoglobulin-like receptors (KIR) and/or killer cell lectin-like Ly49 receptors. Genes encoding highly variable NK cell receptors (NKR) represent rapidly evolving genomic regions. No single conservative model of NKR genes was observed in mammals. Single-copy low polymorphic NKR genes present in one mammalian species may expand into highly polymorphic multigene families in other species. In contrast to other non-rodent mammals, multiple Ly49-like genes appear to exist in the horse, while no functional KIR genes were observed in this species. In this study, Ly49 and KIR were sought and their evolution was characterized in the entire family Equidae. Genomic sequences retrieved showed the presence of at least five highly conserved polymorphic Ly49 genes in horses, asses and zebras. These findings confirmed that the expansion of Ly49 occurred in the entire family. Several KIR-like sequences were also identified in the genome of Equids. Besides a previously identified non-functional KIR-Immunoglobulin-like transcript fusion gene (KIR-ILTA) and two putative pseudogenes, a KIR3DL-like sequence was analyzed. In contrast to previous observations made in the horse, the KIR3DL sequence, genomic organization and mRNA expression suggest that all Equids might produce a functional KIR receptor protein molecule with a single non-mutated immune tyrosine-based inhibition motif (ITIM) domain. No evidence for positive selection in the KIR3DL gene was found. Phylogenetic analysis including rhinoceros and tapir genomic DNA and deduced amino acid KIR-related sequences showed differences between families and even between species within the order Perissodactyla. The results suggest that the order Perissodactyla and its family Equidae with expanded Ly49 genes and with a potentially functional KIR gene may represent an interesting model for evolutionary biology of NKR genes.

Futas, Jan; Horin, Petr

2013-01-01

95

Peroxisome Proliferator-Activated Receptor Alpha Target Genes  

PubMed Central

The peroxisome proliferator-activated receptor alpha (PPAR?) is a ligand-activated transcription factor involved in the regulation of a variety of processes, ranging from inflammation and immunity to nutrient metabolism and energy homeostasis. PPAR? serves as a molecular target for hypolipidemic fibrates drugs which bind the receptor with high affinity. Furthermore, PPAR? binds and is activated by numerous fatty acids and fatty acid-derived compounds. PPAR? governs biological processes by altering the expression of a large number of target genes. Accordingly, the specific role of PPAR? is directly related to the biological function of its target genes. Here, we present an overview of the involvement of PPAR? in lipid metabolism and other pathways through a detailed analysis of the different known or putative PPAR? target genes. The emphasis is on gene regulation by PPAR? in liver although many of the results likely apply to other organs and tissues as well.

Rakhshandehroo, Maryam; Knoch, Bianca; Muller, Michael; Kersten, Sander

2010-01-01

96

Gene number determination and genetic polymorphism of the gamma delta T cell co-receptor WC1 genes  

PubMed Central

Background WC1 co-receptors belong to the scavenger receptor cysteine-rich (SRCR) superfamily and are encoded by a multi-gene family. Expression of particular WC1 genes defines functional subpopulations of WC1+ ?? T cells. We have previously identified partial or complete genomic sequences for thirteen different WC1 genes through annotation of the bovine genome Btau_3.1 build. We also identified two WC1 cDNA sequences from other cattle that did not correspond to sequences in the Btau_3.1 build. Their absence in the Btau_3.1 build may have reflected gaps in the genome assembly or polymorphisms among animals. Since the response of ?? T cells to bacterial challenge is determined by WC1 gene expression, it was critical to understand whether individual cattle or breeds differ in the number of WC1 genes or display polymorphisms. Results Real-time quantitative PCR using DNA from the animal whose genome was sequenced (“Dominette”) and sixteen other animals representing ten breeds of cattle, showed that the number of genes coding for WC1 co-receptors is thirteen. The complete coding sequences of those thirteen WC1 genes is presented, including the correction of an error in the WC1-2 gene due to mis-assembly in the Btau_3.1 build. All other cDNA sequences were found to agree with the previous annotation of complete or partial WC1 genes. PCR amplification and sequencing of the most variable N-terminal SRCR domain (domain 1 which has the SRCR “a” pattern) of each of the thirteen WC1 genes showed that the sequences are highly conserved among individuals and breeds. Of 160 sequences of domain 1 from three breeds of cattle, no additional sequences beyond the thirteen described WC1 genes were found. Analysis of the complete WC1 cDNA sequences indicated that the thirteen WC1 genes code for three distinct WC1 molecular forms. Conclusion The bovine WC1 multi-gene family is composed of thirteen genes coding for three structural forms whose sequences are highly conserved among individual cattle and breeds. The sequence diversity necessary for WC1 genes to function as a multi-genic pattern recognition receptor array is encoded in the genome, rather than generated by recombinatorial diversity or hypermutation.

2012-01-01

97

Genomic organization, annotation, and ligand-receptor inferences of chicken chemokines and chemokine receptor genes based on comparative genomics  

Microsoft Academic Search

BACKGROUND: Chemokines and their receptors play important roles in host defense, organogenesis, hematopoiesis, and neuronal communication. Forty-two chemokines and 19 cognate receptors have been found in the human genome. Prior to this report, only 11 chicken chemokines and 7 receptors had been reported. The objectives of this study were to systematically identify chicken chemokines and their cognate receptor genes in

Jixin Wang; David L Adelson; Ahmet Yilmaz; Sing-Hoi Sze; Yuan Jin; James J Zhu

2005-01-01

98

Androgen receptor gene mutation, rearrangement, polymorphism  

PubMed Central

Genetic aberrations of the androgen receptor (AR) caused by mutations, rearrangements, and polymorphisms result in a mutant receptor that has varied functions compared to wild type AR. To date, over 1,000 mutations have been reported in the AR with most of these being associated with androgen insensitivity syndrome (AIS). While mutations of AR associated with prostate cancer occur less often in early stage localized disease, mutations in castration-resistant prostate cancer (CRPC) patients treated with anti-androgens occur more frequently with 10–30% of these patients having some form of mutation in the AR. Resistance to anti-androgen therapy usually results from gain-of-function mutations in the LBD such as is seen with bicalutamide and more recently with enzalutamide (MDV3100). Thus, it is crucial to investigate these new AR mutations arising from drug resistance to anti-androgens and other small molecule pharmacological agents.

Eisermann, Kurtis; Wang, Dan; Jing, Yifeng; Pascal, Laura E.; Wang, Zhou

2014-01-01

99

Resolution of the novel immune-type receptor gene cluster in zebrafish  

PubMed Central

The novel immune-type receptor (NITR) genes encode a unique multigene family of leukocyte regulatory receptors, which possess an extracellular Ig variable (V) domain and may function in innate immunity. Artificial chromosomes that encode zebrafish NITRs have been assembled into a contig spanning ?350 kb. Resolution of the complete NITR gene cluster has led to the identification of eight previously undescribed families of NITRs and has revealed the presence of C-type lectins within the locus. A maximum haplotype of 36 NITR genes (138 gene sequences in total) can be grouped into 12 distinct families, including inhibitory and activating receptors. An extreme level of interindividual heterozygosity is reflected in allelic polymorphisms, haplotype variation, and family-specific isoform complexity. In addition, the exceptional diversity of NITR sequences among species suggests divergent evolution of this multigene family with a birth-and-death process of member genes. High-confidence modeling of Nitr V-domain structures reveals a significant shift in the spatial orientation of the Ig fold, in the region of highest interfamily variation, compared with Ig V domains. These studies resolve a complete immune gene cluster in zebrafish and indicate that the NITRs represent the most complex family of activating/inhibitory surface receptors thus far described.

Yoder, Jeffrey A.; Litman, Ronda T.; Mueller, M. Gail; Desai, Salil; Dobrinski, Kimberly P.; Montgomery, Jennifer S.; Buzzeo, Matthew P.; Ota, Tatsuya; Amemiya, Chris T.; Trede, Nikolaus S.; Wei, Sheng; Djeu, Julie Y.; Humphray, Sean; Jekosch, Kerstin; Hernandez Prada, Jose A.; Ostrov, David A.; Litman, Gary W.

2004-01-01

100

Receptor-Mediated Gene Transfer Vectors: Progress Towards Genetic Pharmaceuticals  

Microsoft Academic Search

Although specific delivery to tissues and specific cell types in vivo has been demonstrated for many non-viral vectors, current methods are still inadequate for human applications, mainly because of limitations on their efficiencies. All the steps required for an efficient receptor-mediated gene transfer process may in principle be exploited to enhance targeted gene delivery. These steps are: DNA\\/vector binding, internalization,

M. Molas; A. G. Gomez-Valades; A. Vidal-Alabro; M. Miguel-Turu; J. Bermudez; R. Bartrons; J. C. Perales

2003-01-01

101

Polymorphisms in chemokine receptor genes and susceptibility to Kawasaki disease  

PubMed Central

Kawasaki disease (KD) is an acute vasculitis occurring in young children. Its aetiology is unknown, but an infectious agent is assumed. Increased levels of proinflammatory cytokines and chemokines have been reported in KD. Genetic variation in these genes and the receptors for these genes could influence the regulation of cytokines and chemokines. In a case–control study of 170 Dutch Caucasian KD patients and 300 healthy Dutch Caucasian controls, common genetic variants in chemokine receptor genes CCR3, CCR2, CCR5, CX3CR1, CXCR1 and CXCR2 were analysed. Of the eight studied single nucleotide polymorphisms (SNPs) in the CCR3–CCR2–CCR5 gene cluster, four showed a significant association with susceptibility to KD. Moreover the CCR5-?32 was observed with an allele frequency of 10·7% in the control population compared to 6·5% in the KD patients (P = 0·04). Two haplotypes of the CCR3–CCR2–CCR5 gene-cluster appear to be at risk haplotypes for KD and one a protective haplotype. No association was observed with the studied SNPs in CX3CR1, CXCR1 and CXCR2. In conclusion, in a Dutch cohort of KD patients an association of KD occurrence with common genetic variants in the chemokine receptor gene-cluster CCR3–CCR2–CCR5 was observed.

Breunis, W B; Biezeveld, M H; Geissler, J; Kuipers, I M; Lam, J; Ottenkamp, J; Hutchinson, A; Welch, R; Chanock, S J; Kuijpers, T W

2007-01-01

102

Allelic association of the D2 dopamine receptor gene with receptor-binding characteristics in alcoholism  

SciTech Connect

The allelic association of the human D2 dopamine receptor gene with the binding characteristics of the D2 dopamine receptor was determined in 66 brains of alcoholic and non-alcoholic subjects. In a blinded experiment, DNA from the cerebral cortex was treated with the restriction endonuclease Taql and probed with a 1.5-kilobase (kb) digest of a clone (lambda hD2G1) of the human D2 dopamine receptor gene. The binding characteristics (Kd (binding affinity) and Bmax (number of binding sites)) of the D2 dopamine receptor were determined in the caudate nuclei of these brains using tritiated spiperone as the ligand. The adjusted Kd was significantly lower in alcoholic than in nonalcoholic subjects. In subjects with the A1 allele, in whom a high association with alcoholism was found, the Bmax was significantly reduced compared with the Bmax of subjects with the A2 allele. Moreover, a progressively reduced Bmax was found in subjects with A2/A2, A1/A2, and A1/A1 alleles, with subjects with A2/A2 having the highest mean values, and subjects with A1/A1, the lowest. The polymorphic pattern of the D2 dopamine receptor gene and its differential expression of receptors suggests the involvement of the dopaminergic system in conferring susceptibility to at least one subtype of severe alcoholism.

Noble, E.P.; Blum, K.; Ritchie, T.; Montgomery, A.; Sheridan, P.J. (Neuropsychiatric Institute, UCLA (USA))

1991-07-01

103

Association between polymorphisms in the progesterone receptor gene and endometriosis  

Microsoft Academic Search

The progesterone receptor (PR) is a candidate gene for the development of endometriosis, a complex disease with strong hormo- nal features, common in women of reproductive age. We typed the 306 base pair Alu insertion (AluIns) polymorphism in intron G of PR in 101 individuals, estimated linkage disequilibrium (LD) between five single-nucleotide polymorphisms (SNPs) across the PR locus in 980

Susan A. Treloar; Zhen Zhen Zhao; Trudi Armitage; David L. Duffy; Jacqueline Wicks; Daniel T. O'Connor; Nicholas G. Martin; Grant W. Montgomery

2005-01-01

104

Vitamin D receptor gene polymorphisms in patients with thyroid cancer  

Microsoft Academic Search

Summary The association between vitamin D receptor (VDR) gene polymorphisms and some diseases such as colorectal cancer, breast cancer, osteoporosis and psoriasis has been extensively investigated during the past few years. This research was performed not only because of the role of vitamin D as an anticancer agent, but also because of the suppressing action of vitamin D on TSH,

Vahid Haghpanah; Seyed H. Ghaffari; Parisa Rahimpour; Avisa Abbasi; Marjan Saeedi; Hale Pak; Foroogh Alborzi; Shaghayegh Barzegar; Ramin Heshmat; Kamran Alimoghadam; Peiman Shoushtarizadeh; Seyed Mohammad Tavangar; Ardeshir Ghavamzadeh; Bagher Larijani

2007-01-01

105

The Glucocorticoid Receptor Gene and Its Association to Metabolic Syndrome  

Microsoft Academic Search

In recent decades, there has been an increasing interest in the role of endogenous glucocorticoids such as cortisol in the pathogenesis of metabolic syndrome. Studies in humans have suggested a positive association between obesity, hypertension, and insulin resistance, with alleles at the glucocorticoid receptor (GR) gene. For instance, the BclI polymorphism within the intron upstream of GR exon 2 has

Roland Rosmond

2002-01-01

106

Association of the TGF-? receptor genes with abdominal aortic aneurysm  

Microsoft Academic Search

Abdominal aortic aneurysm (AAA) is a multifactorial condition. The transforming growth factor ? (TGF-?) pathway regulates vascular remodeling and mutations in its receptor genes, TGFBR1 and TGFBR2, cause syndromes with thoracic aortic aneurysm (TAA). The TGF-? pathway may be involved in aneurysm development in general. We performed an association study by analyzing all the common genetic variants in TGFBR1 and

A F Baas; J Medic; R van't Slot; C G de Kovel; A Zhernakova; R H Geelkerken; S E Kranendonk; S M van Sterkenburg; D E Grobbee; A P Boll; C Wijmenga; J D Blankensteijn; Y M Ruigrok

2010-01-01

107

Association between alcoholism and the dopamine D4 receptor gene  

Microsoft Academic Search

A point mutation in the aldehyde dehydrogenase 2 gene (ALDH2(2) allele) is considered to be a genetic deterrent for alcoholism; however, 80 of 655 Japanese alcoholics had the mutant allele. Genotype factors that might increase susceptibility by overriding the deterrent showed a higher frequency of a five repeat allele of the dopamine D4 receptor 48 bp repeat polymorphism in alcoholics

T Muramatsu; S Higuchi; M Murayama; S Matsushita; M Hayashida

1996-01-01

108

Reciprocal activation of Xenobiotic response genes by nuclear receptors SXR/PXR and CAR  

PubMed Central

The cytochrome P450 (CYP) gene products such as CYP3A and CYP2B are essential for the metabolism of steroid hormones and xenochemicals including prescription drugs. Nuclear receptor SXR/PXR (steroid and xenobiotic receptor/pregnenolone X receptor) has been shown both biochemically and genetically to activate CYP3A genes, while similar studies have established constitutive androstane receptor (CAR) as a CYP2B regulator. The response elements in these genes are also distinct, furthering the concept of independent regulation. Unexpectedly, we found that SXR can regulate CYP2B, both in cultured cells and in transgenic mice via adaptive recognition of the phenobarbital response element (PBRE). In a type of functional symmetry, orphan receptor CAR was also found to activate CYP3A through previously defined SXR/PXR response elements. These observations not only provide a rational explanation for the activation of multiple CYP gene classes by certain xenobiotics, but also reveal the existence of a metabolic safety net that confers a second layer of protection to the harmful effects of toxic compounds and at the same time increases the propensity for drug–drug interactions.

Xie, Wen; Barwick, Joyce L.; Simon, Cynthia M.; Pierce, Alexis M.; Safe, Stephen; Blumberg, Bruce; Guzelian, Philip S.; Evans, Ronald M.

2000-01-01

109

Cooperative Activation of Gene Expression by Agonists and Antagonists Mediated by Estrogen Receptor Heteroligand Dimer Complexes  

PubMed Central

Estrogen receptor (ER) antagonists are generally thought to inhibit estrogen action through competitive inhibition, resulting in receptor binding to antagonist rather than agonist. However, microarray analyses reveal a group of genes for which ER agonist and antagonist cooperatively regulate expression, suggesting additional models of combined agonist/antagonist action must exist. In conjunction with a chimeric reporter gene and two modified ERs, one [ER?(GSCKV)] with a mutation in the DNA-binding domain and the other (ER?-G521R) with a ligand-binding specificity mutation, we herein demonstrate that ER agonist and antagonist cooperatively activate gene expression through an ER heteroligand dimer complex (ER-HLD) consisting of one subunit of the receptor dimer bound to agonist and another occupied by antagonist. Coimmunoprecipitation experiments confirmed interaction between the agonist-bound and antagonist-bound receptors. This cooperative activation of gene expression was enhanced by steroid receptor coactivator 3 coactivator, and required each ligand-bound subunit of the dimer to bind to DNA, as well as both activation function 1 domains for maximal transcriptional activity. Ligand combinations able to induce ER-HLD transcriptional activity include the agonists 17?-estradiol or conjugated estrogens with the antagonists tamoxifen, raloxifene, bazedoxifene, or fulvestrant. Moreover, ER-HLD can activate transcription in the context of a natural promoter. Taken together, these findings broaden our understanding of the complex relationship between ER agonist and antagonist, and suggest a novel model by which cell and tissue selective effects of antiestrogens may be achieved.

Liu, Shuang; Han, Sang Jun

2013-01-01

110

Mice with an Increased Glucocorticoid Receptor Gene Dosage Show Enhanced Resistance to Stress and Endotoxic Shock  

Microsoft Academic Search

Targeted mutagenesis of the glucocorticoid receptor has revealed an essential function for survival and the regulation of multiple physiological processes. To investigate the effects of an increased gene dosage of the receptor, we have generated transgenic mice carrying two additional copies of the glucocorticoid receptor gene by using a yeast artificial chromosome. Interestingly, overexpression of the glucocorticoid receptor alters the

HOLGER M. REICHARDT; THORSTEN UMLAND; ANTON BAUER; OLIVER KRETZ; GUNTHER SCHUTZ

2000-01-01

111

The low-density lipoprotein receptor gene family: multiple roles in lipid metabolism  

Microsoft Academic Search

The low-density lipoprotein receptor gene family encompasses a class of endocytic receptors that exhibit structural similarities\\u000a to the low-density lipoprotein receptor. Members of this gene family are present in both vertebrate and nonvertebrate species.\\u000a The identification of naturally occurring mutations and the application of gene targeting to inactivate receptor genes enabled\\u000a us to develop animal models to investigate the consequences

Thomas E. Willnow

1999-01-01

112

Gene expression profiles of estrogen receptor positive and estrogen receptor negative breast cancers are detectable in histologically normal breast epithelium  

PubMed Central

Purpose Previously, we found that gene expression in histologically normal breast epithelium (NlEpi) from women at high breast cancer risk can resemble gene expression in NlEpi from cancer-containing breasts. Therefore, we hypothesized that gene expression characteristic of a cancer subtype might be seen in NlEpi of breasts containing that subtype. Experimental Design We examined gene expression in 46 cases of microdissected NlEpi from untreated women undergoing breast cancer surgery. From 30 age-matched cases (15 estrogen receptor (ER)+, 15 ER-) we used Affymetryix U133A arrays. From 16 independent cases (9 ER+, 7 ER-), we validated selected genes using qPCR. We then compared gene expression between NlEpi and invasive breast cancer using 4 publicly available datasets. Results We identified 198 genes that are differentially expressed between NlEpi from breasts with ER+ (NlEpiER+) compared to ER- cancers (NlEpiER-). These include genes characteristic of ER+ and ER- cancers (e.g., ESR1, GATA3, and CX3CL1, FABP7). QPCR validated the microarray results in both the 30 original cases and the 16 independent cases. Gene expression in NlEpiER+ and NlEpiER- resembled gene expression in ER+ and ER- cancers, respectively: 25-53% of the genes or probes examined in 4 external datasets overlapped between NlEpi and the corresponding cancer subtype. Conclusions Gene expression differs in NlEpi of breasts containing ER+ compared to ER- breast cancers. These differences echo differences in ER+ and ER- invasive cancers. NlEpi gene expression may help elucidate subtype-specific risk signatures, identify early genomic events in cancer development and locate targets for prevention and therapy.

Graham, Kelly; Ge, Xijin; de las Morenas, Antonio; Tripathi, Anusri; Rosenberg, Carol L.

2010-01-01

113

The nuclear receptors pregnane X receptor and constitutive androstane receptor contribute to the impact of fipronil on hepatic gene expression linked to thyroid hormone metabolism.  

PubMed

Fipronil is described as a thyroid disruptor in rat. Based on the hypothesis that this results from a perturbation of hepatic thyroid hormone metabolism, our goal was to investigate the pathways involved in fipronil-induced liver gene expression regulations. First, we performed a microarray screening in the liver of rats treated with fipronil or vehicle. Fipronil treatment led to the upregulation of several genes involved in the metabolism of xenobiotics, including the cytochrome P450 Cyp2b1, Cyp2b2 and Cyp3a1, the carboxylesterases Ces2 and Ces6, the phase II enzymes Ugt1a1, Sult1b1 and Gsta2, and the membrane transporters Abcc2, Abcc3, Abcg5, Abcg8, Slco1a1 and Slco1a4. Based on a large overlap with the target genes of constitutive androstane receptor (CAR) and pregnane X receptor (PXR), we postulated that these two nuclear receptors are involved in mediating the effects of fipronil on liver gene expression in rodents. We controlled that liver gene expression changes induced by fipronil were generally reproduced in mice, and then studied the effects of fipronil in wild-type, CAR- and PXR-deficient mice. For most of the genes studied, the gene expression modulations were abolished in the liver of PXR-deficient mice and were reduced in the liver of CAR-deficient mice. However, CAR and PXR activation in mouse liver was not associated with a marked increase of thyroid hormone clearance, as observed in rat. Nevertheless, our data clearly indicate that PXR and CAR are key modulators of the hepatic gene expression profile following fipronil treatment which, in rats, may contribute to increase thyroid hormone clearance. PMID:23962444

Roques, Béatrice B; Leghait, Julien; Lacroix, Marlène Z; Lasserre, Frédéric; Pineau, Thierry; Viguié, Catherine; Martin, Pascal G P

2013-10-01

114

Identical Splicing of Aberrant Epidermal Growth Factor Receptor Transcripts from Amplified Rearranged Genes in Human Glioblastomas  

Microsoft Academic Search

The epidermal growth factor receptor gene has been found to be amplified and rearranged in human glioblastomas in vivo. Here we present the sequence across a splice junction of aberrant epidermal growth factor receptor transcripts derived from corresponding and uniquely rearranged genes that are coamplified and coexpressed with non-rearranged epidermal growth factor receptor genes in six primary human glioblastomas. Each

Noriaki Sugawa; A. Jonas Ekstrand; C. David James; V. Peter Collins

1990-01-01

115

Mu opioid receptor gene expression in immune cells.  

PubMed

We have previously demonstrated that administering morphine sulfate to rhesus monkeys alters the cell-mediated as well as humoral immune responses of these primates. Furthermore, morphine treatment greatly reduces the chemotactic and phagocytotic activities of primate polymorphonuclear (PMN) cells. The present study describes the identification and isolation of mRNA encoding the mu opioid receptor gene sequence from human and monkey immune cells. Through the use of primer sequences designed from the human brain mu opioid receptor cDNA sequence, specific opioid receptor segments in mRNA transcripts were amplified, cloned, and sequenced. The mu opioid receptor gene was therefore found expressed in the following cell types: CEM x174 (a hybrid of human T and B cells), Raji (human B cells), human CD4+ cells, human monocytes/macrophages, human PMN, monkey peripheral blood mononuclear cells (PBMC), and monkey PMN. These studies present the first evidence to demonstrate that cells of human and monkey immune systems constitutively express mu opioid receptor mRNA. PMID:7488213

Chuang, T K; Killam, K F; Chuang, L F; Kung, H F; Sheng, W S; Chao, C C; Yu, L; Chuang, R Y

1995-11-22

116

The Natural History of Class I Primate Alcohol Dehydrogenases Includes Gene Duplication, Gene Loss, and Gene Conversion  

PubMed Central

Background Gene duplication is a source of molecular innovation throughout evolution. However, even with massive amounts of genome sequence data, correlating gene duplication with speciation and other events in natural history can be difficult. This is especially true in its most interesting cases, where rapid and multiple duplications are likely to reflect adaptation to rapidly changing environments and life styles. This may be so for Class I of alcohol dehydrogenases (ADH1s), where multiple duplications occurred in primate lineages in Old and New World monkeys (OWMs and NWMs) and hominoids. Methodology/Principal Findings To build a preferred model for the natural history of ADH1s, we determined the sequences of nine new ADH1 genes, finding for the first time multiple paralogs in various prosimians (lemurs, strepsirhines). Database mining then identified novel ADH1 paralogs in both macaque (an OWM) and marmoset (a NWM). These were used with the previously identified human paralogs to resolve controversies relating to dates of duplication and gene conversion in the ADH1 family. Central to these controversies are differences in the topologies of trees generated from exonic (coding) sequences and intronic sequences. Conclusions/Significance We provide evidence that gene conversions are the primary source of difference, using molecular clock dating of duplications and analyses of microinsertions and deletions (micro-indels). The tree topology inferred from intron sequences appear to more correctly represent the natural history of ADH1s, with the ADH1 paralogs in platyrrhines (NWMs) and catarrhines (OWMs and hominoids) having arisen by duplications shortly predating the divergence of OWMs and NWMs. We also conclude that paralogs in lemurs arose independently. Finally, we identify errors in database interpretation as the source of controversies concerning gene conversion. These analyses provide a model for the natural history of ADH1s that posits four ADH1 paralogs in the ancestor of Catarrhine and Platyrrhine primates, followed by the loss of an ADH1 paralog in the human lineage.

Carrigan, Matthew A.; Uryasev, Oleg; Davis, Ross P.; Zhai, LanMin; Hurley, Thomas D.; Benner, Steven A.

2012-01-01

117

Chromosomal localization of the human V3 pituitary vasopressin receptor gene (AVPR3) to 1q32  

SciTech Connect

Vasopressin exerts its physiological effects on liver metabolism, fluid osmolarity, and corticotrophic response to stress through a set of at least three receptors, V1a, V2, and V3 (also called V1b), respectively. These receptors constitute a distinct group of the superfamily of G-protein-coupled cell surface receptors. When bound to vasopressin, they couple to G proteins activating phospholipase C for the V1a and V3 types and adenylate cyclase for the V2. The vasopressin receptor subfamily also includes the receptor for oxytocin, a structurally related hormone that signals through the activation of phospholipase C. The chromosomal position of the V2 receptor gene has been assigned to Xq28-qter by PCR-based screening of somatic cell hybrids, whereas the oxytocin receptor gene has been mapped to chromosome 3q26.2 by fluorescence in situ hybridization (FISH). The chromosomal location of the V1a gene is currently unknown. We recently cloned the cDNA and the gene coding for the human pituitary-specific V3 receptor (HGMW-approved symbol AVPR3). We report here the chromosomal localization of this gene by two distinct in situ hybridization techniques using radioactive and fluorescent probes. 11 refs., 1 fig.

Rousseau-Merck, M.F.; Derre, J.; Berger, R. [INSERM, Paris (France)] [and others

1995-11-20

118

Association of estrogen receptor gene polymorphisms with endometriosis  

Microsoft Academic Search

Objective: To explore the association of the estrogen receptor two-allele (point) polymorphism and multiallele (microsatellite) polymorphism with endometriosis.Design: Case-control study.Setting: Genetics and Endoscopy Unit, Department of Obstetrics and Gynecology, Ioannina University Hospital, Ioannina, Greece.Patient(s): Fifty-seven women with surgically and histologically diagnosed endometriosis of stages I–IV.Intervention(s): Diagnostic laparoscopy.Main Outcome Measure(s): Frequency and distribution of the estrogen receptor gene polymorphisms.Result(s): There was

Ioannis Georgiou; Maria Syrrou; Ioanna Bouba; Nikolaos Dalkalitsis; Minas Paschopoulos; Iordanis Navrozoglou; Dimitrios Lolis

1999-01-01

119

Gene expression profiling reveals upregulation of Tlr4 receptors in Cckb receptor deficient mice  

Microsoft Academic Search

The cholecystokinin B (2) receptor knockout (Cckbr KO) protects against allodynia induced by chronic constriction injury (CCI). The mechanism of this phenomenon is unknown, but must involve persistent changes in pain modulation and\\/or inflammatory pathways. We performed a gene expression study in two brain areas (midbrain and medulla) after surgical induction of CCI in Cckbr KO and wild-type (wt) control

Sulev Kõks; Cathy Fernandes; Kaido Kurrikoff; Eero Vasar; Leonard C. Schalkwyk

2008-01-01

120

The nicotinic acetylcholine receptor CHRNA5/A3/B4 gene cluster: Dual role in nicotine addiction and lung cancer  

PubMed Central

More than 1 billion people around the world smoke, with 10 million cigarettes sold every minute. Cigarettes contain thousands of harmful chemicals including the psychoactive compound, nicotine. Nicotine addiction is initiated by the binding of nicotine to nicotinic acetylcholine receptors, ligand-gated cation channels activated by the endogenous neurotransmitter, acetylcholine. These receptors serve as prototypes for all ligand-gated ion channels and have been extensively studied in an attempt to elucidate their role in nicotine addiction. Many of these studies have focused on heteromeric nicotinic acetylcholine receptors containing ?4 and ?2 subunits and homomeric nicotinic acetylcholine receptors containing the ?7 subunit, two of the most abundant subtypes expressed in the brain. Recently however, a series of linkage analyses, candidate-gene analyses and genome-wide association studies have brought attention to three other members of the nicotinic acetylcholine receptor family: the ?5, ?3 and ?4 subunits. The genes encoding these subunits lie in a genomic cluster that contains variants associated with increased risk for several diseases including nicotine dependence and lung cancer. The underlying mechanisms for these associations have not yet been elucidated but decades of research on the nicotinic receptor gene family as well as emerging data provide insight on how these receptors may function in pathological states. Here, we review this body of work, focusing on the clustered nicotinic acetylcholine receptor genes and evaluating their role in nicotine addiction and lung cancer.

Improgo, Ma. Reina D.; Scofield, Michael D.; Tapper, Andrew R.; Gardner, Paul D.

2010-01-01

121

Parallel evolution of domesticated Caenorhabditis species targets pheromone receptor genes  

PubMed Central

Evolution can follow predictable genetic trajectories1, indicating that discrete environmental shifts can select for reproducible genetic changes2-4. Conspecific individuals are an important feature of an animal's environment, and a potential source of selective pressures. We show here that adaptation of two Caenorhabditis species to growth at high density, a feature common to domestic environments, occurs by reproducible genetic changes to pheromone receptor genes. Chemical communication through pheromones that accumulate during high-density growth causes young nematode larvae to enter the long-lived but non-reproductive dauer stage. Two strains of Caenorhabditis elegans grown at high density have independently acquired multigenic resistance to pheromone-induced dauer formation. In each strain, resistance to the pheromone ascaroside C3 results from a deletion that disrupts the adjacent chemoreceptor genes serpentine receptor class g (srg)-36 and -37. Through misexpression experiments, we show that these genes encode redundant G protein-coupled receptors for ascaroside C3. Multigenic resistance to dauer formation has also arisen in high-density cultures of a different nematode species, Caenorhabditis briggsae, resulting in part from deletion of an srg gene paralogous to srg-36 and srg-37. These results demonstrate rapid remodeling of the chemoreceptor repertoire as an adaptation to specific environments, and indicate that parallel changes to a common genetic substrate can affect life history traits across species.

McGrath, Patrick T.; Xu, Yifan; Ailion, Michael; Garrison, Jennifer L.; Butcher, Rebecca A.; Bargmann, Cornelia I.

2011-01-01

122

The HLA class I gene family includes at least six genes and twelve pseudogenes and gene fragments  

SciTech Connect

The authors report the characterization of eight HLA class I homologous sequences isolated from cosmid and lambda libraries made from lymphoblastoid cell line 721 DNA. Four of these sequences, each contained within HindIII fragments of 1.7, 2.1, 3.0, and 8.0 kb, have class I homology extending over short intron-exon regions. The remaining four are found within 7.5-, 8.0-, 9.0-, and 16.0-kb HindIII fragments, the first having homology to the 5[prime] half of a class I gene whereas the latter three are homologous to the 3[prime] portion of a class I gene. When combined with the characterization of other class I clones, this work brings the total number of HLA class I homologous sequences cloned and characterized to 18. Restriction mapping of cosmid clones showed that some of these sequences are linked to one another and to other class I pseudogenes and genes within 50-kb regions. Reconstruction experiments using the 18 class I genes and pseudogenes were performed that indicated that all of the members of the HLA class I gene family detectable using HLA-A2 genomic DNA as probe had been cloned. An additional 19th member of the class I gene family was identified using an HLA-E cDNA probe. Further Southern analysis with other class I probes indicated the 19 sequences comprise the entire class I gene family in LCL 721. Locus-specific probes were isolated from five of the eight clones and were used in Southern analysis of diverse genomic DNA to examine the polymorphism of the pseudogene sequences, demonstrating that some of them were highly polymorphic and some were missing entirely in certain haplotypes. An additional class I sequence, not contained within the 721 genome, was identified and may be found in association with the HLA-A11-Bw60 haplotype. Sequence comparisons were carried out to examine the evolutionary relationships among the pseudogenes. Hypothetical events in the evolution of the class I region are discussed. 59 refs., 8 figs., 4 tabs.

Geraghty, D.E. (Fred Hutchinson Cancer Research Center, Seattle, WA (United States)); Koller, B.H.; Orr, H.T. (Univ. of Minnesota, Minneapolis, MN (United States)); Hansen, J.A. (Univ. of Washington, Seattle, WA (United States))

1992-09-15

123

Diagnostic tool for the identification of MLL rearrangements including unknown partner genes  

PubMed Central

Approximately 50 different chromosomal translocations of the human MLL gene are currently known and associated with high-risk acute leukemia. The large number of different MLL translocation partner genes makes a precise diagnosis a demanding task. After their cytogenetic identification, only the most common MLL translocations are investigated by RT-PCR analyses, whereas infrequent or unknown MLL translocations are excluded from further analyses. Therefore, we aimed at establishing a method that enables the detection of any MLL rearrangement by using genomic DNA isolated from patient biopsy material. This goal was achieved by establishing a universal long-distance inverse-PCR approach that allows the identification of any kind of MLL rearrangement if located within the breakpoint cluster region. This method was applied to biopsy material derived from 40 leukemia patients known to carry MLL abnormalities. Thirty-six patients carried known MLL fusions (34 with der(11) and 2 with reciprocal alleles), whereas 3 patients were found to carry novel MLL fusions to ACACA, SELB, and SMAP1, respectively. One patient carried a genomic fusion between MLL and TIRAP, resulting from an interstitial deletion. Because of this interstitial deletion, portions of the MLL and TIRAP genes were deleted, together with 123 genes located within the 13-Mbp interval between both chromosomal loci. Therefore, this previously undescribed diagnostic tool has been proven successful for analyzing any MLL rearrangement including previously unrecognized partner genes. Furthermore, the determined patient-specific fusion sequences are useful for minimal residual disease monitoring of MLL associated acute leukemias.

Meyer, Claus; Schneider, Bjoern; Reichel, Martin; Angermueller, Sieglinde; Strehl, Sabine; Schnittger, Susanne; Schoch, Claudia; Jansen, Mieke W. J. C.; van Dongen, Jacques J.; Pieters, Rob; Haas, Oskar A.; Dingermann, Theo; Klingebiel, Thomas; Marschalek, Rolf

2005-01-01

124

A network of heterochronic genes including Imp1 regulates temporal changes in stem cell properties  

PubMed Central

Stem cell properties change over time to match the changing growth and regeneration demands of tissues. We showed previously that adult forebrain stem cell function declines during aging because of increased expression of let-7 microRNAs, evolutionarily conserved heterochronic genes that reduce HMGA2 expression. Here we asked whether let-7 targets also regulate changes between fetal and adult stem cells. We found a second let-7 target, the RNA binding protein IMP1, that is expressed by fetal, but not adult, neural stem cells. IMP1 expression was promoted by Wnt signaling and Lin28a expression and opposed by let-7 microRNAs. Imp1-deficient neural stem cells were prematurely depleted in the dorsal telencephalon due to accelerated differentiation, impairing pallial expansion. IMP1 post-transcriptionally inhibited the expression of differentiation-associated genes while promoting the expression of self-renewal genes, including Hmga2. A network of heterochronic gene products including Lin28a, let-7, IMP1, and HMGA2 thus regulates temporal changes in stem cell properties. DOI: http://dx.doi.org/10.7554/eLife.00924.001

Nishino, Jinsuke; Kim, Sunjung; Zhu, Yuan; Zhu, Hao; Morrison, Sean J

2013-01-01

125

Regulation of Proteome Maintenance Gene Expression by Activators of Peroxisome Proliferator-Activated Receptor ?  

PubMed Central

The nuclear receptor peroxisome proliferator-activated receptor ? (PPAR?) is activated by a large number of xenobiotic and hypolipidemic compounds called peroxisome proliferator chemicals (PPCs). One agonist of PPAR? (WY-14,643) regulates responses in the mouse liver to chemical stress in part by altering expression of genes involved in proteome maintenance (PM) including protein chaperones in the heat shock protein (Hsp) family and proteasomal genes (Psm) involved in proteolysis. We hypothesized that other PPAR? activators including diverse hypolipidemic and xenobiotic compounds also regulate PM genes in the rat and mouse liver. We examined the expression of PM genes in rat and mouse liver after exposure to 7 different PPCs (WY-14,643, clofibrate, fenofibrate, valproic acid, di-(2-ethylhexyl) phthalate, perfluorooctanoic acid, and perfluorooctane sulfonate) using Affymetrix microarrays. In rats and mice, 174 or 380?PM genes, respectively, were regulated by at least one PPC. The transcriptional changes were, for the most part, dependent on PPAR?, as most changes were not observed in similarly treated PPAR?-null mice and the changes were not consistently observed in rats treated with activators of the nuclear receptors CAR or PXR. In rats and mice, PM gene expression exhibited differences compared to typical direct targets of PPAR? (e.g., Cyp4a family members). PM gene expression was usually delayed and in some cases, it was transient. Dose-response characterization of protein expression showed that Hsp86 and Hsp110 proteins were induced only at higher doses. These studies demonstrate that PPAR?, activated by diverse PPC, regulates the expression of a large number of genes involved in protein folding and degradation and support an expanded role for PPAR? in the regulation of genes that protect the proteome.

Ren, Hongzu; Vallanat, Beena; Brown-Borg, Holly M.; Currie, Richard; Corton, J. Christopher

2010-01-01

126

A comparison of reptilian and avian olfactory receptor gene repertoires: Species-specific expansion of group ? genes in birds  

PubMed Central

Background The detection of odorants is mediated by olfactory receptors (ORs). ORs are G-protein coupled receptors that form a remarkably large protein superfamily in vertebrate genomes. We used data that became available through recent sequencing efforts of reptilian and avian genomes to identify the complete OR gene repertoires in a lizard, the green anole (Anolis carolinensis), and in two birds, the chicken (Gallus gallus) and the zebra finch (Taeniopygia guttata). Results We identified 156 green anole OR genes, including 42 pseudogenes. The OR gene repertoire of the two bird species was substantially larger with 479 and 553 OR gene homologs in the chicken and zebra finch, respectively (including 111 and 221 pseudogenes, respectively). We show that the green anole has a higher fraction of intact OR genes (~72%) compared with the chicken (~66%) and the zebra finch (~38%). We identified a larger number and a substantially higher proportion of intact OR gene homologs in the chicken genome than previously reported (214 versus 82 genes and 66% versus 15%, respectively). Phylogenetic analysis showed that lizard and bird OR gene repertoires consist of group ?, ? and ? genes. Interestingly, the vast majority of the avian OR genes are confined to a large expansion of a single branch (the so called ?-c clade). An analysis of the selective pressure on the paralogous genes of each ?-c clade revealed that they have been subjected to adaptive evolution. This expansion appears to be bird-specific and not sauropsid-specific, as it is lacking from the lizard genome. The ?-c expansions of the two birds do not intermix, i.e., they are lineage-specific. Almost all (group ?-c) OR genes mapped to the unknown chromosome. The remaining OR genes mapped to six homologous chromosomes plus three to four additional chromosomes in the zebra finch and chicken. Conclusion We identified a surprisingly large number of potentially functional avian OR genes. Our data supports recent evidence that avian olfactory ability may be better developed than previously thought. We hypothesize that the radiation of the group ?-c OR genes in each bird lineage parallels the evolution of specific olfactory sensory functions.

Steiger, Silke S; Kuryshev, Vladimir Y; Stensmyr, Marcus C; Kempenaers, Bart; Mueller, Jakob C

2009-01-01

127

Association of 5HT1B receptor gene and antisocial behavior in alcoholism  

Microsoft Academic Search

Summary. The 5-HT1B receptor gene has been postulated to play a modulatory role in alcohol consumption and alcohol dependence, and was considered a candidate gene for alcoholism. More recently, the association of the 5-HT receptor gene polymorphism and antisocial personality traits in alcoholism has been discussed. This possible association was studied using material from our gene bank for alcoholism. The

M. Soyka; U. W. Preuss; G. Koller; P. Zill; B. Bondy

2004-01-01

128

Chronic schizophrenia is associated with over-expression of the interleukin-2 receptor gamma gene.  

PubMed

Altered immune response, including low-grade inflammatory processes, is involved in the pathogenesis of schizophrenia, a chronic psychiatric disorder with complex etiology. Distinct gene variants of a number of pro-inflammatory and chemotactic cytokines together with their receptors associate with this disorder. Interleukin-2 receptor gamma (IL-2RG) represents an important signaling component of many interleukin receptors and so far, no data on the functional state of this receptor in schizophrenia have been reported. The aim of this study was to investigate mRNA expression of the IL2RG gene (IL2RG) in schizophrenia patients in comparison with healthy subjects (controls). Total RNA was isolated from peripheral blood of 66 schizophrenia patients and 99 healthy subjects of Armenian population. The mRNA expression was determined by quantitative real-time polymerase chain reaction (RT-PCR) using PSMB2 as housekeeping gene. IL2RG mRNA expression was upregulated in peripheral blood of patients in comparison with controls (patients vs. controls, median [interquartile range]: 2.080 [3.428-1.046] vs. 0.324 [0.856-0.000], p<0.0001). In conclusion, our findings suggest that over-expression of the IL2RG gene may be implicated in altered immune response in schizophrenia and contribute to the pathomechanisms of this disorder. PMID:24713359

Ghazaryan, Hovsep; Petrek, Martin; Boyajyan, Anna

2014-07-30

129

Organization and developmental expression of the mosquito vitellogenin receptor gene.  

PubMed

Vitellogenin is a precursor of the major yolk protein, vitellin. It is internalized by developing oocytes via receptor-mediated endocytosis. Previously, we characterized the vitellogenin receptor (VgR) from oocytes of the mosquito Aedes aegypti [Sappington, T.W., Kokoza,V.A., Cho,W.L. and Raikhel,A.S. (1996) Molecular characterization of the mosquito vitellogenin receptor reveals unexpected high homology to the Drosophila yolk protein receptor. Proc Natl Acad Sci USA 93: 8934-8939]. The VgR receptor has a unique structure with two putative ligand-binding domains. In order to understand the regulation of this important molecule, we characterized the VgR gene structure and its expression during vitellogenesis in the mosquito A. aegypti. We report here that the VgR gene was separated by five introns that have an average length of 60 bp, except for the second intron which was more than 20 kb long. Most introns were located within the coding regions of the first protein domain. We isolated two allelic variations of the VgR gene, VgR1 and VgR2, the nucleotide sequences of which differing only in their 5'-flanking regions. Considering their frequency in the mosquito genome, VgR2 appeared to be a major allele. The expression of VgR mRNA was studied by the Northern blot analysis and in situ hybridization. The level of the VgR transcript started to rise in the ovary one day post-eclosion. It continued its dramatic rise during the vitellogenic period, reaching its peak at 24 h PBM. The VgR transcript was present exclusively in ovaries where it was seen in oocytes and nurse cells of primary follicles and germ-line cells of the germarium. PMID:11881811

Cho, K H; Raikhel, A S

2001-10-01

130

Association of Retinoic Acid Receptor Genes with Meningomyelocele  

PubMed Central

BACKGROUND Neural tube defects (NTDs) occur in as many as 0.5–2 per 1000 live births in the United ‘States. One of the most common and severe neural tube defects is meningomyelocele (MM) resulting from failed closure of the caudal end of the neural tube. MM has been induced by retinoic acid teratogenicity in rodent models. We hypothesized that genetic variants influencing retinoic acid (RA) induction via retinoic acid receptors (RARs) may be associated with risk for MM. METHODS We analyzed 47 single nucleotide polymorphisms (SNPs) that span across the three retinoic acid receptor genes using the SNPlex genotyping platform. Our cohort consisted of 610 MM families. RESULTS One variant in the RARA gene (rs12051734), three variants in the RARB gene (rs6799734, rs12630816, rs17016462), and a single variant in the RARG gene (rs3741434) were found to be statistically significant at p < 0.05. CONCLUSION RAR genes were associated with risk for MM. For all associated SNPs, the rare allele conferred a protective effect for MM susceptibility.

Tran, Phong X.; Au, Kit Sing; Morrison, Alanna C.; Fletcher, Jack M.; Ostermaier, Kathryn K.; Tyerman, Gayle H.; Northrup, Hope

2011-01-01

131

Kinin B1 receptor gene ablation affects hypothalamic CART productionb.  

PubMed

A role for the kinin B1 receptor in energy-homeostatic processes was implicated in previous studies; notably, the studies where kinin B1 receptor knockout mice (B1-/-) were shown to have impaired adiposity, impaired leptin and insulin production, lower feed efficiency, protection from liver steatosis and diet-induced obesity when fed a high fat diet (HFD). In particular, in a model where the B1 receptor is expressed exclusively in the adipose tissue, it rescues the plasma insulin concentration and the weight gain seen in wild type mice. Taking into consideration that leptin participates in the formation of hypothalamic nuclei, which modulate energy expenditure, and feeding behavior, we hypothesized that these brain regions could also be altered in B1-/- mice. We observed for the first time a difference in the gene expression pattern of cocaine and amphetamine related transcript (CART) in the (lateral hypothalamic area (LHA) resulting from the deletion of the kinin B1 receptor gene. The correlation between CART expression in the LHA and the thwarting of diet-induced obesity corroborates independent correlations between CART and obesity. Furthermore, it seems to indicate that the mechanism underlying the 'lean' phenotype of B1-/- mice does not stem solely from changes in peripheral tissues but may also receive contributions from changes in the hypothalamic machinery involved in energy homeostasis processes. PMID:23585179

Torres, Hugo A M; Louise Motta, Fabiana; Sales, Vicencia Micheline; Batista, Carolina; da Silva, Joelcimar M; Vignoli, Thiago; Barnabé, Gabriela F; Goeldner, Francine O; D'Almeida, Vânia; Bittencourt, Jackson C; Sinigaglia-Coimbra, Rita; Bader, Michael; Mello, Luiz Eugênio A M; Pesquero, João Bosco

2013-07-01

132

Differential expression of olfactory genes in the southern house mosquito and insights into unique odorant receptor gene isoforms.  

PubMed

The southern house mosquito, Culex quinquefasciatus, has one of the most acute and eclectic olfactory systems of all mosquito species hitherto studied. Here, we used Illumina sequencing to identify olfactory genes expressed predominantly in antenna, mosquito's main olfactory organ. Less than 50% of the trimmed reads generated by high-quality libraries aligned to a transcript, but approximately 70% of them aligned to the genome. Differential expression analysis, which was validated by quantitative real-time PCR on a subset of genes, showed that approximately half of the 48 odorant-binding protein genes were enriched in antennae, with the other half being predominantly expressed in legs. Similar patterns were observed with chemosensory proteins, "plus-C" odorant-binding proteins, and sensory neuron membrane proteins. Transcripts for as many as 43 ionotropic receptors were enriched in female antennae, thus making the ionotropic receptor family the largest of antennae-rich olfactory genes, second only to odorant receptor (OR) genes. As many as 177 OR genes have been identified, including 36 unique transcripts. The unique OR genes differed from previously annotated ORs in internal sequences, splice variants, and extended N or C terminus. One of the previously unknown transcripts was validated by cloning and functional expression. When challenged with a large panel of physiologically relevant compounds, CquiOR95b responded in a dose-dependent manner to ethyl 2-phenylacteate, which was demonstrated to repel Culex mosquitoes, and secondarily to citronellal, a known insect repellent. This transcriptome study led to identification of key molecular components and a repellent for the southern house mosquito. PMID:24167245

Leal, Walter S; Choo, Young-Moo; Xu, Pingxi; da Silva, Cherre S B; Ueira-Vieira, Carlos

2013-11-12

133

Transient Receptor Potential Genes and Human Inherited Disease  

Microsoft Academic Search

\\u000a Transient receptor potential (TRP) genes have been implicated in a wide array of human disorders, from cancers to bipolar\\u000a disorder. The extraordinary range of diseases in whose pathogenesis they may play a role exemplifies the equally broad range\\u000a of functions of the TRP proteins. TRP proteins primarily form homomeric or heteromeric channels in the cell membrane but there\\u000a may also

Kate V. Everett

134

Melanocortin-3-receptor gene variants in morbid obesity  

Microsoft Academic Search

BACKGROUND: Linkage and knock-out mice studies suggest that the melanocortin-3-receptor (MC3R) is a candidate gene for obesity.OBJECTIVE: To evaluate whether MC3R mutations underlie morbid obesity.SUBJECTS AND METHODS: MC3R coding and 5?-flanking regions were sequenced in 48 subjects and the detected variants genotyped in 252 morbidly obese (BMI?40 kg\\/m2) Finns. Gel shifts were used to examine whether a mutation in the

C Schalin-Jäntti; K Valli-Jaakola; L Oksanen; E Martelin; K Laitinen; T Krusius; P Mustajoki; M Heikinheimo; K Kontula

2003-01-01

135

Mapping and microsatellite marker development for the porcine leukemia inhibitory factor receptor (LIFR) and epidermal growth factor receptor (EGFR) genes  

Microsoft Academic Search

Leukemia inhibitory factor receptor (LIFR), epidermal growth factor receptor (EGFR), and their respective ligands have been implicated in regulating growth and development of the early pig conceptus. We isolated a PAC clone containing the porcine gene for LIFR and a BAC clone with the porcine EGFR gene, respectively. On each of these clones one microsatellite marker was identified by sequencing

A. Spötter; C. Drögemüller; H. Kuiper; B. Brenig; T. Leeb; O. Distl

2002-01-01

136

Insight into adenosine receptor function using antisense and gene-knockout approaches.  

PubMed

The extensive role of adenosine in discriminating input from the extracellular environment is effected through a series of cell membrane-spanning proteins--the adenosine A1, A2A, A2B and A3 receptors. New genetic and epigenetic tools have emerged that facilitate the elucidation of the function of these receptors with greater specificity than is generally possible with traditional antagonist drugs. These tools include antisense oligonucleotides (epigenetic) and gene 'knockin' and 'knockout' mice (genetic) and are discussed in this article by Jonathan Nyce. PMID:10101969

Nyce, J W

1999-02-01

137

Evolution of olfactory receptor genes in primates dominated by birth-and-death process.  

PubMed

Olfactory receptor (OR) is a large family of G protein-coupled receptors that can detect odorant in order to generate the sense of smell. They constitute one of the largest multiple gene families in animals including primates. To better understand the variation in odor perception and evolution of OR genes among primates, we computationally identified OR gene repertoires in orangutans, marmosets, and mouse lemurs and investigated the birth-and-death process of OR genes in the primate lineage. The results showed that 1) all the primate species studied have no more than 400 intact OR genes, fewer than rodents and canine; 2) Despite the similar number of OR genes in the genome, the makeup of the OR gene repertoires between different primate species is quite different as they had undergone dramatic birth-and-death evolution with extensive gene losses in the lineages leading to current species; 3) Apes and Old World monkey (OWM) have similar fraction of pseudogenes, whereas New World monkey (NWM) have fewer pseudogenes. To measure the selective pressure that had affected the OR gene repertoires in primates, we compared the ratio of nonsynonymous with synonymous substitution rates by using 70 one-to-one orthologous quintets among five primate species. We found that OR genes showed relaxed selective constraints in apes (humans, chimpanzees, and orangutans) than in OWMs (macaques) and NWMs (marmosets). We concluded that OR gene repertoires in primates have evolved in such a way to adapt to their respective living environments. Differential selective constraints might play important role in the primate OR gene evolution in each primate species. PMID:20333195

Dong, Dong; He, Guimei; Zhang, Shuyi; Zhang, Zhaolei

2009-01-01

138

Evolution of Olfactory Receptor Genes in Primates Dominated by Birth-and-Death Process  

PubMed Central

Olfactory receptor (OR) is a large family of G protein–coupled receptors that can detect odorant in order to generate the sense of smell. They constitute one of the largest multiple gene families in animals including primates. To better understand the variation in odor perception and evolution of OR genes among primates, we computationally identified OR gene repertoires in orangutans, marmosets, and mouse lemurs and investigated the birth-and-death process of OR genes in the primate lineage. The results showed that 1) all the primate species studied have no more than 400 intact OR genes, fewer than rodents and canine; 2) Despite the similar number of OR genes in the genome, the makeup of the OR gene repertoires between different primate species is quite different as they had undergone dramatic birth-and-death evolution with extensive gene losses in the lineages leading to current species; 3) Apes and Old World monkey (OWM) have similar fraction of pseudogenes, whereas New World monkey (NWM) have fewer pseudogenes. To measure the selective pressure that had affected the OR gene repertoires in primates, we compared the ratio of nonsynonymous with synonymous substitution rates by using 70 one-to-one orthologous quintets among five primate species. We found that OR genes showed relaxed selective constraints in apes (humans, chimpanzees, and orangutans) than in OWMs (macaques) and NWMs (marmosets). We concluded that OR gene repertoires in primates have evolved in such a way to adapt to their respective living environments. Differential selective constraints might play important role in the primate OR gene evolution in each primate species.

Dong, Dong; He, Guimei; Zhang, Shuyi

2009-01-01

139

Ron receptor-dependent gene regulation of Kupffer cells during endotoxemia  

PubMed Central

Background We have previously shown that Ron receptor tyrosine kinase signaling in macrophages, including Kupffer cells and alveolar macrophages, suppresses endotoxin-induced proinflammatory chemokine/cytokine production. Further, we have also identified genes from Ron replete and Ron deplete livers that were differentially expressed during the progression of liver inflammation associated with acute liver failure in mice by microarray analyses. While important genes and signaling pathways have been identified downstream of Ron signaling during progression of inflammation by this approach, the precise role that Ron receptor plays in regulating the transcriptional landscape in macrophages, and particular in isolated Kupffer cells, has still not been investigated. Methods Kupffer cells were isolated from wild-type (TK+/+) and Ron tyrosine kinase (TK?/?) deficient mice. Ex vivo, the cells were treated with lipopolysaccharide (LPS) in the presence or absence of the Ron ligand, Hepatocyte growth factor-like protein (HGFL). Microarray and qRT-PCR analyses were utilized to identify alterations in gene expression between genotypes. Results Microarray analyses identified genes expressed differentially in TK+/+ and TK?/? Kupffer cells basally as well as after HGFL and LPS treatment. Interestingly, our studies identified Mefv, a gene that codes for the anti-inflammatory protein pyrin, as an HGFL-stimulated Ron-dependent gene. Moreover, Lcn2 (Lipocalin 2), a proinflammatory gene, which is induced by LPS, was significantly suppressed by HGFL treatment. Microarray results were validated by qRT-PCR studies on Kupffer cells treated with LPS and HGFL. Conclusions The studies herein suggest a novel mechanism whereby HGFL-induced Ron receptor activation promotes the expression of anti-inflammatory genes while inhibiting genes involved in inflammation with a net effect of diminished inflammation in macrophages.

Kulkarni, Rishikesh M.; Stuart, William D.; Waltz, Susan E.

2014-01-01

140

Gene expression profiling of skeletal muscles treated with a soluble activin type IIB receptor.  

PubMed

Inhibition of the myostatin signaling pathway is emerging as a promising therapeutic means to treat muscle wasting and degenerative disorders. Activin type IIB receptor (ActRIIB) is the putative myostatin receptor, and a soluble activin receptor (ActRIIB-Fc) has been demonstrated to potently inhibit a subset of transforming growth factor (TGF)-? family members including myostatin. To determine reliable and valid biomarkers for ActRIIB-Fc treatment, we assessed gene expression profiles for quadriceps muscles from mice treated with ActRIIB-Fc compared with mice genetically lacking myostatin and control mice. Expression of 134 genes was significantly altered in mice treated with ActRIIB-Fc over a 2-wk period relative to control mice (fold change > 1.5, P < 0.001), whereas the number of significantly altered genes in mice treated for 2 days was 38, demonstrating a time-dependent response to ActRIIB-Fc in overall muscle gene expression. The number of significantly altered genes in Mstn(-/-) mice relative to control mice was substantially higher (360), but for most of these genes the expression levels in the 2-wk treated mice were closer to the levels in the Mstn(-/-) mice than in control mice (P < 10?³?). Expression levels of 30 selected genes were further validated with quantitative real-time polymerase chain reaction (qPCR), and a correlation of ? 0.89 was observed between the fold changes from the microarray analysis and the qPCR analysis. These data suggest that treatment with ActRIIB-Fc results in overlapping but distinct gene expression signatures compared with myostatin genetic mutation. Differentially expressed genes identified in this study can be used as potential biomarkers for ActRIIB-Fc treatment, which is currently in clinical trials as a therapeutic agent for muscle wasting and degenerative disorders. PMID:21266502

Rahimov, Fedik; King, Oliver D; Warsing, Leigh C; Powell, Rachel E; Emerson, Charles P; Kunkel, Louis M; Wagner, Kathryn R

2011-04-27

141

SUMOylation regulates the chromatin occupancy and anti-proliferative gene programs of glucocorticoid receptor  

PubMed Central

In addition to the glucocorticoids, the glucocorticoid receptor (GR) is regulated by post-translational modifications, including SUMOylation. We have analyzed how SUMOylation influences the activity of endogenous GR target genes and the receptor chromatin binding by using isogenic HEK293 cells expressing wild-type GR (wtGR) or SUMOylation-defective GR (GR3KR). Gene expression profiling revealed that both dexamethasone up- and downregulated genes are affected by the GR SUMOylation and that the affected genes are significantly associated with pathways of cellular proliferation and survival. The GR3KR-expressing cells proliferated more rapidly, and their anti-proliferative response to dexamethasone was less pronounced than in the wtGR-expressing cells. ChIP-seq analyses indicated that the SUMOylation modulates the chromatin occupancy of GR on several loci associated with cellular growth in a fashion that parallels with their differential dexamethasone-regulated expression between the two cell lines. Moreover, chromatin SUMO-2/3 marks, which were associated with active GR-binding sites, showed markedly higher overlap with the wtGR cistrome than with the GR3KR cistrome. In sum, our results indicate that the SUMOylation does not simply repress the GR activity, but regulates the activity of the receptor in a target locus selective fashion, playing an important role in controlling the GR activity on genes influencing cell growth.

Paakinaho, Ville; Kaikkonen, Sanna; Makkonen, Harri; Benes, Vladimir; Palvimo, Jorma J.

2014-01-01

142

The histamine H3 receptor: from gene cloning to H3 receptor drugs.  

PubMed

Since the cloning of the histamine H(3) receptor cDNA in 1999 by Lovenberg and co-workers, this histamine receptor has gained the interest of many pharmaceutical companies as a potential drug target for the treatment of various important disorders, including obesity, attention-deficit hyperactivity disorder, Alzheimer's disease, schizophrenia, as well as for myocardial ischaemia, migraine and inflammatory diseases. Here, we discuss relevant information on this target protein and describe the development of various H(3) receptor agonists and antagonists, and their effects in preclinical animal models. PMID:15665857

Leurs, Rob; Bakker, Remko A; Timmerman, Henk; de Esch, Iwan J P

2005-02-01

143

Mapping of the genes encoding mouse prostaglandin D, E, and F and prostacyclin receptors  

SciTech Connect

Prostaglandins and prostacyclin are metabolites of arachidonic acid and exert a variety of actions to maintain local homeostasis in the body. Their actions are mediated by cell surface receptors specific to the respective ligands. Using a panel of interspecific back-cross mice, we have mapped the prostaglandin D receptor gene (Ptgdr), prostaglandin E receptor subtype EP{sub 1} gene (Ptgerep1), prostaglandin F receptor gene (Ptgfr), and prostacyclin receptor gene (Ptgir). Ptgdr mapped to proximal Chr 14, Ptgfr mapped to distal Chr 3, Ptgerep1 mapped to middle Chr 8, and Ptgir mapped to proximal Chr 7. 50 refs., 1 fig., 1 tab.

Ishikawa, Tomo-o; Tamai, Yoshitaka; Taketo, Makoto M. [Banyu Tsukuba Research Inst. (Merck), Tsukuba (Japan)] [and others] [Banyu Tsukuba Research Inst. (Merck), Tsukuba (Japan); and others

1996-03-01

144

Haploinsufficiency of STK11 and neighboring genes cause a contiguous gene syndrome including Peutz-Jeghers phenotype.  

PubMed

We report on clinical and molecular findings of a 15-year-old female referred to our genetics clinic for a diagnostic evaluation due to mild developmental delay, submucosal cleft palate, and seizure disorder. Chromosomal microarray technology revealed a cancer predisposition due to a terminal deletion on chromosome 19p that includes the tumor suppressor gene STK11. In addition to abnormal lip pigmentation on exam, further diagnostic workup with upper and lower gastrointestinal screening confirmed polyps consistent with Peutz-Jeghers syndrome. The purpose of this study is to present a full clinical description of a patient with a rare 19p13.3 chromosomal deletion and review the current literature of this newly emerging contiguous gene deletion syndrome. It also supports the screening for complications of Peutz-Jeghers syndrome in all patients with this deletion. PMID:22987620

Scollon, Sarah; McWalter, Kirsty; Abe, Keith; King, Jeremy; Kimata, Kevin; Slavin, Thomas P

2012-11-01

145

Aberrant firing of replication origins potentially explains intragenic nonrecurrent rearrangements within genes, including the human DMD gene  

PubMed Central

Non-allelic homologous recombination (NAHR), non-homologous end joining (NHEJ), and microhomology-mediated replication-dependent recombination (MMRDR) have all been put forward as mechanisms to explain DNA rearrangements associated with genomic disorders. However, many nonrecurrent rearrangements in humans remain unexplained. To further investigate the mutation mechanisms of these copy number variations (CNVs), we performed breakpoint mapping analysis for 62 clinical cases with intragenic deletions in the human DMD gene (50 cases) and other known disease-causing genes (one PCCB, one IVD, one DBT, three PAH, one STK11, one HEXB, three DBT, one HRPT1, and one EMD cases). While repetitive elements were found in only four individual cases, three involving DMD and one HEXB gene, microhomologies (2–10 bp) were observed at breakpoint junctions in 56% and insertions ranging from 1 to 48 bp were seen in 16 of the total 62 cases. Among these insertions, we observed evidence for tandem repetitions of short segments (5–20 bp) of reference sequence proximal to the breakpoints in six individual DMD cases (six repeats in one, four repeats in three, two repeats in one, and one repeat in one case), strongly indicating attempts by the replication machinery to surpass the stalled replication fork. We provide evidence of a novel template slippage event during replication rescue. With a deeper insight into the complex process of replication and its rescue during origin failure, brought forward by recent studies, we propose a hypothesis based on aberrant firing of replication origins to explain intragenic nonrecurrent rearrangements within genes, including the DMD gene.

Ankala, Arunkanth; Kohn, Jordan N.; Hegde, Anisha; Meka, Arjun; Ephrem, Chin Lip Hon; Askree, Syed H.; Bhide, Shruti; Hegde, Madhuri R.

2012-01-01

146

The CAG Repeat within the Androgen Receptor Gene and its Relationship to Prostate Cancer  

Microsoft Academic Search

The length of a polymorphic CAG repeat sequence, occurring in the androgen receptor gene, is inversely correlated with transcriptional activity by the androgen receptor. Because heightened androgenic stimulation may increase risk of prostate cancer development and progression, we examined whether shorter CAG repeats in the androgen receptor gene are related to higher risk of prostate cancer. We conducted a nested

Edward Giovannucci; Meir J. Stampfer; Krishna Krithivas; Myles Brown; Adam Brufsky; James Talcott; Charles H. Hennekens; Philip W. Kantoff

1997-01-01

147

Feedback-Inducible Nuclear-Receptor-Driven Reporter Gene Expression in Transgenic Mice  

Microsoft Academic Search

Understanding nuclear receptor signaling in vivo would be facilitated by an efficient methodology to determine where a nuclear receptor is active. Herein, we present a feedback-inducible expression system in transgenic mice to detect activated nuclear receptor effector proteins by using an inducible reporter gene. With this approach, reporter gene induction is not limited to a particular tissue, and, thus, this

Alexander Mata de Urquiza; Ludmila Solomin; Thomas Perlmann

1999-01-01

148

Different pattern of gene mutations in Iranian patients with severe congenital neutropenia (including 2 new mutations).  

PubMed

Severe congenital neutropenia (SCN) is a rare primary immunodeficiency disease. Different genes are found to be associated with SCN, including ELA2, HAX1, WAS, GFI1, G-CSFR and G6PC3. The aim of this study was to find different gene mutations responsible for SCN in Iranian patients. Twenty-seven patients with SCN referred to Immunology, Asthma and Allergy Research Institute during a five year priod 5 years (May 2007 and May 2012), were included in this study. Neutropenia related exons and flanking regions of ELA2, HAX1, WAS, GFI1, G-CSFR and G6PC3 were amplified by PCR and the sequences were analyzed. The results showed different mutations including 4 ELANE mutations, 11 HAX1 mutations and 2 G6PC3 mutations. None of the patients had GFI1 mutation and also one mutation was found in G-CSFR in a patient with ELANE mutation. Ten patients had unknown genetic diagnosis which was compatible with other studies. According to these results, most of the patients showed HAX1 mutations and this finding which significantly differed from other reports, might be related to differences in Iranian ethnicity and also in high rate of consanguineous marriages in Iran. PMID:23454784

Alizadeh, Zahra; Fazlollahi, Mohammad Reza; Houshmand, Massoud; Maddah, Marzieh; Chavoshzadeh, Zahra; Hamidieh, Amir Ali; Shamsian, Bibi Shahin; Eshghi, Payman; Bolandghamat Pour, Samaneh; Sadaaie Jahromi, Hoda; Mansouri, Mahboobeh; Movahedi, Masoud; Nayebpour, Mohsen; Pourpak, Zahra; Moin, Mostafa

2013-03-01

149

Plant Receptor-Like Kinase Gene Family: Diversity, Function, and Signaling  

NSDL National Science Digital Library

A basic feature of all biological systems is the ability to sense and process information from chemical signals via cell-surface receptors. One prevalent class of receptors in both plants and animals is the receptor protein kinases. These proteins contain a signal-binding region located outside the cell linked to a region inside the cell called the protein kinase domain. The protein kinase domain transmits information to other cellular components by catalyzing the transfer of a phosphate group from adenosine triphosphate (ATP) to an amino acid residue on the target proteins. In animals and humans, the well-studied family of receptor tyrosine kinases (RTKs) mediates a wide range of signaling events at the cell surface. The importance of receptor protein kinases in plant biology was revealed by the discovery of a family of more than 400 genes coding for receptor-like kinases (RLKs) present in the recently sequenced genome of the model plant Arabidopsis. Unlike most animal RTKs, the plant RLKs use serine and threonine residues in proteins as targets for phosphorylation. Detailed studies of a handful of plant RLK genes have implicated them in the control of plant growth and development and in responses to pathogens. Multiple signals can be sensed by different RLKs, including peptides produced by neighboring cells, steroid hormones, and pathogen cell-wall proteins and carbohydrates. Major challenges for the future will include understanding the wide range of specific signaling functions performed by this large family of receptors and discovering how the information from this multitude of signal initiation points is integrated by the plant's cells.

Shin-Han Shiu (University of Wisconsin-Madison;The Department of Botany REV); Anthony B. Bleecker (University of Wisconsin-Madison;The Department of Botany REV)

2001-12-18

150

Alterations of the DR5\\/TRAIL Receptor 2 Gene in Non-Small Cell Lung Cancers1  

Microsoft Academic Search

Chromosome 8p21-22 is a frequent site of allelic deletions in many types of human tumors, including non-small cell lung cancer (NSCLC). Tumor necrosis factor-related apoptosis-inducing ligand-receptor 2 (TRAIL-R2) is a cell-surface receptor involved in cell death signaling. The TRAIL-R2 gene recently has been mapped to chromosome 8p21-22. To explore the possibility that the TRAIL-R2 gene might be the relevant gene

Sug Hyung Lee; Min Sun Shin; Hong Sug Kim; Hun Kyung Lee; Won Sang Park; Su Young Kim; Jong Heun Lee; Seo Young Han; Jik Young Park; Ro Ra Oh; June Jang; Ji Youn Han; Nam Jin Yoo

1999-01-01

151

Association between equine temperament and polymorphisms in dopamine D4 receptor gene  

Microsoft Academic Search

The variable number of tandem repeats (VNTR) polymorphism of the dopamine D4 receptor (DRD4) gene has been reported to be associated with the personality trait of novelty-seeking in humans. In the genus Equus, this region includes an 18-bp repeat unit and there are inter- and intraspecies differences in the number of repetitions. Because horses are unique among livestock species in

Yukihide Momozawa; Yukari Takeuchi; Ryo Kusunose; Takefumi Kikusui; Yuji Mori

2005-01-01

152

A functional polymorphism of the µ-opioid receptor gene is associated with completed suicides  

Microsoft Academic Search

Summary.  A recent linkage study suggested that a putative locus for suicidal behavior independent of psychiatric disease phenotypes\\u000a lies at 5? upstream of the µ-opioid receptor (OPRM1) gene. We explored an association between suicide and genetic variations of the OPRM1 using a case-control study of 183 completed suicides and 374 control subjects. We genotyped four single nucleotide polymorphisms\\u000a (SNPs) including a

A. Hishimoto; H. Cui; K. Mouri; H. Nushida; Y. Ueno; K. Maeda; O. Shirakawa

2008-01-01

153

Characterization of the human growth hormone receptor gene and demonstration of a partial gene deletion in two patients with Laron-type dwarfism.  

PubMed Central

Laron-type dwarfism is an autosomal recessive genetic disorder that is characterized by high levels of growth hormone and low levels of insulin-like growth factor I in the circulation. Several lines of evidence suggest that this disease is caused by a defect in the growth hormone receptor. In order to analyze the receptor gene in patients with Laron-type dwarfism and with other growth disorders, we have first determined the gene structure in normal individuals. There are nine exons that encode the receptor and several additional exons in the 5' untranslated region. The coding exons span at least 87 kilobase pairs of chromosome 5. Characterization of the growth hormone receptor gene from nine patients with Laron-type dwarfism shows that two individuals have a deletion of a large portion of the extracellular, hormone binding domain of the receptor gene. Interestingly, this deletion includes nonconsecutive exons, suggesting that an unusual rearrangement may have occurred. Thus, we provide direct evidence that Laron-type dwarfism can result from a defect in the structural gene for the growth hormone receptor. Images

Godowski, P J; Leung, D W; Meacham, L R; Galgani, J P; Hellmiss, R; Keret, R; Rotwein, P S; Parks, J S; Laron, Z; Wood, W I

1989-01-01

154

Evidence of selection at insulin receptor substrate-1 gene loci.  

PubMed

Type 2 diabetes mellitus (T2DM) is a complex disease characterized by insulin resistance and defect of insulin secretion. The worldwide prevalence of T2DM is steadily increasing. T2DM is also significantly associated with obesity, coronary artery disease (CAD), and metabolic syndrome. There is a clear difference in the prevalence of T2DM among populations, and T2DM is highly heritable. Human adaptations to environmental changes in food supply, lifestyle, and geography may have pressured the selection of genes associated with the metabolism of glucose, lipids, carbohydrates, and energy. The insulin receptor substrate-1 (IRS1) gene is considered a major T2DM gene, and common genetic variations near the IRS1 gene were found to be associated with T2DM, insulin resistance, adiposity, and CAD. Here, we aimed to find evidence of selection at the IRS1 gene loci using the HapMap population data. We investigated a 3-step test procedure-Wright's F statistics (Fst), the long-range haplotype (LRH) test, and the integrated haplotype score (iHS) test-to detect selection at the IRS1 gene loci using the HapMap population data. We observed that 1 CAD-associated SNP (rs2943634) and 1 adiposity- and insulin resistance-associated SNP (rs2943650) exhibited high Fst values. We also found selection at the IRS1 gene loci by the LRH test and the iHS test. These findings suggest evidence of selection at the IRS1 gene loci and that further studies should examine the adaptive evolution of T2DM genes. PMID:22797928

Yoshiuchi, Issei

2013-10-01

155

Molecular diagnostics for congenital hearing loss including 15 deafness genes using a next generation sequencing platform  

PubMed Central

Background Hereditary hearing loss (HL) can originate from mutations in one of many genes involved in the complex process of hearing. Identification of the genetic defects in patients is currently labor intensive and expensive. While screening with Sanger sequencing for GJB2 mutations is common, this is not the case for the other known deafness genes (> 60). Next generation sequencing technology (NGS) has the potential to be much more cost efficient. Published methods mainly use hybridization based target enrichment procedures that are time saving and efficient, but lead to loss in sensitivity. In this study we used a semi-automated PCR amplification and NGS in order to combine high sensitivity, speed and cost efficiency. Results In this proof of concept study, we screened 15 autosomal recessive deafness genes in 5 patients with congenital genetic deafness. 646 specific primer pairs for all exons and most of the UTR of the 15 selected genes were designed using primerXL. Using patient specific identifiers, all amplicons were pooled and analyzed using the Roche 454 NGS technology. Three of these patients are members of families in which a region of interest has previously been characterized by linkage studies. In these, we were able to identify two new mutations in CDH23 and OTOF. For another patient, the etiology of deafness was unclear, and no causal mutation was found. In a fifth patient, included as a positive control, we could confirm a known mutation in TMC1. Conclusions We have developed an assay that holds great promise as a tool for screening patients with familial autosomal recessive nonsyndromal hearing loss (ARNSHL). For the first time, an efficient, reliable and cost effective genetic test, based on PCR enrichment, for newborns with undiagnosed deafness is available.

2012-01-01

156

Perilipin, a critical regulator of fat storage and breakdown, is a target gene of estrogen receptor-related receptor {alpha}  

SciTech Connect

Perilipin is a protein localized on lipid droplet surfaces in adipocytes and steroidogenic cells, playing a central role in regulated lipolysis. Expression of the perilipin gene is markedly induced during adipogenesis. We found that transcription from the perilipin gene promoter is activated by an orphan nuclear receptor, estrogen receptor-related receptor (ERR){alpha}. A response element to this receptor was identified in the promoter region by a gene reporter assay, the electrophoretic-gel mobility-shift assay and the chromatin immunoprecipitation assay. Peroxisome proliferator-activated receptor {gamma} coactivator (PGC)-1{alpha} enhanced, whereas small heterodimer partner (SHP) repressed, the transactivating function of ERR{alpha} on the promoter. Thus, the perilipin gene expression is regulated by a transcriptional network controlling energy metabolism, substantiating the functional importance of perilipin in the maintenance of body energy balance.

Akter, Mst. Hasina; Yamaguchi, Tomohiro; Hirose, Fumiko [Graduate School of Life Science, Himeji Institute of Technology, University of Hyogo, 3-2-1 Koto, Kamigori, Hyogo 678-1297 (Japan); Osumi, Takashi [Graduate School of Life Science, Himeji Institute of Technology, University of Hyogo, 3-2-1 Koto, Kamigori, Hyogo 678-1297 (Japan)], E-mail: osumi@sci.u-hyogo.ac.jp

2008-04-11

157

Evolution of the chicken Toll-like receptor gene family: A story of gene gain and gene loss  

PubMed Central

Background Toll-like receptors (TLRs) perform a vital role in disease resistance through their recognition of pathogen associated molecular patterns (PAMPs). Recent advances in genomics allow comparison of TLR genes within and between many species. This study takes advantage of the recently sequenced chicken genome to determine the complete chicken TLR repertoire and place it in context of vertebrate genomic evolution. Results The chicken TLR repertoire consists of ten genes. Phylogenetic analyses show that six of these genes have orthologs in mammals and fish, while one is only shared by fish and three appear to be unique to birds. Furthermore the phylogeny shows that TLR1-like genes arose independently in fish, birds and mammals from an ancestral gene also shared by TLR6 and TLR10. All other TLRs were already present prior to the divergence of major vertebrate lineages 550 Mya (million years ago) and have since been lost in certain lineages. Phylogenetic analysis shows the absence of TLRs 8 and 9 in chicken to be the result of gene loss. The notable exception to the tendency of gene loss in TLR evolution is found in chicken TLRs 1 and 2, each of which underwent gene duplication about 147 and 65 Mya, respectively. Conclusion Comparative phylogenetic analysis of vertebrate TLR genes provides insight into their patterns and processes of gene evolution, with examples of both gene gain and gene loss. In addition, these comparisons clarify the nomenclature of TLR genes in vertebrates.

Temperley, Nicholas D; Berlin, Sofia; Paton, Ian R; Griffin, Darren K; Burt, David W

2008-01-01

158

Intrahepatic expression of genes related to metabotropic receptors in chronic hepatitis  

PubMed Central

AIM: To screen for genes related to metabotropic receptors that might be involved in the development of chronic hepatitis. METHODS: Assessment of 20 genes associated with metabotropic receptors was performed in liver specimens obtained by punch biopsy from 12 patients with autoimmune and chronic hepatitis type B and C. For this purpose, a microarray with low integrity grade and with oligonucleotide DNA probes complementary to target transcripts was used. Evaluation of gene expression was performed in relation to transcript level, correlation between samples and grouping of clinical parameters used in chronic hepatitis assessment. Clinical markers of chronic hepatitis included alanine and aspartate aminotransferase, ?-glutamyltranspeptidase, alkaline phosphatase and cholinesterase activity, levels of iron ions, total cholesterol, triglycerides, albumin, glucose, hemoglobin, platelets, histological analysis of inflammatory and necrotic status, fibrosis according to METAVIR score, steatosis, as well as anthropometric body mass index, waist/hip index, percentage of adipose tissue and liver size in ultrasound examination. Gender, age, concomitant diseases and drugs were also taken into account. Validation of oligonucleotide microarray gene expression results was done with the use of quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: The highest (0.002 < P < 0.046) expression among genes encoding main components of metabotropic receptor pathways, such as the ? subunit of G-coupled protein, phosphoinositol-dependent protein kinase or arrestin was comparable to that of angiotensinogen synthesized in the liver. Carcinogenesis suppressor genes, such as chemokine ligand 4, transcription factor early growth response protein 1 and lysophosphatidic acid receptor, were characterized by the lowest expression (0.002 < P < 0.046), while the factor potentially triggering hepatic cancer, transcription factor JUN-B, had a 20-fold higher expression. The correlation between expression of genes of protein kinases PDPK1, phosphoinositide 3-kinase and protein kinase A (Spearman’s coefficient range: 0.762-0.769) confirmed a functional link between these enzymes. Gender (P = 0.0046) and inflammation severity, measured by alanine aminotransferase activity (P = 0.035), were characterized by diverse metabotropic receptor gene expression patterns. The Pearson’s coefficient ranging from -0.35 to 0.99 from the results of qRT-PCR and microarray indicated that qRT-PCR had certain limitations as a validation tool for oligonucleotide microarray studies. CONCLUSION: A microarray-based analysis of hepatocyte metabotropic G-protein-related gene expression can reveal the molecular basis of chronic hepatitis.

Ciesla, Andrzej; Kusmider, Maciej; Faron-Gorecka, Agata; Dziedzicka-Wasylewska, Marta; Bociaga-Jasik, Monika; Owczarek, Danuta; Ciecko-Michalska, Irena; Cibor, Dorota; Mach, Tomasz

2012-01-01

159

Mapping of the mouse macrophage inflammatory protein-1{alpha} receptor gene Scya3r and two related mouse {beta} chemokine receptor-like genes to chromosome 9  

SciTech Connect

Macrophage inflammatory protein-1{alpha} (MIP-1{alpha}) and RANTES are members of the {beta} chemokine family of leukocyte chemoattractants. We have previously cloned three mouse genes by cross-hybridization with the human MIP-1{alpha}/RANTES receptor gene CMKBR1. One of the mouse genes, Scya3r, encodes a functional MIP-1{alpha} receptor. The functions of the other two, Scya3r-rs1 and Scya3r-rs2, are not known. We have now mapped Scya3r, Scya3r-rs1, and Scya3r-rs2 to chromosome 9, in a region of conserved synteny with the location of CMKBR1. Thus, like chemokine genes and {alpha} chemokine receptor genes, this group of {Beta} chemokine receptor genes arose by tandem duplication. 17 refs., 2 figs.

Kozak, C.A.; Gao, Ji-Liang; Murphy, P.M. [National Institutes of Health, Bethesda, MD (United States)] [National Institutes of Health, Bethesda, MD (United States)

1995-09-01

160

Molecular cloning and characterization of a Toll receptor gene from Macrobrachium rosenbergii.  

PubMed

Toll receptors are cell surface molecules acting as pattern recognition receptors (PRRs) that have been implicated in the signaling pathway of innate immune responses. In this study, the full-length cDNA of a Toll receptor gene of Macrobrachium rosenbergii, designated MrToll, was successfully isolated using designed degenerate primers and the rapid amplification of cDNA ends (RACE). The MrToll gene sequence contained an open reading frame (ORF) of 2799 nucleotides encoding a protein of 932 amino acid residues. The protein contained distinct structural motifs of the Toll-like receptor (TLR) family, including an extracellular domain containing 15 leucine-rich repeats (LRRs), a transmembrane segment of 23 amino acids, and a cytoplasmic Toll/interleukin-1R (TIR) domain of 139 residues. Phylogenetic analysis revealed that MrToll and Toll receptor of Marsupenaeus japonicus (MjToll) evolved closely. However, the MrToll ORF demonstrated only 48-49% identity with shrimp Toll1, suggesting that MrToll isolated from a palaemonid shrimp might belong to a novel class of Toll receptors in shrimp. The transcripts of the MrToll gene were constitutively expressed in various tissues, with high levels in hemocytes, the stomach and muscle. A reverse transcriptase PCR assay demonstrated that the expression patterns of MrToll were distinctly modulated after Aeromonas caviae stimulation, with significant enhancement at 3-12 h post-challenge and a decline to basal levels at 24 h post-challenge. In addition, when MrToll-silenced shrimp were challenged with A. caviae, there was a significant increase in mortality and bacterial CFU counts. These results suggest that MrToll might be involved in host innate defense, especially against the pathogen A. caviae. PMID:24398262

Srisuk, Chutima; Longyant, Siwaporn; Senapin, Saengchan; Sithigorngul, Paisarn; Chaivisuthangkura, Parin

2014-02-01

161

Genomic organization, annotation, and ligand-receptor inferences of chicken chemokines and chemokine receptor genes based on comparative genomics  

PubMed Central

Background Chemokines and their receptors play important roles in host defense, organogenesis, hematopoiesis, and neuronal communication. Forty-two chemokines and 19 cognate receptors have been found in the human genome. Prior to this report, only 11 chicken chemokines and 7 receptors had been reported. The objectives of this study were to systematically identify chicken chemokines and their cognate receptor genes in the chicken genome and to annotate these genes and ligand-receptor binding by a comparative genomics approach. Results Twenty-three chemokine and 14 chemokine receptor genes were identified in the chicken genome. All of the chicken chemokines contained a conserved CC, CXC, CX3C, or XC motif, whereas all the chemokine receptors had seven conserved transmembrane helices, four extracellular domains with a conserved cysteine, and a conserved DRYLAIV sequence in the second intracellular domain. The number of coding exons in these genes and the syntenies are highly conserved between human, mouse, and chicken although the amino acid sequence homologies are generally low between mammalian and chicken chemokines. Chicken genes were named with the systematic nomenclature used in humans and mice based on phylogeny, synteny, and sequence homology. Conclusion The independent nomenclature of chicken chemokines and chemokine receptors suggests that the chicken may have ligand-receptor pairings similar to mammals. All identified chicken chemokines and their cognate receptors were identified in the chicken genome except CCR9, whose ligand was not identified in this study. The organization of these genes suggests that there were a substantial number of these genes present before divergence between aves and mammals and more gene duplications of CC, CXC, CCR, and CXCR subfamilies in mammals than in aves after the divergence.

Wang, Jixin; Adelson, David L; Yilmaz, Ahmet; Sze, Sing-Hoi; Jin, Yuan; Zhu, James J

2005-01-01

162

Tazarotene-Induced Gene 1 (TIG1), a Novel Retinoic Acid Receptor-Responsive Gene in Skin  

Microsoft Academic Search

Retinoids exert their effect through ligand-dependent transcription factors, retinoic acid receptors (RAR&?, ?, and ?) and retinoid X receptor (RXR?, ?, and ?), which belong to the superfamily of steroid\\/ thyroid\\/vitamin D3 nuclear receptors. Using a subtraction hybridization approach, we have identified a cDNA sequence, Tazarotene Induced Gene 1 (TIG1), which is highly upregulated in skin raft cultures by an

Sunil Nagpal; Sheetal Patel; Arisa T. Asano; Alan T. Johnson; Madeleine Duvic; Roshantha A. S. Chandraratna

1996-01-01

163

The mouse (Mus musculus) T cell receptor alpha (TRA) and delta (TRD) variable genes.  

PubMed

'The Mouse (Mus musculus) T cell receptor alpha (TRA) and delta (TRD) variable genes' 'IMGT Locus in Focus' report provides the first complete list of the mouse TRAV and TRDV genes which span 1550 kb on chromosome 14 at 19.7 cM. The total number of TRAV genes per haploid genome is 98 belonging to 23 subgroups. This includes 10 TRAV/DV genes which belong to seven subgroups. The functional TRAV genomic repertoire comprises 72-82 TRAV (including 9-10 TRAV/DV) belonging to 19 subgroups. The total number of TRDV genes per haploid genome is 16 (including the 10 TRAV/DV) belonging to 12 subgroups. The functional TRDV genomic repertoire comprises 14-15 genes (5 TRDV and 9-10 TRAV/DV) belonging to 11-12 subgroups. The eight tables and three figures of this report are available at the IMGT Marie-Paule page of IMGT. The international ImMunoGeneTics information system (http://imgt.cines.fr) created by Marie-Paule Lefranc, Université Montpellier II, CNRS, France. PMID:12697305

Bosc, Nathalie; Lefranc, Marie-Paule

2003-01-01

164

Polymorphism and genetic mapping of the human oxytocin receptor gene on chromosome 3  

SciTech Connect

Centrally administered oxytocin has been reported to facilitate affiliative and social behaviors, in functional harmony with its well-known peripheral effects on uterine contraction and milk ejection. The biological effects of oxytocin could be perturbed by mutations occurring in the sequence of the oxytocin receptor gene, and it would be of interest to establish the position of this gene on the human linkage map. Therefore we identified a polymorphism at the human oxytocin receptor gene. A portion of the 3{prime} untranslated region containing a 30 bp CA repeat was amplified by polymerase chain reaction (PCR), revealing a polymorphism with two alleles occurring with frequencies of 0.77 and 0.23 in a sample of Caucasian CEPH parents (n = 70). The CA repeat polymorphism we detected was used to map the human oxytocin receptor to chromosome 3p25-3p26, in a region which contains several important genes, including loci for Von Hippel-Lindau disease (VHL) and renal cell carcinoma. 53 refs., 2 figs., 1 tab.

Michelini, S.; Urbanek, M.; Goldman, D. [National Institute of Health-National Institute of Alcohol Abuse and Alcoholism, Rockville, MD (United States)] [and others

1995-06-19

165

Analysis of the murine Dtk gene identifies conservation of genomic structure within a new receptor tyrosine kinase subfamily  

SciTech Connect

The receptor tyrosine kinase Dtk/Tyro 3/Sky/rse/brt/tif is a member of a new subfamily of receptors that also includes Axl/Ufo/Ark and Eyk/Mer. These receptors are characterized by the presence of two immunoglobulin-like loops and two fibronectin type III repeats in their extracellular domains. The structure of the murine Dtk gene has been determined. The gene consists of 21 exons that are distributed over 21 kb of genomic DNA. An isoform of Dtk is generated by differential splicing of exons from the 5{prime} region of the gene. The overall genomic structure of Dtk is virtually identical to that determined for the human UFO gene. This particular genomic organization is likely to have been duplicated and closely maintained throughout evolution. 38 refs., 3 figs., 1 tab.

Lewis, P.M.; Crosier, K.E.; Crosier, P.S. [Univ. of Auckland (New Zealand)] [and others] [Univ. of Auckland (New Zealand); and others

1996-01-01

166

Metformin suppresses pregnane X receptor (PXR)-regulated transactivation of CYP3A4 gene.  

PubMed

Metformin is widely used in the treatment of type-2 diabetes. The pleotropic effects of metformin on glucose and lipid metabolism have been proposed to be mediated by the activation of AMP-activated protein kinase (AMPK) and the subsequent up-regulation of small heterodimer partner (SHP). SHP suppresses the functions of several nuclear receptors involved in the regulation of hepatic metabolism, including pregnane X receptor (PXR), which is referred to as a "master regulator" of drug/xenobiotic metabolism. In this study, we hypothesize that metformin suppresses the expression of CYP3A4, a main detoxification enzyme and a target gene of PXR, due to SHP up-regulation. We employed various gene reporter assays in cell lines and qRT-PCR in human hepatocytes and in Pxr(-/-) mice. We show that metformin dramatically suppresses PXR-mediated expression of CYP3A4 in hepatocytes. Consistently, metformin significantly suppressed the up-regulation of Cyp3a11 mRNA in the liver and intestine of wild-type mice, but not in Pxr(-/-) mice. A mechanistic investigation of the phenomenon showed that metformin does not significantly up-regulate SHP in human hepatocytes. We further demonstrate that AMPK activation is not involved in this process. We show that metformin disrupts PXR's interaction with steroid receptor coactivator-1 (SRC1) in a two-hybrid assay independently of the PXR ligand binding pocket. Metformin also inhibited vitamin D receptor-, glucocorticoid receptor- and constitutive androstane receptor (CAR)-mediated induction of CYP3A4 mRNA in human hepatocytes. We show, therefore, a suppressive effect of metformin on PXR and other ligand-activated nuclear receptors in transactivation of the main detoxification enzyme CYP3A4 in human hepatocytes. PMID:21920351

Krausova, Lucie; Stejskalova, Lucie; Wang, Hongwei; Vrzal, Radim; Dvorak, Zdenek; Mani, Sridhar; Pavek, Petr

2011-12-01

167

Gene expression of muscarinic, tachykinin, and purinergic receptors in porcine bladder: comparison with cultured cells  

PubMed Central

Urothelial cells, myofibroblasts, and smooth muscle cells are important cell types contributing to bladder function. Multiple receptors including muscarinic (M3/M5), tachykinin (NK1/NK2), and purinergic (P2X1/P2Y6) receptors are involved in bladder motor and sensory actions. Using female pig bladder, our aim was to differentiate between various cell types in bladder by genetic markers. We compared the molecular expression pattern between the fresh tissue layers and their cultured cell counterparts. We also examined responses to agonists for these receptors in cultured cells. Urothelial, suburothelial (myofibroblasts), and smooth muscle cells isolated from pig bladder were cultured (10–14 days) and identified by marker antibodies. Gene (mRNA) expression level was demonstrated by real-time PCR. The receptor expression pattern was very similar between suburothelium and detrusor, and higher than urothelium. The gene expression of all receptors decreased in culture compared with the fresh tissue, although the reduction in cultured urothelial cells appeared less significant compared to suburothelial and detrusor cells. Cultured myofibroblasts and detrusor cells did not contract in response to the agonists acetylcholine, neurokinin A, and ?,?-MeATP, up to concentrations of 0.1 and 1 mM. The significant reduction of M3, NK2, and P2X1 receptors under culture conditions may be associated with the unresponsiveness of cultured suburothelial and detrusor cells to their respective agonists. These results suggest that under culture conditions, bladder cells lose the receptors that are involved in contraction, as this function is no longer required. The study provides further evidence that cultured cells do not necessarily mimic the actions exerted by intact tissues.

Bahadory, Forough; Moore, Kate H.; Liu, Lu; Burcher, Elizabeth

2013-01-01

168

Gene expression of muscarinic, tachykinin, and purinergic receptors in porcine bladder: comparison with cultured cells.  

PubMed

Urothelial cells, myofibroblasts, and smooth muscle cells are important cell types contributing to bladder function. Multiple receptors including muscarinic (M3/M5), tachykinin (NK1/NK2), and purinergic (P2X1/P2Y6) receptors are involved in bladder motor and sensory actions. Using female pig bladder, our aim was to differentiate between various cell types in bladder by genetic markers. We compared the molecular expression pattern between the fresh tissue layers and their cultured cell counterparts. We also examined responses to agonists for these receptors in cultured cells. Urothelial, suburothelial (myofibroblasts), and smooth muscle cells isolated from pig bladder were cultured (10-14 days) and identified by marker antibodies. Gene (mRNA) expression level was demonstrated by real-time PCR. The receptor expression pattern was very similar between suburothelium and detrusor, and higher than urothelium. The gene expression of all receptors decreased in culture compared with the fresh tissue, although the reduction in cultured urothelial cells appeared less significant compared to suburothelial and detrusor cells. Cultured myofibroblasts and detrusor cells did not contract in response to the agonists acetylcholine, neurokinin A, and ?,?-MeATP, up to concentrations of 0.1 and 1 mM. The significant reduction of M3, NK2, and P2X1 receptors under culture conditions may be associated with the unresponsiveness of cultured suburothelial and detrusor cells to their respective agonists. These results suggest that under culture conditions, bladder cells lose the receptors that are involved in contraction, as this function is no longer required. The study provides further evidence that cultured cells do not necessarily mimic the actions exerted by intact tissues. PMID:24348420

Bahadory, Forough; Moore, Kate H; Liu, Lu; Burcher, Elizabeth

2013-01-01

169

Construction of chimeric antibodies: cloning of immunoglobulin genes including their promoter regions by PCR.  

PubMed

In the production of recombinant antibodies, it is necessary to have an immunoglobulin gene promoter for driving the expression of the antibody genes. Here we describe a simple PCR method that allows cloning of the immunoglobulin genes together with their own promoters despite the fact that the sequence of the upstream part of the gene is unknown. PMID:1571141

Mocikat, R; Kütemeier, G; Harloff, C

1992-03-01

170

Rebalancing immune specificity and function in cancer by T-cell receptor gene therapy  

PubMed Central

Adoptive immunotherapy with tumor-specific T lymphocytes has demonstrated clinical benefit in some cancers, particularly melanoma. Yet isolating and expanding tumor-specific cells from patients is challenging, and there is limited ability to control T cell affinity and response characteristics. T cell receptor (TCR) gene therapy, in which T lymphocytes for immunotherapy are redirected using introduced rearranged TCR, has emerged as an important alternative. Successful TCR gene therapy requires consideration of a number of issues, including TCR specificity and affinity, optimal gene therapy constructs, types of T cells administered, and the survival and activity of the modified cells. In this review, we highlight the rationale for and experience with, as well as new approaches to enhance TCR gene therapy.

Udyavar, Akshata; Geiger, Terrence L.

2010-01-01

171

Regulation of cyp3a gene transcription by the pregnane x receptor.  

PubMed

The pregnane X receptor (PXR) is a promiscuous nuclear receptor that has evolved to protect the body from toxic chemicals. PXR is activated by a structurally diverse collection of xenobiotics, including several widely used prescription drugs. Various lipophilic compounds produced by the body, such as bile acids and steroids, also activate PXR. PXR stimulates the transcription of cytochrome P450 3A monooxygenases and other genes involved in the detoxification and elimination of these potentially harmful chemicals. Assays that detect PXR activation have important implications for the design of future drugs in two respects. On the one hand, PXR activation assays can be used to determine whether candidate drugs are likely to induce CYP3A gene expression and interact with other medicines. On the other hand, PXR agonists may prove useful in the treatment of diseases in which toxic metabolites accumulate, such as cholestatic liver disease. PMID:11807162

Goodwin, Bryan; Redinbo, Matthew R; Kliewer, Steven A

2002-01-01

172

Enhancement of gene transactivation activity of androgen receptor by hepatitis B virus X protein  

SciTech Connect

Hepatitis B virus (HBV) X protein (HBx) is a regulatory protein that is required for efficient replication of HBV in its natural host. In this report, we demonstrate by co-immunoprecipitation experiments that HBx can physically bind to the androgen receptor (AR), which is a nuclear hormone receptor that is expressed in many different tissues including the liver. This observation is further supported by confocal microscopy, which reveals that HBx can alter the subcellular localization of the AR both in the presence and in the absence of dihydrotestosterone (DHT). Further studies indicate that HBx can enhance the gene transactivation activity of AR by enhancing its DNA binding activity in a DHT-dependent manner. However, HBx does not remain associated with AR on the DNA. As AR can regulate the expression of a number of cellular genes, our results raise the possibility that HBV pathogenesis may be mediated in part via the interaction between HBx and AR.

Zheng Yanyan [Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, HMR-401, Los Angeles, CA 90033 (United States); Chen Wenling [Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, HMR-401, Los Angeles, CA 90033 (United States); Ma, W.-L. Maverick [George Whipple Lab for Cancer Research, Department of Pathology, Urology, Radiation Oncology and the Cancer Center, University of Rochester Medical Center, Rochester, NY (United States); Chang Chawnshang [George Whipple Lab for Cancer Research, Department of Pathology, Urology, Radiation Oncology and the Cancer Center, University of Rochester Medical Center, Rochester, NY (United States); Ou, J.-H. James [Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, HMR-401, Los Angeles, CA 90033 (United States)]. E-mail: jamesou@hsc.usc.edu

2007-07-05

173

Influence of exonic polymorphisms in the gene for LDL receptor- related protein (LRP) on risk of coronary artery disease  

Microsoft Academic Search

The low density lipoprotein (LDL) receptor-related protein (LRP) is a multifunctional receptor involved in numerous biological processes relevant to vascular biology including lipoprotein metabolism. Several polymorphisms in the LRP gene have been described and in this study we examined their influence on coronary artery disease (CAD). We compared the frequencies of the exon 3 (C766T), exon 6 (C663T), exon 22

Anothai Pocathikorn; Britt Granath; Els Thiry; Fred Van Leuven; Roger Taylor; Cyril Mamotte

174

Rapid identification and cloning of bacterial transferrin and lactoferrin receptor protein genes.  

PubMed Central

The sequences of genes encoding the transferrin and lactoferrin receptor proteins from several bacterial species were analyzed for areas of identity in the predicted protein sequences. Degenerate oligonucleotide primers were designed and tested for their ability to amplify portions of the receptor genes. Primer pairs capable of amplifying products of the tbpA/lbpA or tbpB/lbpB genes from all species possessing these receptors were identified.

Ogunnariwo, J A; Schryvers, A B

1996-01-01

175

The 5HT1D? Receptor Gene in Bipolar Disorder: A Family-based Association Study  

Microsoft Academic Search

The serotonin (5HT) receptor genes are considered good candidates for Major Depression (MD), Bipolar Disorder (BP), and Obsessive-Compulsive Disorder (OCD). The 5HT1D? receptor gene has at least three polymorphisms known: G861C, T-261G, and the functional T371G (Phe-124-Cys). The aim of this study was to investigate for the presence of linkage disequilibrium between the 5HT1D? receptor gene and BP. Two hundred

Emanuela Mundo; Gwyneth Zai; Lisa Lee; Sagar V Parikh; James L Kennedy

2001-01-01

176

Abnormal methylation of estrogen receptor gene and reduced estrogen receptor RNA levels in human endometrial carcinomas.  

PubMed

Demethylation of specific sites or restricted genomic regions has been reported to correlate with gene activation and also with carcinogenesis. As abnormal expression of Estrogen Receptor (ER) could be involved in the genesis or progression of tumors in estrogen target tissues, the methylation of ER gene has been compared in 8 endometrial carcinomas and 29 normal endometria. In order to look for a correlation between methylation and expression, levels of ER RNA were also measured. While the 5' region of ER gene was found to be demethylated in both normal and carcinomatous tissues, there was demethylation of some specific sites in the internal part of the gene only in the carcinomas examined. In addition, in the carcinomatous tissues the levels of ER RNA were low, indicating that an increase of ER gene hypomethylation does not raise, and even may reduce, the ER expression in endometrium. The abnormal undermethylation observed in ER gene appears to be unrelated to general DNA hypomethylation which is frequently present in neoplastic tissues; nor has it been found in ER DNA isolated from breast carcinomas. These data strongly support the hypothesis that such a methylation is specifically related to endometrial transformation and therefore it can be considered an additional marker of this disease. PMID:2913392

Piva, R; Kumar, V L; Hanau, S; Rimondi, A P; Pansini, S; Mollica, G; del Senno, L

1989-01-01

177

Vitamin D receptor gene polymorphisms and risk of osteoarthritis: A meta-analysis.  

PubMed

The vitamin D receptor (VDR) gene polymorphisms have been reported to be involved in the development of many musculoskeletal disorders, including osteoarthritis (OA). However, results were inconsistent and there is no definite conclusion regarding the association between any VDR polymorphism and the risk of OA. In this study, we conducted a meta-analysis to determine whether BsmI, TaqI, and ApaI polymorphisms in the VDR gene are associated with OA susceptibility. Literature research was performed using PubMed and EMBASE databases. Studies illustrating the association between the three VDR polymorphisms and OA were included, and their qualities were assessed using Newcastle-Ottawa scale. Eight eligible studies, recruiting 1626 cases and 2024 controls were identified. Their methodological qualities were generally good, with scores ranging from 6 to 8 points. However, throughout all summary analyses, which were performed for multiple categories and on four contrasts (allele contrast, contrast of homozygotes, recessive and dominant models), none of the VDR BsmI, TaqI, and ApaI gene polymorphisms were found to be significantly associated with the risk of OA. On the other hand, there was no significant publication bias. Results from this meta-analysis suggested that the VDR BsmI, TaqI, and ApaI gene polymorphisms might not be important predictors of OA. More studies further investigating these associations, especially taking into account of gene-gene, gene-environment interactions, and other confounding factors are warranted. PMID:24603077

Liu, Huifang; He, Hongchen; Li, Shasha; Yang, Lin; Wang, Pu; Liu, Chuan; Wei, Xiaofei; Wu, Taixiang; He, Chengqi

2014-05-01

178

Identification of Homeotic Target Genes in Drosophila Melanogaster Including Nervy, a Proto-Oncogene Homologue  

PubMed Central

In Drosophila, the specific morphological characteristics of each segment are determined by the homeotic genes that regulate the expression of downstream target genes. We used a subtractive hybridization procedure to isolate activated target genes of the homeotic gene Ultrabithorax (Ubx). In addition, we constructed a set of mutant genotypes that measures the regulatory contribution of individual homeotic genes to a complex target gene expression pattern. Using these mutants, we demonstrate that homeotic genes can regulate target gene expression at the start of gastrulation, suggesting a previously unknown role for the homeotic genes at this early stage. We also show that, in abdominal segments, the levels of expression for two target genes increase in response to high levels of Ubx, demonstrating that the normal down-regulation of Ubx in these segments is functional. Finally, the DNA sequence of cDNAs for one of these genes predicts a protein that is similar to a human proto-oncogene involved in acute myeloid leukemias. These results illustrate potentially general rules about the homeotic control of target gene expression and suggest that subtractive hybridization can be used to isolate interesting homeotic target genes.

Feinstein, P. G.; Kornfeld, K.; Hogness, D. S.; Mann, R. S.

1995-01-01

179

The ste3 pheromone receptor gene of Pneumocystis carinii is surrounded by a cluster of signal transduction genes.  

PubMed Central

Although the clinical aspects of Pneumocystis carinii pneumonia are well characterized, the basic biology of the causative organism is poorly understood. Most proposed life cycles of P. carinii include both asexual and sexual replicative cycles. The two most prominent morphological forms are a trophic form, thought to undergo asexual replication by binary fission, and a cystic form or ascus containing intracystic bodies or ascospores, the products of sexual replication. To facilitate the Pneumocystis genome project, a P. carinii f. sp. carinii genomic cosmid library and an additional lambda cDNA library were generated. A partial expressed sequence tag database, created as part of the genome project, revealed the transcription of meiosis-specific genes and other genes related to sexual reproduction. The ortholog of Ste3, an a-factor pheromone receptor, was cloned and genes surrounding the ste3 locus were examined. Clustered around the ste3 gene are genes encoding elements functional in the pheromone response signal transduction cascade of model fungal organisms. These include the Ste20 protein kinase, the Ste12 homoeodomain transcriptional regulator, a potential pheromone mating factor, and other DNA-binding proteins. The genomic organization of the ste3 locus bears significant similarity to that of the mating locus recently described in Cryptococcus neoformans. The P. carinii genome contains much of the genetic machinery necessary for pheromone responsiveness, and these data support the existence of a sexual replication cycle.

Smulian, A G; Sesterhenn, T; Tanaka, R; Cushion, M T

2001-01-01

180

Chromosomal localization of gene for human glutamate receptor subunit-7  

SciTech Connect

The authors isolated a human glutamate receptor subunit 7 (GluR-7) cosmid after high stringency screening of a human genomic placental library using a rat GluR-7 cDNA as a probe. A 614-bp fragment of the GluR-7 cosmid was sequenced, and an exon that encodes 53 amino acids was found between two introns. The exon exhibited 89% and 96% identity at the nucleotide and amino acid levels, respectively, with the corresponding region of rat GluR-7. The human GluR-7 was classified as a kainate subtype glutamate receptor based on its homology to rat GluR07. Using somatic cell hybrid analysis, human GluR-7 was localized to chromosome 1. Fine mapping analysis using FISH localized the gene to 1p33-34. Since glutamate receptors of the kainate subtype have been implicated in neurodegenerative disorders, establishing the precise map position of human GluR-7 subunit is an important step towards evaluating this locus as a candidate for mutations in neurodegenerative disorders.

Puranam, R.S.; Eubanks, J.H.; McNamara, J.O. (Duke Univ., Durham, NC (United States)); Heinemann, S.F. (Salk Institute for Biological Sciences, La Jolla, CA (United States))

1993-11-01

181

DNA methylation analysis of steroid hormone receptor genes.  

PubMed

Steroid hormone receptors (SHR) are important transcription factors for regulating different physiological and pathological processes. Their altered expression has been strongly associated to cancer progression. Epigenetic marks such as DNA methylation have been proposed as one of the regulatory mechanisms for SHR expression in cancer. DNA methylation occurs at CpG dinucleotides, which form clusters known as CpG islands. These islands are mostly observed at promoter regions of housekeeping genes, and their aberrant methylation in cancer cells is associated with silencing of tumor-suppressor gene expression. SHR genes are characterized for presenting alternative promoters with different CpG island content, which are prone to be methylated. The method of choice for studying DNA methylation is bisulfite sequencing, since it provides information about the methylation pattern at single-nucleotide level. The method is based on the deamination of cytosine residues to uracil after treatment with sodium bisulfite. The converted DNA is amplified by a polymerase chain reaction, cloned, and sequenced. Here, we describe a protocol for bisulfite sequencing suitable for analyzing different CpG regions in SHR genes. PMID:24839021

Camacho-Arroyo, Ignacio; Hansberg-Pastor, Valeria; Rodríguez-Dorantes, Mauricio

2014-01-01

182

Variability of the Transferrin Receptor 2 Gene in AMD  

PubMed Central

Oxidative stress is a major factor in the pathogenesis of age-related macular degeneration (AMD). Iron may catalyze the Fenton reaction resulting in overproduction of reactive oxygen species. Transferrin receptor 2 plays a critical role in iron homeostasis and variability in its gene may influence oxidative stress and AMD occurrence. To verify this hypothesis we assessed the association between polymorphisms of the TFR2 gene and AMD. A total of 493 AMD patients and 171 matched controls were genotyped for the two polymorphisms of the TFR2 gene: c.1892C>T (rs2075674) and c.?258+123T>C (rs4434553). We also assessed the modulation of some AMD risk factors by these polymorphisms. The CC and TT genotypes of the c.1892C>T were associated with AMD occurrence but the latter only in obese patients. The other polymorphism was not associated with AMD occurrence, but the CC genotype was correlated with an increasing AMD frequency in subjects with BMI < 26. The TT genotype and the T allele of this polymorphism decreased AMD occurrence in subjects above 72 years, whereas the TC genotype and the C allele increased occurrence of AMD in this group. The c.1892C>T and c.?258+123T>C polymorphisms of the TRF2 gene may be associated with AMD occurrence, either directly or by modulation of risk factors.

Blasiak, Janusz; Dorecka, Mariola; Kowalska, Marta; Pawlowska, Elzbieta; Szaflik, Jerzy; Szaflik, Jacek Pawel

2014-01-01

183

Vitamin E activates gene expression via the pregnane X receptor.  

PubMed

Tocopherols and tocotrienols are metabolized by side chain degradation via initial omega-oxidation and subsequent beta-oxidation. omega-Oxidation is performed by cytochrome P450 (CYP) enzymes which are often regulated by their substrates themselves. Results presented here show that all forms of Vitamin E are able to activate gene expression via the pregnane X receptor (PXR), a nuclear receptor regulating a variety of drug metabolizing enzymes. In HepG2 cells transfected with the human PXR and the chloramphenicol acetyl transferase (CAT) gene linked to two PXR responsive elements, CAT activity was most strongly induced by alpha- and gamma-tocotrienol followed by rifampicin, delta-, alpha- and gamma-tocopherol. The inductive efficacy was concentration-dependent; its specificity was underscored by a lower response when cotransfection with PXR was omitted. Up-regulation of endogenous CYP3A4 and CYP3A5 mRNA was obtained by gamma-tocotrienol, the most potent activator of PXR, with the same efficacy as with rifampicin. This points to a potential interference of individual forms of Vitamin E with the metabolism and efficacy of drugs. PMID:12504802

Landes, Nico; Pfluger, Paul; Kluth, Dirk; Birringer, Marc; Rühl, Ralph; Böl, Gaby-Fleur; Glatt, Hansruedi; Brigelius-Flohé, Regina

2003-01-15

184

Altered Glucose Homeostasis and Hepatic Function in Obese Mice Deficient for Both Kinin Receptor Genes  

PubMed Central

The Kallikrein-Kinin System (KKS) has been implicated in several aspects of metabolism, including the regulation of glucose homeostasis and adiposity. Kinins and des-Arg-kinins are the major effectors of this system and promote their effects by binding to two different receptors, the kinin B2 and B1 receptors, respectively. To understand the influence of the KKS on the pathophysiology of obesity and type 2 diabetes (T2DM), we generated an animal model deficient for both kinin receptor genes and leptin (obB1B2KO). Six-month-old obB1B2KO mice showed increased blood glucose levels. Isolated islets of the transgenic animals were more responsive to glucose stimulation releasing greater amounts of insulin, mainly in 3-month-old mice, which was corroborated by elevated serum C-peptide concentrations. Furthermore, they presented hepatomegaly, pronounced steatosis, and increased levels of circulating transaminases. This mouse also demonstrated exacerbated gluconeogenesis during the pyruvate challenge test. The hepatic abnormalities were accompanied by changes in the gene expression of factors linked to glucose and lipid metabolisms in the liver. Thus, we conclude that kinin receptors are important for modulation of insulin secretion and for the preservation of normal glucose levels and hepatic functions in obese mice, suggesting a protective role of the KKS regarding complications associated with obesity and T2DM.

Barros, Carlos C.; Haro, Anderson; Russo, Fernanda J. V. P.; Schadock, Ines; Almeida, Sandro S.; Ribeiro, Rosane A.; Vanzela, Emerielle C.; Lanzoni, Valeria P.; Barros, Flavio C.; Moraes, Milton R.; Mori, Marcelo A.; Bacurau, Reury F. P.; Wurtele, Martin; Boschero, Antonio C.; Carneiro, Everardo M.; Bader, Michael; Pesquero, Joao B.; Araujo, Ronaldo C.

2012-01-01

185

Bioinformatics Analysis of the FREM1 Gene--Evolutionary Development of the IL-1R1 Co-Receptor, TILRR  

PubMed Central

The TLRs and IL-1 receptors have evolved to coordinate the innate immune response following pathogen invasion. Receptors and signalling intermediates of these systems are generally characterised by a high level of evolutionary conservation. The recently described IL-1R1 co-receptor TILRR is a transcriptional variant of the FREM1 gene. Here we investigate whether innate co-receptor differences between teleosts and mammals extend to the expression of the TILRR isoform of FREM1. Bioinformatic and phylogenetic approaches were used to analyse the genome sequences of FREM1 from eukaryotic organisms including 37 tetrapods and five teleost fish. The TILRR consensus peptide sequence was present in the FREM1 gene of the tetrapods, but not in fish orthologs of FREM1, and neither FREM1 nor TILRR were present in invertebrates. The TILRR gene appears to have arisen via incorporation of adjacent non-coding DNA with a contiguous exonic sequence after the teleost divergence. Comparing co-receptors in other systems, points to their origin during the same stages of evolution. Our results show that modern teleost fish do not possess the IL-1RI co-receptor TILRR, but that this is maintained in tetrapods as early as amphibians. Further, they are consistent with data showing that co-receptors are recent additions to these regulatory systems and suggest this may underlie differences in innate immune responses between mammals and fish.

Hudson, Richard C.; Gray, Caroline; Kiss-Toth, Endre; Chico, Timothy J. A.; Qwarnstrom, Eva E.

2012-01-01

186

Receptor protein kinase gene encoded at the self-incompatibility locus  

DOEpatents

Described herein is a S receptor kinase gene (SRK), derived from the S locus in Brassica oleracea, having a extracellular domain highly similar to the secreted product of the S-locus glycoprotein gene.

Nasrallah, June B. (Ithaca, NY); Nasrallah, Mikhail E. (Ithaca, NY); Stein, Joshua (Cortland, NY)

1996-01-01

187

The human genome and sport, including epigenetics, gene doping, and athleticogenomics.  

PubMed

Hugh Montgomery's discovery of the first of more than 239 fitness genes together with rapid advances in human gene therapy have created a prospect of using genes, genetic elements, and cells that have the capacity to enhance athletic performance (to paraphrase the World Anti-Doping Agency's definition of gene doping). This brief overview covers the main areas of interface between genetics and sport, attempts to provide a context against which gene doping may be viewed, and predicts a futuristic legitimate use of genomic (and possibly epigenetic) information in sport. PMID:20122459

Sharp, N C Craig

2010-03-01

188

Identification of Duplicated Fourth  2Adrenergic Receptor Subtype by Cloning and Mapping of Five Receptor Genes in Zebrafish  

Microsoft Academic Search

The a2-adrenergic receptors (a2-ARs) belong to the large family of rhodopsinlike G-protein-coupled receptors that share a common structure of seven transmembrane (TM) a-helices. The aims of this study were (1) to determine the number of a2-AR genes in a teleost fish, the zebrafish (Danio rerio), (2) to study the gene duplication events that generated the a2- AR subtypes, and (3)

Jori O. Ruuskanen; Henri Xhaard; Anne Marjamaki; Erik Salaneck; Tiina Salminen; Yi-Lin Yan; John H. Postlethwait; Mark S. Johnson; Dan Larhammar; Mika Scheinin

2003-01-01

189

Estrogen receptor ? can selectively repress dioxin receptor-mediated gene expression by targeting DNA methylation  

PubMed Central

Selective inhibitory crosstalk has been known to occur within the signaling pathways of the dioxin (AhR) and estrogen (ER?) receptors. More specifically, ER? represses a cytochrome P450-encoding gene (CYP1A1) that converts cellular estradiol into a metabolite that inhibits the cell cycle, while it has no effect on a P450-encoding gene (CYP1B1) that converts estrodiol into a genotoxic product. Here we show that ER? represses CYP1A1 by targeting the Dnmt3B DNA methyltransferase and concomitant DNA methylation of the promoter. We also find that histone H2A.Z can positively contribute to CYP1A1 gene expression, and its presence at that gene is inversely correlated with DNA methylation. Taken together, our results provide a framework for how ER? can repress transcription, and how that impinges on the production of an enzyme that generates genotoxic estradiol metabolites, and potential breast cancer progression. Finally, our results reveal a new mechanism for how H2A.Z can positively influence gene expression, which is by potentially competing with DNA methylation events in breast cancer cells.

Marques, Maud; Laflamme, Liette; Gaudreau, Luc

2013-01-01

190

T Cell Receptor-Independent Basal Signaling via Erk and Abl Kinases Suppresses RAG Gene Expression  

PubMed Central

Signal transduction pathways guided by cellular receptors commonly exhibit low-level constitutive signaling in a continuous, ligand-independent manner. The dynamic equilibrium of positive and negative regulators establishes such a tonic signal. Ligand-independent signaling by the precursors of mature antigen receptors regulates development of B and T lymphocytes. Here we describe a basal signal that controls gene expression profiles in the Jurkat T cell line and mouse thymocytes. Using DNA microarrays and Northern blots to analyze unstimulated cells, we demonstrate that expression of a cluster of genes, including RAG-1 and RAG-2, is repressed by constitutive signals requiring the adapter molecules LAT and SLP-76. This TCR-like pathway results in constitutive low-level activity of Erk and Abl kinases. Inhibition of Abl by the drug STI-571 or inhibition of signaling events upstream of Erk increases RAG-1 expression. Our data suggest that physiologic gene expression programs depend upon tonic activity of signaling pathways independent of receptor ligation.

2003-01-01

191

Dopamine D1 Receptors, Regulation of Gene Expression in the Brain, and Neurodegeneration  

PubMed Central

Dopamine (DA), the most abundant catecholamine in the basal ganglia, participates in the regulation of motor functions and of cognitive processes such as learning and memory. Abnormalities in dopaminergic systems are thought to be the bases for some neuropsychiatric disorders including addiction, Parkinson’s disease, and Schizophrenia. DA exerts its arrays of functions via stimulation of D1-like (D1 and D5) and D2-like (D2, D3, and D4) DA receptors which are located in various regions of the brain. The DA D1 and D2 receptors are very abundant in the basal ganglia where they exert their functions within separate neuronal cell types. The present paper focuses on a review of the effects of stimulation of DA D1 receptors on diverse signal transduction pathways and gene expression patterns in the brain. We also discuss the possible involvement of the DA D1 receptors in DA-mediated toxic effects observed both in vitro and in vivo. Future studies using more selective agonist and antagonist agents and the use of genetically modified animals should help to further clarify the role of these receptors in the normal physiology and in pathological events that involve DA.

Cadet, Jean Lud; Jayanthi, Subramaniam; McCoy, Michael T.; Beauvais, Genevieve; Cai, Ning Sheng

2013-01-01

192

Two novel mutations in the thyrotropin (TSH) receptor gene in a child with resistance to TSH.  

PubMed

The TSH receptor is a G protein-coupled receptor that mediates the effects of TSH in thyroid development, growth, and synthetic function. We report here that a child with features of TSH resistance, including markedly increased serum TSH concentrations and low normal thyroid hormone levels, is a compound heterozygote for two novel mutations in the TSH receptor gene. One allele has a G to A transition corresponding to an arginine to glutamine change at codon 109 (R109Q) in the extracellular domain of the receptor. The other allele has a G to A transition corresponding to a premature termination codon at tryptophan 546 (W546X) in the fourth transmembrane segment. Each parent is heterozygous for one mutation, and both parents have normal thyroid function. Cells transiently transfected with the R109Q mutant exhibited reduced membrane binding of [125I]TSH and impaired signal transduction in response to TSH. In contrast, the W546X mutant was nonfunctional, with negligible membrane radioligand binding. Our findings indicate that a single normal TSH receptor allele is sufficient for normal thyroid function, but that the compound abnormality in the proband leads to TSH resistance. PMID:9100579

Clifton-Bligh, R J; Gregory, J W; Ludgate, M; John, R; Persani, L; Asteria, C; Beck-Peccoz, P; Chatterjee, V K

1997-04-01

193

Cloning and characterization of a receptor-class phosphotyrosine phosphatase gene expressed on central nervous system axons in Drosophila melanogaster.  

PubMed Central

We have cloned and characterized cDNAs coding for a receptor-class phosphotyrosine phosphatase gene from Drosophila melanogaster. The gene maps to the polytene chromosome bands 99A7-8. The cDNA clones code for a polypeptide of 1301 amino acids with a predicted molecular mass of 145 kDa. The extracellular domain includes two fibronectin-type III-like domains. The cytoplasmic region contains two tandemly repeated phosphotyrosine phosphatase-like domains. Residues shown crucial for catalytic activity are absent in the second domain. This Drosophila receptor-class phosphotyrosine phosphatase polypeptide is expressed on axons of the embryonic central nervous system. Images

Hariharan, I K; Chuang, P T; Rubin, G M

1991-01-01

194

Association of Estrogen Receptor-? Gene & Metallothionein-1 Gene Polymorphisms in Type 2 Diabetic Women of Andhra Pradesh.  

PubMed

Type 2 diabetes mellitus (DM) is a multifactorial disease where both genetic and environmental factors contribute to its pathogenesis. Estrogen plays an important role in type 2 DM pathogenesis. A number of polymorphisms have been reported in the estrogen receptor (ESR1), including the XbaI and PvuII restriction enzyme polymorphisms of ESR1,which may be involved in disease pathogenesis. Metallothioneins (MT) act as potent antioxidants against various oxidative damages. Very few studies have indicated the association between Estrogen Receptor-?, MT1 gene polymorphisms with type2 DM. A total of 100 type 2 diabetic women and 100 age, sex matched controls were recruited. Using the PCR based RFLP method, the PvuII and XbaI polymorphisms of ESR1 and in MT1A (rs8052394 and rs11076161) gene polymorphisms were analysed. The genotype distribution and frequency of mutated allele showed no significant differences between diabetic and non-diabetic groups in PvuII (?2 = 2.443; P = 0.1181) or XbaI (?2 = 1.789; P = 0.1812) and rs8052394 (?2 = 1.154; P = 0.2840) or rs11076161 (?2 = 0.4141; P = 0.5199), polymorphisms. This is the first Indian study to conclude that ESR1 and MT1 gene polymorphisms are not associated with increased susceptibility to type 2 diabetes in Indian women. PMID:23277715

Ganasyam, Shilpa Reddy; Rao, Talluri Bhaskar; Murthy, Y S R; Jyothy, Akka; Sujatha, Madireddy

2012-01-01

195

Haplotype structure and linkage disequilibrium in chemokine and chemokine receptor genes  

PubMed Central

To dissect the haplotype structure of candidate genes for disease association studies, it is important to understand the nature of genetic variation at these loci in different populations. We present a survey of haplotype structure and linkage disequilibrium of chemokine and chemokine receptor genes in 11 geographically-distinct population samples (n = 728). Chemokine proteins are involved in intercellular signalling and the immune response. These molecules are important modulators of human immunodeficiency virus (HIV)-1 infection and the progression of the acquired immune deficiency syndrome, tumour development and the metastatic process of cancer. To study the extent of genetic variation in this gene family, single nucleotide polymorphisms (SNPs) from 13 chemokine and chemokine receptor genes were genotyped using the 5' nuclease assay (TaqMan). SNP haplotypes, estimated from unphased genotypes using the Expectation-Maximization-algorithm, are described in a cluster of four CC-chemokine receptor genes (CCR3, CCR2, CCR5 and CCRL2) on chromosome 3p21, and a cluster of three CC-chemokine genes [MPIF-1 (CCL23) PARC (CCL18) and MIP- 1? (CCL3)] on chromosome 17q11-12. The 32 base pair (bp) deletion in exon 4 of CCR5 was also included in the haplotype analysis of 3p21. A total of 87.5 per cent of the variation of 14 biallelic loci scattered over 150 kilobases of 3p21 is explained by 11 haplotypes which have a frequency of at least 1 per cent in the total sample. An analysis of haplotype blocks in this region indicates recombination between CCR2 and CCR5, although long-range pairwise linkage disequilibrium across the region appears to remain intact on two common haplotypes. A reduced-median network demonstrates a clear relationship between 3p21 haplotypes, rooted by the putative ancestral haplotype determined by direct sequencing of four primate species. Analysis of six SNPs on 17q11-12 indicates that 97.5 per cent of the variation is explained by 15 haplotypes, representing at least 1 per cent of the total sample. Additionally, a possible signature of selection at a non-synonymous coding SNP (M106V) in the MPIF-1 (CCL23) gene warrants further study. We anticipate that the results of this study of chemokine and chemokine receptor variation will be applicable to more extensive surveys of long-range haplotype structure in these gene regions and to association studies of HIV-1 disease and cancer.

2004-01-01

196

Homeodomain binding motifs modulate the probability of odorant receptor gene choice in transgenic mice.  

PubMed

Odorant receptor (OR) genes constitute with 1200 members the largest gene family in the mouse genome. A mature olfactory sensory neuron (OSN) is thought to express just one OR gene, and from one allele. The cell bodies of OSNs that express a given OR gene display a mosaic pattern within a particular region of the main olfactory epithelium. The mechanisms and cis-acting DNA elements that regulate the expression of one OR gene per OSN - OR gene choice - remain poorly understood. Here, we describe a reporter assay to identify minimal promoters for OR genes in transgenic mice, which are produced by the conventional method of pronuclear injection of DNA. The promoter transgenes are devoid of an OR coding sequence, and instead drive expression of the axonal marker tau-?-galactosidase. For four mouse OR genes (M71, M72, MOR23, and P3) and one human OR gene (hM72), a mosaic, OSN-specific pattern of reporter expression can be obtained in transgenic mice with contiguous DNA segments of only ~300 bp that are centered around the transcription start site (TSS). The ~150bp region upstream of the TSS contains three conserved sequence motifs, including homeodomain (HD) binding sites. Such HD binding sites are also present in the H and P elements, DNA sequences that are known to strongly influence OR gene expression. When a 19mer encompassing a HD binding site from the P element is multimerized nine times and added upstream of a MOR23 minigene that contains the MOR23 coding region, we observe a dramatic increase in the number of transgene-expressing founders and lines and in the number of labeled OSNs. By contrast, a nine times multimerized 19mer with a mutant HD binding site does not have these effects. We hypothesize that HD binding sites in the H and P elements and in OR promoters modulate the probability of OR gene choice. PMID:21111823

Vassalli, Anne; Feinstein, Paul; Mombaerts, Peter

2011-02-01

197

Naturally Occurring Mutations in the Melanocortin Receptor 3 Gene Are Not Associated with Type 2 Diabetes Mellitus in French Caucasians  

Microsoft Academic Search

Familial genetic studies of type 2 diabetes (T2DM) of different human populations, including the French Caucasians, suggested ev- idence for linkage of T2DM and human chromosome 20q13, a region where maps the melanocortin 3 receptor gene (MC3R). Likewise, its homologous MC4R in human obesity, MC3R gene is also a good candidate for genetic susceptibility to glucose intolerance and T2DM. We

EL HABIB HANI; SOPHIE DUPONT; EMMANUELLE DURAND; CHRISTIAN DINA; SOPHIE GALLINA; IRA GANTZ; PHILIPPE FROGUEL

2010-01-01

198

Analysis of Wnt Gene Expression in Prostate Cancer: Mutual Inhibition by WNT11 and the Androgen Receptor  

Microsoft Academic Search

The Wnt signaling pathway is aberrantly activated in many tumor types, including those of the prostate, in which -catenin accumulates in cell nuclei and acts as a transcriptional coregulator for the androgen receptor. Because activating mutations in the -catenin gene are rare in prostate cancer, we have looked for altered expression of other compo- nents of the Wnt signaling pathway

Hanneng Zhu; Michal Mazor; Yoshiaki Kawano; Marjorie M. Walker; Hing Y. Leung; Kelly Armstrong; Jonathan Waxman; Robert M. Kypta

2004-01-01

199

Linkage map of the human major histocompatibility complex including the tumor necrosis factor genes  

Microsoft Academic Search

The tumor necrosis factor (TNF) ..cap alpha.. and ..beta.. gene pair has been linked in the human major histocompatibility complex to HLA-B, HLA-C, and, tentatively, HLA-E and HLA-A on one side and to the class III complement\\/steroid 21-hydroxylase gene cluster on the other by pulsed-field gel electrophoresis. The TNF genes are located 200 kilobases (kb) centromeric of HLA-B and about

M. C. Carroll; P. Katzman; E. M. Alicot; B. H. Koller; D. E. Geraghty; H. T. Orr; J. L. Strominger; T. Spies

1987-01-01

200

The Dopamine D2 Receptor Gene, Perceived Parental Support, and Adolescent Loneliness: Longitudinal Evidence for Gene-Environment Interactions  

ERIC Educational Resources Information Center

Background: Loneliness is a common problem in adolescence. Earlier research focused on genes within the serotonin and oxytocin systems, but no studies have examined the role of dopamine-related genes in loneliness. In the present study, we focused on the dopamine D2 receptor gene (DRD2). Methods: Associations among the DRD2, sex, parental support,…

van Roekel, Eeske; Goossens, Luc; Scholte, Ron H. J.; Engels, Rutger C. M. E.; Verhagen, Maaike

2011-01-01

201

T cell receptor gene therapy for autoimmune diseases.  

PubMed

The current quality of autoimmune disease treatments is not satisfactory in regard to efficacy and safety. Antigen-specific immunotherapy is a future therapy that could achieve maximal efficacy with minimal adverse effects. T cells are essential components in antigen-specific immunity. However, we do not have a sufficient strategy for manipulating antigen-specific T cells. We propose that T cell receptor (TCR) gene transfer is a hopeful approach for antigen-specific immunotherapy. We confirmed the efficacy of TCR gene therapy in animal models of systemic autoimmune disease and arthritis. In lupus-prone NZB/W F1 mice, nucleosome-specific TCR and CTLA4Ig transduced cells suppressed autoantibody production and nephritis development. In the therapeutic experiment of collagen-induced arthritis (CIA), arthritis-related TCRs were isolated from single T cells accumulating in the arthritis site. Arthritis-related TCR and TNFRIg transduced cells or TCR and Foxp3 transduced cells suppressed arthritis progression and bone destruction. Therefore, engineered antigen-specific cells manipulated to express appropriate functional genes could be applied to specific immunotherapy. PMID:17911437

Fujio, Keishi; Okamura, Tomohisa; Okamoto, Akiko; Yamamoto, Kazuhiko

2007-09-01

202

The Alpha2Adrenergic Receptor Gene and Body Fat Content and Distribution: The HERITAGE Family Study  

Microsoft Academic Search

Background: Among adrenergic receptor subtypes that regulate lipid mobilization, the ? 2-adrenergic receptor is involved in the inhibition of fatty acid mobilization from adipose tissue. A C-1291G polymorphism is located in the ? 2-adrenergic receptor gene (ADRA2A) but no association with body fat accumulation has been reported yet. Materials and Methods: Body mass index (BMI), fat mass (FAT), percentage body

Christophe Garenc; Louis Pérusse; Yvon C. Chagnon; Tuomo Rankinen; JacquesGagnon; Ingrid B. Borecki; Arthur S. Leon; James S. Skinner; Jack H. Wilmore; D. C. Rao; Claude Bouchard

2002-01-01

203

Angiotensin II Type 2 Receptor-Mediated Gene Expression Profiling in Human Coronary Artery Endothelial Cells  

Microsoft Academic Search

Despite intensive investigation, the molecular mechanism by which the angiotensin II type 2 (AT2) receptor exerts its cellular and physiological actions remains elusive. In the present study, we have used microarray expression analysis to identify genes whose expression was regulated by this receptor and to determine its cellular consequences. Lentiviral vector was used to express the AT2 receptor in human

Beverly L. Falcon; Shereeni J. Veerasingham; Colin Sumners; Mohan K. Raizada

2010-01-01

204

Adult attachment and gene polymorphisms of the dopamine D4 receptor and serotonin transporter (5-HTT)  

Microsoft Academic Search

Recently, the Dopamine D4 Receptor Gene (DRD4) and the Serotonin Transporter Gene (5-HTT) have been found to be candidate genes for infant attachment disorganization. The present study aimed to explore the relationship of these genes to adult attachment representations. The Adult Attachment Interview was used to assess attachment representations in 167 German adults. DNA from buccal cells was genotyped for

Iris Reiner; Gottfried Spangler

2010-01-01

205

Expressed Sequence Tags from Cephalic Chemosensory Organs of the Northern Walnut Husk Fly, Rhagoletis suavis, Including a Putative Canonical Odorant Receptor  

PubMed Central

Rhagoletis fruit flies are important both as major agricultural pests and as model organisms for the study of adaptation to new host plants and host race formation. Response to fruit odor plays a critical role in such adaptation. To better understand olfaction in Rhagoletis, an expressed sequence tag (EST) study was carried out on the antennae and maxillary palps of Rhagoletis suavis (Loew) (Diptera: Tephritidae), a common pest of walnuts in eastern United States. After cDNA cloning and sequencing, 544 ESTs were annotated. Of these, 66% had an open reading frame and could be matched to a previously sequenced gene. Based on BLAST sequence homology, 9% (49 of 544 sequences) were nuclear genes potentially involved in olfaction. The most significant finding is a putative odorant receptor (OR), RSOr1, that is homologous to Drosophila melanogaster Or49a and Or85f. This is the first tephritid OR discovered that might recognize a specific odorant. Other olfactory genes recovered included odorant binding proteins, chemosensory proteins, and putative odorant degrading enzymes.

Ramsdell, Karlene M. M.; Lyons-Sobaski, Sheila A.; Robertson, Hugh M.; Walden, Kimberly K. O.; Feder, Jeffrey L.; Wanner, Kevin; Berlocher, Stewart H.

2010-01-01

206

The nicotinic acetylcholine receptor gene family of the silkworm, Bombyx mori  

PubMed Central

Background Nicotinic acetylcholine receptors (nAChRs) mediate fast synaptic cholinergic transmission in the insect central nervous system. The insect nAChR is the molecular target of a class of insecticides, neonicotinoids. Like mammalian nAChRs, insect nAChRs are considered to be made up of five subunits, coded by homologous genes belonging to the same family. The nAChR subunit genes of Drosophila melanogaster, Apis mellifera and Anopheles gambiae have been cloned previously based on their genome sequences. The silkworm Bombyx mori is a model insect of Lepidoptera, among which are many agricultural pests. Identification and characterization of B. mori nAChR genes could provide valuable basic information for this important family of receptor genes and for the study of the molecular mechanisms of neonicotinoid action and resistance. Results We searched the genome sequence database of B. mori with the fruit fly and honeybee nAChRs by tBlastn and cloned all putative silkworm nAChR cDNAs by reverse transcriptase-polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE) methods. B. mori appears to have the largest known insect nAChR gene family to date, including nine ?-type subunits and three ?-type subunits. The silkworm possesses three genes having low identity with others, including one ? and two ? subunits, ?9, ?2 and ?3. Like the fruit fly and honeybee counterparts, silkworm nAChR gene ?6 has RNA-editing sites, and ?4, ?6 and ?8 undergo alternative splicing. In particular, alternative exon 7 of Bm?8 may have arisen from a recent duplication event. Truncated transcripts were found for Bm?4 and Bm?5. Conclusion B. mori possesses a largest known insect nAChR gene family characterized to date, including nine ?-type subunits and three ?-type subunits. RNA-editing, alternative splicing and truncated transcripts were found in several subunit genes, which might enhance the diversity of the gene family.

Shao, Ya-Ming; Dong, Ke; Zhang, Chuan-Xi

2007-01-01

207

Identification and phenotypical characterization of a cluster of fix genes, including a nif regulatory gene, from Rhizobium leguminosarum PRE  

Microsoft Academic Search

A nif regulatory gene in R. leguminosarum PRE was identified by interspecies DNA hybridization and site-directed Tn5 mutagenesis. Significant homology was found with the K. pneumoniae nifA locus, a R. meliloti symbiotic regulatory gene and E. coli ntrC; Tn5 insertions within this nifA gene inhibit the expression of the nifHDK operon, encoding synthesis of the nitrogenase polypeptides.

Resie M. P. Schetgens; Jan G. J. Hontelez; Rommert C. Bos; Albert Kammen

1985-01-01

208

Characterizing the expression of the human olfactory receptor gene family using a novel DNA microarray  

Microsoft Academic Search

BACKGROUND: Olfactory receptor (OR) genes were discovered more than a decade ago, when Buck and Axel observed that, in rats, certain G-protein coupled receptors are expressed exclusively in the olfactory epithelium. Subsequently, protein sequence similarity was used to identify entire OR gene repertoires of a number of mammalian species, but only in mouse were these predictions followed up by expression

Xiaohong Zhang; Omar De la Cruz; Jayant M Pinto; Dan Nicolae; Stuart Firestein; Yoav Gilad

2007-01-01

209

Inorganic phosphate regulates multiple genes during osteoblast differentiation, including Nrf2  

Microsoft Academic Search

The process of osteoblast differentiation and matrix mineralization requires a rise in alkaline phosphatase enzymatic activity resulting in the generation of free phosphate. The ability of inorganic phosphate to regulate gene transcription and cellular function represents a potentially novel extracellular signaling mechanism. Using microarray analysis we have identified a discrete set of genes that are either positively or negatively regulated

George R Beck; Elizabeth Moran; Nicole Knecht

2003-01-01

210

Hepatic gene therapy: adenovirus enhancement of receptor-mediated gene delivery and expression in primary hepatocytes.  

PubMed Central

We have combined a receptor-mediated DNA delivery system with the endosomal lysis ability of adenovirus and shown that DNA can be delivered into primary hepatocytes, resulting in a high level of gene expression. When asialoorosomucoid conjugated with poly(L-lysine) was used to deliver the Escherichia coli beta-galactosidase gene into primary hepatocytes through binding with the hepatic asialoglycoprotein receptor, only a low level of beta-galactosidase was detectable, with less than 0.1% of the hepatocytes being transfected. This level of activity can be greatly enhanced by the cointernalization of the DNA.protein complex with a replication-defective adenovirus, resulting in 100% of the hepatocytes staining blue with 5-bromo-4-chloro-3-indolyl beta-D-galactoside. Quantitative analysis of beta-galactosidase expression also showed a 1000-fold enhancement of activity. To test the applicability of this DNA delivery system for the correction of phenylketonuria, a metabolic disorder that causes severe mental retardation in children, we have delivered the human phenylalanine hydroxylase (PAH) gene to hepatocytes derived from a PAH-deficient mouse strain and demonstrated complete reconstitution of enzymatic activity. This method shows great promise for efficient gene delivery to the liver for correction of hepatic disorders. Images Fig. 2 Fig. 3

Cristiano, R J; Smith, L C; Woo, S L

1993-01-01

211

Genetic Evidence Implicating Multiple Genes in the MET Receptor Tyrosine Kinase Pathway in Autism Spectrum Disorder  

PubMed Central

A functional promoter variant of the gene encoding the MET receptor tyrosine kinase alters SP1 and SUB1 transcription factor binding, and is associated with autism spectrum disorder (ASD). Recent analyses of postmortem cerebral cortex from ASD patients revealed altered expression of MET protein and three transcripts encoding proteins that regulate MET signaling, hepatocyte growth factor (HGF), urokinase plasminogen activator receptor (PLAUR) and plasminogen activator inhibitor-1 (SERPINE1). To address potential risk conferred by multiple genes in the MET signaling pathway, we screened all exons and 5? promoter regions for variants in the five genes encoding proteins that regulate MET expression and activity. Identified variants were genotyped in 664 families (2,712 individuals including 1,228 with ASD) and 312 unrelated controls. Replicating our initial findings, family-based association test (FBAT) analyses demonstrated that the MET promoter variant rs1858830 C allele was associated with ASD in 101 new families (P=0.033). Two other genes in the MET signaling pathway also may confer risk. A haplotype of the SERPINE1 gene exhibited significant association. In addition, the PLAUR promoter variant rs344781 T allele was associated with ASD by both FBAT (P=0.006) and case-control analyses (P=0.007). The PLAUR promoter rs344781 relative risk was 1.93 (95% Confidence Interval [CI]: 1.12?3.31) for genotype TT and 2.42 (95% CI: 1.38?4.25) for genotype CT compared to genotype CC. Gene-gene interaction analyses suggested a significant interaction between MET and PLAUR. These data further support our hypothesis that genetic susceptibility impacting multiple components of the MET signaling pathway contributes to ASD risk.

Campbell, Daniel B.; Li, Chun; Sutcliffe, James S.; Persico, Antonio M.; Levitt, Pat

2008-01-01

212

Male-fertility genes expressed in male flower buds of Silene latifolia include homologs of anther-specific genes.  

PubMed

When the female plant of Silene latifolia is infected with the smut fungus Microbotryum violaceum, its rudimentary stamens develop into anthers which contain fungus teliospores instead of pollen. To identify genes required for maturation of anthers in S. latifolia, we performed a cDNA subtraction approach with healthy male buds and female buds infected with M. violaceum. We isolated five cDNA clones, which were preferentially expressed in healthy male buds during stages associated with a burst in tapetal activity. These five cDNAs are predicted to encode a mandelonitrile lyase protein (SlMDL1), a strictosidine synthase protein (SlSs), a glycosyl hydrolase 17 protein (SlGh17), a proline-rich protein APG precursor (SlAPG), and a chalcone-synthase-like protein (SlChs). All five genes showed expression in both healthy and fungus-infected male buds, but not expressed in either healthy or infected female buds. The first three genes were highly expressed in both tapetum and pollen grains while the last two genes were expressed only inside the tapetum of male flower buds. Phylogenetic analysis results showed that SlChs and SlGh17 belong to anther-specific subgroups of chalcone-synthase-like genes and glycosyl hydrolase 17 family genes, respectively. Our results suggest that the isolated five genes are related to the fertility of the anther leading to the development of fertile pollen. The smut fungus was not able to induce the expression of the five genes in the infected female buds. This raises the possibility that these genes are under the control of master gene(s) on the Y chromosome. PMID:16501309

Ageez, Amr; Kazama, Yusuke; Sugiyama, Ryuji; Kawano, Shigeyuki

2005-12-01

213

Type 2 vasopressin receptor gene, the gene responsible nephrogenic diabetes insipidus, maps to Xq28 close to the LICAM gene.  

PubMed

Although long contigs have been assembled in Xq28, the interval between the anonymous probe St14 and the color vision locus is still incompletely defined. We report here that the recently cloned gene for type 2 vasopressin receptor (V2R) is physically linked to L1CAM using YACs and cosmids across about 180 kb of the region. Since it is known that L1CAM maps near the color pigment genes, this finding locates V2R in Xq28 in the area where nephrogenic diabetes insipidus (NDI) has been mapped by linkage analysis. The PFGE analysis of the clones positions V2R about 40 kb from the L1CAM gene in a region that appears to contain other unknown genes, since at least four putative CpG islands were identified by restriction analysis with rare cutter enzymes. PMID:8323561

Frattini, A; Zucchi, I; Villa, A; Patrosso, C; Repetto, M; Susani, L; Strina, D; Redolfi, E; Vezzoni, P; Romano, G

1993-06-30

214

Haplotypes of the porcine peroxisome proliferator-activated receptor delta gene are associated with backfat thickness  

Microsoft Academic Search

BACKGROUND: Peroxisome proliferator-activated receptor delta belongs to the nuclear receptor superfamily of ligand-inducible transcription factors. It is a key regulator of lipid metabolism. The peroxisome proliferator-activated receptor delta gene (PPARD) has been assigned to a region on porcine chromosome 7, which harbours a quantitative trait locus for backfat. Thus, PPARD is considered a functional and positional candidate gene for backfat

Karina Meidtner; Hermann Schwarzenbacher; Maren Scharfe; Simone Severitt; Helmut Blöcker; Ruedi Fries

2009-01-01

215

Differential expressions and DNA methylation patterns of lysophosphatidic acid receptor genes in human colon cancer cells  

Microsoft Academic Search

Lysophosphatidic acid (LPA), which is a bioactive phospholipid, interacts with specific G protein-coupled transmembrane receptors.\\u000a Recently, alterations of LPA receptor genes have been reported in some tumor cells. In this study, we examined the expression\\u000a profiles and DNA methylation status of LPA receptor 1–5 (LPA1–5) genes in human colon cancer cells and also looked for the\\u000a mutations. Reverse transcription–polymerase chain

Megumu Tsujino; Minako Fujii; Kyoko Okabe; Toshio Mori; Nobuyuki Fukushima; Toshifumi Tsujiuchi

2010-01-01

216

Recent advances in gene manipulation and nicotinic acetylcholine receptor biology  

PubMed Central

Pharmacological and immunological methods have been valuable for both identifying some native nicotinic acetylcholine receptor (nAChR) subtypes that exist in vivo and determining the neurobiological and behavioral role of certain nAChR subtypes. However, these approaches suffer from shortage of subtype specific ligands and reliable immunological reagents. Consequently, genetic approaches have been developed to complement earlier approaches to identify native nAChR subtypes and to assess the contribution of nAChRs to brain function and behavior. In this review we describe how assembly partners, knock-in mice and targeted lentiviral re-expression of genes have been utilized to improve our understanding of nAChR neurobiology. In addition, we summarize emerging genetic tools in nAChR research.

Tammimaki, Anne; Horton, William J.; Stitzel, Jerry A.

2011-01-01

217

Gene therapy of gliomas: receptor and transcriptional targeting.  

PubMed

Through incremental increases in the overall therapeutic ratio of combined modality regimens, each addition of unique selective toxicity to a tumor moves one step closer to a cure. The primary advantage of adding gene therapy strategies to current oncologic regimens is the ability to design multiple levels of unique biologic selectivity into vectors using recombinant technology. This article presents an overview of current and potential methods for designing vectors targeted to high grade gliomas through selective cell entry or transcriptional regulation. Cell entry based methodologies are founded on increasing relative uptake of the vector through the chemical or recombinant addition of epitopes which bind to receptors selectively expressed on target cells. Transcriptional targeting utilizes promoter and enhancer systems which have potential for selectively activating transcription for transgene expression or vector propagation in target cells. PMID:9858886

Spear, M A

1998-01-01

218

Respiratory Syncytial Virus Represses Glucocorticoid Receptor-Mediated Gene Activation  

PubMed Central

Respiratory syncytial virus (RSV) is a common cause of bronchiolitis in infants. Although antiinflammatory in nature, glucocorticoids have been shown to be ineffective in the treatment of RSV-induced bronchiolitis and wheezing. In addition, the effectiveness of glucocorticoids at inhibiting RSV-induced proinflammatory cytokine production in cell culture has been questioned. In this study, we have investigated the effect of RSV infection on glucocorticoid-induced gene activation in lung epithelium-derived cells. We show that RSV infection inhibits dexamethasone induction of three glucocorticoid receptor (GR)-regulated genes (glucocorticoid-inducible leucine zipper, FK506 binding protein, and MAPK phosphatase 1) in A549, BEAS-2B cells, and primary small airway epithelial cells. UV irradiation of the virus prevents this repression, suggesting that viral replication is required. RSV is known to activate the nuclear factor ?B (NF?B) pathway, which is mutually antagonistic towards the GR pathway. However, specific inhibition of NF?B had no effect on the repression of GR-induced genes by RSV infection, indicating that RSV repression of GR is independent of NF?B. RSV infection of A549 cells does not alter GR protein levels or GR nuclear translocation but does reduce GR binding to the promoters of the glucocorticoid responsive genes analyzed in this study. Repression of GR by RSV infection may account for the apparent clinical ineffectiveness of glucocorticoids in RSV bronchiolitis therapy. In addition, this data adds to our previously published data suggesting that GR may be a general target for infectious agents. Identifying the mechanisms through which this suppression occurs may lead to the development of novel therapeutics.

Hinzey, Adam; Alexander, Jacob; Corry, Jacqueline; Adams, Kathleen M.; Claggett, Amanda M.; Traylor, Zachary P.; Davis, Ian C.

2011-01-01

219

Innate immune genes including a mucin-like gene, mul-1, induced by ionizing radiation in Caenorhabditis elegans.  

PubMed

The effect of radiation on the intestine has been studied for more than one hundred years. It remains unclear, however, whether this organ uses specific defensive mechanisms against ionizing radiation. The infection with Pseudomonas aeruginosa (PA14) in Caenorhabditis elegans induces up-regulation of innate immune response genes. Here, we found that exposure to ionizing radiation also induces certain innate immune response genes such as F49F1.6 (termed mul-1), clec-4, clec-67, lys-1 and lys-2 in the intestine. Moreover, pre-treatment with ionizing radiation before seeding on PA14 lawn plate significantly increased survival rate in the nematode. We also studied transcription pathway of the mul-1 in response to ionizing radiation. Induction of mul-1 gene was highly dependent on the ELT-2 transcription factor and p38 MAPK. Moreover, the insulin/IGF-1 signal pathway works to enhance induction of this gene. The mul-1 gene showed a different induction pattern from the DNA damage response gene, ced-13, which implies that the expression of this gene might be triggered as an indirect effect of radiation. Silencing of the mul-1 gene led to growth retardation after treatment with ionizing radiation. We describe the cross-tolerance between the response to radiation exposure and the innate immune system. PMID:22967128

Kimura, Takafumi; Takanami, Takako; Sakashita, Tetsuya; Wada, Seiichi; Kobayashi, Yasuhiko; Higashitani, Atsushi

2012-10-01

220

Paternal uniparental isodisomy of chromosome 6 causing a complex syndrome including complete IFN-gamma receptor 1 deficiency.  

PubMed

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency associated with clinical disease caused by weakly virulent mycobacterial species. Interferon gamma receptor 1 (IFN-gammaR1) deficiency is a genetic etiology of MSMD. We describe the clinical and genetic features of a 7-year-old Italian boy suffering from MSMD associated with a complex phenotype, including neonatal hyperglycemia, neuromuscular disease, and dysmorphic features. The child also developed necrotizing pneumonia caused by Rhodococcus equi. The child is homozygous for a nonsense mutation in exon 3 of IFNGR1 as a result of paternal uniparental disomy (UPD) of the entire chromosome 6. This is the first reported case of uniparental disomy resulting in a complex phenotype including MSMD. PMID:20186794

Prando, Carolina; Boisson-Dupuis, Stéphanie; Grant, Audrey V; Kong, Xiao-Fei; Bustamante, Jacinta; Feinberg, Jacqueline; Chapgier, Ariane; Rose, Yoann; Jannière, Lucile; Rizzardi, Elena; Zhang, Qiuping; Shanahan, Catherine M; Viollet, Louis; Lyonnet, Stanislas; Abel, Laurent; Ruga, Ezia Maria; Casanova, Jean-Laurent

2010-03-01

221

Progesterone receptor gene variants and risk of endometrial cancer  

PubMed Central

Prolonged excessive estrogen exposure unopposed by progesterone is widely accepted to be a risk factor for endometrial cancer development. The physiological function of progesterone is dependent upon the presence of its receptor [progesterone receptor (PGR)] and several studies have reported single nucleotide polymorphisms (SNPs) in the PGR gene to be associated with endometrial cancer risk. We sought to confirm the associations with endometrial cancer risk previously reported for four different PGR polymorphisms. A maximum of 2888 endometrial cancer cases and 4483 female control subjects from up to three studies were genotyped for four PGR polymorphisms (rs1042838, rs10895068, rs11224561 and rs471767). Logistic regression with adjustment for age, study, ethnicity and body mass index was performed to calculate odds ratios (ORs) and associated 95% confidence intervals (CIs) and P-values. Of the four SNPs investigated, only rs11224561 in the 3? region of the PGR gene was found to be significantly associated with endometrial cancer risk. The A allele of the rs11224561 SNP was associated with increased risk of endometrial cancer (OR per allele 1.31; 95% CI 1.12–1.53, P = 0.001, adjusted for age and study), an effect of the same magnitude and direction as reported previously. We have validated the endometrial cancer risk association with a tagSNP in the 3? untranslated region of PGR previously reported in an Asian population. Replication studies will be required to refine the risk estimate and to establish if this, or a correlated SNP, is the underlying causative variant.

O'Mara, Tracy A.; Fahey, Paul; Ferguson, Kaltin; Marquart, Louise; Lambrechts, Diether; Despierre, Evelyn; Vergote, Ignace; Amant, Frederic; Hall, Per; Liu, Jianjun; Czene, Kamila; Rebbeck, Timothy R.; Ahmed, Shahana; Dunning, Alison M.; Gregory, Catherine S.; Shah, Mitul; Webb, Penelope M.; Spurdle, Amanda B.

2011-01-01

222

Endogenous estradiol and its association with estrogen receptor gene polymorphisms.  

PubMed

We evaluated potential associations between single nucleotide polymorphism (SNP) variants of the estrogen receptor genes ESR1 and ESR2 and circulating estradiol (E2) concentrations in women of 4 races/ethnicities. The study population was drawn from participants in the Study of Women's Health Across the Nation (SWAN). A total of 1,538 African American, Caucasian, Chinese, and Japanese women from SWAN participated in the Sex Steroid Hormone Genetics Protocol by providing blood for sex steroid hormone analyses and consenting to lymphocyte transformation from which DNA was extracted and genotyped. We evaluated 4 ESR1 SNPs (ESR1 rs9340799, ESR1 rs2234693, ESR1 rs728524, and ESR1 rs3798577), and 3 ESR2 SNPs (ESR2 rs1255998, ESR2 rs1256030, and ESR2 rs1256065). Mean E2 level was 196.0 +/- 4.0 pmol/L in women who were premenopausal and perimenopausal (with blood drawn on days 2 through 5 of the menstrual cycle follicular phase); however, mean E2 levels in Chinese and Japanese women were lower (155.7 +/- 10.6 pmol/L and 170.0 +/- 10.3 pmol/L, respectively) than in African American (196.4 +/- 8.1 pmol/L, P <0.05) or Caucasian women (210.7 +/- 5.9 pmol/L, P <0.002). The ESR1 rs3798577 CC genotype was associated with lower circulating E2 concentrations in African American women (P <0.07) and explained about 1% of the variation in circulating E2 concentrations. In Japanese women, the GC genotype of ESR2 rs1255998 was associated with significantly lower circulating E2 concentrations that explained about 4% of the variation. Circulating E2 concentrations were not strongly or consistently associated with selected polymorphisms for the estrogen receptor genes. The 2 strongest associations explained <4% of the total variation in the circulating E2 concentrations. PMID:16949384

Sowers, MaryFran R; Jannausch, Mary L; McConnell, Daniel S; Kardia, Sharon R; Randolph, John F

2006-09-01

223

Gene silencing to investigate the roles of receptor-like proteins in Arabidopsis.  

PubMed

Receptor-like proteins (RLPs) are cell surface receptors that play important roles in various processes. In several plant species RLPs have been found to play a role in disease resistance, including the tomato Cf and Ve proteins and the apple HcrVf proteins that mediate resistance against the fungal pathogens Cladosporium fulvum, Verticillium spp., and Venturia inaequalis, respectively. The Arabidopsis genome contains 57 AtRLP genes. Two of these, CLV2 (AtRLP10) and TMM (AtRLP17), have well-characterized functions in meristem and stomatal development, respectively, while AtRLP52 is required for defense against powdery mildew. We recently reported the assembly of a genome-wide collection of T-DNA insertion lines for the Arabidopsis AtRLP genes. This collection was functionally analyzed with respect to plant growth, development and sensitivity to various stress responses including pathogen susceptibility. Only few new phenotypes were discovered; while AtRLP41 was found to mediate abscisic acid sensitivity, AtRLP30 (and possibly AtRLP18) was found to be required for full non-host resistance to a bacterial pathogen. Possibly, identification of novel phenotypes is obscured by functional redundancy. Therefore, RNA interference (RNAi) to target the expression of multiple AtRLP genes simultaneously was employed followed by functional analysis of the RNAi lines. PMID:19704533

Ellendorff, Ursula; Zhang, Zhao; Thomma, Bart Phj

2008-10-01

224

Control of Energy Balance by Hypothalamic Gene Circuitry Involving Two Nuclear Receptors, Neuron-Derived Orphan Receptor 1 and Glucocorticoid Receptor  

PubMed Central

Nuclear receptors (NRs) regulate diverse physiological processes, including the central nervous system control of energy balance. However, the molecular mechanisms for the central actions of NRs in energy balance remain relatively poorly defined. Here we report a hypothalamic gene network involving two NRs, neuron-derived orphan receptor 1 (NOR1) and glucocorticoid receptor (GR), which directs the regulated expression of orexigenic neuropeptides agouti-related peptide (AgRP) and neuropeptide Y (NPY) in response to peripheral signals. Our results suggest that the anorexigenic signal leptin induces NOR1 expression likely via the transcription factor cyclic AMP response element-binding protein (CREB), while the orexigenic signal glucocorticoid mobilizes GR to inhibit NOR1 expression by antagonizing the action of CREB. Also, NOR1 suppresses glucocorticoid-dependent expression of AgRP and NPY. Consistently, relative to wild-type mice, NOR1-null mice showed significantly higher levels of AgRP and NPY and were less responsive to leptin in decreasing the expression of AgRP and NPY. These results identify mutual antagonism between NOR1 and GR to be a key rheostat for peripheral metabolic signals to centrally control energy balance.

Kim, Sun-Gyun; Lee, Bora; Kim, Dae-Hwan; Kim, Juhee; Lee, Soo-Kyung

2013-01-01

225

Cortical synaptic NMDA receptor deficits in ?7 nicotinic acetylcholine receptor gene deletion models: implications for neuropsychiatric diseases.  

PubMed

Microdeletion of the human CHRNA7 gene (?7 nicotinic acetylcholine receptor, nAChR) as well as dysfunction in N-methyl-d-aspartate receptors (NMDARs) have been associated with cortical dysfunction in a broad spectrum of neurodevelopmental and neuropsychiatric disorders including schizophrenia. However, the pathophysiological roles of synaptic vs. extrasynaptic NMDARs and their interactions with ?7 nAChRs in cortical dysfunction remain largely uncharacterized. Using a combination of in vivo and in vitro models, we demonstrate that ?7 nAChR gene deletion leads to specific loss of synaptic NMDARs and their coagonist, d-serine, as well as glutamatergic synaptic deficits in mouse cortex. ?7 nAChR null mice had decreased cortical NMDAR expression and glutamatergic synapse formation during postnatal development. Similar reductions in NMDAR expression and glutamatergic synapse formation were revealed in cortical cultures lacking ?7 nAChRs. Interestingly, synaptic, but not extrasynaptic, NMDAR currents were specifically diminished in cultured cortical pyramidal neurons as well as in acute prefrontal cortical slices of ?7 nAChR null mice. Moreover, d-serine responsive synaptic NMDAR-mediated currents and levels of the d-serine synthetic enzyme serine racemase were both reduced in ?7 nAChR null cortical pyramidal neurons. Our findings thus identify specific loss of synaptic NMDARs and their coagonist, d-serine, as well as glutamatergic synaptic deficits in ?7 nAChR gene deletion models of cortical dysfunction, thereby implicating ?7 nAChR-mediated control of synaptic NMDARs and serine racemase/d-serine pathways in cortical dysfunction underlying many neuropsychiatric and neurodevelopmental disorders, particularly those associated with deletion of human CHRNA7. PMID:24326163

Lin, Hong; Hsu, Fu-Chun; Baumann, Bailey H; Coulter, Douglas A; Lynch, David R

2014-03-01

226

Liver x receptor modulation of gene expression leading to proluteolytic effects in primate luteal cells.  

PubMed

The expressions of genes involved in cholesterol efflux increase, whereas those involved in extracellular cholesterol uptake decrease, during spontaneous functional regression of the primate corpus luteum (CL). This may result from liver x receptor (LXR) alpha (official symbol NR1H3) and/or beta (official symbol NR1H2) control of luteal gene transcription, because these nuclear receptor superfamily members are key regulators of cellular cholesterol homeostasis. Therefore, studies were conducted to assess endogenous LXR ligands in the primate CL through the luteal phase, and to determine the effect of synthetic or natural LXR ligands on cholesterol efflux and uptake in functional primate luteal cells. Using high-performance liquid chromatography tandem mass spectrometry, three LXR ligands were identified and quantified in the rhesus macaque CL, including 22R-hydroxycholesterol (22ROH), 27-hydroxycholesterol (27OH), and desmosterol. Levels of 22ROH paralleled serum progesterone concentrations, whereas mean levels of 27OH tended to be higher following the loss of progesterone synthesis. Desmosterol was present throughout the luteal phase. Functional macaque luteal cells treated with the synthetic LXR agonist T0901317 or physiologically relevant concentrations of the endogenous luteal ligands 22ROH, 27OH, and desmosterol had increased expression of various known LXR target genes and greater cholesterol efflux. Additionally, T0901317 reduced low-density lipoprotein receptor protein and extracellular low-density lipoprotein uptake, whereas 27OH decreased low-density lipoprotein receptor protein, most likely via a posttranslational mechanism. Collectively, these data support the hypothesis that LXR activation causes increased cholesterol efflux and decreased extracellular cholesterol uptake. In theory, these effects could deplete the primate CL of cholesterol needed for steroidogenesis, ultimately contributing to functional regression. PMID:22156476

Bogan, Randy L; Debarber, Andrea E; Hennebold, Jon D

2012-03-01

227

Androgen Receptor Gene Expression in Prostate Cancer is Directly Suppressed by the Androgen Receptor Through Recruitment of Lysine Specific Demethylase 1  

PubMed Central

SUMMARY Androgen receptor (AR) is reactivated in castration resistant prostate cancer (CRPC) through mechanisms including marked increases in AR gene expression. We identify an enhancer in the AR second intron contributing to increased AR expression at low androgen levels in CRPC. Moreover, at increased androgen levels the AR binds this site and represses AR gene expression through recruitment of lysine specific demethylase 1 (LSD1) and H3K4me1,2 demethylation. AR similarly represses expression of multiple genes mediating androgen synthesis, DNA synthesis and proliferation, while stimulating genes mediating lipid and protein biosynthesis. Androgen levels in CRPC appear adequate to stimulate AR activity on enhancer elements, but not suppressor elements, resulting in increased expression of AR and AR repressed genes that contribute to cellular proliferation.

Cai, Changmeng; He, Housheng Hansen; Chen, Sen; Coleman, Ilsa; Wang, Hongyun; Fang, Zi; Chen, Shaoyong; Nelson, Peter S.; Liu, X. Shirley; Brown, Myles; Balk, Steven P.

2011-01-01

228

Characterization of the hormone responsive element involved in the regulation of the progesterone receptor gene.  

PubMed Central

The transcription of the progesterone receptor gene is induced by estrogens and decreased by progestins. Studies were performed to define the regions of the gene and the molecular mechanisms involved. No hormonal regulation could be observed using 5' flanking regions of the gene up to -2762 in front of a heterologous gene. Estrogen and progestin regulation could be observed only when using fragments of the gene extending down to +788. Progressive deletions from the 5' and 3' ends, site-directed mutagenesis and DNase protection experiments with purified estrogen receptor suggested that the biologically active estrogen responsive element (ERE) is present at +698/+723, overlapping the initiation of translation. An oligonucleotide was synthesized bearing this ERE and shown to impart estrogen inducibility to a heterologous gene. Its regulation by anti-estrogens corresponded to that of the in situ progesterone receptor gene since tamoxifen was a partial agonist whereas ICI 164384 was a full antagonist. This ERE also mediated down-regulation by progestins in the presence of the progesterone receptor, even though it has no progesterone receptor binding ability. DNase footprinting showed that this effect was not due to a decrease of estrogen receptor affinity for the ERE in the presence of progesterone receptor. Finally, use of deletion mutants of the progesterone receptor showed that the steroid binding and the DNA binding domains were necessary for down-regulation whereas deletions of various parts of the N-terminal domain were without effect. Images

Savouret, J F; Bailly, A; Misrahi, M; Rauch, C; Redeuilh, G; Chauchereau, A; Milgrom, E

1991-01-01

229

Regulation of dev, an Operon That Includes Genes Essential for Myxococcus xanthus Development and CRISPR-Associated Genes and Repeats?  

PubMed Central

Expression of dev genes is important for triggering spore differentiation inside Myxococcus xanthus fruiting bodies. DNA sequence analysis suggested that dev and cas (CRISPR-associated) genes are cotranscribed at the dev locus, which is adjacent to CRISPR (clustered regularly interspaced short palindromic repeats). Analysis of RNA from developing M. xanthus confirmed that dev and cas genes are cotranscribed with a short upstream gene and at least two repeats of the downstream CRISPR, forming the dev operon. The operon is subject to strong, negative autoregulation during development by DevS. The dev promoter was identified. Its ?35 and ?10 regions resemble those recognized by M. xanthus ?A RNA polymerase, the homolog of Escherichia coli ?70, but the spacer may be too long (20 bp); there is very little expression during growth. Induction during development relies on at least two positive regulatory elements located in the coding region of the next gene upstream. At least two positive regulatory elements and one negative element lie downstream of the dev promoter, such that the region controlling dev expression spans more than 1 kb. The results of testing different fragments for dev promoter activity in wild-type and devS mutant backgrounds strongly suggest that upstream and downstream regulatory elements interact functionally. Strikingly, the 37-bp sequence between the two CRISPR repeats that, minimally, are cotranscribed with dev and cas genes exactly matches a sequence in the bacteriophage Mx8 intP gene, which encodes a form of the integrase needed for lysogenization of M. xanthus.

Viswanathan, Poorna; Murphy, Kimberly; Julien, Bryan; Garza, Anthony G.; Kroos, Lee

2007-01-01

230

Liver X Receptor Gene Polymorphisms in Tuberculosis: Effect on Susceptibility  

PubMed Central

Objectives The Liver X receptors (LXRs), Liver X receptor A (LXRA) and Liver X receptor B (LXRB), regulate lipid metabolism and antimicrobial response. LXRs have a crucial role in the control of Mycobacterium tuberculosis (M.tb). Lacking LXRs mice is more susceptibility to infection M.tb, developing higher bacterial burdens and an increase in the size and number of granulomatous lesions. We aimed to assess the associations between single nucleotide polymorphisms (SNPs) in LXRs and risk of tuberculosis. Methods We sequenced the LXRs genes to detect SNPs and to examine genotypic frequencies in 600 patients and 620 healthy controls to investigate for associations with tuberculosis (TB) in the Chinese Han population. DNA re-sequencing revealed eight common variants in the LXRs genes. Results The G allele of rs1449627 and the T allele of rs1405655 demonstrated an increased risk of developing TB (p<0.001, p?=?0.002), and the T allele of rs3758673, the T allele of rs2279238, and the C allele of rs1449626 in LXRA and the C allele of rs17373080, the G allele of rs2248949, and the C allele of rs1052677 in LXRB were protective against TB patients compared to healthy controls (p?=?0.0002, p?=?0.006, p<0.001, p?=?0.004, p?=?0.008, p?=?0.003, respectively). All SNP genotypes were significantly associated with TB. An estimation of the frequencies of haplotypes revealed two potential risk haplotypes,GGCG in LXRB (p?=?0.004,) and TTCG in LXRA (p<0.001, p?=?0.004). Moreover, three protective haplotypes, TTAT and CCAT in LXRA and CATC in LXRB, were significantly “protective” (p?=?0.008, p<0.001, p?=?0.031) for TB. Furthermore, we determined that the LXRs SNPs were nominally associated with the clinical pattern of disease. Conclusions Our study data supported that LXRs play a fundamental role in the genetic susceptibility to TB and to different clinical patterns of disease. Thus, further investigation is required in larger populations and in additional areas.

Liu, Li-rong; Yue, Jun; Zhao, Yan-lin; Xiao, He-ping

2014-01-01

231

Sequence variation in the promoter region of the cholinergic receptor muscarinic 3 gene and asthma and atopy  

Microsoft Academic Search

Background: Muscarinic acetylcholine receptors are members of the superfamily of G protein–coupled, 7 transmembrane– spanning proteins. They are important in the development of airway hyperresponsiveness. In the lung the M3 receptor, encoded by the cholinergic receptor muscarinic 3 gene, is present in airway smooth muscle and mediates smooth muscle contraction. Objective: We considered the cholinergic receptor muscarinic 3 gene as

Joseph Donfack; Paul Kogut; Sean Forsythe; Julian Solway; Carole Ober

2003-01-01

232

Gene rearrangements in hormone receptor negative breast cancers revealed by mate pair sequencing  

PubMed Central

Background Chromosomal rearrangements in the form of deletions, insertions, inversions and translocations are frequently observed in breast cancer genomes, and a subset of these rearrangements may play a crucial role in tumorigenesis. To identify novel somatic chromosomal rearrangements, we determined the genome structures of 15 hormone-receptor negative breast tumors by long-insert mate pair massively parallel sequencing. Results We identified and validated 40 somatic structural alterations, including the recurring fusion between genes DDX10 and SKA3 and translocations involving the EPHA5 gene. Other rearrangements were found to affect genes in pathways involved in epigenetic regulation, mitosis and signal transduction, underscoring their potential role in breast tumorigenesis. RNA interference-mediated suppression of five candidate genes (DDX10, SKA3, EPHA5, CLTC and TNIK) led to inhibition of breast cancer cell growth. Moreover, downregulation of DDX10 in breast cancer cells lead to an increased frequency of apoptotic nuclear morphology. Conclusions Using whole genome mate pair sequencing and RNA interference assays, we have discovered a number of novel gene rearrangements in breast cancer genomes and identified DDX10, SKA3, EPHA5, CLTC and TNIK as potential cancer genes with impact on the growth and proliferation of breast cancer cells.

2013-01-01

233

Neurotensin Receptor 1 Gene (NTSR1) Polymorphism Is Associated with Working Memory  

PubMed Central

Background Recent molecular genetics studies showed significant associations between dopamine-related genes (including genes for dopamine receptors, transporters, and degradation) and working memory, but little is known about the role of genes for dopamine modulation, such as those related to neurotensin (NT), in working memory. A recent animal study has suggested that NT antagonist administration impaired working memory in a learning task. The current study examined associations between NT genes and working memory among humans. Methods Four hundred and sixty healthy undergraduate students were assessed with a 2-back working memory paradigm. 5 SNPs in the NTSR1 gene were genotyped. 5 ANOVA tests were conducted to examine whether and how working memory differed by NTSR1 genotype, with each SNP variant as the independent variable and the average accuracy on the working memory task as the dependent variable. Results ANOVA results suggested that two SNPs in the NTSR1 gene (rs4334545 and rs6090453) were significantly associated with working memory. These results survived corrections for multiple comparisons. Conclusions Our results demonstrated that NTSR1 SNP polymorphisms were significantly associated with variance in working memory performance among healthy adults. This result extended previous rodent studies showing that the NT deficiency impairs the working memory function. Future research should replicate our findings and extend to an examination of other dopamine modulators.

Li, Jin; Chen, Chuansheng; Chen, Chunhui; He, Qinghua; Li, He; Li, Jun; Moyzis, Robert K.; Xue, Gui; Dong, Qi

2011-01-01

234

Physical mapping of the retinoid X receptor B gene in mouse and human  

SciTech Connect

Retinoid X receptors (RXRs) are zinc finger-containing nuclear transcription factors. They belong to the nuclear receptor superfamily that contains retinoid receptors, vitamin D receptors, thyroid hormone receptors, and steroid hormone receptors as well as the so-called orphan receptors. We previously mapped all three RXR genes on mouse chromosomes, using a panel of Mus spretus-Mus musculus interspecific backcross mice: namely, the RXRA-gene (Rxra) on Chr 2 near the centromere, the RXRB gene (Rxrb) on Chr 17 in the H2 region, and the RXRG gene (Rxrg) on distal Chr 1. Using cosmid clones that cover the major histocompatibility complex (MHC) region, we determined the precise physical map positions of the gene encoding mouse and human RXRB, respectively. The mouse gene (Rxrb) maps between H2-Ke4 and H2-Ke5: namely, immediately telomeric to H2-Ke4 which encodes a histidine-rich transmembrane protein, and 12 kilobases centromeric to H2-Ke5 which is expressed in lymphoid tissues, Rxrb and H2-Ke4 are transcribed into opposite directions from a CpG-rich promoter of about 250 base pairs. This gene organization is well conserved also in the human genome at the HLA-DP subregion of Chr 6p, underscoring the strong conservation of the gene organization in the MHC region between the two mammals. 54 refs., 4 figs.

Nagata, T.; Kitagawa, K.; Taketo, M. [Banyu Tsukuba Research Institute, Tsukuba (Japan); Weiss, E.H. [Ludwig-Maximilians-Univ., Munich (Germany); Abe, K. [Kumamoto Univ. School of Medicine, Kumamoto (Japan); Ando, A.; Yara-Kikuti, Y.; Inoko, H. [Tokai Univ. School of Medicine, Isehara (Japan); Seldin, M.F. [Duke Univ. Medical Center, Durham, NC (United States); Ozato, K. [National Institutes of Health, Bethesda, MD (United States)

1995-01-11

235

Glucocorticoid receptor gene polymorphisms and susceptibility to rheumatoid arthritis  

PubMed Central

Background A defect in hypothalamic-pituitary-adrenal (HPA) axis function has been suggested to contribute to susceptibility to rheumatoid arthritis (RA). Objective To investigate polymorphisms of the glucocorticoid receptor (GR) gene and determine any associations with RA. Methods Three GR polymorphisms that tag 95% of all haplotypes across the GR gene were genotyped. These are an intron B Bcl1 polymorphism, a ttg insertion/deletion within intron F (rs2307674) and the single nucleotide polymorphism (SNP) lying in the 3? untranslated region of exon 9b (rs6198). The dye terminator-based SNaPshot method or size resolution by capillary electrophoresis was performed. The study population comprised 198 UK Caucasian RA cases and 393 ethnically matched controls. Results No significant single point or haplotypic associations were found for GR polymorphisms with RA susceptibility. Furthermore, no evidence for GR polymorphisms with aspects of RA severity was seen. Conclusion In this study of the most comprehensive coverage of GR polymorphisms with RA, no significant contributing role for GR polymorphisms with RA was found.

Donn, Rachelle; Payne, Debbie; Ray, David

2007-01-01

236

FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium.  

PubMed

Background:Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium.Methods:Data were combined from 49 studies, including 53?835 cases and 50?156 controls, of which 89?050 (46?450 cases and 42?600 controls) were of European ancestry, 12?893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression.Results:Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2.Conclusion:Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2. PMID:24548884

Agarwal, D; Pineda, S; Michailidou, K; Herranz, J; Pita, G; Moreno, L T; Alonso, M R; Dennis, J; Wang, Q; Bolla, M K; Meyer, K B; Menéndez-Rodríguez, P; Hardisson, D; Mendiola, M; González-Neira, A; Lindblom, A; Margolin, S; Swerdlow, A; Ashworth, A; Orr, N; Jones, M; Matsuo, K; Ito, H; Iwata, H; Kondo, N; Hartman, M; Hui, M; Lim, W Y; Iau, P T -C; Sawyer, E; Tomlinson, I; Kerin, M; Miller, N; Kang, D; Choi, J -Y; Park, S K; Noh, D -Y; Hopper, J L; Schmidt, D F; Makalic, E; Southey, M C; Teo, S H; Yip, C H; Sivanandan, K; Tay, W -T; Brauch, H; Brüning, T; Hamann, U; Dunning, A M; Shah, M; Andrulis, I L; Knight, J A; Glendon, G; Tchatchou, S; Schmidt, M K; Broeks, A; Rosenberg, E H; van't Veer, L J; Fasching, P A; Renner, S P; Ekici, A B; Beckmann, M W; Shen, C -Y; Hsiung, C -N; Yu, J -C; Hou, M -F; Blot, W; Cai, Q; Wu, A H; Tseng, C -C; Van Den Berg, D; Stram, D O; Cox, A; Brock, I W; Reed, M W R; Muir, K; Lophatananon, A; Stewart-Brown, S; Siriwanarangsan, P; Zheng, W; Deming-Halverson, S; Shrubsole, M J; Long, J; Shu, X -O; Lu, W; Gao, Y -T; Zhang, B; Radice, P; Peterlongo, P; Manoukian, S; Mariette, F; Sangrajrang, S; McKay, J; Couch, F J; Toland, A E; Yannoukakos, D; Fletcher, O; Johnson, N; dos Santos Silva, I; Peto, J; Marme, F; Burwinkel, B; Guénel, P; Truong, T; Sanchez, M; Mulot, C; Bojesen, S E; Nordestgaard, B G; Flyer, H; Brenner, H; Dieffenbach, A K; Arndt, V; Stegmaier, C; Mannermaa, A; Kataja, V; Kosma, V -M; Hartikainen, J M; Lambrechts, D; Yesilyurt, B T; Floris, G; Leunen, K; Chang-Claude, J; Rudolph, A; Seibold, P; Flesch-Janys, D; Wang, X; Olson, J E; Vachon, C; Purrington, K; Giles, G G; Severi, G; Baglietto, L; Haiman, C A; Henderson, B E; Schumacher, F; Marchand, L Le; Simard, J; Dumont, M; Goldberg, M S; Labréche, F; Winqvist, R; Pylkäs, K; Jukkola-Vuorinen, A; Grip, M; Devilee, P; Tollenaar, R A E M; Seynaeve, C; García-Closas, M; Chanock, S J; Lissowska, J; Figueroa, J D; Czene, K; Eriksson, M; Humphreys, K; Darabi, H; Hooning, M J; Kriege, M; Collée, J M; Tilanus-Linthorst, M; Li, J; Jakubowska, A; Lubinski, J; Jaworska-Bieniek, K; Durda, K; Nevanlinna, H; Muranen, T A; Aittomäki, K; Blomqvist, C; Bogdanova, N; Dörk, T; Hall, P; Chenevix-Trench, G; Easton, D F; Pharroah, P D P; Arias-Perez, J I; Zamora, P; Benítez, J; Milne, R L

2014-02-18

237

The phylogenetic history of the MHC class I gene families in pig, including a fossil gene predating mammalian radiation.  

PubMed

More than 990 kb of the 1200 kb in the SLA class I region of the pig major histocompatibility complex (MHC) have been sequenced. The present study was designed to establish the evolution of this region which was best understood by distinguishing three periods. The most recent period, which extended from 40 to 15 mya, probably corresponded to five rounds of duplication of a basic unit. This unit consisted of a single class I gene linked to widely dispersed repeats, and one SLA-specific repeat motif. The duplications gave rise to six SLA classical class I genes. The second evolutionary period corresponded to the emergence of the SLA nonclassical class I genes, i.e. after the suidae separated from the other artiodactyl species about 65 mya. The third period appeared to correspond to a much more remote age when the ancestor of the gene SLA-11 existed. Comparative studies of the human and pig sequences of the class I-containing segments indeed revealed the presence within the human HSR1-ZNF segment of relics of a human class I fossil gene which appeared to be orthologous to the 5' moiety of the SLA-11 pseudogene. This was the first evidence that a class I gene existed in this location at least 110-120 mya in the MHC class I region of the precursor of the mammalian species. Human/pig sequence comparison also revealed that the presumably functional pig MIC2 gene was probably orthologous to the human functional MICA or MICB genes. PMID:14708575

Renard, Christine; Chardon, Patrick; Vaiman, Marcel

2003-10-01

238

Glucocorticoid Receptor Concentration Modulates Glucocorticoid-Regulated Gene Expression in Rat Pancreatic AR42J Cells  

Microsoft Academic Search

In this study we investigated the effects of altered intracellular glucocorticoid receptor (GR) concentrations on glucocorticoid-regulated gene expression in the rat pancreatic acinar cell line AR42J. Incubation of AR42J cells with dexa-methasone results in a time-dependent transcriptional stimulation of amylase gene expression (about 5-fold) and a transcriptional inhibition of bombesin receptor (BR) gene expression. Decreasing the intracellular GR concentration to

Astrid Kaiser; Ute Stier; Ernst-Otto Riecken; Stefan Rosewicz

1996-01-01

239

Association between olfactory receptor genes, eating behavior traits and adiposity: results from the Quebec Family Study.  

PubMed

Obesity is a major health problem that can be influenced by eating behaviors. Evidence suggests that the sensory properties of food influence eating behaviors and lead to overeating and overweight. A previous genome-wide linkage scan for eating behavior traits assessed with the Three-Factor Eating Questionnaire (cognitive dietary restraint, disinhibition and hunger) performed in the Quebec Family Study (QFS) revealed a quantitative trait locus for disinhibition on chromosome 19p13. This region encodes a cluster of seven olfactory receptor (OR) genes, including OR7D4, previously associated with odor perceptions. Direct sequencing of the OR7D4 gene revealed 16 sequence variants. Nine OR7D4 sequence variants with minor allele frequency (MAF)>1% as well as 100 SNPs spanning the cluster of OR genes on 19p13 were tested for association with age- and sex-adjusted eating behaviors as well as adiposity traits in 890 subjects. One OR7D4 sequence variant (rs2878329 G>A) showed evidence of association with reduced levels of adiposity (p=0.03), cognitive dietary restraint (p=0.05) and susceptibility to hunger (p=0.008). None of the OR7D4 SNPs was associated with disinhibition, but a SNP (rs2240927) in another OR gene (OR7E24) showed evidence of association (p=0.03). Another SNP in the OR7G3 gene (rs10414255) was also found to be associated with adiposity and eating behaviors. These results are the first to suggest that variations in human olfactory receptor genes can influence eating behaviors and adiposity. The associations reported in the present study should be interpreted with caution considering the number of tests performed and considered as potential new hypotheses about the effects OR polymorphisms on eating behaviors and obesity that need to be further explored in other populations. PMID:22044667

Choquette, Anne C; Bouchard, Luigi; Drapeau, Vicky; Lemieux, Simone; Tremblay, Angelo; Bouchard, Claude; Vohl, Marie-Claude; Pérusse, Louis

2012-02-01

240

Estrogen-related receptor {alpha} modulates the expression of adipogenesis-related genes during adipocyte differentiation  

SciTech Connect

Estrogen-related receptor {alpha} (ERR{alpha}) is an orphan nuclear receptor that regulates cellular energy metabolism by modulating gene expression involved in fatty acid oxidation and mitochondrial biogenesis in brown adipose tissue. However, the physiological role of ERR{alpha} in adipogenesis and white adipose tissue development has not been well studied. Here, we show that ERR{alpha} and ERR{alpha}-related transcriptional coactivators, peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) coactivator-1{alpha} (PGC-1{alpha}) and PGC-1{beta}, can be up-regulated in 3T3-L1 preadipocytes at mRNA levels under the adipogenic differentiation condition including the inducer of cAMP, glucocorticoid, and insulin. Gene knockdown by ERR{alpha}-specific siRNA results in mRNA down-regulation of fatty acid binding protein 4, PPAR{gamma}, and PGC-1{alpha} in 3T3-L1 cells in the adipogenesis medium. ERR{alpha} and PGC-1{beta} mRNA expression can be also up-regulated in another preadipocyte lineage DFAT-D1 cells and a pluripotent mesenchymal cell line C3H10T1/2 under the differentiation condition. Furthermore, stable expression of ERR{alpha} in 3T3-L1 cells up-regulates adipogenic marker genes and promotes triglyceride accumulation during 3T3-L1 differentiation. These results suggest that ERR{alpha} may play a critical role in adipocyte differentiation by modulating the expression of various adipogenesis-related genes.

Ijichi, Nobuhiro [Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama (Japan); Ikeda, Kazuhiro [Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama (Japan); Horie-Inoue, Kuniko [Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama (Japan); Yagi, Ken [Division of Functional Genomics and Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Saitama (Japan); Okazaki, Yasushi [Division of Functional Genomics and Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Saitama (Japan); Inoue, Satoshi [Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama (Japan) and Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655 (Japan)]. E-mail: INOUE-GER@h.u-tokyo.ac.jp

2007-07-06

241

Olfactory receptor gene polymorphisms and nonallergic vasomotor rhinitis.  

PubMed

We sought a genotype-phenotype association: between single-nucleotide polymorphisms (SNPs) in olfactory receptor (OR) genes from the two largest OR gene clusters and odor-triggered nonallergic vasomotor rhinitis (nVMR). In the initial pedigree screen, using transmission disequilibrium test (TDT) analysis, six SNPs showed "significant" p-values between 0.0449 and 0.0043. In a second case-control population, the previously identified six SNPs did not re-emerge, whereas four new SNPs showed p-values between 0.0490 and 0.0001. Combining both studies, none of the SNPs in the TDT analysis survived the Bonferroni correction. In the population study, one SNP showed an empirical p-value of 0.0066 by shuffling cases and controls with 10(5) replicates; however, the p-value for this SNP was 0.83 in the pedigree study. This study emphasizes that underpowered studies having p-values between < 0.05 and 0.0001 should be regarded as inconclusive and require further replication before concluding the study is "informative." However, we believe that our hypothesis that an association between OR genotypes and the nVMR phenotype remains feasible. Future studies using either a genomewide association study of all OR gene-pseudogene regions throughout the genome--at the current recommended density of 2.5 to 5 kb per tag SNP--or studies incorporating microarray analyses of the entire "OR genome" in well-characterized nVMR patients are required. PMID:18446592

Bernstein, Jonathan A; Zhang, Ge; Jin, Li; Abbott, Carol; Nebert, Daniel W

2008-05-01

242

Distinct functions of acj6 splice forms in odor receptor gene choice  

PubMed Central

Individual olfactory receptor neurons (ORNs) selectively express one or a small number of odor receptors from among a large receptor repertoire. The expression of an odor receptor dictates the odor response spectrum of the ORN. The process of receptor gene choice relies in part on a combinatorial code of transcription factors. In Drosophila, the POU domain transcription factor Acj6 is one element of the transcription factor code. In acj6 null mutants, many ORNs do not express an appropriate odor receptor gene and thus are not correctly specified. We find that acj6 is alternatively spliced to yield many structurally distinct transcripts in the olfactory organs. We generate flies that express single splice forms of acj6 in an acj6? background. We find that different splice forms are functionally distinct; they differ in their abilities to specify ORN identities. Some individual splice forms can fully rescue the specification of some ORNs. Individual splice forms can function both positively and negatively in receptor gene regulation. ORNs differ in their requirements for splice forms; some are not fully rescued by any single splice form tested, suggesting that some ORNs may require the combinatorial action of multiple splice forms. Late expression of some acj6 splice forms is sufficient to rescue some ORN classes, consistent with a direct role for Acj6 isoforms in receptor gene expression. The results indicate that alternative splicing may add another level of richness to the regulatory code that underlies the process of odor receptor gene choice.

Bai, Lei; Carlson, John R.

2010-01-01

243

A polyketide biosynthetic gene cluster from Streptomyces antibioticus includes a LysR-type transcriptional regulator  

Microsoft Academic Search

In the search for Type II polyketide synthases (PKSs) a DNA fragment was isolated from Streptomyces antibioticus ATCC 11891 (a producer of oleandomycin). DNA sequencing of the cloned fragment revealed six complete ORFs whose deduced products showed similarities to those of other genes known to be involved in polyketide biosynthesis. Several S. coelicolor strains mutated in different steps of actinorhodin

Victoria Colombo; Maria Fern; Francisco Malpartida

2001-01-01

244

Genetic manipulation to analyze pheromone responses: knockouts of multiple receptor genes.  

PubMed

Gene targeting in the mouse is an essential technique to study gene function in vivo. Multigene families encoding vomeronasal receptor (VR) type 1 and type 2 consist of ~300 intact genes, which are clustered at multiple loci in the mouse genome. To understand the function of VRs and neurons expressing a particular VR in vivo, individual endogenous receptor genes can be manipulated by conventional gene targeting to create loss-of-function mutations or to visualize neurons and their axons expressing the VR. Multiple receptor genes in a cluster can also be deleted simultaneously by chromosome engineering, allowing analysis of function of a particular VR subfamily. Here, we describe protocols for conventional gene targeting and chromosome engineering for deleting a large genomic region in mouse embryonic stem (ES) cells. PMID:24014359

Ishii, Tomohiro

2013-01-01

245

Allelic association of human dopamine D sub 2 receptor gene in alcoholism  

SciTech Connect

In a blinded experiment, the authors report the first allelic association of the dopamine D{sub 2} receptor gene in alcoholism. From 70 brain samples of alcoholics and nonalcoholics, DNA was digested with restriction endonucleases and probed with a clone that contained the entire 3{prime} coding exon, the polyadenylation signal, and approximately 16.4 kilobases of noncoding 3{prime} sequence of the human dopamine D{sub 2} receptor gene ({lambda}hD2G1). In the present samples, the presence of A1 allele of the dopamine D{sub 2} receptor gene correctly classified 77% of alcoholics, and its absence classified 72% of nonalcoholics. The polymorphic pattern of this receptor gene suggests that a gene that confers susceptibility to at least one form of alcoholism is located on the q22-q23 region of chromosome 11.

Blum, K.; Sheridan, P.J.; Montgomery, A.; Jagadeeswaran, P.; Nogami, H.; Briggs, A.H. (Univ. of Texas Health Science Center, San Antonio (USA)); Noble, E.P.; Ritchie, T.; Cohn, J.B. (Univ. of California, Los Angeles (USA))

1990-04-18

246

Androgen receptor activities of p, p?DDE, fenvalerate and phoxim detected by androgen receptor reporter gene assay  

Microsoft Academic Search

In this study, we have developed a transient human androgen receptor (hAR) reporter gene assay using African monkey kidney cell line CV-1. The assay displayed appropriate response to the known androgen receptor (AR) agonist 5?-dihydrotestosterone (DHT) and AR antagonist nilutamide. DHT induced AR-mediated transcriptional activity in a concentration-dependent manner with median effective concentration (EC50) value of 3.90×10?10M. Nilutamide exhibited potent

Li-Chun Xu; Hong Sun; Jian-Feng Chen; Qian Bian; Ling Song; Xin-Ru Wang

2006-01-01

247

Association of polymorphisms in the melanocortin receptor type 2 ( MC2R, ACTH receptor) gene with heroin addiction  

Microsoft Academic Search

The melanocortin receptor type 2 (MC2R or adrenocorticotropic hormone, ACTH receptor) gene (MC2R) encodes a protein involved in regulation of adrenal cortisol secretion, important in the physiological response to stressors. A variant of MC2R, ?179A>G, results in reduction of promoter activity and less adrenal action. We hypothesize that altered stress responsivity plays a key role in the initiation of substance

Dmitri Proudnikov; Sara Hamon; Jurg Ott; Mary Jeanne Kreek

2008-01-01

248

Submicroscopic deletion of 12q13 including HOXC gene cluster with skeletal anomalies and global developmental delay.  

PubMed

We report on a patient with a submicroscopic deletion of 12q13 detected by array-CGH and confirmed by FISH. He was haploinsufficient for the HOXC gene cluster and some other neighboring genes. HOX genes have an important role in the initial formation of the body. The patient showed characteristic features including severe kyphoscoliosis, digital abnormalities, cardiac anomaly, expressive language, and global developmental delay. Radiologic features of the fingers had some similarities with those for multiple synostosis syndrome. No human genetic disorders due to HOXC abnormalities are yet known. We tentatively assume that his skeletal anomalies are associated with haploinsufficiency of the HOXC gene cluster. Further studies are necessary to determine the clinical importance of haploinsufficiency of the HOXC gene cluster. PMID:22069146

Okamoto, Nobuhiko; Tamura, Daisuke; Nishimura, Gen; Shimojima, Keiko; Yamamoto, Toshiyuki

2011-12-01

249

Estrogen Receptor a Gene Polymorphisms and Bone Mineral Density in Healthy Children and Young Adults  

Microsoft Academic Search

The accretion of peak bone mass is largely under genetic control, and one of the potential candidate genes is the estrogen receptor a (ERa) gene. The association of ERa gene polymorphisms with bone mineral density (BMD) was investigated in a group of 147 healthy caucasian children, adolescents, and young adults (57 boys and 90 girls) in a cross-sectional and longitudinal

A. M. Boot; I. M. van der Sluis; S. M. P. F. de Muinck Keizer-Schrama; J. B. J. van Meurs; E. P. Krenning; H. A. P. Pols; A. G. Uitterlinden

2004-01-01

250

DAF-16-dependent and independent expression targets of DAF-2 insulin receptor-like pathway in Caenorhabditis elegans include FKBPs 1 1 Edited by S. Reed  

Microsoft Academic Search

The daf-2 insulin-like receptor pathway regulates development and life-span in Caenorhabditis elegans. Reduced DAF-2 signaling leads to changes in downstream targets via the daf-16 gene, a fork-head transcription factor which is regulated by DAF-2, and results in extended life-span. Here, we describe the first identification of genes whose expression is controlled by the DAF-2 signaling cascade. dao-1, dao-2, dao-3, dao-4,

Hui Yu; Pamela L Larsen

2001-01-01

251

Extraordinary variation in a diversified family of immune-type receptor genes  

PubMed Central

Immune inhibitory receptor genes that encode a variable (V) region, a unique V-like C2 (V/C2) domain, a transmembrane region, and a cytoplasmic tail containing immunoreceptor tyrosine-based inhibition motifs (ITIMs) have been described previously in two lineages of bony fish. In the present study, eleven related genes encoding distinct structural forms have been identified in Ictalurus punctatus (channel catfish), a well characterized immunological model system that represents a third independent bony fish lineage. Each of the different genes encodes an N-terminal V region but differs in the number of extracellular Ig domains, number and location of joining (J) region-like motifs, presence of transmembrane regions, presence of charged residues in transmembrane regions, presence of cytoplasmic tails, and/or distribution of ITIM(s) within the cytoplasmic tails. Variation in the numbers of genomic copies of the different gene types, their patterns of expression, and relative levels of expression in mixed leukocyte cultures (MLC) is reported. V region-containing immune-type genes constitute a far more complex family than recognized originally and include individual members that might function in inhibitory or, potentially activatory manners.

Hawke, Noel A.; Yoder, Jeffrey A.; Haire, Robert N.; Mueller, M. Gail; Litman, Ronda T.; Miracle, Ann L.; Stuge, Tor; Shen, Linling; Miller, Norman; Litman, Gary W.

2001-01-01

252

Structure and variation of three canine genes involved in serotonin binding and transport: the serotonin receptor 1A gene (htr 1A), serotonin receptor 2A gene (htr 2A), and serotonin transporter gene (slc6A4)  

Microsoft Academic Search

Aggressive behavior is the most frequently encountered behavioral problem in dogs. Abnormalities in brain serotonin me- tabolism have been described in aggressive dogs. We studied canine serotonergic genes to investigate genetic factors un- derlying canine aggression. Here, we describe the characterization of three genes of the canine serotonergic system: the serotonin receptor 1A and 2A gene (htr1A and htr2A) and

L. van den Berg; L. Kwant; M. S. Hestand; B. A. van Oost; P. A. J. Leegwater

2005-01-01

253

Use of an Activated Beta-Catenin to Identify Wnt Pathway Target Genes in Caenorhabditis elegans, Including a Subset of Collagen Genes Expressed in Late Larval Development.  

PubMed

The Wnt signaling pathway plays a fundamental role during metazoan development, where it regulates diverse processes, including cell fate specification, cell migration, and stem cell renewal. Activation of the beta-catenin-dependent/canonical Wnt pathway up-regulates expression of Wnt target genes to mediate a cellular response. In the nematode Caenorhabditis elegans, a canonical Wnt signaling pathway regulates several processes during larval development; however, few target genes of this pathway have been identified. To address this deficit, we used a novel approach of conditionally activated Wnt signaling during a defined stage of larval life by overexpressing an activated beta-catenin protein, then used microarray analysis to identify genes showing altered expression compared with control animals. We identified 166 differentially expressed genes, of which 104 were up-regulated. A subset of the up-regulated genes was shown to have altered expression in mutants with decreased or increased Wnt signaling; we consider these genes to be bona fide C. elegans Wnt pathway targets. Among these was a group of six genes, including the cuticular collagen genes, bli-1 col-38, col-49, and col-71. These genes show a peak of expression in the mid L4 stage during normal development, suggesting a role in adult cuticle formation. Consistent with this finding, reduction of function for several of the genes causes phenotypes suggestive of defects in cuticle function or integrity. Therefore, this work has identified a large number of putative Wnt pathway target genes during larval life, including a small subset of Wnt-regulated collagen genes that may function in synthesis of the adult cuticle. PMID:24569038

Jackson, Belinda M; Abete-Luzi, Patricia; Krause, Michael W; Eisenmann, David M

2014-01-01

254

Use of an Activated Beta-Catenin to Identify Wnt Pathway Target Genes in Caenorhabditis elegans, Including a Subset of Collagen Genes Expressed in Late Larval Development  

PubMed Central

The Wnt signaling pathway plays a fundamental role during metazoan development, where it regulates diverse processes, including cell fate specification, cell migration, and stem cell renewal. Activation of the beta-catenin?dependent/canonical Wnt pathway up-regulates expression of Wnt target genes to mediate a cellular response. In the nematode Caenorhabditis elegans, a canonical Wnt signaling pathway regulates several processes during larval development; however, few target genes of this pathway have been identified. To address this deficit, we used a novel approach of conditionally activated Wnt signaling during a defined stage of larval life by overexpressing an activated beta-catenin protein, then used microarray analysis to identify genes showing altered expression compared with control animals. We identified 166 differentially expressed genes, of which 104 were up-regulated. A subset of the up-regulated genes was shown to have altered expression in mutants with decreased or increased Wnt signaling; we consider these genes to be bona fide C. elegans Wnt pathway targets. Among these was a group of six genes, including the cuticular collagen genes, bli-1col-38, col-49, and col-71. These genes show a peak of expression in the mid L4 stage during normal development, suggesting a role in adult cuticle formation. Consistent with this finding, reduction of function for several of the genes causes phenotypes suggestive of defects in cuticle function or integrity. Therefore, this work has identified a large number of putative Wnt pathway target genes during larval life, including a small subset of Wnt-regulated collagen genes that may function in synthesis of the adult cuticle.

Jackson, Belinda M.; Abete-Luzi, Patricia; Krause, Michael W.; Eisenmann, David M.

2014-01-01

255

PLK1 signaling in breast cancer cells cooperates with estrogen receptor-dependent gene transcription.  

PubMed

Polo-like kinase 1 (PLK1) is a key regulator of cell division and is overexpressed in many types of human cancers. Compared to its well-characterized role in mitosis, little is known about PLK1 functions in interphase. Here, we report that PLK1 mediates estrogen receptor (ER)-regulated gene transcription in human breast cancer cells. PLK1 interacts with ER and is recruited to ER cis-elements on chromatin. PLK1-coactivated genes included classical ER target genes such as Ps2, Wisp2, and Serpina3 and were enriched in developmental and tumor-suppressive functions. Performing large-scale phosphoproteomics of estradiol-treated MCF7 cells in the presence or absence of the specific PLK1 inhibitor BI2536, we identified several PLK1 end targets involved in transcription, including the histone H3K4 trimethylase MLL2, the function of which on ER target genes was impaired by PLK1 inhibition. Our results propose a mechanism for the tumor-suppressive role of PLK1 in mammals as an interphase transcriptional regulator. PMID:23770244

Wierer, Michael; Verde, Gaetano; Pisano, Paola; Molina, Henrik; Font-Mateu, Jofre; Di Croce, Luciano; Beato, Miguel

2013-06-27

256

Association of Estrogen Receptor ? Gene Polymorphisms with Cytokine Genes Expression in Systemic Lupus Erythematosus  

PubMed Central

Aim To analyze the association of estrogen receptor ? (OR?) gene polymorphisms with cytokine genes expression in patients with systemic lupus erythematosus (SLE) and controls. Methods Genomic DNA was extracted and polymorphisms of Xba? (XX, Xx, or xx genotype) and PvuII (PP, Pp, or pp) in intron 1 of OR? gene were detected by polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) method. The messenger RNA (mRNA) levels of interleukin (IL)-10, IL-4, interferon (IFN)-?, and IL-2 were assessed by semiquantitative reverse transcription polymerase chain reaction (RT-PCR). Results In patients with SLE with PpXx genotype, IL-10 and IL-4 mRNA expression was higher (P?gene polymorphism may be associated with the expression of IL-10, IL-4, IL-2, and IFN-? in patients with SLE.

Lu, Zhi-Ming; Wang, Zi-E; Liu, Yi-Qing; Wu, Chun-Xiao; Wang, Chang-Yin; Zhang, Bing-Chang; Shao, Song; Jiao, Yu-Lian; Che, Zhi-Xiang; Chen, Zi-Jiang; Zhao, Yue-Ran

2009-01-01

257

Molecular cloning and chromosomal localization of one of the human glutamate receptor genes  

SciTech Connect

Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are classified on the basis of their activation by different agonists. The agonists kainate and {alpha}-amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid define a class of glutamate receptors termed kainate receptors. The authors have isolated and sequenced a human glutamate receptor (GluHI) cDNA and determined the chromosomal localization of its gene. The DNA sequence of GluHI would encode a 907-amino acid protein that has a 97% identity to one of the rodent kainate receptor subunits. Many of the changes between the predicted amino acid sequence of GluHI and the most similar rodent kainate receptor (GluRI) occur in a region of the protein encoded in rodents by an alternatively spliced exon. The extreme conservation between the human and rat kainate receptor subunits suggests that a similar gene family will encode human kainate receptors. The GluHI mRNA is widely expressed in human brain. The human gene encoding the GluHI subunit is located at 5q33. While the GluHI gene is not located near a chromosomal region associated with any human neurogenetic disorders, the homologous region on mouse chromosome 11 contains the sites of five neurologic mutations.

Puckett, C.; Gomez, C.M.; Tung, H.; Meier, T.J.; Hood, L. (California Inst. of Technology, Pasadena (United States)); Korenberg, J.R.; Xiao Ning Chen (Cedar Sinai Medical Center, Los Angeles, CA (United States))

1991-09-01

258

Epigenetic regulation of olfactory receptor gene expression by the Myb-MuvB/dREAM complex  

PubMed Central

In both mammals and insects, an olfactory neuron will usually select a single olfactory receptor and repress remaining members of large receptor families. Here we show that a conserved multiprotein complex, Myb–MuvB (MMB)/dREAM, plays an important role in mediating neuron-specific expression of the carbon dioxide (CO2) receptor genes (Gr63a/Gr21a) in Drosophila. Activity of Myb in the complex is required for expression of Gr63a/Gr21a and acts in opposition to the histone methyltransferase Su(var)3-9. Consistent with this, we observed repressive dimethylated H3K9 modifications at the receptor gene loci, suggesting a mechanism for silencing receptor gene expression. Conversely, other complex members, Mip120 (Myb-interacting protein 120) and E2F2, are required for repression of Gr63a in inappropriate neurons. Misexpression in mutants is accompanied by an increase in the H3K4me3 mark of active chromatin at the receptor gene locus. Nuclei of CO2 receptor-expressing neurons contain reduced levels of the repressive subunit Mip120 compared with surrounding neurons and increased levels of Myb, suggesting that activity of the complex can be regulated in a cell-specific manner. Our evidence suggests a model in which olfactory receptors are regulated epigenetically and the MMB/dREAM complex plays a critical role in specifying, maintaining, and modulating the receptor-to-neuron map.

Sim, Choon Kiat; Perry, Sarah; Tharadra, Sana Khalid; Lipsick, Joseph S.; Ray, Anandasankar

2012-01-01

259

Molecular cloning and chromosomal localization of one of the human glutamate receptor genes.  

PubMed Central

Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are classified on the basis of their activation by different agonists. The agonists kainate and alpha-amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid define a class of glutamate receptors termed kainate receptors. We have isolated and sequenced a human glutamate receptor (GluHI) cDNA and determined the chromosomal localization of its gene. The DNA sequence of GluHI would encode a 907-amino acid protein that has a 97% identity to one of the rodent kainate receptor subunits. Many of the changes between the predicted amino acid sequence of GluHI and the most similar rodent kainate receptor (GluRI) occur in a region of the protein encoded in rodents by an alternatively spliced exon. The extreme conservation between the human and rat kainate receptor subunits suggests that a similar gene family will encode human kainate receptors. The GluHI mRNA is widely expressed in human brain. The human gene encoding the GluHI subunit is located at 5q33. While the GluHI gene is not located near a chromosomal region associated with any human neurogenetic disorders, the homologous region on mouse chromosome 11 contains the sites of five neurologic mutations. Images

Puckett, C; Gomez, C M; Korenberg, J R; Tung, H; Meier, T J; Chen, X N; Hood, L

1991-01-01

260

Structure and genomic organization of the human B1 receptor gene for kinins (BDKRB1).  

PubMed

Two subtypes of mammalian bradykinin receptors, B1 and B2 (BDKRB1 and BDKRB2), have been defined based on their pharmacological properties. The B1 type kinin receptors have weak affinity for intact BK or Lys-BK but strong affinity for kinin metabolites without the C-terminal arginine (e.g., des-Arg9-BK and Lys-des-Arg9-BK, also called des-Arg10-kallidin), which are generated by kininase I. The B1 receptor expression is up-regulated following tissue injury and inflammation (hyperemia, exudation, hyperalgesia, etc.). In the present study, we have cloned and sequenced the gene encoding human B1 receptor from a human genomic library. The human B1 receptor gene contains three exons separated by two introns. The first and the second exon are noncoding, while the coding region and the 3'-flanking region are located entirely on the third exon. The exon-intron arrangement of the human B1 receptor gene shows significant similarity with the genes encoding the B2 receptor subtype in human, mouse, and rat. Sequence analysis of the 5'-flanking region revealed the presence of a consensus TATA box and of numerous candidate transcription factor binding sequences. Primer extension experiments have shown the existence of multiple transcription initiation sites situated downstream and upstream from the consensus TATA box. Genomic Southern blot analysis indicated that the human B1 receptor is encoded by a single-copy gene. PMID:8660997

Bachvarov, D R; Hess, J F; Menke, J G; Larrivée, J F; Marceau, F

1996-05-01

261

Molecular cloning of a novel chemokine receptor-like gene from early stage chick embryos.  

PubMed

Proliferation, differentiation and regulated trafficking of cells are the hallmarks of development and embryogenesis. This led us to speculate a role for chemokines and their receptors in this process. Here, we report the molecular cloning of AvCRL1, a novel member of the G-protein coupled receptor family from early stage 3 days old chick embryos. While the function and ligand for this receptor remain unknown, its sequence and gene structure indicates that it is most related to the family of chemokine receptors, with highest homology to the virally induced human BLR-1 and the CXCR3 or gammaIP-10/Mig-1 receptors. PMID:9584981

Gupta, S K; Pillarisetti, K; Gray, S L; Stadel, J M

1998-04-01

262

Induction of oxytocin receptor gene expression in rabbit amnion cells.  

PubMed

Oxytocin (OT)-stimulated PGE2 release by rabbit amnion is enhanced by the up-regulation of oxytocin receptors (OTR), which increase about 200-fold at the end of pregnancy. As recent studies have shown that PGs are essential for parturition, the rise in amnion OTR and associated PGE2 synthesis are probably essential for labor initiation. The present work was directed toward understanding the mechanisms of OTR up-regulation. Levels of agents that stimulate adenylyl cyclase activity and cortisol are increased in amniotic fluid at the end of pregnancy. Addition of either forskolin or cortisol to cultured amnion cells caused an increase in OTR ligand-binding sites and steady state OTR messenger RNA (mRNA) levels. Forskolin treatment elevated OTR mRNA levels rapidly, but transiently, whereas cortisol's effects were slower and sustained. Actinomycin or cycloheximide, added 3 h after forskolin, led to a sustained elevation in OTR mRNA levels, suggesting that forskolin increases the activities of OTR mRNA-destabilizing factors along with increasing OTR mRNA concentration. Cortisol did not appear to affect OTR mRNA stability. Measurement of OTR mRNA transcription rates showed that forskolin's effects were maximal within 1 h of treatment. In contrast, cortisol-induced transcription was not apparent until 8 h. The effects of forskolin and cortisol on OTR gene transcription were synergistic. Thus, the increase in OTR mRNA levels occurring after either forskolin or cortisol treatments is the result of induction of OTR gene expression, but the effects of the two agents appear to occur at separate sites. PMID:9681495

Jeng, Y J; Lolait, S J; Soloff, M S

1998-08-01

263

Hemodynamic significance of histamine synthesis and histamine H1- and H2-receptor gene expression during endotoxemia.  

PubMed

The hypothesis that endotoxemia may modify histamine synthesis or histamine receptor expression and that these changes may contribute to cardiovascular dysfunction was tested in rabbits which were rendered endotoxemic by lipopolysaccharide (LPS; 100 micro g/kg, i.v.). The plasma histamine concentration was elevated shortly after LPS, remaining elevated (a 50-fold increase) over the experimental period of 6 h. The sustained increase in plasma histamine was associated with a time-dependent increase in expression of histidine decarboxylase (HDC) in different tissues including atrium, as determined by Western blot analysis. The H(1)-receptor antagonist diphenhydramine significantly shortened the duration of the initial hypotension and the H(2)-receptor antagonist ranitidine greatly suppressed the lasting tachycardia following LPS injection. Northern blot analysis showed that LPS dramatically induced gene expressions of histamine H(1)- and H(2)-receptors in cardiac tissues. In right atrium isolated from the septic animal, the positive chronotropic effect of histamine was significantly diminished. This was possibly due to a marked reduction in G(s)(alpha) protein expression, indicating the impaired H(2)-receptor cellular signaling. In conclusion, LPS-induced endotoxemia causes prominent increases in production of histamine through induction of HDC and in gene expression of histamine receptors. We suggest that overproduction of histamine may be partly responsible for the hemodynamic alterations of endotoxemia. PMID:12444491

Matsuda, Naoyuki; Hattori, Yuichi; Sakuraya, Fumika; Kobayashi, Masanobu; Zhang, Xiao-Hong; Kemmotsu, Osamu; Gando, Satoshi

2002-12-01

264

Family structure and phylogenetic analysis of odorant receptor genes in the large yellow croaker (Larimichthys crocea)  

PubMed Central

Background Chemosensory receptors, which are all G-protein-coupled receptors (GPCRs), come in four types: odorant receptors (ORs), vomeronasal receptors, trace-amine associated receptors and formyl peptide receptor-like proteins. The ORs are the most important receptors for detecting a wide range of environmental chemicals in daily life. Most fish OR genes have been identified from genome databases following the completion of the genome sequencing projects of many fishes. However, it remains unclear whether these OR genes from the genome databases are actually expressed in the fish olfactory epithelium. Thus, it is necessary to clone the OR mRNAs directly from the olfactory epithelium and to examine their expression status. Results Eighty-nine full-length and 22 partial OR cDNA sequences were isolated from the olfactory epithelium of the large yellow croaker, Larimichthys crocea. Bayesian phylogenetic analysis classified the vertebrate OR genes into two types, with several clades within each type, and showed that the L. crocea OR genes of each type are more closely related to those of fugu, pufferfish and stickleback than they are to those of medaka, zebrafish and frog. The reconciled tree showed 178 duplications and 129 losses. The evolutionary relationships among OR genes in these fishes accords with their evolutionary history. The fish OR genes have experienced functional divergence, and the different clades of OR genes have evolved different functions. The result of real-time PCR shows that different clades of ORs have distinct expression levels. Conclusion We have shown about 100 OR genes to be expressed in the olfactory epithelial tissues of L. crocea. The OR genes of modern fishes duplicated from their common ancestor, and were expanded over evolutionary time. The OR genes of L. crocea are closely related to those of fugu, pufferfish and stickleback, which is consistent with its evolutionary position. The different expression levels of OR genes of large yellow croaker may suggest varying roles of ORs in olfactory function.

2011-01-01

265

Corticosteroid receptors in the brain: gene targeting studies  

Microsoft Academic Search

Corticosteroids are released by the adrenal cortex with a diurnal rhythm and in response to stressful environmental changes. They not only act on peripheral organs, but also regulate brain physiology, thereby affecting mental processes like emotion and cognition. Here, we discuss the role of the two known corticosteroid receptors—glucocorticoid receptor (GR) and mineralocorticoid receptor (MR)—in the brain by summarizing the

Christoph Kellendonk; Peter Gass; Oliver Kretz; Günther Schütz; François Tronche

2002-01-01

266

Association study of dopamine D3 receptor gene and schizophrenia  

SciTech Connect

Several groups have reported an association between schizophrenia and the MscI polymorphism in the first exon of the dopamine D3 receptor gene (DRD3). We studied this polymorphism using a North American sample (117 patients plus 188 controls) and an Italian sample (97 patients plus 64 controls). In the first part of the study, we compared allele frequencies of schizophrenia patients and unmatched controls and observed a significant difference in the total sample (P = 0.01). The second part of the study involved a case control approach in which each schizophrenia patient was matched to a control of the same sex, and of similar age and ethnic background. The DRD3 allele frequencies of patients and controls revealed no significant difference between the two groups in the Italian (N = 53) or the North American (N = 54) matched populations; however, when these two matched samples were combined, a significant difference was observed (P = 0.026). Our results suggest that the MscI polymorphism may be associated with schizophrenia in the populations studied. 32 refs., 2 tabs.

Kennedy, J.L.; Billett, E.A.; Macciardi, F.M. [Univ. of Toronto, Ontario (Canada)] [and others

1995-12-18

267

Association of vitamin D receptor gene polymorphisms and bronchopulmonary dysplasia.  

PubMed

Background:Vitamin D and its receptor (VDR) have important roles in perinatal lung development. The aim of this study was to investigate the relationship between VDR gene polymorphism and bronchopulmonary dysplasia (BPD) in preterm infants.Methods:VDR Fok I, Bsm I, Apa I, and Taq I polymorphisms were genotyped using restriction fragment length polymorphism in 109 preterm infants (47 with BPD, 62 without BPD).Results:In univariate analysis, Ff (odds ratio (OR) = 3.937, P = 0.022, 95% confidence interval (CI) = 1.22-12.69) and ff (OR = 5.23, P = 0.004, 95% CI = 1.69-16.23) genotypes of Fok I were associated with the increased risk of BPD; whereas tt genotype of Taq 1 was associated with a protective effect against BPD (OR = 0.30, P = 0.04, 95% CI = 0.09-0.94). In multivariate logistic regression analysis, variant Fok 1 genotype increased risk of BPD (OR = 4.11, 95% CI = 1.08-15.68, P = 0.038) independent of patent ductus arteriosus, sepsis, mechanical ventilation, and surfactant treatment. Taq 1, Bsm 1, and Apa 1 polymorphisms did not have any effect.Conclusion:After adjusting for multiple confounders, VDR Fok 1 polymorphism was associated with the increased frequency of BPD. Further studies are needed to assess the contribution of VDR signaling to the pathogenesis of BPD and to determine if VDR polymorphisms may be suitable for identifying infants at high risk for BPD. PMID:24796371

Koroglu, Ozge Altun; Onay, Huseyin; Cakmak, Bilin; Bilgin, Betul; Yalaz, Mehmet; Tunc, Seckin; Ozkinay, Ferda; Kultursay, Nilgun

2014-08-01

268

The evolution of the Gp-Rbp-1 gene in Globodera pallida includes multiple selective replacements  

PubMed Central

The Globodera pallida SPRYSEC Gp-Rbp-1 gene encodes a secreted protein which induces effector-triggered immunity (ETI) mediated by the Solanum tuberosum disease resistance gene Gpa2. Nonetheless, it is not known how the Andes orogeny, the richness in Solanum species found along the Cordillera or the introduction of the nematode into Europe have affected the diversity of Gp-Rbp-1 and its recognition by Gpa2. We generated a dataset of 157 highly polymorphic Gp-Rbp-1 sequences and identified three Gp-Rbp-1 evolutionary pathways: the ‘Northern Peru’, ‘Peru clade I/European’ and ‘Chilean’ paths. These may have been shaped by passive dispersion of the nematode and by climatic variations that have influenced the nature and diversity of wild host species. We also confirmed that, by an analysis of the selection pressures acting on Gp-Rbp-1, this gene has evolved under positive/diversifying selection, but differently among the three evolutionary pathways described. Using this extended sequence dataset, we were able to detect eight sites under positive selection. Six sites appear to be of particular interest because of their predicted localization to the extended loops of the B30.2 domain and/or support by several computational methods. The P/S 187 position was previously identified for its effect on the interaction with GPA2. The functional importance of the other five amino acid polymorphisms observed was investigated using Agrobacterium transient transformation assays. None of these new residues, however, appears to be directly involved in Gpa2-mediated plant defence mechanisms. Thus, the P/S polymorphism observed at position 187 remains the sole variation sufficient to explain the recognition of Gp-Rbp-1 by Gpa2.

Carpentier, Jean; Esquibet, Magali; Fouville, Didier; Manzanares-Dauleux, Maria J; Kerlan, Marie-Claire; Grenier, Eric

2012-01-01

269

Using phylogenies of pheromone receptor genes in the Microbotryum violaceum species complex to investigate possible speciation by hybridization.  

PubMed

Several cases of speciation by hybridization have been reported in fungi, mostly involving recent hybridization between closely related species. In the basidiomycete genus Microbotryum by contrast some species were suspected to have arisen by hybridization between moderately distant species. In particular two species, M. lagerheimii and M. silenes-acaulis, had different placements in phylogenetic trees depending on the genes considered. Microbotryum species exhibit bipolar heterothallism, and here we analyzed sequences of the two alternate pheromone receptors to obtain further insights on the occurrence of hybridization. Indeed because mating-type loci are always heterozygous homoploid hybrid speciation should leave a permanent footprint at the mating-type locus by retaining the alternate alleles from their respective parental species. The trees obtained with each of the two pheromone receptors were well resolved, and the species relationships were in agreement with published phylogenies. Fungal pheromone receptor genes of basidiomycetes thus appear useful for phylogenetic studies, although it may not be true for the homobasidiomycetes where duplications of these genes have occurred. Furthermore an incongruence between the phylogenies of the two pheromone receptors was found for one species, M. lagerheimii, as previously observed between other nuclear genes. However additional species analyzed here revealed that the incongruence involved the whole clade including both M. lagerheimii and the Microbotryum species parasitizing Lychnis flos-cucucli. The ancestor of these species thus possibly arose via hybridization between distant ancestral lineages, although further studies should address alternative hypotheses, such as chance events during lineage sorting. PMID:20524600

Devier, Benjamin; Aguileta, Gabriela; Hood, Michael E; Giraud, Tatiana

2010-01-01

270

Effects of nuclear receptor transactivation on steroid hormone synthesis and gene expression in porcine Leydig cells.  

PubMed

Male pigs are routinely castrated at a young age to prevent the formation of androstenone, a 16-androstene testicular steroid that is a major component of boar taint. The practice of castration has been increasingly viewed as unfavorable, due to both economic considerations and animal welfare concerns. Other means of controlling boar taint, including reducing the synthesis of androstenone in the testes, would eliminate the need for castration. In this study, we determined the effects of transactivation of three nuclear receptors, the constitutive androstane receptor (CAR), pregnane X receptor (PXR), and farnesoid X receptor (FXR), on gene expression and steroid hormone metabolism in primary porcine Leydig cells. Primary cells were isolated from mature boars, and transcript expression levels were assayed using real-time PCR. The transcripts of interest included porcine orthologs of common phase I and phase II metabolic enzymes, enzymes involved in steroidogenesis, and transcripts previously shown to be differentially expressed in boars with high androstenone and boar taint levels. Transactivation of CAR, PXR, or FXR increased the expression of several genes involved in steroidogenesis, including cytochrome B5A (CYB5A) and cytochrome B5 reductase 1 (CYB5R1), as well as hydroxysteroid (17-beta) dehydrogenase 4 (HSD17B4) and retinol dehydrogenase 12 (RDH12). Treatment with (6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime (CITCO), a CAR agonist, or rifampicin (RIF), a PXR agonist, resulted in significantly (p<0.05) decreased sex steroid production and significantly (p<0.05) increased production of 16-androstene steroids. Treatment with the FXR agonist chenodeoxycholic acid (CDCA) resulted in significantly (p<0.05) decreased sex steroid production. These results indicate that transactivation of these nuclear receptors may lead to increased levels of 16-androstene steroids, likely by altering the activity of CYP17A1 through CYB5A and CYB5R1 to the andien-? synthase reaction and away from the 17?-hydroxylase and C17, 20 lyase reactions. PMID:23000191

Gray, Matthew A; Squires, E James

2013-01-01

271

An atypical case of fragile X syndrome caused by a deletion that includes the FMR-1 gene  

SciTech Connect

Fragile X syndrome results from the transcriptional inactivation of the FMR-1 gene. This is commonly caused by the expansion of an unstable CGG trinucleotide repeat in the first exon of the FMR-1 gene. We describe here an atypical case of fragile X syndrome caused by a deletion that includes the FMR-1 gene. RK is a 6-year-old hyperactive, mentally retarded male. Southern analysis of PstI digested genomic DNA was performed using a 558 bp XhoI-PstI fragment specific for the 5`-end of the FMR-1 gene. This analysis revealed the absence of the normal 1.0 kb PstI fragment, indicating the deletion of at least a portion of the FMR-1 gene. PCR analysis using Xq27.3 microsatellite and STS markers confirmed the presence of a deletion of at least 600 kb encompassing the FMR-1 gene. Southern blot and PCR analysis demonstrated that this deletion was maternally transmitted and arose as a new mutation on the grandpaternal X-chromosome. High resolution chromosome banding revealed an extremely small deletion of a portion of band Xq27 which was confirmed by fluorescent in situ hybridrization (FISH) analysis using a 34 kb cosmid containing the FMR-1 gene. As expected, RK manifests physical features typical of fragile X syndrome, including a high arched palate, prognathism, and large ears. Interestingly, RK also presents with anal atresia, obesity and short stature, features not part of fragile X syndrome. In addition, RK has normal sized testicles and does not exhibit the characteristic gaze avoidance, hand-flapping, and crowd anxiety behaviors. These atypical features may result from the deletion of additional genes in the vicinity of the FMR-1 gene. Further work is underway to determine more precisely the extent of the deletion in RK`s DNA.

Quan, F.; Johnson, D.B.; Anoe, K.S. [Oregon Health Sciences Univ., Portland OR (United States)] [and others

1994-09-01

272

Detection of Fc receptor genes from Staphylococcus aureus and streptococci by polymerase chain reaction.  

PubMed

A method based upon the polymerase chain reaction (PCR) for detecting genes encoding the Fc receptors of Staphylococcus aureus and streptococci is described. Primers were designed from the nucleotide sequences of the five Fc receptor genes encoding protein A, protein G, protein H, FcRA and protein V. Amplification products corresponding in size to the protein A and protein G genes were detected in S. aureus strain Cowan 1 and Streptococcus pyogenes strain G148, respectively, as expected. Str. pyogenes strain AR1 was shown to possess the type H receptor gene. Two clinical isolates of Str. pyogenes, strains IP-28 and ES-21L, were shown to possess genes for Fc receptor types FcRA and protein G, respectively. The identification of all these products was confirmed by restriction endonuclease analysis. Amplification of protein H genes from two other clinical isolates of streptococci, MS-4 and MS-38, yielded a product larger than expected and with a different restriction fragment pattern to strain AR1, indicating a new type of Fc receptor gene. This PCR method provides a DNA-based method for the determination of Fc receptor type in S. aureus and streptococci. PMID:8958259

Yamada, S; Yamagishi, J; Matsumoto, A

1996-12-01

273

[Novel therapy for malignant lymphoma: adoptive immuno-gene therapy using chimeric antigen receptor(CAR)-expressing T lymphocytes].  

PubMed

Adoptive T-cell therapy using chimeric antigen receptor (CAR) technology is a novel approach to cancer immuno-gene therapy. CARs are hybrid proteins consisting of target-antigen-specific single-chain antibody fragment fused to intracellular T-cell activation domains (CD28 or CD137/CD3 zeta receptor). CAR-expressing engineered T lymphocytes can directly recognize and kill tumor cells in an HLA independent manner. In the United States, promising results have been obtained in the clinical trials of adoptive immuno-gene therapy using CD19-CAR-T lymphocytes for the treatment of refractory B-cell malignancies, including chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL). In this review article, CD19-CAR-T gene therapy for refractory B-cell non-Hodgkin lymphoma is discussed. PMID:24724418

Ozawa, Keiya

2014-03-01

274

Severe phenotype in MPS II patients associated with a large deletion including contiguous genes.  

PubMed

Hunter disease or mucopolysaccharidosis type II (MPS II) is an X-linked recessive lysosomal disorder caused by the deficiency of iduronate-2-sulfatase, which is involved in the catabolism of the glycosaminoglycans (GAGs) heparan and dermatan sulphate. Our aim was to analyze three patients with severe Hunter syndrome that showed a total deletion of the iduronate-2-sulphatase (IDS) gene, after exon by exon PCR. DNA was used as a template for PCR synthesis of IDS, FRAXA, FRAXE, and DXS1113 specific amplicons. The DNA analysis for all three patients demonstrated a complete deletion of IDS, FRAXA, and FRAXE contiguous genes. We further performed SNP-array to delineate the deletion breakpoints and to characterize the deletion extension in the different patients. The results indicated a ?9.4 Mb deletion in Patient 1, a ?3.9 Mb deletion of the Xq27.3-Xq28 and a ?3.1 Mb duplication of the X q28 region in Patient 2 and a ?41.8 Kb deletion in Patient 3. SNP-array was shown to be important to map for deletion breakpoints. A comprehensive molecular analysis in patients with Hunter syndrome, especially in the ones presenting the severe form, is important to the understanding of the genetic determinants of the phenotype and for the genetic counseling to be provided to the families. PMID:22492741

Brusius-Facchin, Ana Carolina; De Souza, Carolina Fischinger Moura; Schwartz, Ida Vanessa D; Riegel, Mariluce; Melaragno, Maria Isabel; Correia, Patrícia; Moraes, Lúcia Marques; Llerena, Juan; Giugliani, Roberto; Leistner-Segal, Sandra

2012-05-01

275

A Drug-Sensitized Zebrafish Screen Identifies Multiple Genes, Including GINS3, as Regulators of Myocardial Repolarization  

PubMed Central

Background Cardiac repolarization, the process by which cardiomyocytes return to their resting potential after each beat, is a highly regulated process that is critical for heart rhythm stability. Perturbations of cardiac repolarization increase the risk for life-threatening arrhythmias and sudden cardiac death. While genetic studies of familial long QT syndromes have uncovered several key genes in cardiac repolarization, the major heritable contribution to this trait remains unexplained. Identification of additional genes may lead to a better understanding of the underlying biology, aid in identification of patients at risk for sudden death, and potentially enable new treatments for susceptible individuals. Methods and Results We extended and refined a zebrafish model of cardiac repolarization by using fluorescent reporters of transmembrane potential. We then conducted a drug-sensitized genetic screen in zebrafish, identifying 15 genes, including GINS3, that affect cardiac repolarization. Testing these genes for human relevance in two concurrently completed genome wide association studies revealed that the human GINS3 ortholog is located in the 16q21 locus which is strongly associated with QT interval. Conclusions This sensitized zebrafish screen identified 15 novel myocardial repolarization genes. Among these genes is GINS3, the human ortholog of which is a major locus in two concurrent human genome wide association studies of QT interval. These results reveal a novel network of genes that regulate cardiac repolarization.

Milan, David J.; Kim, Albert M.; Winterfield, Jeffrey R.; Jones, Ian L.; Pfeufer, Arne; Sanna, Serena; Arking, Dan E.; Amsterdam, Adam H.; Sabeh, Khaled M.; Mably, John D.; Rosenbaum, David S.; Peterson, Randall T.; Chakravarti, Aravinda; Kaab, Stefan; Roden, Dan M.; MacRae, Calum A.

2009-01-01

276

Differential Regulation of ?7 Nicotinic Receptor Gene (CHRNA7) Expression in Schizophrenic Smokers  

PubMed Central

The ?7 neuronal nicotinic receptor gene (CHRNA7) has been implicated in the pathophysiology of schizophrenia by genetic and pharmacological studies. Expression of the ?7* receptor, as measured by [125I]?-bungarotoxin autoradiography, is decreased in postmortem brain of schizophrenic subjects compared to non-mentally ill controls. Most schizophrenic patients are heavy smokers, with high levels of serum cotinine. Smoking changes the expression of multiple genes and differentially regulates gene expression in schizophrenic hippocampus. We examined the effects of smoking on CHRNA7 expression in the same tissue and find that smoking differentially regulates expression of both mRNA and protein for this gene. CHRNA7 mRNA and protein levels are significantly lower in schizophrenic nonsmokers compared to control nonsmokers and are brought to control levels in schizophrenic smokers. Sufficient protein but low surface expression of the ?7* receptor, seen in the autoradiographic studies, suggests aberrant assembly or trafficking of the receptor.

Mexal, Sharon; Berger, Ralph; Logel, Judy; Ross, Randal G.; Freedman, Robert

2009-01-01

277

Genes Dysregulated to Different Extent or Oppositely in Estrogen Receptor-Positive and Estrogen Receptor-Negative Breast Cancers  

PubMed Central

Background Directly comparing gene expression profiles of estrogen receptor-positive (ER+) and estrogen receptor-negative (ER?) breast cancers cannot determine whether differentially expressed genes between these two subtypes result from dysregulated expression in ER+ cancer or ER? cancer versus normal controls, and thus would miss critical information for elucidating the transcriptomic difference between the two subtypes. Principal Findings Using microarray datasets from TCGA, we classified the genes dysregulated in both ER+ and ER? cancers versus normal controls into two classes: (i) genes dysregulated in the same direction but to a different extent, and (ii) genes dysregulated to opposite directions, and then validated the two classes in RNA-sequencing datasets of independent cohorts. We showed that the genes dysregulated to a larger extent in ER+ cancers than in ER? cancers enriched in glycerophospholipid and polysaccharide metabolic processes, while the genes dysregulated to a larger extent in ER? cancers than in ER+ cancers enriched in cell proliferation. Phosphorylase kinase and enzymes of glycosylphosphatidylinositol (GPI) anchor biosynthesis were upregulated to a larger extent in ER+ cancers than in ER? cancers, whereas glycogen synthase and phospholipase A2 were downregulated to a larger extent in ER+ cancers than in ER? cancers. We also found that the genes oppositely dysregulated in the two subtypes significantly enriched with known cancer genes and tended to closely collaborate with the cancer genes. Furthermore, we showed the possibility that these oppositely dysregulated genes could contribute to carcinogenesis of ER+ and ER? cancers through rewiring different subpathways. Conclusions GPI-anchor biosynthesis and glycogenolysis were elevated and hydrolysis of phospholipids was depleted to a larger extent in ER+ cancers than in ER? cancers. Our findings indicate that the genes oppositely dysregulated in the two subtypes are potential cancer genes which could contribute to carcinogenesis of both ER+ and ER? cancers through rewiring different subpathways.

Zhou, Xianxiao; Shi, Tongwei; Li, Bailiang; Zhang, Yuannv; Shen, Xiaopei; Li, Hongdong; Hong, Guini; Liu, Chunyang; Guo, Zheng

2013-01-01

278

Antisense inhibition of the Nr gene restores normal ripening to the tomato Never-ripe mutant, consistent with the ethylene receptor-inhibition model.  

PubMed

The hormone ethylene regulates many aspects of plant growth and development, including fruit ripening. In transgenic tomato (Lycopersicon esculentum) plants, antisense inhibition of ethylene biosynthetic genes results in inhibited or delayed ripening. The dominant tomato mutant, Never-ripe (Nr), is insensitive to ethylene and fruit fail to ripen. The Nr phenotype results from mutation of the ethylene receptor encoded by the NR gene, such that it can no longer bind the hormone. NR has homology to the Arabidopsis ethylene receptors. Studies on ethylene perception in Arabidopsis have demonstrated that receptors operate by a "receptor inhibition" mode of action, in which they actively repress ethylene responses in the absence of the hormone, and are inactive when bound to ethylene. In ripening tomato fruit, expression of NR is highly regulated, increasing in expression at the onset of ripening, coincident with increased ethylene production. This expression suggests a requirement for the NR gene product during the ripening process, and implies that ethylene signaling via the tomato NR receptor might not operate by receptor inhibition. We used antisense inhibition to investigate the role of NR in ripening tomato fruit and determine its mode of action. We demonstrate restoration of normal ripening in Nr fruit by inhibition of the mutant Nr gene, indicating that this receptor is not required for normal ripening, and confirming receptor inhibition as the mode of action of the NR protein. PMID:11080285

Hackett, R M; Ho, C W; Lin, Z; Foote, H C; Fray, R G; Grierson, D

2000-11-01

279

Gender, variation in opioid receptor genes and sensitivity to experimental pain  

PubMed Central

Background Pain tolerance is subject to considerable inter-individual variation, which may be influenced by a number of genetic and non-genetic factors. The mu, delta and kappa opioid receptors play a role in pain perception and are thought to mediate different pain modalities. The aim of this study was to explore associations between pain thresholds and gender and genetic variants in the three opioid receptor genes (OPRM, OPRD and OPRK). Experimental multi-modal pain data from previously published studies carried out in healthy Caucasian volunteers were used in order to limit the number of confounders to the study outcome. Data on thermal skin pain (n=36), muscle pressure pain (n=31) and mechanical visceral pain (n=50)) tolerance thresholds were included. Results Nineteen genetic polymorphisms were included in linear regression modeling. Males were found to tolerate higher thermal and muscle pressure pain than females (p=0.003 and 0.02). Thirty four percent of variability in thermal skin pain was accounted for by a model consisting of OPRK rs6473799 and gender. This finding was just outside significance when correction for multiple testing was applied. Variability in muscle pressure pain tolerance was associated with OPRK rs7016778 and rs7824175. These SNPs accounted for 43% of variability in muscle pressure pain sensitivity and these findings remained significant after adjustment for multiple testing. No association was found with mechanical visceral pain. Conclusion This is a preliminary and hypothesis generating study due to the relatively small study size. However, significant association between the opioid receptor genes and experimental pain sensitivity supports the influence of genetic variability in pain perception. These findings may be used to generate hypotheses for testing in larger clinical trials of patients with painful conditions.

2013-01-01

280

Association between the serotonin 2A receptor gene and tardive dyskinesia in chronic schizophrenia  

Microsoft Academic Search

Tardive dyskinesia (TD) is a long-term adverse effect of antipsychotic drugs that are dopamine D2 receptor blockers.1 Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extrapyramidal effects profile of atypical antipsychotic drugs.2 We examined the association of three polymorphisms in the 5-HT2A receptor gene (HTR2A) with TD susceptibility—T102C3 and his452tyr4 in the coding region

R H Segman; U Heresco-Levy; B Finkel; T Goltser; R Shalem; M Schlafman; A Dorevitch; A Yakir; D Greenberg; A Lerner; B Lerer

2001-01-01

281

In Vivo Gene Modification Elucidates Subtype-Specific Functions of a2Adrenergic Receptors 1  

Microsoft Academic Search

Mice with altered a2-adrenergic receptor genes have become important tools in elucidating the subtype-specific functions of the three a2-adrenergic receptor subtypes because of the lack of sufficiently subtype-selective pharmacological agents. Mice with a deletion (knockout) of the a2A-, a2B-, or a2C-gene as well as a point mutation of the a2A-gene (a2A-D79N) and a 3-fold overexpression of the a2C-gene have been

JOSEPH W. KABLE; L. CHARLES MURRIN; DAVID B. BYLUND

282

Craniofacial Dysmorphogenesis Including Cleft Palate in Mice with an Insertional Mutation in the discs large Gene  

PubMed Central

The discs large (Dlg) protein, or synapse-associated protein 97 (SAP97), is a member of the membrane-associated guanylate kinase family of multidomain scaffolding proteins which recruits transmembrane and signaling molecules to localized plasma membrane sites. Murine dlg is the homologue of the Drosophila dlg tumor suppressor gene. The loss of dlg function in Drosophila disrupts cellular growth control, apicobasal polarity, and cell adhesion of imaginal disc epithelial cells, resulting in embryonic lethality. In this study, we isolated a mutational insertion in the murine dlg locus by gene trapping in totipotent embryonic stem cells. This insertion results in a truncated protein product that contains the N-terminal three PSD-95/DLG/ZO-1 domains of Dlg fused to the LacZ reporter and subsequently lacks the src homology 3 (SH3), protein 4.1 binding, and guanylate kinase (GUK)-like domains. The Dlg-LacZ fusion protein is expressed in epithelial, mesenchymal, neuronal, endothelial, and hematopoietic cells during embryogenesis. Mice homozygous for the dlg mutation exhibit growth retardation in utero, have hypoplasia of the premaxilla and mandible, have a cleft secondary palate, and die perinatally. Consistent with this phenotype, Dlg-LacZ is expressed in mesenchymal and epithelial cells throughout palatal development. Our genetic and phenotypic analysis of dlg mutant mice suggests that protein-protein interactions involving the SH3, protein 4.1 binding, and/or GUK-like domains are essential to the normal function of murine Dlg within craniofacial and palatal morphogenesis.

Caruana, Georgina; Bernstein, Alan

2001-01-01

283

Observations on the evolution of the melanocortin receptor gene family: distinctive features of the melanocortin-2 receptor.  

PubMed

The melanocortin receptors (MCRs) are a gene family in the rhodopsin class of G protein-coupled receptors. Based on the analysis of several metazoan genome databases it appears that the MCRs are only found in chordates. The presence of five genes in the family (i.e., mc1r, mc2r, mc3r, mc4r, mc5r) in representatives of the tetrapods indicates that the gene family is the result of two genome duplication events and one local gene duplication event during the evolution of the chordates. The MCRs are activated by melanocortin ligands (i.e., ACTH, ?-MSH, ?-MSH, ?-MSH, ?-MSH) which are all derived from the polypeptide hormone/neuropeptide precursor, POMC, and as a result the functional evolution of the MCRs is intimately associated with the co-evolution of POMC endocrine and neuronal circuits. This review will consider the origin of the MCRs, and discuss the evolutionary relationship between MC2R, MC5R, and MC4R. In addition, this review will analyze the functional evolution of the mc2r gene in light of the co-evolution of the MRAP (Melanocortin-2 Receptor Accessory Protein) gene family. PMID:23596380

Dores, Robert M

2013-01-01

284

Melatonin Receptor 1A Gene Polymorphism Associated with Polycystic Ovary Syndrome  

Microsoft Academic Search

Background\\/Aims: Melatonin receptor 1A (MTNR1A) gene is a regulator of circadian rhythms and reproductive processes. The MTNR1A gene is also a potential candidate gene of polycystic ovary syndrome (PCOS). The aim of the present study was to determine whether or not the MTNR1A gene polymorphism is associated with a predisposition to PCOS. Methods: The single nucleotide polymorphism (SNP) rs2119882 in

Chao Li; Yuhua Shi; Li You; Laicheng Wang; Zi-Jiang Chen

2011-01-01

285

Activated Notch1 Target Genes during Embryonic Cell Differentiation Depend on the Cellular Context and Include Lineage Determinants and Inhibitors  

PubMed Central

Background Notch receptor signaling controls developmental cell fates in a cell-context dependent manner. Although Notch signaling directly regulates transcription via the RBP-J/CSL DNA binding protein, little is known about the target genes that are directly activated by Notch in the respective tissues. Methodology/Principal Findings To analyze how Notch signaling mediates its context dependent function(s), we utilized a Tamoxifen-inducible system to activate Notch1 in murine embryonic stem cells at different stages of mesodermal differentiation and performed global transcriptional analyses. We find that the majority of genes regulated by Notch1 are unique for the cell type and vary widely dependent on other signals. We further show that Notch1 signaling regulates expression of genes playing key roles in cell differentiation, cell cycle control and apoptosis in a context dependent manner. In addition to the known Notch1 targets of the Hes and Hey families of transcriptional repressors, Notch1 activates the expression of regulatory transcription factors such as Sox9, Pax6, Runx1, Myf5 and Id proteins that are critically involved in lineage decisions in the absence of protein synthesis. Conclusion/Significance We suggest that Notch signaling determines lineage decisions and expansion of stem cells by directly activating both key lineage specific transcription factors and their repressors (Id and Hes/Hey proteins) and propose a model by which Notch signaling regulates cell fate commitment and self renewal in dependence of the intrinsic and extrinsic cellular context.

Meier-Stiegen, Franziska; Schwanbeck, Ralf; Bernoth, Kristina; Martini, Simone; Hieronymus, Thomas; Ruau, David; Zenke, Martin; Just, Ursula

2010-01-01

286

The evolution of animal chemosensory receptor gene repertoires: roles of chance and necessity  

Microsoft Academic Search

Chemosensory receptors are essential for the survival of organisms that range from bacteria to mammals. Recent studies have shown that the numbers of functional chemosensory receptor genes and pseudogenes vary enormously among the genomes of different animal species. Although much of the variation can be explained by the adaptation of organisms to different environments, it has become clear that a

Yoshihito Niimura; Masafumi Nozawa; Masatoshi Nei

2008-01-01

287

Regulation of Blood Pressure by the Type 1A Angiotensin II Receptor Gene  

Microsoft Academic Search

The renin-angiotensin system plays a critical role in sodium and fluid homeostasis. Genetic or acquired alterations in the expression of components of this system are strongly implicated in the pathogenesis of hypertension. To specifically examine the physiological and genetic functions of the type 1A receptor for angiotensin II, we have disrupted the mouse gene encoding this receptor in embryonic stem

Masaki Ito; Michael I. Oliverio; Peter J. Mannon; Christopher F. Best; Nobuyo Maeda; Oliver Smithies; Thomas M. Coffman

1995-01-01

288

Differential gene expression of the three natriuretic peptides and natriuretic peptide receptor subtypes in human liver  

Microsoft Academic Search

BACKGROUND: Various effects of atrial natriuretic peptide (ANP) on the liver have been observed. However, there is limited information about the types of receptors for natriuretic peptides expressed by the human liver. AIM: To investigate gene expression of the three NP receptor types (NPR) as well as of the NP in human liver. METHODS: Presence of mRNA coding for all

A M Vollmar; G Paumgartner; A L Gerbes

1997-01-01

289

Peroxisome proliferator-activated receptors: Lipid binding proteins controling gene expression  

Microsoft Academic Search

The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. Since their discovery in the beginning of the nineties the three isoforms (PPARa, ß\\/d and ?, encoded by different genes) have been implicated in the regulation of almost every single aspect of lipid metabolism and, consequently, in diseases that involve disturbances in lipid metabolism (obesity, diabetes, atherosclerosis,

Marc van Bilsen; Ger J. van der Vusse; Andries J. Gilde; Martijn Lindhout; Karin A. J. M. van der Lee

2002-01-01

290

Localization of the human luteinizing hormone\\/choriogonadotropin receptor gene (LHCGR) to chromosome 2p21  

Microsoft Academic Search

Probes corresponding to human and porcine LH (luteinizing hormone) receptor cDNA were used for in situ hybridization to human chromosomes. This allowed us to assign the LH receptor gene to chromosome 2p21.Copyright © 1990 S. Karger AG, Basel

M. F. Rousseau-Merck; M. Misrahi; M. Atger; H. Loosfelt; E. Milgrom; R. Berger

1990-01-01

291

Androgen receptor (AR) differential roles in hormone-related tumors including prostate, bladder, kidney, lung, breast and liver.  

PubMed

The androgen receptor (AR) is expressed in many cell types and the androgen/AR signaling has been found to have important roles in modulating tumorigenesis and metastasis in several cancers including prostate, bladder, kidney, lung, breast and liver. However, whether AR has differential roles in the individual cells within these tumors that contain a variety of cell types remains unclear. Generation of AR knockout (ARKO) mouse models with deletion of AR in selective cells within tumors indeed have uncovered many unique AR roles in the individual cell types during cancer development and progression. This review will discuss the results obtained from various ARKO mice and different human cell lines with special attention to the cell type- and tissue-specific ARKO models. The understanding of various results showing the AR indeed has distinct and contrasting roles in each cell type within many hormone-related tumors (as stimulator in bladder, kidney and lung metastases vs as suppressor in prostate and liver metastases) may eventually help us to develop better therapeutic approaches by targeting the AR or its downstream signaling in individual cell types to better battle these hormone-related tumors in different stages. PMID:23873027

Chang, C; Lee, S O; Yeh, S; Chang, T M

2014-06-19

292

Frequent gene amplification and overexpression of decoy receptor 3 in glioblastoma  

Microsoft Academic Search

The decoy receptor 3 (DcR3) gene is amplified at high frequency in human lung, colon, and liver cancers. DcR3 has been demonstrated to produce a secreted member of the tumor necrosis factor receptor superfamily that negatively regulates Fas-mediated apoptosis. In this study we examined DcR3 gene amplification, DcR3 mRNA expression, and DcR3 protein expression in 46 human astrocytic brain tumors

Yasuaki Arakawa; Osamu Tachibana; Mitsuhiro Hasegawa; Tadao Miyamori; Junkoh Yamashita; Yutaka Hayashi

2005-01-01

293

Involvement of a polymorphism in the 5HT2A receptor gene in impulsive behavior  

Microsoft Academic Search

Rationale and objective  Impulsive behavior has been suggested to occur due to a dysfunction of serotonergic 5-HT neurotransmission. After evaluation by a self-reporting measure, a polymorphism in the promoter of the 5-HT2A receptor gene has been proposed to underlie the impulsive behavior; however, this hypothesis is not convincing. In this study, we examined whether this 5-HT2A receptor gene polymorphism is involved

Michio Nomura; Ichiro Kusumi; Masayuki Kaneko; Takuya Masui; Makoto Daiguji; Takeji Ueno; Tsukasa Koyama; Yasuyuki Nomura

2006-01-01

294

Basic fibroblast growth factor enhances nerve growth factor receptor gene promoter activity in human neuroblastoma cell line CHP100.  

PubMed Central

The human neuroblastoma cell line CHP100 provides a useful model system in which to study the molecular mechanisms of transcriptional regulation of the low-affinity nerve growth factor receptor (NGFR) gene during neuronal development. Basic fibroblast growth factor (bFGF) induced morphological changes in CHP100 cells, including flattening of cell bodies and neurite outgrowth. bFGF also increased p75NGFR immunoreactivity, as assessed by immunocytochemistry, and increased p75NGFR mRNA levels, as assessed by Northern (RNA) blot analysis. A chimeric gene consisting of 6.7 kb of the 5'-flanking region of the human NGFR gene linked to the chloramphenicol acetyltransferase gene was constructed. In stable transformants of CHP100 cells, 10 ng of bFGF per ml induced an eightfold increase in chloramphenicol acetyltransferase activity. These results indicate that upstream elements of the NGFR gene mediate transcriptional regulation by bFGF. Images

Taiji, M; Taiji, K; Deyerle, K L; Bothwell, M

1992-01-01

295

Molecular characterization, expression profile, and polymorphism of goose dopamine D1 receptor gene.  

PubMed

Dopamine D1 receptor (DRD1) is one of the dopamine receptors with seven transmembrane domains that are coupled to the G protein. In the present study, we cloned the full coding region of DRD1 gene by the reverse transcription polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends from the goose hypothalamus tissues. Results showed that the goose DRD1 cDNA (GenBank: KF156790) contained a 1,356 bp open reading frame encoding a protein 452 amino acid with a molecular weight of 50.52 kDa and a isoelectric point of 6.96. Bioinformatics analysis indicated that the deduced amino acid sequence was 71-98 % identical to the DRD1 protein of other species, contained seven transmembrane domains and four N-glycosylation sites. A phylogenetic tree analysis revealed that the deduced goose DRD1 protein had a close genetic relationship and evolutional distance with that of duck, chicken, and zebra finch. The semi-quantitative RT-PCR analysis displayed goose DRD1 gene was widely expressed in all detected tissues, including heart, lung, liver, spleen, kidney, breast muscle, duodenum, sebum, pituitary, hypothalamus, ovary and oviduct. Eighteen single nucleotide polymorphisms were indentified in 3,169 bp length of this gene. For G90A mutation, the genotyping analysis of PCR-TspRI-RFLP showed the allele G was in dominance in all detected goose breeds, and the allele frequencies of this polymorphism were significantly different between Chinese goose breeds and foreign breeds (P < 0.01). These findings will help us understand the functions of the DRD1 gene and the molecular breeding in geese. PMID:24452723

Wang, Cui; Liu, Yi; Wang, Huiying; Wu, Huali; Gong, Shaoming; He, Daqian

2014-05-01

296

Evolution of a bitter taste receptor gene cluster in a New World sparrow.  

PubMed

Bitter taste perception likely evolved as a protective mechanism against the ingestion of harmful compounds in food. The evolution of the taste receptor type 2 (TAS2R) gene family, which encodes the chemoreceptors that are directly responsible for the detection of bitter compounds, has therefore been of considerable interest. Though TAS2R repertoires have been characterized for a number of species, to date the complement of TAS2Rs from just one bird, the chicken, which had a notably small number of TAS2Rs, has been established. Here, we used targeted mapping and genomic sequencing in the white-throated sparrow (Zonotrichia albicollis) and sample sequencing in other closely related birds to reconstruct the history of a TAS2R gene cluster physically linked to the break points of an evolutionary chromosomal rearrangement. In the white-throated sparrow, this TAS2R cluster encodes up to 18 functional bitter taste receptors and likely underwent a large expansion that predates and/or coincides with the radiation of the Emberizinae subfamily into the New World. In addition to signatures of gene birth-and-death evolution within this cluster, estimates of Ka/Ks for the songbird TAS2Rs were similar to those previously observed in mammals, including humans. Finally, comparison of the complete genomic sequence of the cluster from two common haplotypes in the white-throated sparrow revealed a number of nonsynonymous variants and differences in functional gene content within this species. These results suggest that interspecies and intraspecies genetic variability does exist in avian TAS2Rs and that these differences could contribute to variation in bitter taste perception in birds. PMID:20624740

Davis, Jamie K; Lowman, Josh J; Thomas, Pamela J; ten Hallers, Boudewijn F H; Koriabine, Maxim; Huynh, Lynn Y; Maney, Donna L; de Jong, Pieter J; Martin, Christa L; Thomas, James W

2010-01-01

297

Evolution of a Bitter Taste Receptor Gene Cluster in a New World Sparrow  

PubMed Central

Bitter taste perception likely evolved as a protective mechanism against the ingestion of harmful compounds in food. The evolution of the taste receptor type 2 (TAS2R) gene family, which encodes the chemoreceptors that are directly responsible for the detection of bitter compounds, has therefore been of considerable interest. Though TAS2R repertoires have been characterized for a number of species, to date the complement of TAS2Rs from just one bird, the chicken, which had a notably small number of TAS2Rs, has been established. Here, we used targeted mapping and genomic sequencing in the white-throated sparrow (Zonotrichia albicollis) and sample sequencing in other closely related birds to reconstruct the history of a TAS2R gene cluster physically linked to the break points of an evolutionary chromosomal rearrangement. In the white-throated sparrow, this TAS2R cluster encodes up to 18 functional bitter taste receptors and likely underwent a large expansion that predates and/or coincides with the radiation of the Emberizinae subfamily into the New World. In addition to signatures of gene birth-and-death evolution within this cluster, estimates of Ka/Ks for the songbird TAS2Rs were similar to those previously observed in mammals, including humans. Finally, comparison of the complete genomic sequence of the cluster from two common haplotypes in the white-throated sparrow revealed a number of nonsynonymous variants and differences in functional gene content within this species. These results suggest that interspecies and intraspecies genetic variability does exist in avian TAS2Rs and that these differences could contribute to variation in bitter taste perception in birds.

Davis, Jamie K.; Lowman, Josh J.; Thomas, Pamela J.; ten Hallers, Boudewijn F. H.; Koriabine, Maxim; Huynh, Lynn Y.; Maney, Donna L.; de Jong, Pieter J.; Martin, Christa L.; Thomas, James W.

2010-01-01

298

Cloning of human genes encoding novel G protein-coupled receptors  

SciTech Connect

We report the isolation and characterization of several novel human genes encoding G protein-coupled receptors. Each of the receptors contained the familiar seven transmembrane topography and most closely resembled peptide binding receptors. Gene GPR1 encoded a receptor protein that is intronless in the coding region and that shared identity (43% in the transmembrane regions) with the opioid receptors. Northern blot analysis revealed that GPR1 transcripts were expressed in the human hippocampus, and the gene was localized to chromosome 15q21.6. Gene GPR2 encoded a protein that most closely resembled an interleukin-8 receptor (51% in the transmembrane regions), and this gene, not expressed in the six brain regions examined, was localized to chromosome 17q2.1-q21.3. A third gene, GPR3, showed identity (56% in the transmembrane regions) with a previously characterized cDNA clone from rat and was localized to chromosome 1p35-p36.1. 31 refs., 5 figs., 1 tab.

Marchese, A.; Docherty, J.M.; Heiber, M. [Univ. of Toronto, (Canada)] [and others] [Univ. of Toronto, (Canada); and others

1994-10-01

299

Differential expressions and DNA methylation patterns of lysophosphatidic acid receptor genes in human colon cancer cells.  

PubMed

Lysophosphatidic acid (LPA), which is a bioactive phospholipid, interacts with specific G protein-coupled transmembrane receptors. Recently, alterations of LPA receptor genes have been reported in some tumor cells. In this study, we examined the expression profiles and DNA methylation status of LPA receptor 1-5 (LPA1-5) genes in human colon cancer cells and also looked for the mutations. Reverse transcription-polymerase chain reaction (PCR) and bisulfite sequencing analyses were carried out. While LPA1, LPA2, and LPA4 genes were expressed in DLD1, SW480, HCT116, CaCo-2, SW48, and LoVo cells, the expressions of LPA3 and LPA5 genes were various. These expression levels were correlated with DNA methylation status in the 5' upstream regions of the LPA receptor genes. Mutation analysis was also performed using a PCR-single-strand conformation polymorphism method. Although no mutations in LPA1, LPA3 and LPA5 genes were found in all types of cells, LPA2 mutations in DLD1 and SW48 cells, and LPA4 mutation were found in DLD1 cells. On the basis of the present results, we demonstrate that these colon cancer cells will be available to understanding the molecular pathway through LPA receptors in the development of tumor cells, and that LPA receptors may be new molecular targets for therapeutic approaches and chemoprevention. PMID:20890765

Tsujino, Megumu; Fujii, Minako; Okabe, Kyoko; Mori, Toshio; Fukushima, Nobuyuki; Tsujiuchi, Toshifumi

2010-12-01

300

Cytokine gene polymorphisms in periodontal disease: a meta-analysis of 53 studies including 4178 cases and 4590 controls  

Microsoft Academic Search

Aim: We conducted a systematic review and a meta-analysis, in order to investigate the potential association of cytokine gene polymorphisms with either aggressive or chronic periodontal disease. Material and Methods: A comprehensive literature search was performed. We retrieved a total of 53 studies summarizing information about 4178 cases and 4590 controls. Six polymorphisms were included in our meta-analysis which are

Georgios K. Nikolopoulos; Niki L. Dimou; Stavros J. Hamodrakas; Pantelis G. Bagos

2008-01-01

301

Resequencing of the auxiliary GABAB receptor subunit gene KCTD12 in chronic tinnitus  

PubMed Central

Tinnitus is a common and often incapacitating hearing disorder marked by the perception of phantom sounds. Susceptibility factors remain largely unknown but GABAB receptor signaling has long been implicated in the response to treatment and, putatively, in the etiology of the disorder. We hypothesized that variation in KCTD12, the gene encoding an auxiliary subunit of GABAB receptors, could help to predict the risk of developing tinnitus. Ninety-five Caucasian outpatients with a diagnosis of chronic tinnitus were systematically screened for mutations in the KCTD12 open reading frame and the adjacent 3? untranslated region by Sanger sequencing. Allele frequencies were determined for 14 known variants of which three (rs73237446, rs34544607, and rs41287030) were polymorphic. When allele frequencies were compared to data from a large reference population of European ancestry, rs34544607 was associated with tinnitus (p = 0.04). However, KCTD12 genotype did not predict tinnitus severity (p = 0.52) and the association with rs34544607 was weakened after screening 50 additional cases (p = 0.07). Pending replication in a larger cohort, KCTD12 may act as a risk modifier in chronic tinnitus. Issues that are yet to be addressed include the effects of neighboring variants, e.g., in the KCTD12 gene regulatory region, plus interactions with variants of GABAB1 and GABAB2.

Sand, P. G.; Langguth, B.; Itzhacki, J.; Bauer, A.; Geis, S.; Cardenas-Conejo, Z. E.; Pimentel, V.; Kleinjung, T.

2012-01-01

302

Five hydrophobin genes in Fusarium verticillioides include two required for microconidial chain formation.  

PubMed

Five hydrophobin genes have been identified in the fungal corn pathogen Fusarium verticillioides. HYD1, HYD2, and HYD3 encode Class I hydrophobins. The predicted structures of Hyd1p and Hyd2p are 80% similar, while Hyd3p has an unusually small number of amino acids between the third and fourth cysteines. HYD4 and HYD5 encode Class II hydrophobins. Mutants with HYD1-5 individually deleted and a hyd1deltahyd2delta double mutant were similar to wild-type strains in the amount of disease caused in a corn seedling infection assay and in the number of microconidia produced. Microconidial chains were rare in hyd1delta and hyd2delta mutants as microconidia were present almost exclusively as false heads. Transformation of hyd1delta and hyd2delta mutants with HYD1 and HYD2, respectively, restored microconidial chain formation, but transformation with HYD1::AcGFP and HYD2::AcGFP did not complement the mutation. HYD1::AcGFP and HYD2::AcGFP localized to the outside of conidia in false heads and in chains. PMID:15288021

Fuchs, Uta; Czymmek, Kirk J; Sweigard, James A

2004-09-01

303

Oestrogen receptor ? gene polymorphisms in systemic lupus erythematosus  

PubMed Central

Objective: To analyse associations of two oestrogen receptor ? (OR?) gene polymorphisms in 260 patients with SLE from northern Sweden. The two polymorphisms, PvuII T/C and the XbaI A/G, are located in the first intron of the OR? gene. Methods: All patients fulfilling at least four of the ACR criteria for SLE were consecutively recruited during one year. The SLEDAI score and SLICC damage index were recorded. 670 individuals from the same geographical area served as controls. DNA from the patients and controls was extracted and genotyped using the 5' nuclease assay with an ABI PRISM 7900HT instrument. The genotype/phenotype relationships were calculated using SPSS. Results: The unusual PvuII C allele was associated with malar rash and the unusual XbaI G allele with photosensitivity (p = 0.001, OR = 2.53, 95% CI = 1.43 to 4.47 and p = 0.007, OR = 2.12, 95% CI = 1.22 to 3.66, respectively). The common XbaI AA genotype was associated with serositis (p = 0.013, OR = 1.92, 95% CI = 1.15 to 3.22). Based on the SLICC damage index associations of the common TT genotype and AA genotype with cognitive impairment were identified (p = 0.018, OR = 2.47, 95% CI = 1.17 to 5.25 and p = 0.018, OR = 2.75, 95% CI = 1.19 to 6.38 respectively). There was also an association of the XbaI AA genotype with the angina/coronary artery bypass variable (p = 0.042, OR = 2.58, 95% CI = 1.03 to 6.43). Of the variables describing disease severity and duration it was found that carriers of the unusual PvuII C allele showed a later onset of SLE (p = 0.02) and carriers of the unusual XbaI G allele a lower SLICC damage index. Conclusions: The unusual PvuII C and XbaI G alleles were associated with a milder form of SLE characterised by skin manifestations, later onset, and less organ damage.

Johansson, M; Arlestig, L; Moller, B; Smedby, T; Rantapaa-Dahlqvis..., S

2005-01-01

304

Evolutionary Analysis of Burkholderia pseudomallei Identifies Putative Novel Virulence Genes, Including a Microbial Regulator of Host Cell Autophagy  

PubMed Central

Burkholderia pseudomallei, the causative agent of melioidosis, contains a large pathogen genome (7.2 Mb) with ?2,000 genes of putative or unknown function. Interactions with potential hosts and environmental factors may induce rapid adaptations in these B. pseudomallei genes, which can be discerned through evolutionary analysis of multiple B. pseudomallei genomes. Here we show that several previously uncharacterized B. pseudomallei genes bearing genetic signatures of rapid adaptation (positive selection) can induce diverse cellular phenotypes when expressed in mammalian cells. Notably, several of these phenotypes are plausibly related to virulence, including multinuclear giant cell formation, apoptosis, and autophagy induction. Specifically, we show that BPSS0180, a type VI cluster-associated gene, is capable of inducing autophagy in both phagocytic and nonphagocytic mammalian cells. Following infection of macrophages, a B. pseudomallei mutant disrupted in BPSS0180 exhibited significantly decreased colocalization with LC3 and impaired intracellular survival; these phenotypes were rescued by introduction of an intact BPSS0180 gene. The results suggest that BPSS0180 may be a novel inducer of host cell autophagy that contributes to B. pseudomallei intracellular growth. More generally, our study highlights the utility of applying evolutionary principles to microbial genomes to identify novel virulence genes.

Singh, Arvind Pratap; Lai, Shu-chin; Nandi, Tannistha; Chua, Hui Hoon; Ooi, Wen Fong; Ong, Catherine; Boyce, John D.; Adler, Ben

2013-01-01

305

A deletion including exon 2 of the TSHR gene is associated with thyroid dysgenesis and severe congenital hypothyroidism.  

PubMed

Abstract Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and 2% of cases have a familial origin. Our aim in this study was to determine the genetic alterations in two siblings with CH coming from a consanguineous family. As CH is often inherited in an autosomal recessive manner in consanguineous/multi case-families, we first performed genetic linkage studies to all known causative CH loci followed by conventional sequencing of the linked gene. The family showed potential linkage to the TSHR locus and our attempts to amplify and sequence exon 2 of the TSHR gene continuously failed. Subsequent RT-PCR analysis using mRNA and corresponding cDNA showed a large deletion including the exon 2 of the gene. The deletion was homozygous in affected cases whilst heterozygous in carrier parents. Here we conclude that CH in both siblings of this study originates from a large deletion including the exon 2 of the TSHR gene. This study demonstrates that full sequence analysis in a candidate CH gene might not always be enough to detect genetic alterations, and additional analyses such as RT-PCR and MLPA might be necessary to describe putative genetic causes of the disease in some cases. It also underlines the importance of detailed molecular genetic studies in the definitive diagnosis and classification of CH. PMID:24690939

Cangul, Hakan; Schoenmakers, Nadia A; Saglam, Halil; Doganlar, Durmus; Saglam, Yaman; Eren, Erdal; Kendall, Michaela; Tarim, Omer; Barrett, Timothy G; Chatterjee, Krish; Maher, Eamonn R

2014-07-01

306

Breed Differences in Dopamine Receptor D4 Gene (DRD4) in Horses  

PubMed Central

Genetic polymorphisms in genes related to neurotransmitters or hormones affect personality or behavioral traits in many animal species including humans. In domestic animals, the allele frequency of such genes has been reported to be different among breeds and it may account for breed differences in behavior. In this study, we investigated breed differences in horses in the dopamine receptor D4 gene (DRD4), which has been reported to affect horse personality. We collected samples from seven horse breeds including those native to Japan and Korea, and compared the sequence of the DRD4 exon3 region among these breeds. We found that there were two types of polymorphisms (VNTR and SNPs) in the exon3 region, and some of them seemed to be breed-specific. In addition, we found that the allele frequency of G292A, reported to be associated with horse personality, differed greatly between native Japanese horses and Thoroughbred horses. The frequency of the A allele which is associated with low curiosity and high vigilance, was much lower in native Japanese horses (Hokkaido, 0.03; Taishu, 0.08) than in Thoroughbreds (0.62). This difference may account for breed differences in personality or behavioral traits. Further studies of the function of these polymorphisms and their effect on behavior are indicated.

HORI, Yusuke; OZAKI, Takatoshi; YAMADA, Yoshimitsu; TOZAKI, Teruaki; KIM, Heui-Soo; TAKIMOTO, Ayaka; ENDO, Maiko; MANABE, Noboru; INOUE-MURAYAMA, Miho; FUJITA, Kazuo

2013-01-01

307

Breed Differences in Dopamine Receptor D4 Gene (DRD4) in Horses.  

PubMed

Genetic polymorphisms in genes related to neurotransmitters or hormones affect personality or behavioral traits in many animal species including humans. In domestic animals, the allele frequency of such genes has been reported to be different among breeds and it may account for breed differences in behavior. In this study, we investigated breed differences in horses in the dopamine receptor D4 gene (DRD4), which has been reported to affect horse personality. We collected samples from seven horse breeds including those native to Japan and Korea, and compared the sequence of the DRD4 exon3 region among these breeds. We found that there were two types of polymorphisms (VNTR and SNPs) in the exon3 region, and some of them seemed to be breed-specific. In addition, we found that the allele frequency of G292A, reported to be associated with horse personality, differed greatly between native Japanese horses and Thoroughbred horses. The frequency of the A allele which is associated with low curiosity and high vigilance, was much lower in native Japanese horses (Hokkaido, 0.03; Taishu, 0.08) than in Thoroughbreds (0.62). This difference may account for breed differences in personality or behavioral traits. Further studies of the function of these polymorphisms and their effect on behavior are indicated. PMID:24833999

Hori, Yusuke; Ozaki, Takatoshi; Yamada, Yoshimitsu; Tozaki, Teruaki; Kim, Heui-Soo; Takimoto, Ayaka; Endo, Maiko; Manabe, Noboru; Inoue-Murayama, Miho; Fujita, Kazuo

2013-01-01

308

Variants in the Dopamine-4-Receptor Gene Promoter Are Not Associated with Sensation Seeking in Skiers  

PubMed Central

Sensation seeking is a personality trait that has been associated with disinhibited behaviours including substance use and gambling, but also with high-risk sport practices including skydiving, paragliding, and downhill skiing. Twin studies have shown that sensation seeking is moderately heritable, and candidate genes encoding components involved in dopaminergic transmission have been investigated as contributing to this type of behaviour. To determine whether variants in the regulatory regions of the dopamine-4-receptor gene (DRD4) influenced sport-specific sensation seeking, we analyzed five polymorphisms (?1106T/C, ?906T/C, ?809G/A, ?291C/T, 120-bp duplication) in the promoter region of the gene in a cohort of skiers and snowboarders (n?=?599) that represented a broad range of sensation seeking behaviours. We grouped subjects by genotype at each of the five loci and compared impulsive sensation seeking and domain-specific (skiing) sensation seeking between groups. There were no significant associations between genotype(s) and general or domain-specific sensation seeking in the skiers and snowboarders, suggesting that while DRD4 has previously been implicated in sensation seeking, the promoter variants investigated in this study do not contribute to sensation seeking in this athlete population.

Thomson, Cynthia J.; Rajala, Amelia K.; Carlson, Scott R.; Rupert, Jim L.

2014-01-01

309

The ltk gene family encodes novel receptor-like kinases with temporal expression in developing maize endosperm  

Microsoft Academic Search

We describe the isolation and characterization of maize cDNAs that are transcribed from a small gene family and encode a novel group of receptor-like kinases (RLKs). The distinctive extracellular domain of these novel RLKs includes a unique number and arrangement of leucine-rich repeats (LRRs), a proline-rich region (PRR), a putative protein degradation target sequence (PEST), and a serine-rich region (SRR).

Zhaohui Li; Eleanore T. Wurtzel

1998-01-01

310

Development and characterization of a mouse cell line expressing the human V2 vasopressin receptor gene.  

PubMed

Human genomic DNA and the HSV tk gene were cotransfected into mouse Ltk- cells and assayed for the acquisition of a Gs-coupled receptor to obtain cell lines expressing human receptors that are so far unavailable. The transfected cells were distributed into 96-well microtitration plates at a density such that after HAT (100 microM hypoxanthine, 1 microM aminopterin, and 10 microM thymidine) selection each well contained, on the average, two to three tk+ cell clones. After replication, half of them were tested for expression of a new phenotype: an adenylyl cyclase stimulatory receptor not normally expressed in the Ltk- recipient cell. The screen yielded a positive result on testing cells arising from the third transfection, the newly expressed receptor is that for arginine vasopressin, commonly referred to as type 2 or V2. DNA from primary transformants (HTB-1 cells) served to obtain secondary transformants by the same technique (HTB-2 cells). Pharmacological properties confirmed that this new receptor, which stimulates adenylyl cyclase activity 7- to 10-fold, is the human V2 receptor and not the activated homologous murine gene. The new cell line provides a permanent accessible source to study the human receptor, by-passing the need for human kidneys. The V2 receptor was susceptible to homologous down-regulation in the HTB-2 cell, but no down-regulation of the cell authentic prostaglandin E1 receptor was observed. The vasopressin receptor did not modify phospholipase-C activity in these cells as expected from V2 receptors. Thus, we successfully applied genomic DNA-mediated gene transfer and were able to develop a cell line expressing a Gs-coupled human receptor of low abundance and poor accessibility. PMID:2139494

Birnbaumer, M; Hinrichs, V; Themmen, A P; Themen, A P

1990-02-01

311

Different expression of TSH receptor and NIS genes in thyroid cancer: role of epigenetics.  

PubMed

The TSH receptor (TSHR) and sodium/iodide symporter (NIS) are key players in radioiodine-based treatment of differentiated thyroid cancers. While NIS (SLC5AS) expression is diminished/lost in most thyroid tumors, TSHR is usually preserved. To examine the mechanisms that regulate the expression of NIS and TSHR genes in thyroid tumor cells, we analyzed their expression after inhibition of ras-BRAF-MAPK and PI3K-Akt-mTOR pathways and the epigenetic control occurring at the gene promoter level in four human thyroid cancer cell lines. Quantitative real-time PCR was used to measure NIS and TSHR mRNA in thyroid cancer cell lines (TPC-1, BCPAP, WRO, and FTC-133). Western blotting was used to assess the levels of total and phosphorylated ERK and Akt. Chromatin immunoprecipitation was performed for investigating histone post-translational modifications of the TSHR and NIS genes. ERK and Akt inhibitors elicited different responses of the cells in terms of TSHR and NIS mRNA levels. Akt inhibition increased NIS transcript levels and reduced those of TSHR in FTC-133 cells but had no significant effects in BCPAP. ERK inhibition increased the expression of both genes in BCPAP cells but had no effects in FTC-133. Histone post-translational modifications observed in the basal state of the four cell lines as well as in BCPAP treated with ERK inhibitor and FTC-133 treated with Akt inhibitor show cell- and gene-specific differences. In conclusion, our data indicate that in thyroid cancer cells the expression of TSHR and NIS genes is differently controlled by multiple mechanisms, including epigenetic events elicited by major signaling pathways involved in thyroid tumorigenesis. PMID:24353283

D'Agostino, Maria; Sponziello, Marialuisa; Puppin, Cinzia; Celano, Marilena; Maggisano, Valentina; Baldan, Federica; Biffoni, Marco; Bulotta, Stefania; Durante, Cosimo; Filetti, Sebastiano; Damante, Giuseppe; Russo, Diego

2014-04-01

312

CAG Repeat Number in the Androgen Receptor Gene and Prostate Cancer.  

PubMed

Prostate cancer (PC) is the second leading cause of cancer deaths in men. The effects of androgens on prostatic tissue are mediated by the androgen receptor (AR) gene. The 5' end of exon 1 of the AR gene includes a polymorphic CAG triplet repeat that numbers between 10 to 36 in the normal population. The length of the CAG repeats is inversely related to the transactivation function of the AR gene. There is controversy over association between short CAG repeat numbers in the AR gene and PC. This retrospective case-control study evaluates the possible effect of short CAG repeats on the AR gene in prostate cancer risk in Macedonian males. A total of 392 male subjects, 134 PC patients, 106 patients with benign prostatic hyperplasia (BPH) and 152 males from the general Macedonian population were enrolled in this study. The CAG repeat length was determined by fluorescent polymerase chain reaction (PCR) amplification of exon1 of the AR gene followed by capillary electrophoresis (CE) on a genetic analyzer. The mean repeat length in PC patients was 21.5 ± 2.65, in controls 22.28 ± 2.86 (p = 0.009) and in BPH patients 22.1 ± 2.52 (p = 0.038). Short CAG repeats (<19) were found in 21.64% of PC patients vs. 9.43% in BPH patients (p = 0.0154). We also found an association of low Gleason score (<7) with short CAG repeat (<19) in PC patients (p = 0.0306), and no association between the age at diagnosis of PC and BPH and CAG repeat length. These results suggest that reduced CAG repeat length may be associated with increased prostate cancer risk in Macedonian men. PMID:24052720

Madjunkova, S; Eftimov, A; Georgiev, V; Petrovski, D; Dimovski, Aj; Plaseska-Karanfilska, D

2012-06-01

313

Homozygous Deletion of Six Olfactory Receptor Genes in a Subset of Individuals with Beta-Thalassemia  

PubMed Central

Progress in the functional studies of human olfactory receptors has been largely hampered by the lack of a reliable experimental model system. Although transgenic approaches in mice could characterize the function of individual olfactory receptors, the presence of over 300 functional genes in the human genome becomes a daunting task. Thus, the characterization of individuals with a genetic susceptibility to altered olfaction coupled with the absence of particular olfactory receptor genes will allow phenotype/genotype correlations and vindicate the function of specific olfactory receptors with their cognate ligands. We characterized a 118 kb ?-globin deletion and found that its 3? end breakpoint extends to the neighboring olfactory receptor region downstream of the ?-globin gene cluster. This deletion encompasses six contiguous olfactory receptor genes (OR51V1, OR52Z1, OR51A1P, OR52A1, OR52A5, and OR52A4) all of which are expressed in the brain. Topology analysis of the encoded proteins from these olfactory receptor genes revealed that OR52Z1, OR52A1, OR52A5, and OR52A4 are predicted to be functional receptors as they display integral characteristics of G-proteins coupled receptors. Individuals homozygous for the 118 kb ?-globin deletion are afflicted with ?-thalassemia due to a homozygous deletion of the ?-globin gene and have no alleles for the above mentioned olfactory receptors genes. This is the first example of a homozygous deletion of olfactory receptor genes in human. Although altered olfaction remains to be ascertained in these individuals, such a study can be carried out in ?-thalassemia patients from Malaysia, Indonesia and the Philippines where this mutation is common. Furthermore, OR52A1 contains a ?-globin enhancer, which was previously shown to confer continuous expression of the fetal ?-globin genes. Thus, the hypothesis that ?-thalassemia individuals, who are homozygous for the 118 kb deletion, may also have an exacerbation of their anemia due to the deletion of two copies of the ?-globin enhancer element is worthy of consideration.

Van Ziffle, Jessica; Yang, Wendy; Chehab, Farid F.

2011-01-01

314

Odorant receptor expressed sequence tags demonstrate olfactory expression of over 400 genes, extensive alternate splicing and unequal expression levels  

Microsoft Academic Search

BACKGROUND: The olfactory receptor gene family is one of the largest in the mammalian genome. Previous computational analyses have identified approximately 1,500 mouse olfactory receptors, but experimental evidence confirming olfactory function is available for very few olfactory receptors. We therefore screened a mouse olfactory epithelium cDNA library to obtain olfactory receptor expressed sequence tags, providing evidence of olfactory function for

Janet M Young; Benjamin M Shykind; Lori Tonnes-Priddy; Joseph A Ross; Megan Walker; Eleanor M Williams; Barbara J Trask

2003-01-01

315

The low density lipoprotein receptor-related protein 1: Unique tissue-specific functions revealed by selective gene knockout studies  

PubMed Central

The low-density lipoprotein (LDL) receptor-related protein (originally called LRP, but now referred to as LRP1) is a large endocytic receptor that is widely expressed in several tissues. LRP1 is a member of the LDL receptor family that plays diverse roles in various biological processes including lipoprotein metabolism, degradation of proteases, activation of lysosomal enzymes and cellular entry of bacterial toxins and viruses. Deletion of the LRP1 gene leads to lethality in mice, revealing a critical, but as of yet, undefined role in development. Tissue-specific gene deletion studies reveal an important contribution of LRP1 in the vasculature, central nervous system, in macrophages and in adipocytes. Three important properties of LRP1 dictate its diverse role in physiology: first, its ability to recognize more than thirty distinct ligands; second, its ability to bind a large number of cytoplasmic adaptor proteins via determinants located on its cytoplasmic domain in a phosphorylation-specific manner; and third, its ability to associate with and modulate the activity of other transmembrane receptors such as integrins and receptor tyrosine kinases.

Lillis, Anna P.; Van Duyn, Lauren B.; Murphy-Ullrich, Joanne E.; Strickland, Dudley K.

2008-01-01

316

Melanoma Antigen Gene Protein MAGE-11 Regulates Androgen Receptor Function by Modulating the Interdomain Interaction  

PubMed Central

Gene activation by steroid hormone receptors involves the recruitment of the steroid receptor coactivator (SRC)/p160 coactivator LXXLL motifs to activation function 2 (AF2) in the ligand binding domain. For the androgen receptor (AR), AF2 also serves as the interaction site for the AR NH2-terminal FXXLF motif in the androgen-dependent NH2-terminal and carboxyl-terminal (N/C) interaction. The relative importance of the AR AF2 site has been unclear, since the AR FXXLF motif interferes with coactivator recruitment by competitive inhibition of LXXLL motif binding. In this report, we identified the X chromosome-linked melanoma antigen gene product MAGE-11 as an AR coregulator that specifically binds the AR NH2-terminal FXXLF motif. Binding of MAGE-11 to the AR FXXLF ?-helical region stabilizes the ligand-free AR and, in the presence of an agonist, increases exposure of AF2 to the recruitment and activation by the SRC/p160 coactivators. Intracellular association between AR and MAGE-11 is supported by their coimmunoprecipitation and colocalization in the absence and presence of hormone and by competitive inhibition of the N/C interaction. AR transactivation increases in response to MAGE-11 and the SRC/p160 coactivators through mechanisms that include but are not limited to the AF2 site. MAGE-11 is expressed in androgen-dependent tissues and in prostate cancer cell lines. The results suggest MAGE-11 is a unique AR coregulator that increases AR activity by modulating the AR interdomain interaction.

Bai, Suxia; He, Bin; Wilson, Elizabeth M.

2005-01-01

317

Molecular Identification and Expressive Characterization of an Olfactory Co-Receptor Gene in the Asian Honeybee, Apis cerana cerana  

PubMed Central

Olfaction recognition process is extraordinarily complex in insects, and the olfactory receptors play an important function in the process. In this paper, a highly conserved olfactory co-receptor gene, AcerOr2 (ortholog to the Drosophila melanogaster Or83b), cloned from the antennae of the Asian honeybee, Apis cerana cerana Fabricius (Hymenoptera: Apidae), using reverse transcriptase PCR and rapid amplification of cDNA ends. The full-length sequence of the gene was 1763 bp long, and the cDNA open reading frame encoded 478 amino acid residues, including 7 putative transmembrane domains. Alignment analysis revealed that AcerOr2 shares high homology (> 74%) with similar olfactory receptors found in other Hymenoptera species. The amino acid identity with the closely related species Apis mellifera reached 99.8%. The developmental expression analysis using quantitative real-time reverse transcriptase PCR suggested that the AcerOr2 transcript was expressed at a relatively low level in the larval stage, whereas it was expressed broadly in the pupal and adult stages, with a significantly high level on the days just before and after eclosion. In situ hybridization showed that AcerOr2 mRNA was expressed in sensilla placodea and on the basal region of the worker antennal cuticle, in accordance with the previous conclusions that the conserved genes are expressed in most olfactory receptor neurons.

Zhao, Huiting; Gao, Pengfei; Zhang, Chunxiang; Ma, Weihua; Jiang, Yusuo

2013-01-01

318

Human gastric inhibitory polypeptide receptor: Cloning of the gene (GIPR) and cDNA  

SciTech Connect

Gastric inhibitory polypeptide (GIP), which is released from the gastrointestinal tract, stimulates insulin secretion from pancreatic {Beta} cells and plays a crucial role in the regulation of insulin secretion during the postprandial phase. We have isolated the human gene (GIPR) and cDNA encoding the GIP receptor by a combination of the conventional screening and polymerase chain reaction procedures. Human GIP receptor cDNA encodes a protein of 466 amino acids that is 81.5 and 81.2% identical to the previously cloned hamster and rat GIP receptor, respectively. Hydropathic analysis shows the presence of a signal peptide and seven potential transmembrane domains, a feature characteristic of the VIP/glucagon/secretin receptor family of G protein-coupled receptors. The human GIPR gene is about 13.8 kb long, consists of 14 exons, and carries 17 Alu repeats. 13 refs., 1 fig., 1 tab.

Yamada, Yuichiro; Hayami, Tadao; Nakamura, Katsuki; Kaisaki, Pamela J. [Kyoto Univ. Faculty of Medicine (Japan)] [and others

1995-10-10

319

Maternal Undernourished Fetal Kidneys Exhibit Differential Regulation of Nephrogenic Genes Including Downregulation of the Notch Signaling Pathway  

PubMed Central

Maternal undernutrition results in offspring nephron number reduction and hypertension that are hypothesized to begin as compensatory changes in fetal gene expression during gestation. To evaluate mechanisms of dysregulated nephrogenesis, pregnant Sprague Dawley rats were 50% food restricted from embryonic day (E) 10 to E20. At E20, fetal male kidneys were examined by microarray analysis. A total of 476 differentially expressed transcripts were detected including those regulating development and differentiation, mitosis and cell cycle, chromatin assembly, and steroid hormone regulation. Differentially regulated genes were detected in MAPK/ERK, Wnt, and Notch signaling pathways. Validation of the microarray results was performed for the Notch signaling pathway, an important pathway in nephron formation. Protein expression of Notch pathway factors by Western blotting showed significantly decreased Notch2 and downstream effector Hey1 protein expression, while Ctbp1 co-repressor was increased. These data together show that maternal undernutrition results in developmental disruption in fetal nephrogenesis gene expression signaling.

Magee, Thomas R.; Tafti, Sanaz A.; Desai, Mina; Liu, Qinghai; Ross, Michael G.; Nast, Cynthia C

2011-01-01

320

Formation of new genes explains lower intron density in mammalian Rhodopsin G protein-coupled receptors  

Microsoft Academic Search

Mammalian G protein-coupled receptor (GPCR) genes are characterised by a large proportion of intronless genes or a lower density of introns when compared with GPCRs of invertebrates. It is unclear which mechanisms have influenced intron density in this protein family, which is one of the largest in the mammalian genomes. We used a combination of Hidden Markov Models (HMM) and

Davids Fridmanis; Robert Fredriksson; Ivo Kapa; Helgi B. Schiöth; Janis Klovins

2007-01-01

321

T-cell receptor genes in tassel-eared squirrels ( Sciurus aberti )  

Microsoft Academic Search

The role of environmental factors in the evolution and maintenance of diversity of antigen receptor gene families which participate in the immune response in mammals is inadequately understood. In order to elucidate the impact of these factors, we have undertaken the analysis of these gene families in the tassel-eared squirrel (Sciurus aberti) which has been separated into discrete subspecies by

Peter J. Wettstein; Ranajit Chakraborty; Jack States; Giuliana Ferrari

1990-01-01

322

Positively Selected Sites in the Arabidopsis Receptor-Like Kinase Gene Family  

Microsoft Academic Search

We analyze members of the receptor-like kinase (RLK) gene family in Arabidopsis thaliana for positive selection. Likelihood analyses find evidence for positive selection in 12 of the 52 RLK family sequences groups. These 12 groups represent 97 of the 403 sequences analyzed. The majority of genes in groups subject to positive selection have not been functionally characterized, but sites under

Errol Strain; Spencer V. Muse

2005-01-01

323

Characterizing exons 11 and 1 promoters of the mu opioid receptor (Oprm) gene in transgenic mice  

Microsoft Academic Search

BACKGROUND: The complexity of the mouse mu opioid receptor (Oprm) gene was demonstrated by the identification of multiple alternatively spliced variants and promoters. Our previous studies have identified a novel promoter, exon 11 (E11) promoter, in the mouse Oprm gene. The E11 promoter is located ~10 kb upstream of the exon 1 (E1) promoter. The E11 promoter controls the expression

Jin Xu; Mingming Xu; Ying-Xian Pan

2006-01-01

324

Identification of the ancestral killer immunoglobulin-like receptor gene in primates  

Microsoft Academic Search

BACKGROUND: Killer Immunoglobulin-like Receptors (KIR) are essential immuno-surveillance molecules. They are expressed on natural killer and T cells, and interact with human leukocyte antigens. KIR genes are highly polymorphic and contribute vital variability to our immune system. Numerous KIR genes, belonging to five distinct lineages, have been identified in all primates examined thus far and shown to be rapidly evolving.

Jennifer G Sambrook; Arman Bashirova; Hanne Andersen; Mike Piatak; George S Vernikos; Penny Coggill; Jeff D Lifson; Mary Carrington; Stephan Beck

2006-01-01

325

Localization of the human progesterone receptor gene to chromosome 11q22–q23  

Microsoft Academic Search

Summary  The human progesterone receptor gene was mapped by in situ hybridization using two cDNA probes corresponding to the 5? and\\u000a 3? part of the coding sequence. This gene was localized to 11q22-q23.

M. F. Rousseau-Merck; M. Misrahi; H. Loosfelt; E. Milgrom; R. Berger

1987-01-01

326

Killer-cell Immunoglobulin-like Receptor gene linkage and copy number variation analysis by droplet digital PCR  

PubMed Central

The Killer-cell Immunoglobulin-like Receptor (KIR) gene complex has considerable biomedical importance. Patterns of polymorphism in the KIR region include variability in the gene content of haplotypes and diverse structural arrangements. Droplet digital PCR (ddPCR) was used to identify different haplotype motifs and to enumerate KIR copy number variants (CNVs). ddPCR detected a variety of KIR haplotype configurations in DNA from well-characterized cell lines. Mendelian segregation of ddPCR-estimated KIR2DL5 CNVs was observed in Gambian families and CNV typing of other KIRs was shown to be accurate when compared to an established quantitative PCR method.

2014-01-01

327

Gene expression profiling in the stress control brain region hypothalamic paraventricular nucleus reveals a novel gene network including Amyloid beta Precursor Protein  

PubMed Central

Background The pivotal role of stress in the precipitation of psychiatric diseases such as depression is generally accepted. This study aims at the identification of genes that are directly or indirectly responding to stress. Inbred mouse strains that had been evidenced to differ in their stress response as well as in their response to antidepressant treatment were chosen for RNA profiling after stress exposure. Gene expression and regulation was determined by microarray analyses and further evaluated by bioinformatics tools including pathway and cluster analyses. Results Forced swimming as acute stressor was applied to C57BL/6J and DBA/2J mice and resulted in sets of regulated genes in the paraventricular nucleus of the hypothalamus (PVN), 4 h or 8 h after stress. Although the expression changes between the mouse strains were quite different, they unfolded in phases over time in both strains. Our search for connections between the regulated genes resulted in potential novel signalling pathways in stress. In particular, Guanine nucleotide binding protein, alpha inhibiting 2 (GNAi2) and Amyloid ? (A4) precursor protein (APP) were detected as stress-regulated genes, and together with other genes, seem to be integrated into stress-responsive pathways and gene networks in the PVN. Conclusions This search for stress-regulated genes in the PVN revealed its impact on interesting genes (GNAi2 and APP) and a novel gene network. In particular the expression of APP in the PVN that is governing stress hormone balance, is of great interest. The reported neuroprotective role of this molecule in the CNS supports the idea that a short acute stress can elicit positive adaptational effects in the brain.

2010-01-01

328

Knockdown of a zebrafish aryl hydrocarbon receptor repressor (AHRRa) affects expression of genes related to photoreceptor development and hematopoiesis.  

PubMed

The aryl hydrocarbon receptor repressor (AHRR) is a transcriptional repressor of aryl hydrocarbon receptor (AHR) and hypoxia-inducible factor (HIF) and is regulated by an AHR-dependent mechanism. Zebrafish (Danio rerio) possess two AHRR paralogs; AHRRa regulates constitutive AHR signaling during development, whereas AHRRb regulates polyaromatic hydrocarbon-induced gene expression. However, little is known about the endogenous roles and targets of AHRRs. The objective of this study was to elucidate the role of AHRRs during zebrafish development using a loss-of-function approach followed by gene expression analysis. Zebrafish embryos were microinjected with morpholino oligonucleotides against AHRRa or AHRRb to knockdown AHRR protein expression. At 72 h postfertilization (hpf), microarray analysis revealed that the expression of 279 and 116 genes was altered by knockdown of AHRRa and AHRRb, respectively. In AHRRa-morphant embryos, 97 genes were up-regulated and 182 genes were down-regulated. Among the down-regulated genes were several related to photoreceptor function, including cone-specific genes such as several opsins (opn1sw1, opn1sw2, opn1mw1, and opn1lw2), phosphodiesterases (pde6H and pde6C), retinol binding protein (rbp4l), phosducin, and arrestins. Down-regulation was confirmed by RT-PCR and with samples from an independent experiment. The four genes tested (opn1sw1, pde6H, pde6C, and arr3b) were not inducible by 2,3,7,8-tetrachlorodibenzo-p-dioxin. AHRRa knockdown also caused up-regulation of embryonic hemoglobin (hbbe3), suggesting a role for AHRR in regulating hematopoiesis. Knockdown of AHRRb caused up-regulation of 31 genes and down-regulation of 85 genes, without enrichment for any specific biological process. Overall, these results suggest that AHRRs may have important roles in development, in addition to their roles in regulating xenobiotic signaling. PMID:24675095

Aluru, Neelakanteswar; Jenny, Matthew J; Hahn, Mark E

2014-06-01

329

Expression of Notch receptors, ligands and target genes during development of the mouse mammary gland  

PubMed Central

Notch genes play a critical role in mammary gland growth, development and tumorigenesis. In the present study we have quantitatively determined the levels and mRNA expression patterns of the Notch receptor genes, their ligands and target genes in the postnatal mouse mammary gland. The steady state levels of Notch3 mRNA are the highest among receptor genes, Jagged1 and Dll3 mRNA levels are the highest among ligand genes and Hey2 mRNA levels are highest among expressed Hes/Hey target genes analyzed during different stages of postnatal mammary gland development. Using an immunohistochemical approach with antibodies specific for each Notch receptor, we show that Notch proteins are temporally regulated in mammary epithelial cells during normal mammary gland development in the FVB/N mouse. The loss of ovarian hormones is associated with changes in the levels of Notch receptor mRNAs (Notch2 higher and Notch3 lower) and ligand mRNAs (Dll1 and Dll4 are higher, whereas Dll3 and Jagged1 are lower) in the mammary gland of ovariectomized mice compared to intact mice. These data define expression of the Notch ligand/receptor system throughout development of the mouse mammary gland and help set the stage for genetic analysis of Notch in this context.

Raafat, Ahmed; Goldhar, Anita S.; Klauzinska, Malgorzata; Xu, Keli; Amirjazil, Idean; McCurdy, David; Lashin, Karim; Salomon, David; Vonderhaar, Barbara K.; Egan, Sean; Callahan, Robert

2010-01-01

330

Positive and negative regulation of odor receptor gene choice in Drosophila by Acj6  

PubMed Central

Little is known about how individual olfactory receptor neurons (ORNs) select, from among many odor receptor genes, which genes to express. Acj6 (Abnormal chemosensory jump 6) is a POU-domain transcription factor essential for the specification of ORN identity and Or (odor receptor) gene expression in the Drosophila maxillary palp, one of the two adult olfactory organs. However, the mechanism by which Acj6 functions in this process has not been investigated. Here we systematically examine the role of Acj6 in the maxillary palp and in a major subset of antennal ORNs. We define an Acj6 binding site by a reiterative in vitro selection process. The site is found upstream of Or genes regulated by Acj6, and Acj6 binds to the site in Or promoters. Mutational analysis shows that the site is essential for Or regulation in vivo. Surprisingly, a novel ORN class in acj6 adults is found to arise from ectopic expression of a larval Or gene, which is repressed in wild-type via an Acj6 binding site. Thus Acj6 acts directly in the process of receptor gene choice; it plays a dual role, positive and negative, in the logic of the process, and acts in partitioning the larval and adult receptor repertoires.

Bai, Lei; Goldman, Aaron L.; Carlson, John R.

2009-01-01

331

Nuclear receptors for retinoic acid and thyroid hormone regulate transcription of keratin genes.  

PubMed Central

In the epidermis, retinoids regulate the expression of keratins, the intermediate filament proteins of epithelial cells. We have cloned the 5' regulatory regions of four human epidermal keratin genes, K#5, K#6, K#10, and K#14, and engineered constructs in which these regions drive the expression of the CAT reporter gene. By co-transfecting the constructs into epithelial cells along with the vectors expressing nuclear receptors for retinoic acid (RA) and thyroid hormone, we have demonstrated that the receptors can suppress the promoters of keratin genes. The suppression is ligand dependent; it is evident both in established cell lines and in primary cultures of epithelial cells. The three RA receptors have similar effects on keratin gene transcription. Our data indicate that the nuclear receptors for RA and thyroid hormone regulate keratin synthesis by binding to negative recognition elements in the upstream DNA sequences of the keratin genes. RA thus has a twofold effect on epidermal keratin expression: qualitatively, it regulates the regulators that effect the switch from basal cell-specific keratins to differentiation-specific ones; and quantitatively, it determines the level of keratin synthesis within the cell by direct interaction of its receptors with the keratin gene promoters. Images

Tomic, M; Jiang, C K; Epstein, H S; Freedberg, I M; Samuels, H H; Blumenberg, M

1990-01-01

332

Variants at serotonin transporter and 2A receptor genes predict cooperative behavior differentially according to presence of punishment  

PubMed Central

Punishment of free-riding has been implicated in the evolution of cooperation in humans, and yet mechanisms for punishment avoidance remain largely uninvestigated. Individual variation in these mechanisms may stem from variation in the serotonergic system, which modulates processing of aversive stimuli. Functional serotonin gene variants have been associated with variation in the processing of aversive stimuli and widely studied as risk factors for psychiatric disorders. We show that variants at the serotonin transporter gene (SLC6A4) and serotonin 2A receptor gene (HTR2A) predict contributions to the public good in economic games, dependent upon whether contribution behavior can be punished. Participants with a variant at the serotonin transporter gene contribute more, leading to group-level differences in cooperation, but this effect dissipates in the presence of punishment. When contribution behavior can be punished, those with a variant at the serotonin 2A receptor gene contribute more than those without it. This variant also predicts a more stressful experience of the games. The diversity of institutions (including norms) that govern cooperation and punishment may create selective pressures for punishment avoidance that change rapidly across time and space. Variant-specific epigenetic regulation of these genes, as well as population-level variation in the frequencies of these variants, may facilitate adaptation to local norms of cooperation and punishment.

Schroeder, Kari B.; McElreath, Richard; Nettle, Daniel

2013-01-01

333

The Reelin receptors ApoER2 and VLDLR are direct target genes of HIC1 (Hypermethylated In Cancer 1).  

PubMed

The tumor suppressor gene HIC1 (Hypermethylated In Cancer 1) is located in 17p13.3 a region frequently hypermethylated or deleted in tumors and in a contiguous-gene syndrome, the Miller-Dieker syndrome which includes classical lissencephaly (smooth brain) and severe developmental defects. HIC1 encodes a transcriptional repressor involved in the regulation of growth control, DNA damage response and cell migration properties. We previously demonstrated that the membrane-associated G-protein-coupled receptors CXCR7, ADRB2 and the tyrosine kinase receptor EphA2 are direct target genes of HIC1. Here we show that ectopic expression of HIC1 in U2OS and MDA-MB-231 cell lines decreases expression of the ApoER2 and VLDLR genes, encoding two canonical tyrosine kinase receptors for Reelin. Conversely, knock-down of endogenous HIC1 in BJ-Tert normal human fibroblasts through RNA interference results in the up-regulation of these two Reelin receptors. Finally, through chromatin immunoprecipitation (ChIP) in BJ-Tert fibroblasts, we demonstrate that HIC1 is a direct transcriptional repressor of ApoER2 and VLDLR. These data provide evidence that HIC1 is a new regulator of the Reelin pathway which is essential for the proper migration of neuronal precursors during the normal development of the cerebral cortex, of Purkinje cells in the cerebellum and of mammary epithelial cells. Deregulation of this pathway through HIC1 inactivation or deletion may contribute to its role in tumor promotion. Moreover, HIC1, through the direct transcriptional repression of ATOH1 and the Reelin receptors ApoER2 and VLDLR, could play an essential role in normal cerebellar development. PMID:24076391

Dubuissez, Marion; Faiderbe, Perrine; Pinte, Sébastien; Dehennaut, Vanessa; Rood, Brian R; Leprince, Dominique

2013-10-25

334

Change in subcutaneous adipose tissue metabolism and gene network expression during the transition period in dairy cows, including differences due to sire genetic merit.  

PubMed

Adipose metabolism is an essential contributor to the efficiency of milk production, and metabolism is controlled by several mechanisms, including gene expression of critical proteins; therefore, the objective of this study was to determine how lactational state and the genetic merit of dairy cattle affects adipose tissue (AT) metabolism and mRNA expression of genes known to control metabolism. Animals of high (HGM) and low genetic merit (LGM) were fed to requirements, and weekly dry matter intake, milk production, blood glucose, and nonesterified fatty acids were measured. Subcutaneous AT biopsies were collected at -21, 7, 28 and 56 d in milk (DIM). The mRNA expression of genes coding for lipogenic enzymes [phosphoenolpyruvate carboxykinase 1 (soluble) (PCK1), fatty acid synthase (FASN), diacylglycerol O-acyltransferase 2 (DGAT2), and stearoyl-coenzyme A desaturase (SCD)], transcription regulators [peroxisome proliferator-activated receptor ? (PPARG), thyroid hormone responsive (THRSP), wingless-type MMTV integration site family, member 10B (WNT10B), sterol regulatory element binding transcription factor 1 (SREBF1), and adiponectin (ADIPOQ)], lipolytic enzymes [hormone-sensitive lipase (LIPE), patatin-like phospholipase domain containing 2 (PNPLA2), monoglyceride lipase (MGLL), adrenoceptor ?-2 (ADRB2), adipose differentiation-related protein (ADFP), and ?-?-hydrolase domain containing 5 (ABHD5)], and genes controlling the sensing of intracellular energy [phosphodiesterase 3A (PDE3A); PDE3B; protein kinase, AMP-activated, ?-1 catalytic subunit (PRKAA1); PRKAA2; and growth hormone receptor (GHR)] was measured. Dry matter intake, blood glucose, and nonesterified fatty acid concentrations did not differ between genetic merit groups. Milk production was greater for HGM cows from 6 to 8 wk postpartum. As expected, the rates of lipogenesis decreased in early lactation, whereas stimulated lipolysis increased. At 7 DIM, lipogenesis in HGM cows increased as a function of substrate availability (0.5, 1, 2, 3, 4, or 8mM acetic acid), whereas the response in LGM cows was much less pronounced. However, the lipogenic response at 28 DIM reversed and rates were greater in tissue from LGM than HGM cows. Peak lipolytic response, regardless of DIM, was observed at the lowest dose of isoproterenol (10(-8)M), and -21 d tissue had a greater lipolysis rate than tissue at 7, 28, and 56 d. In HGM compared with LGM cows, stimulated lipolysis at 7 and 28 DIM was greater but peaked at 10(-7)M isoproterenol, suggesting differences in tissue responsiveness due to genetic merit. Regardless of genetic merit, the expression of lipogenic genes decreased markedly in early lactation, whereas those controlling lipolysis stayed similar or decreased slightly. Cows of HGM had lower expression of lipogenic genes after parturition and through 56 DIM. In contrast, the expression of most of the lipolytic enzymes, receptors and proteins was similar in all cows pre- and postpartum. These results confirm that gene transcription is a major control mechanism for AT lipogenesis during early lactation, but that control of lipolysis is likely primarily by posttranslational mechanisms. PMID:23415532

Khan, M J; Hosseini, A; Burrell, S; Rocco, S M; McNamara, J P; Loor, J J

2013-04-01

335

Precise mapping of the brain [alpha][sub 2]-adrenergic receptor gene within chromosome 4p16  

SciTech Connect

The gene encoding the brain [alpha][sub 2]-adrenergic receptor (ADRA2C) is located on human chromosome 4. It has been circumstantially associated with a number of human disorders, including Parkinson disease, panic disorders, and Huntington disease (HD). Using somatic cell hybrids, the authors localized the gene to chromosome 4p16 distal to P8 (D4S62). To investigate this locus further, they isolated several cosmid clones covering the entire gene. The gene was found to be intronless. Two (GT)[sub n] repeats in close proximity to the ADRAC2 gene were analyzed and used to define its precise location. Linkage disequilibrium studies of one microsatellite in HD families showed strong nonrandom association to the HD mutation, indicating its tight linkage to the HD gene. The investigation of families carrying recombinant chromosomes, pulsed-field analysis, and genomic walking mapped the ADRAC2 gene adjacent to D4S81, 500 kb proximal to the HD gene. The newly defined microsatellites at the ADRAC2 locus, its precise localization within 4p16, and the detailed PCR conditions facilitate the identification of any defect caused by this gene. 22 refs., 4 figs., 2 tabs.

Riess, O.; Siedlaczck, I.; Potisek, S.; Epplen, J.T. (Ruhr Univ., Bochum (Germany)); Thies, U. (Univ. of Goettingen (Germany)); Graham, R.; Theilmann, J.; Hayden, M.R. (Univ. of British Columbia, Vancouver (Canada)); Grimm, T. (Univ. of Wuerzburg (Germany))

1994-01-15

336

Evidence for association between polymorphisms in the cannabinoid receptor 1 (CNR1) gene and cannabis dependence.  

PubMed

Genomic studies of cannabis use disorders have been limited. The cannabinoid receptor 1 gene (CNR1) on chromosome 6q14-15 is an excellent candidate gene for cannabis dependence due to the important role of the G-protein coupled receptor encoded by this gene in the rewarding effects of Delta9-tetrahydrocannabinol. Previous studies have found equivocal evidence for an association between SNPs in CNR1 and a general vulnerability to substance use disorders. We investigate the association between 9 SNPs spanning CNR1 and cannabis dependence in 1,923 individuals. Two SNPs that were previously associated with cannabis dependence in other studies were also significant with this phenotype in our analyses [rs806368 (P = 0.05) and rs806380 (P = 0.009)]. Haplotype analyses revealed the association to be largely driven by the SNP rs806380. These results suggest a role for the cannabinoid receptor 1 gene in cannabis dependence. PMID:19016476

Agrawal, Arpana; Wetherill, Leah; Dick, Danielle M; Xuei, Xiaoling; Hinrichs, Anthony; Hesselbrock, Victor; Kramer, John; Nurnberger, John I; Schuckit, Marc; Bierut, Laura J; Edenberg, Howard J; Foroud, Tatiana

2009-07-01

337

Evidence for association between polymorphisms in the Cannabinoid Receptor 1 (CNR1) gene and cannabis dependence  

PubMed Central

Genomic studies of cannabis use disorders have been limited. The cannabinoid receptor 1 gene (CNR1) on chromosome 6q14–15 is an excellent candidate gene for cannabis dependence due to the important role of the G-protein coupled receptor encoded by this gene in the rewarding effects of ?9-tetrahydrocannabinol. Previous studies have found equivocal evidence for an association between SNPs in CNR1 and a general vulnerability to substance use disorders. We investigate the association between 9 SNPs spanning CNR1 and cannabis dependence in 1,923 individuals. Two SNPs that were previously associated with cannabis dependence in other studies were also significant with this phenotype in our analyses [rs806368 (p = 0.05) and rs806380 (p = 0.009)]. Haplotype analyses revealed the association to be largely driven by the SNP rs806380. These results suggest a role for the cannabinoid receptor 1 gene in cannabis dependence.

Agrawal, Arpana; Wetherill, Leah; Dick, Danielle M.; Xuei, Xiaoling; Hinrichs, Anthony; Hesselbrock, Victor; Kramer, John; Nurnberger, John I.; Schuckit, Marc; Bierut, Laura J.; Edenberg, Howard J.; Foroud, Tatiana

2009-01-01

338

Molecular cloning and chromosomal localization of the human [alpha][sub 7]-nicotinic receptor subunit gene (CHRNA7)  

SciTech Connect

The authors have isolated cDNA and genomic clones coding for the human [alpha][sub 7] neuronal nicotinic receptor subunit, the major component of brain nicotinic receptors that are blocked by [alpha]-bungarotoxin. The human [alpha][sub 7] neuronal nicotinic cDNA encodes a mature protein of 479 amino acids that is highly homologous to the rat [alpha][sub 7] neuronal nicotinic subunit (90%). The authors have mapped the human [alpha][sub 7]-nicotinic receptor subunit gene to chromosome 15, band q14, a region frequently rearranged in patients carrying a bisatellite 15 chromosome, large inv dup (15), whose clinical features include mental retardation and seizures. 15 refs., 2 figs.

Chini, B.; Raimond, E.; Moralli, D.; Balzaretti, M. (Dip. Genetica e Microbioligia, Pavia (Italy)); Elgoyhen, A.B.; Heinemann, S. (Salk Institute, La Jolla, CA (United States))

1994-01-15

339

Odorant receptor expressed sequence tags demonstrate olfactory expression of over 400 genes, extensive alternate splicing and unequal expression levels  

PubMed Central

Background The olfactory receptor gene family is one of the largest in the mammalian genome. Previous computational analyses have identified approximately 1,500 mouse olfactory receptors, but experimental evidence confirming olfactory function is available for very few olfactory receptors. We therefore screened a mouse olfactory epithelium cDNA library to obtain olfactory receptor expressed sequence tags, providing evidence of olfactory function for many additional olfactory receptors, as well as identifying gene structure and putative promoter regions. Results We identified more than 1,200 odorant receptor cDNAs representing more than 400 genes. Using real-time PCR to confirm expression level differences suggested by our screen, we find that transcript levels in the olfactory epithelium can differ between olfactory receptors by up to 300-fold. Differences for one gene pair are apparently due to both unequal numbers of expressing cells and unequal transcript levels per expressing cell. At least two-thirds of olfactory receptors exhibit multiple transcriptional variants, with alternative isoforms of both 5' and 3' untranslated regions. Some transcripts (5%) utilize splice sites within the coding region, contrary to the stereotyped olfactory receptor gene structure. Most atypical transcripts encode nonfunctional olfactory receptors, but can occasionally increase receptor diversity. Conclusions Our cDNA collection confirms olfactory function of over one-third of the intact mouse olfactory receptors. Most of these genes were previously annotated as olfactory receptors based solely on sequence similarity. Our finding that different olfactory receptors have different expression levels is intriguing given the one-neuron, one-gene expression regime of olfactory receptors. We provide 5' untranslated region sequences and candidate promoter regions for more than 300 olfactory receptors, valuable resources for computational regulatory motif searches and for designing olfactory receptor microarrays and other experimental probes.

Young, Janet M; Shykind, Benjamin M; Lane, Robert P; Tonnes-Priddy, Lori; Ross, Joseph A; Walker, Megan; Williams, Eleanor M; Trask, Barbara J

2003-01-01

340

Dopamine D4 Receptor Gene Associated with Fairness Preference in Ultimatum Game  

PubMed Central

In experimental economics, the preference for reciprocal fairness has been observed in the controlled and incentivized laboratory setting of the ultimatum game, in which two individuals decide on how to divide a sum of money, with one proposing the share while the second deciding whether to accept. Should the proposal be accepted, the amount is divided accordingly. Otherwise, both would receive no money. A recent twin study has shown that fairness preference inferred from responder behavior is heritable, yet its neurogenetic basis remains unknown. The D4 receptor (DRD4) exon3 is a well-characterized functional polymorphism, which is known to be associated with attention deficit hyperactivity disorder and personality traits including novelty seeking and self-report altruism. Applying a neurogenetic approach, we find that DRD4 is significantly associated with fairness preference. Additionally, the interaction among this gene, season of birth, and gender is highly significant. This is the first result to link preference for reciprocal fairness to a specific gene and suggests that gene × environment interactions contribute to economic decision making.

Zhong, Songfa; Israel, Salomon; Shalev, Idan; Xue, Hong; Ebstein, Richard P.; Chew, Soo Hong

2010-01-01

341

Zinc finger transcription factor Slug is a novel target gene of aryl hydrocarbon receptor  

SciTech Connect

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor. We previously showed that AhR localizes predominantly in the cytoplasm under high cell densities of a keratinocytes cell line, HaCaT, but accumulates in the nucleus at low cell densities. In the current report, we show that the Slug, which is a member of the snail/slug family of zinc finger transcriptional repressors critical for induction of epithelial-mesenchymal transitions (EMT), is activated transcriptionally in accordance with nuclear accumulation of AhR. By reporter assay of the promoter of the Slug gene, gel shift and chromatin immunoprecipitation analyses showed AhR directly binds to xenobiotic responsive element 5 at - 0.7 kb of the gene. AhR-targeted gene silencing by small interfering RNA duplexes led to the abolishment of not only CYP1A1 but also Slug induction by 3-methycholanthrene. The Slug was co-localized to the AhR at the wound margins of HaCaT cells, where apparent nuclear distribution of AhR and Slug was observed. The induced Slug was associated with reduction of an epithelial marker of cytokeratin-18 and with an increase in the mesenchymal marker, fibronectin. Taken together, these findings suggest that AhR participated in Slug induction, which, in turn, regulates cellular physiology including cell adhesion and migration.

Ikuta, Togo [Research Institute for Clinical Oncology, Saitama Cancer Center, 818 Komuro, Ina-machi, Kitaadachi-gun, Saitama 362-0806 (Japan); Kawajiri, Kaname [Research Institute for Clinical Oncology, Saitama Cancer Center, 818 Komuro, Ina-machi, Kitaadachi-gun, Saitama 362-0806 (Japan) and Solution Oriented Research for Science and Technology (SORST), Japan Science and Technology Agency, 4-1-8 Honmachi, Kawaguchi, Saitama 331-0012 (Japan)]. E-mail: kawajiri@cancer-c.pref.saitama.jp

2006-11-01

342

Zinc finger transcription factor Slug is a novel target gene of aryl hydrocarbon receptor.  

PubMed

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor. We previously showed that AhR localizes predominantly in the cytoplasm under high cell densities of a keratinocytes cell line, HaCaT, but accumulates in the nucleus at low cell densities. In the current report, we show that the Slug, which is a member of the snail/slug family of zinc finger transcriptional repressors critical for induction of epithelial-mesenchymal transitions (EMT), is activated transcriptionally in accordance with nuclear accumulation of AhR. By reporter assay of the promoter of the Slug gene, gel shift and chromatin immunoprecipitation analyses showed AhR directly binds to xenobiotic responsive element 5 at -0.7 kb of the gene. AhR-targeted gene silencing by small interfering RNA duplexes led to the abolishment of not only CYP1A1 but also Slug induction by 3-methycholanthrene. The Slug was co-localized to the AhR at the wound margins of HaCaT cells, where apparent nuclear distribution of AhR and Slug was observed. The induced Slug was associated with reduction of an epithelial marker of cytokeratin-18 and with an increase in the mesenchymal marker, fibronectin. Taken together, these findings suggest that AhR participated in Slug induction, which, in turn, regulates cellular physiology including cell adhesion and migration. PMID:16952353

Ikuta, Togo; Kawajiri, Kaname

2006-11-01

343

ADHD Diagnosis May Influence the Association between Polymorphisms in Nicotinic Acetylcholine Receptor Genes and Tobacco Smoking.  

PubMed

Polymorphisms in the CHRNA5-CHRNA3-CHRNB4 gene cluster have been shown to be involved in tobacco smoking susceptibility. Considering that attention deficit/hyperactivity disorder (ADHD) not only increases the risk but may also influence the molecular mechanisms of tobacco smoking, we analyzed the association between polymorphisms in the nicotinic acetylcholine receptor genes and tobacco smoking among individuals with or without ADHD. The sample included 1,118 subjects divided into four groups according to smoking status and ADHD diagnosis. Our results demonstrate that the minor alleles of two polymorphisms (rs578776 and rs3743078) in the CHRNA3 gene are associated with an increased risk of tobacco smoking only among patients with ADHD. These alleles have been shown in previous studies to be protective factors for smoking in subjects without ADHD. These findings add to existing evidence that ADHD may exert an important modifying effect on the genetic risk of smoking and should be considered in tobacco smoking association studies. PMID:24375168

Polina, Evelise R; Rovaris, Diego L; de Azeredo, Lucas A; Mota, Nina R; Vitola, Eduardo S; Silva, Katiane L; Guimarães-da-Silva, Paula O; Picon, Felipe A; Belmonte-de-Abreu, Paulo; Rohde, Luis A; Grevet, Eugenio H; Bau, Claiton H D

2014-06-01

344

Association of the luteinizing hormone/choriogonadotropin receptor gene polymorphism with polycystic ovary syndrome.  

PubMed

Abstract This study aimed at evaluating possible associations of the single nucleotide polymorphism (SNP) in luteinizing hormone/choriogonadotropin receptor (LHCGR) gene G935A and polycystic ovary syndrome (PCOS) phenotype. The study included 100 PCOS female patients and 60 healthy female control subjects. The patients were recruited from the Gynecology out-patient clinic, Kasr Al-Aini Hospital, Cairo University. All candidates underwent full history taking and clinical examination with calculation of body mass index. Serum and EDTA samples were collected from each patient after a written consent. A hormonal profile was done for each patient as well as DNA analysis of the G935A polymorphism of LHCGR gene. In PCOS group, 26% were homozygous (AA), 27% were heterozygous (GA) and 47% were wild genotype (GG), while in controls 30% were heterozygous and 70% were wild genotype (OR: 2.25; CI: 1.16-4.386; p value: 0.012). The homozygous 935A individuals were at higher risk to develop PCOS than controls (OR: 1.80; CI: 1.54-2.09; p value < 0.001).We found a genetic variant, which is associated with PCOS in a sample of the Egyptian population. These results may provide an opportunity to test this SNP at the LHCGR gene in fertile or infertile women with family history to assess their risk of PCOS. PMID:24592983

Bassiouny, Yasmin Ahmed; Rabie, Walaa Ahmed; Hassan, Ayman Ahmed; Darwish, Rania Kamal

2014-06-01

345

Gene Expression of Growth Factors and Growth Factor Receptors for Potential Targeted Therapy of Canine Hepatocellular Carcinoma  

PubMed Central

ABSTRACT The purpose of this study was to evaluate the gene expression of growth factors and growth factor receptors of primary hepatic masses, including hepatocellular carcinoma (HCC) and nodular hyperplasia (NH), in dogs. Quantitative real-time reverse transcriptase-polymerase chain reaction was performed to measure the expression of 18 genes in 18 HCCs, 10 NHs, 11 surrounding non-cancerous liver tissues and 4 healthy control liver tissues. Platelet-derived growth factor-B (PDGF-B), transforming growth factor-?, epidermal growth factor receptor, epidermal growth factor and hepatocyte growth factor were found to be differentially expressed in HCC compared with NH and the surrounding non-cancerous and healthy control liver tissues. PDGF-B is suggested to have the potential to become a valuable ancillary target for the treatment of canine HCC.

IIDA, Gentoku; ASANO, Kazushi; SEKI, Mamiko; SAKAI, Manabu; KUTARA, Kenji; ISHIGAKI, Kumiko; KAGAWA, Yumiko; YOSHIDA, Orie; TESHIMA, Kenji; EDAMURA, Kazuya; WATARI, Toshihiro

2013-01-01

346

Mapping the human melanocortin 2 receptor (adrenocorticotropic hormone receptor; ACTHR) gene (MC2R) to the small arm of chromosome 18 (18p11. 21-pter)  

SciTech Connect

The human adrenocorticotropic hormone receptor (ACTHR) was recently cloned and shown to belong to the superfamily of membrane receptors that couple to guanine nucleotide-binding proteins and adenylyl cyclase. A genetically heterogeneous (including both X-linked and autosomally recessive forms) congenital syndrome of general hereditary adrenal unresponsiveness to ACTH has been documented in several kindreds. This inherited defect affects one of the steps in the cascade of events of ACTH action on glucocorticoid biosynthesis, without altering mineralocorticoid productions. Since candidate targets for pathophysiological manifestations of deficient responsiveness to ACTH include lesions of the ACTHR gene, the authors undertook to map it to a chromosomal location. They first used polymerase chain reaction (PCR) amplification of NIGMS Panel 1 DNA template to assign a 960-bp-long fragment of the human ACTHR gene to chromosome 18. Subsequently, they determined the location of the ACTHR gene within human chromosome 18 by PCR amplification of genomic DNA template from somatic cell hybrids that contain deletions of this chromosome.

Vamvakopoulos, N.C.; Chrousos, G.P. (National Institute of Child Health and Human Development, Bethesda, MD (United States)); Rojas, K.; Overhauser, J. (Thomas Jefferson Univ., Philadelphia, PA (United States)); Durkin, A.S.; Nierman, W.C. (American Type Collection, Rockville, MD (United States))

1993-11-01

347

A common polymorphism in the LDL receptor gene has multiple effects on LDL receptor function  

PubMed Central

A common synonymous single nucleotide polymorphism in exon 12 of the low-density lipoprotein receptor (LDLR) gene, rs688, has been associated with increased plasma total and LDL cholesterol in several populations. Using immortalized lymphoblastoid cell lines from a healthy study population, we confirmed an earlier report that the minor allele of rs688 is associated with increased exon 12 alternative splicing (P < 0.05) and showed that this triggered nonsense-mediated decay (NMD) of the alternatively spliced LDLR mRNA. However, since synonymous single nucleotide polymorphisms may influence structure and function of the encoded proteins by co-translational effects, we sought to test whether rs688 was also functional in the full-length mRNA. In HepG2 cells expressing LDLR cDNA constructs engineered to contain the major or minor allele of rs688, the latter was associated with a smaller amount of LDLR protein at the cell surface (?21.8 ± 0.6%, P = 0.012), a higher amount in the lysosome fraction (+25.7 ± 0.3%, P = 0.037) and reduced uptake of fluorescently labeled LDL (?24.3 ± 0.7%, P < 0.01). Moreover, in the presence of exogenous proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that reduces cellular LDL uptake by promoting lysosomal degradation of LDLR, the minor allele resulted in reduced capacity of a PCSK9 monoclonal antibody to increase LDL uptake. These findings are consistent with the hypothesis that rs688, which is located in the ?-propeller region of LDLR, has effects on LDLR activity beyond its role in alternative splicing due to impairment of LDLR endosomal recycling and/or PCSK9 binding, processes in which the ?-propeller is critically involved.

Gao, Feng; Ihn, Hansel E.; Medina, Marisa W.; Krauss, Ronald M.

2013-01-01

348

Age- and Sex-Associated Plasma Proteomic Changes in Growth Hormone Receptor Gene-Disrupted Mice  

PubMed Central

Growth hormone receptor gene–disrupted (GHR?/?) mice are dwarf, insulin sensitive, and long lived despite being obese. In order to identify characteristics associated with their increased longevity, we studied age-related plasma proteomic changes in these mice. Male and female GHR?/? mice and their littermate controls were followed longitudinally at 8, 16, and 24 months of ages for plasma proteomic analysis. Relative to control littermates, GHR?/? mice had increased levels of apolipoprotein A-4 and retinol-binding protein-4 and decreased levels of apolipoprotein E, haptoglobin, and mannose-binding protein-C. Female GHR?/? mice showed decreased inflammatory cytokines including interleukin-1? and monocyte chemotactic protein-1. Additionally, sex differences were found in specific isoforms of apolipoprotein E, RBP-4, haptoglobin, albumin, and hemoglobin subunit beta. In conclusion, we find plasma proteomic changes in GHR?/? mice that favor a longer life span as well as sex differences indicative of an improved health span in female mice.

Ding, Juan; Berryman, Darlene E.; Jara, Adam

2012-01-01

349

Prognostic significance of mutations in the p53 gene, particularly in the zinc-binding domains, in lymph node- and steroid receptor positive breast cancer patients  

Microsoft Academic Search

The aim of our study was to evaluate if p53 mutations, especially those in the L2\\/L3 domains of the p53 gene, add prognostic information for node-positive and steroid receptor positive breast cancer patients. Two hundred and five tumour samples from a randomised clinical trial of 596 lymph node- and steroid receptor positive breast cancer patients were included. All patients had

E. Kucera; P. Speiser; M. Gnant; L. Szabo; H. Samonigg; H. Hausmaninger; M. Mittlböck; M. Fridrik; M. Seifert; E. Kubista; A. Reiner; R. Zeillinger; R. Jakesz

1999-01-01

350

The ERBB3 receptor in cancer and cancer gene therapy  

Microsoft Academic Search

ERBB3, a member of the epidermal growth factor receptor (EGFR) family, is unique in that its tyrosine kinase domain is functionally defective. It is activated by neuregulins, by other ERBB and nonERBB receptors as well as by other kinases, and by novel mechanisms. Downstream it interacts prominently with the phosphoinositol 3-kinase\\/AKT survival\\/mitogenic pathway, but also with GRB, SHC, SRC, ABL,

G Sithanandam; L M Anderson

2008-01-01

351

Polyunsaturated Fatty Acids Including Docosahexaenoic and Arachidonic Acid Bind to the Retinoid X Receptor   Ligand-binding Domain  

Microsoft Academic Search

Nuclear receptors (NRs) constitute a large and highly con- served family of ligand-activated transcription factors that regulate diverse biological processes such as development, metabolism, and reproduction. As such, NRs have become important drug targets, and the identification of novel NR ligands is a subject of much interest. The retinoid X recep- tor (RXR) belongs to a subfamily of NRs that

Johan Lengqvist; Alexander Mata de Urquiza; Ann-Charlotte Bergman; Timothy M. Willson; Jan Sjovall; Thomas Perlmann; William J. Griffiths

2004-01-01

352

Gene Deficiency in Activating Fc? Receptors Influences the Macrophage Phenotypic Balance and Reduces Atherosclerosis in Mice  

PubMed Central

Immunity contributes to arterial inflammation during atherosclerosis. Oxidized low-density lipoproteins induce an autoimmune response characterized by specific antibodies and immune complexes in atherosclerotic patients. We hypothesize that specific Fc? receptors for IgG constant region participate in atherogenesis by regulating the inflammatory state of lesional macrophages. In vivo we examined the role of activating Fc? receptors in atherosclerosis progression using bone marrow transplantation from mice deficient in ?-chain (the common signaling subunit of activating Fc? receptors) to hyperlipidemic mice. Hematopoietic deficiency of Fc? receptors significantly reduced atherosclerotic lesion size, which was associated with decreased number of macrophages and T lymphocytes, and increased T regulatory cell function. Lesions of Fc? receptor deficient mice exhibited increased plaque stability, as evidenced by higher collagen and smooth muscle cell content and decreased apoptosis. These effects were independent of changes in serum lipids and antibody response to oxidized low-density lipoproteins. Activating Fc? receptor deficiency reduced pro-inflammatory gene expression, nuclear factor-?B activity, and M1 macrophages at the lesion site, while increasing anti-inflammatory genes and M2 macrophages. The decreased inflammation in the lesions was mirrored by a reduced number of classical inflammatory monocytes in blood. In vitro, lack of activating Fc? receptors attenuated foam cell formation, oxidative stress and pro-inflammatory gene expression, and increased M2-associated genes in murine macrophages. Our study demonstrates that activating Fc? receptors influence the macrophage phenotypic balance in the artery wall of atherosclerotic mice and suggests that modulation of Fc? receptor-mediated inflammatory responses could effectively suppress atherosclerosis.

Mallavia, Benat; Oguiza, Ainhoa; Lopez-Franco, Oscar; Recio, Carlota; Ortiz-Munoz, Guadalupe; Lazaro, Iolanda; Lopez-Parra, Virginia; Egido, Jesus; Gomez-Guerrero, Carmen

2013-01-01

353

NR4A nuclear receptors mediate carnitine palmitoyltransferase 1A gene expression by the rexinoid HX600  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer The function of RXR heterodimers with NR4 receptors remains unknown. Black-Right-Pointing-Pointer The RXR ligand HX600 induces expression of carnitine palmitoyltransferase 1A (CPT1A). Black-Right-Pointing-Pointer HX600-induced CPT1A expression is mediated by the NR4 receptors, Nur77 and NURR1. Black-Right-Pointing-Pointer CPT1A induction by HX600 is not mediated by de novo protein synthesis. Black-Right-Pointing-Pointer CPT1A could be a target of the Nur77-RXR and NURR1-RXR heterodimers. -- Abstract: Retinoid X receptors (RXRs) are members of the nuclear receptor superfamily and can be activated by 9-cis retinoic acid (9CRA). RXRs form homodimers and heterodimers with other nuclear receptors such as the retinoic acid receptor and NR4 subfamily nuclear receptors, Nur77 and NURR1. Potential physiological roles of the Nur77-RXR and NURR1-RXR heterodimers have not been elucidated. In this study, we identified a gene regulated by these heterodimers utilizing HX600, a selective RXR agonist for Nur77-RXR and NURR1-RXR. While 9CRA induced many genes, including RAR-target genes, HX600 effectively induced only carnitine palmitoyltransferase 1A (CPT1A) in human teratocarcinoma NT2/D1 cells, which express RXR{alpha}, Nur77 and NURR1. HX600 also increased CPT1A expression in human embryonic kidney (HEK) 293 cells and hepatocyte-derived HepG2 cells. Although HX600 induced CPT1A less effectively than 9CRA, overexpression of Nur77 or NURR1 increased the HX600 response to levels similar to 9CRA in NT2/D1 and HEK293 cells. A dominant-negative form of Nur77 or NURR1 repressed the induction of CPT1A by HX600. A protein synthesis inhibitor did not alter HX600-dependent CPT1A induction. Thus, the rexinoid HX600 directly induces expression of CPT1A through a Nur77 or NURR1-mediated mechanism. CPT1A, a gene involved in fatty acid {beta}-oxidation, could be a target of RXR-NR4 receptor heterodimers.

Ishizawa, Michiyasu [Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610 (Japan)] [Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610 (Japan); Kagechika, Hiroyuki [Graduate School of Biomedical Science, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062 (Japan)] [Graduate School of Biomedical Science, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062 (Japan); Makishima, Makoto, E-mail: makishima.makoto@nihon-u.ac.jp [Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610 (Japan)] [Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610 (Japan)

2012-02-24

354

Effects of Vitamin A and D Receptor Gene Polymorphisms/Haplotypes on Immune Responses to Measles Vaccine  

PubMed Central

OBJECTIVE Vitamin A and D, and their receptors, are important regulators of the immune system, including vaccine immune response. We assessed the association between polymorphisms in the vitamin A (RARA, RARB and RARG) and vitamin D receptor (VDR)/RXRA genes and inter-individual variations in immune responses after two doses of measles vaccine in 745 subjects. METHODS Using a tagSNP approach, we genotyped 745 healthy children for the 391 polymorphisms in vitamin A and D receptor genes. RESULTS The RARB haplotype (rs6800566/rs6550976/rs9834818) was significantly associated with variations in both measles antibody (global p=0.013) and cytokine secretion levels, such as IL-10 (global p=0.006), IFN-? (global p=0.008), and TNF-? (global p=0.039) in the Caucasian subgroup. Specifically, the RARB haplotype AAC was associated with higher (t-statistic 3.27, p=0.001) measles antibody levels. At the other end of the spectrum, haplotype GG for rs6550978/rs6777544 was associated with lower antibody levels (t-statistic ?2.32, p=0.020) in the Caucasian subgroup. In a sensitivity analysis, the RARB haplotype CTGGGCAA remained marginally significant (p<0.02) when the single SNP rs12630816 was included in the model for IL-10 secretion levels. A significant association was found between lower measles-specific IFN-? Elispot responses and haplotypes rs11102986/rs11103473/rs11103482/rs10776909/rs12004589/rs35780541/rs2266677/rs875444 (global p=0.004) and rs6537944/rs3118571 (global p<0.001) in the RXRA gene for Caucasians. We also found associations between multiple RARB, VDR and RXRA SNPs/haplotypes and measles-specific IL-2, IL-6, IL-10, IFN-?, IFN-?, IFN?-1, and TNF-? cytokine secretion. CONCLUSION Our results suggest that specific allelic variations and haplotypes in the vitamin A and D receptor genes may influence adaptive immune responses to measles vaccine.

Ovsyannikova, Inna G.; Haralambieva, Iana H.; Vierkant, Robert A.; O'Byrne, Megan M.; Jacobson, Robert M.; Poland, Gregory A.

2011-01-01

355

Gustatory expression pattern of the human TAS2R bitter receptor gene family reveals a heterogenous population of bitter responsive taste receptor cells.  

PubMed

Human bitter taste is mediated by approximately 25 members of the human TAS2 receptor (hTAS2R) gene family. The hTAS2R genes are expressed in taste buds of gustatory papillae on the tongue surface. Because many naturally occurring bitter compounds are toxic, bitter taste receptors are believed to serve as warning sensors against the ingestion of toxic food compounds. An important question is whether bitter taste receptor cells are a homogeneous, broadly tuned population of cells, which uniformly express all bitter taste receptor genes, or not. Gene expression analyses in rodents demonstrated an essentially overlapping expression of TAS2R genes indicating a broad tuning, whereas functional in vivo analyses suggest a narrow tuning. The present study demonstrates the expression of all 25 human TAS2R genes in taste receptor cells of human circumvallate papillae. As shown by in situ hybridization experiments, the expression of hTAS2R genes differs in both the apparent level of expression and the number of taste receptor cells expressing these genes, suggesting a heterogeneous bitter taste receptor cell population. Differences in gene expression levels were verified by quantitative reverse transcription-PCR experiments for a subset of hTAS2R genes. Direct evidence for the heterogeneity of bitter taste receptor cells is provided by dual-labeling in situ hybridizations with selected pairs of hTAS2R gene-specific probes. Functional coexpression experiments in heterologous cells show competition among hTAS2Rs, indicating a possible biological reason for the observed expression pattern. From the data, we conclude that human bitter taste receptor cells are tuned to detect a limited subset of bitter stimuli. PMID:18003842

Behrens, Maik; Foerster, Susann; Staehler, Frauke; Raguse, Jan-Dirk; Meyerhof, Wolfgang

2007-11-14

356

Mutation screen in the GWAS derived obesity gene SH2B1 including functional analyses of detected variants  

PubMed Central

Background The SH2B1 gene (Src-homology 2B adaptor protein 1 gene) is a solid candidate gene for obesity. Large scale GWAS studies depicted markers in the vicinity of the gene; animal models suggest a potential relevance for human body weight regulation. Methods We performed a mutation screen for variants in the SH2B1 coding sequence in 95 extremely obese children and adolescents. Detected variants were genotyped in independent childhood and adult study groups (up to 11,406 obese or overweight individuals and 4,568 controls). Functional implications on STAT3 mediated leptin signalling of the detected variants were analyzed in vitro. Results We identified two new rare mutations and five known SNPs (rs147094247, rs7498665, rs60604881, rs62037368 and rs62037369) in SH2B1. Mutation g.9483C/T leads to a non-synonymous, non-conservative exchange in the beta (?Thr656Ile) and gamma (?Pro674Ser) splice variants of SH2B1. It was additionally detected in two of 11,206 (extremely) obese or overweight children, adolescents and adults, but not in 4,506 population-based normal-weight or lean controls. The non-coding mutation g.10182C/A at the 3’ end of SH2B1 was only detected in three obese individuals. For the non-synonymous SNP rs7498665 (Thr484Ala) we observed nominal over-transmission of the previously described risk allele in 705 obesity trios (nominal p?=?0.009, OR?=?1.23) and an increased frequency of the same allele in 359 cases compared to 429 controls (nominal p?=?0.042, OR?=?1.23). The obesity risk-alleles at Thr484Ala and ?Thr656Ile/?Pro674Ser had no effect on STAT3 mediated leptin receptor signalling in splice variants ? and ?. Conclusion The rare coding mutation ?Thr656Ile/?Pro674Ser (g.9483C/T) in SH2B1 was exclusively detected in overweight or obese individuals. Functional analyzes did not reveal impairments in leptin signalling for the mutated SH2B1.

2012-01-01

357

Massive Losses of Taste Receptor Genes in Toothed and Baleen Whales  

PubMed Central

Taste receptor genes are functionally important in animals, with a surprising exception in the bottlenose dolphin, which shows extensive losses of sweet, umami, and bitter taste receptor genes. To examine the generality of taste gene loss, we examined seven toothed whales and five baleen whales and sequenced the complete repertoire of three sweet/umami (T1Rs) and ten bitter (T2Rs) taste receptor genes. We found all amplified T1Rs and T2Rs to be pseudogenes in all 12 whales, with a shared premature stop codon in 10 of the 13 genes, which demonstrated massive losses of taste receptor genes in the common ancestor of whales. Furthermore, we analyzed three genome sequences from two toothed whales and one baleen whale and found that the sour taste marker gene Pkd2l1 is a pseudogene, whereas the candidate salty taste receptor genes are intact and putatively functional. Additionally, we examined three genes that are responsible for taste signal transduction and found the relaxation of functional constraints on taste signaling pathways along the ancestral branch leading to whales. Together, our results strongly suggest extensive losses of sweet, umami, bitter, and sour tastes in whales, and the relaxation of taste function most likely arose in the common ancestor of whales between 36 and 53 Ma. Therefore, whales represent the first animal group to lack four of five primary tastes, probably driven by the marine environment with high concentration of sodium, the feeding behavior of swallowing prey whole, and the dietary switch from plants to meat in the whale ancestor.

Feng, Ping; Zheng, Jinsong; Rossiter, Stephen J.; Wang, Ding; Zhao, Huabin

2014-01-01

358

Massive losses of taste receptor genes in toothed and baleen whales.  

PubMed

Taste receptor genes are functionally important in animals, with a surprising exception in the bottlenose dolphin, which shows extensive losses of sweet, umami, and bitter taste receptor genes. To examine the generality of taste gene loss, we examined seven toothed whales and five baleen whales and sequenced the complete repertoire of three sweet/umami (T1Rs) and ten bitter (T2Rs) taste receptor genes. We found all amplified T1Rs and T2Rs to be pseudogenes in all 12 whales, with a shared premature stop codon in 10 of the 13 genes, which demonstrated massive losses of taste receptor genes in the common ancestor of whales. Furthermore, we analyzed three genome sequences from two toothed whales and one baleen whale and found that the sour taste marker gene Pkd2l1 is a pseudogene, whereas the candidate salty taste receptor genes are intact and putatively functional. Additionally, we examined three genes that are responsible for taste signal transduction and found the relaxation of functional constraints on taste signaling pathways along the ancestral branch leading to whales. Together, our results strongly suggest extensive losses of sweet, umami, bitter, and sour tastes in whales, and the relaxation of taste function most likely arose in the common ancestor of whales between 36 and 53 Ma. Therefore, whales represent the first animal group to lack four of five primary tastes, probably driven by the marine environment with high concentration of sodium, the feeding behavior of swallowing prey whole, and the dietary switch from plants to meat in the whale ancestor. PMID:24803572

Feng, Ping; Zheng, Jinsong; Rossiter, Stephen J; Wang, Ding; Zhao, Huabin

2014-01-01

359

Insertional translocation leading to a 4q13 duplication including the EPHA5 gene in two siblings with attention-deficit hyperactivity disorder.  

PubMed

An insertional translocation (IT) can result in pure segmental aneusomy for the inserted genomic segment allowing to define a more accurate clinical phenotype. Here, we report on two siblings sharing an unbalanced IT inherited from the mother with a history of learning difficulty. An 8-year-old girl with developmental delay, speech disability, and attention-deficit hyperactivity disorder (ADHD), showed by GTG banding analysis a subtle interstitial alteration in 21q21. Oligonucleotide array comparative genomic hybridization (array-CGH) analysis showed a 4q13.1-q13.3 duplication spanning 8.6 Mb. Fluorescence in situ hybridization (FISH) with bacterial artificial chromosome (BAC) clones confirmed the rearrangement, a der(21)ins(21;4)(q21;q13.1q13.3). The duplication described involves 50 RefSeq genes including the EPHA5 gene that encodes for the EphA5 receptor involved in embryonic development of the brain and also in synaptic remodeling and plasticity thought to underlie learning and memory. The same rearrangement was observed in a younger brother with behavioral problems and also exhibiting ADHD. ADHD is among the most heritable of neuropsychiatric disorders. There are few reports of patients with duplications involving the proximal region of 4q and a mild phenotype. To the best of our knowledge this is the first report of a duplication restricted to band 4q13. This abnormality could be easily missed in children who have nonspecific cognitive impairment. The presence of this behavioral disorder in the two siblings reinforces the hypothesis that the region involved could include genes involved in ADHD. PMID:23824631

Matoso, Eunice; Melo, Joana B; Ferreira, Susana I; Jardim, Ana; Castelo, Teresa M; Weise, Anja; Carreira, Isabel M

2013-08-01

360

Identification of Gene Markers for Activation of the Nuclear Receptor Pregnane X Receptor  

EPA Science Inventory

Many environmentally-relevant chemicals and drugs activate the nuclear receptor pregnane X receptor (PXR). Activation of PXR in the mouse liver can lead to increases in liver weight in part through increased hepatocyte replication similar to chemicals that activate other nuclear ...

361

The gp49A gene has extensive sequence conservation with the gp49B gene and provides gp49A protein, a unique member of a large family of activating and inhibitory receptors of the immunoglobulin superfamily  

Microsoft Academic Search

Members of the gp49-related family of mouse and human immunoglobulin (Ig) superfamily receptors have significant amino acid\\u000a sequence homology in their C2-type, Ig-like domains and include the killer cell Ig-like receptors (KIRs) for major histocompatibility\\u000a complex class I molecules. We now report the cloning, complete sequence, and organization of the mouse gp49A gene that encodes the only member of this

Michael J. McCormick; Mariana C. Castells; K. Frank Austen; Howard R. Katz

1999-01-01

362

Receptor Revision of Immunoglobulin Heavy Chain Variable Region Genes in Normal Human B Lymphocytes  

PubMed Central

Contrary to the general precepts of the clonal selection theory, several recent studies have provided evidence for the secondary rearrangement of immunoglobulin (Ig) genes in peripheral lymphoid tissues. These analyses typically used transgenic mouse models and have only detected secondary recombination of Ig light chain genes. Although Ig heavy chain variable region (VH) genes encode a substantial element of antibody combining site specificity, there is scant evidence for VH gene rearrangement in the periphery, leaving the physiological importance of peripheral recombination questionable. The extensive somatic mutations and clonality of the IgD+Strictly-IgM?CD38+ human tonsillar B cell subpopulation have now allowed detection of the first clear examples of receptor revision of human VH genes. The revised VDJ genes contain “hybrid” VH gene segments consisting of portions from two separate germline VH genes, a phenomenon previously only detected due to the pressures of a transgenic system.

Wilson, Patrick C.; Wilson, Kenneth; Liu, Yong-Jun; Banchereau, Jacques; Pascual, Virginia; Capra, J. Donald

2000-01-01

363

Global Footprints of Purifying Selection on Toll-Like Receptor Genes Primarily Associated with Response to Bacterial Infections in Humans  

PubMed Central

Toll-like receptors (TLRs) are directly involved in host–pathogen interactions. Polymorphisms in these genes are associated with susceptibility to infectious diseases. To understand the influence of environment and pathogen diversity on the evolution of TLR genes, we have undertaken a large-scale population-genetic study. Our study included two hunter–gatherer tribal populations and one urbanized nontribal population from India with distinct ethnicities (n = 266) and 14 populations inhabiting four different continents (n = 1,092). From the data on DNA sequences of cell-surface TLR genes, we observed an excess of rare variants and a large number of low frequency haplotypes in each gene. Nonsynonymous changes were few in every population and the commonly used statistical tests for detecting natural selection provided evidence of purifying selection. The evidence of purifying selection acting on the cell-surface TLRs of the innate immune system is not consistent with Haldane’s theory of coevolution of immunity genes, at least of innate immunity genes, with pathogens. Our study provides evidence that genes of the cell-surface TLRs, that is, TLR2 and TLR4, have been so optimized to defend the host against microbial infections that new mutations in these genes are quickly eliminated.

Mukherjee, Souvik; Ganguli, Debdutta; Majumder, Partha P.

2014-01-01

364

Structure-activity relationships for a family of benzothiophene selective estrogen receptor modulators including raloxifene and arzoxifene.  

PubMed

The search for the "ideal" selective estrogen receptor modulator (SERM) as a substitute for hormone replacement therapy (HRT) or use in cancer chemoprevention has focused on optimization of estrogen receptor (ER) ligand binding. Based on the clinical and preclinical benzothiophene SERMs, raloxifene and arzoxifene, a family of SERMs has been developed to modulate activity and oxidative lability. Antiestrogenic potency measured in human endometrial and breast cancer cells, and ER ligand binding data were correlated and seen to provide a guide to SERM design only when viewed in toto. The in vitro studies were extended to the juvenile rat model, in which the desired antiestrogenic profile and putative cardiovascular benefits of SERMs were observed. PMID:17654759

Overk, Cassia R; Peng, Kuan-Wei; Asghodom, Rezene T; Kastrati, Irida; Lantvit, Daniel D; Qin, Zhihui; Frasor, Jonna; Bolton, Judy L; Thatcher, Gregory R J

2007-10-01

365

Molecular Characterization of the Aphis gossypii Olfactory Receptor Gene Families  

PubMed Central

The cotton aphid, Aphis gossypii Glover, is a polyphagous pest that inflicts great damage to cotton yields worldwide. Antennal olfaction, which is extremely important for insect survival, mediates key behaviors such as host preference, mate choice, and oviposition site selection. In insects, odor detection is mediated by odorant receptors (ORs) and ionotropic receptors (IRs), which ensure the specificity of the olfactory sensory neuron responses. In this study, our aim is to identify chemosensory receptors in the cotton aphid genome, as a means to uncover olfactory encoding of the polyphagous feeding habits as well as to aid the discovery of new targets for behavioral interference. We identified a total of 45 candidate ORs and 14 IRs in the cotton aphid genome. Among the candidate AgoORs, 9 are apparent pseudogenes, while 19 can be clustered with ORs from the pea aphid, forming 16 AgoOR/ApOR orthologous subgroups. Among the candidate IRs, we identified homologs of the two highly conserved co-receptors IR8a and IR25a; no AgoIR retain the complete glutamic acid binding domain, suggesting that putative AgoIRs bind different ligands. Our results provide the necessary information for functional characterization of the chemosensory receptors of A. gossypii, with potential for new or refined applications of semiochemicals-based control of this pest insect.

Walker, William B.; Li, Jianhong; Wang, Guirong

2014-01-01

366

Expression of the c-erbB-2 gene encoding a growth factor receptor.  

PubMed

The c-erbB-2 gene is a v-erbB-related proto-oncogene which encodes a protein similar to but distinct from the epidermal growth factor (EGF) receptor. In situ hybridization of metaphase spread showed that this gene is located on human chromosome 17 at q21, a specific breakpoint observed in a translocation associated with acute promyelocytic leukemia. The c-erbB-2 DNA probe hybridized with a 4.6 kb mRNA which directs the synthesis of a 185 kd glycoprotein. The 185 kd c-erbB-2 protein is associated with tyrosine kinase activity and is possibly phosphorylated by C-kinase on its serine and threonine residues. In addition, the c-erbB-2 protein is suggested to be a substrate for EGF receptor tyrosine kinase, since EGF binding to the EGF receptor rapidly induced phosphorylation of the c-erbB-2 protein on its tyrosine residue. Southern blot hybridization analysis of DNAs from human tumors demonstrated amplification of the c-erbB-2 gene restricted to adenocarcinomas. Finally, the promoter of the c-erbB-2 gene contains the typical TATA box and CAAT box as well as a GC box-like sequence. This is in contrast with the promoter of the EGF receptor gene, since the latter contains only GC-boxes. Therefore, it is suggested that the two genes are under different transcriptional control. PMID:3455415

Yamamoto, T; Akiyama, T; Yokota, J; Mori, S; Toyoshima, K

1986-01-01

367

Genetic Characterization of the Region of the Drosophila Genome Known to Include the Histone Structural Gene Sequences  

PubMed Central

This report describes a genetic study of salivary map region 39DE of the Drosophila genome, which is known to include the histone gene sequences (Pardue 1975; Lifton et al. 1977). Small deficiences extending proximally into 39DE were constructed by the segmental aneuploid method of Lindsley et al. (1972). The translocational deficiencies obtained in this manner were ?-irradiated to remove the Y translocational arms. One of these newly reconstituted deficiencies was then used to screen 10,000 ?-irradiated second chromosomes for lethal mutations. The 32 lethals recovered from the screen were tested against several deficiencies and markers, crossed inter se and categorized according to their genetic properties. From these data, a preliminary complementation map was constructed of salivary region 39A-39F. The salivary map positions of certain of the complementation groups suggest that the mutants in these groups may affect histone gene functions.

Siegel, Jacqueline G.

1981-01-01

368

From in vivo gene targeting of oestrogen receptors to optimization of their modulation in menopause  

PubMed Central

The ancestral status of oestrogen receptor (ER) in the family of the steroid receptors has probably contributed to the pleiotropic actions of oestrogens, and in particular, that of 17?-oestradiol (E2). Indeed, in addition to their well-described role in sexual development and reproduction, they influence most of the physiological processes. The pathophysiological counterpart of these actions includes prevention of osteoporosis, atheroma and type 2 diabetes, and also the promotion of uterus and breast cancer growth. Thus, the major challenge consists in uncoupling some beneficial actions from other deleterious ones, that is, selective ER modulation. Tamoxifen and raloxifene are already used, as they prevent the recurrence of breast cancer and mimic oestrogen action mainly on bone. Both E2 and tamoxifen exhibit a proliferative and, thus, a protumoural action on the endometrium. Activation of ER? and ER? regulates target gene transcription (genomic action) through two independent activation functions, AF-1 and AF-2, but can also elicit rapid membrane-initiated steroid signals. In the present review, we attempted to summarize recent advances provided by the in vivo molecular ‘dissection’ of ER?, allowing the uncoupling of some of its actions and potentially paving the way to optimized selective ER modulators.

Arnal, Jean-Francois; Lenfant, Francoise; Flouriot, Gilles; Tremollieres, Florence; Laurell, Henrik; Fontaine, Coralie; Krust, Andree; Chambon, Pierre; Gourdy, Pierre

2012-01-01

369

Multigenic Control of Measles Vaccine Immunity Mediated by Polymorphisms in Measles Receptor, Innate Pathway, and Cytokine Genes  

PubMed Central

Measles infection and vaccine response are complex biological processes that involve both viral and host genetic factors. We have previously investigated the influence of genetic polymorphisms on vaccine immune response, including measles vaccines, and have shown that polymorphisms in HLA, cytokine, cytokine receptor, and innate immune response genes are associated with variation in vaccine response but do not account for all of the inter-individual variance seen in vaccinated populations. In the current study we report the findings of a multigenic analysis of measles vaccine immunity, indicating a role for the measles virus receptor CD46, innate pattern-recognition receptors (DDX58, TLR2, 4, 5,7 and 8) and intracellular signaling intermediates (MAP3K7, NFKBIA), and key antiviral molecules (VISA, OAS2, MX1, PKR) as well as cytokines (IFNA1, IL4, IL6, IL8, IL12B) and cytokine receptor genes (IL2RB, IL6R, IL8RA) in the genetic control of both humoral and cellular immune responses. This multivariate approach provided additional insights into the genetic control of measles vaccine responses over and above the information gained by our previous univariate SNP association analyses.

Kennedy, Richard B.; Ovsyannikova, Inna G.; Haralambieva, Iana H.; O'Byrne, Megan; Jacobson, Robert M.; Pankratz, V. Shane; Poland, Gregory A.

2012-01-01

370

The pyrimidine biosynthesis operon of the thermophile Bacillus caldolyticus includes genes for uracil phosphoribosyltransferase and uracil permease.  

PubMed Central

A 3-kb DNA segment of the Bacillus caldolyticus genome including the 5' end end of the pyr cluster has been cloned and sequenced. The sequence revealed the presence of two open reading frames, pyrR and pyrP, located immediately upstream of the previously sequenced pyrB gene encoding the pyrimidine biosynthesis enzyme aspartate transcarbamoylase. The pyrR and pyrP genes encoded polypeptides with calculated molecular masses of 19.9 and 45.2 kDa, respectively. Expression of these ORFs was confirmed by analysis of plasmid-encoded polypeptides in minicells. Sequence alignment and complementation analyses identified the pyrR gene product as a uracil phosphoribosyltransferase and the pyrP gene product as a membrane-bound uracil permease. By using promoter expression vectors, a 650-bp EcoRI-HincII fragment, including the 5' end of pyrR and its upstream region, was found to contain the pyr operon promoter. The transcriptional start point was located by primer extension at a position 153 bp upstream of the pyrR translation initiation codon, 7 bp 3' of a sequence resembling a sigma A-dependent Bacillus subtilis promoter. This established the following organization of the ten cistrons within the pyr operon: promoter-pyrR-pyrP-pyrB-pyrC-pyrAa-pyrA b-orf2-pyrD-pyrF-pyrE. The nucleotide sequences of the region upstream of pyrR and of the pyrR-pyrP and pyrP-pyrB intercistronic regions indicated that the transcript may form two mutually exclusive secondary structures within each of these regions. One of these structures resembled a rho-independent transcriptional terminator. The possible implication of these structures for pyrimidine regulation of the operon is discussed. Images

Ghim, S Y; Neuhard, J

1994-01-01

371

Association of peroxisome proliferator-activated receptor-gamma gene polymorphisms with the development of asthma  

Microsoft Academic Search

Summary Background: The peroxisome proliferator-activated receptors (PPAR) are the nuclear hormone receptor superfamily of ligand-activated transcriptional factors. PPAR-gamma (PPARG) activation downregulates production of Th2 type cytokines and eosinophil function. Addition- ally, treatment with a synthetic PPARG ligand can reduce lung inflammation and IFN-gamma, IL-4, and IL-2 production in experimental allergic asthma. In patients with asthma, PPARG gene expression is known

Sun-Hee Oh; Se-Min Park; Yoo Hoon Lee; Ji Yeon Cha; Ji-Yeon Lee; Eun Kyong Shin; Jong-Sook Park; Byeong-Lae Park; Hyoung Doo Shin; Choon-Sik Park

2009-01-01

372

Coexpression of Receptors for Adrenomedullin, Calcitonin Gene-Related Peptide, and Amylin in Pancreatic  Cells  

Microsoft Academic Search

Three receptors have been characterized by their ability to bind adrenomedullin (AM): L1, RDC1, and CRLR. Immunohistochemical analysis and RT-PCR showed that all three receptors are expressed by the insulin-producing cells of the islets of Langerhans. RDC1 and CRLR in the presence of particular modifying proteins can also bind calcitonin gene-related peptide (CGRP). Such data suggest that the inhibitory effect

ALFREDO MARTINEZ; SUPRIYA KAPAS; MAE-JEAN MILLER; YVONA WARD; FRANK CUTTITTA

2000-01-01

373

HLA and NK Cell Inhibitory Receptor Genes in Resolving Hepatitis C Virus Infection  

Microsoft Academic Search

Natural killer (NK) cells provide a central defense against viral infection by using inhibitory and activation receptors for major histocompatibility complex class I molecules as a means of controlling their activity. We show that genes encoding the inhibitory NK cell receptor KIR2DL3 and its human leukocyte antigen C group1 (HLA-C1) ligand directly influence resolution of hepatitis C virus (HCV) infection.

Salim I. Khakoo; Chloe L. Thio; Maureen P. Martin; Collin R. Brooks; Xiaojiang Gao; Jacquie Astemborski; Jie Cheng; James J. Goedert; David Vlahov; Margaret Hilgartner; Steven Cox; Ann-Margeret Little; Graeme J. Alexander; Matthew E. Cramp; Stephen J. O'Brien; William M. C. Rosenberg; David L. Thomas; Mary Carrington

2004-01-01

374

No evidence for oncogenic mutations in the adrenocorticotropin receptor gene in human adrenocortical neoplasms  

SciTech Connect

The mechanism(s) of tumorigenesis for the majority of adrenocortical neoplasms remain unknown. G-Protein-coupled receptors were recently proposed as candidate protooncogenes. That activating mutations of this class of receptors might be important for tumor induction or progression of endocrine neoplasms was strengthened by the recent identification of such mutations in hyperfunctioning thyroid adenomas. To examine whether the ACTH receptor (ACTH-R) gene could be an oncogene in human adrenocortical tumors, we amplified by the polymerase chain reaction and directly sequenced the entire exon of the ACTH-R gene in 25 adrenocortical tumors (17 adenomas and 8 carcinomas) and 2 adrenocortical cancer cell lines. We found no missense point mutations or even silent polymorphisms in any of the tumors and cell lines studied. We conclude that activating mutations of the ACTH-R gene do not represent a frequent mechanism of human adrenocortical tumorigenesis. 15 refs., 2 tabs.

Latronico, A.C.; Reincke, M.; Mendonca, B.B. [National Inst. of Child Health and Human Development, Bethesda, MD (United States)] [and others] [National Inst. of Child Health and Human Development, Bethesda, MD (United States); and others

1995-03-01

375

Regulation of human growth hormone receptor gene transcription by human growth hormone binding protein.  

PubMed

The hypothesis that growth hormone binding protein (GHBP) has an effect on its own on the regulation of the GH-receptor/GHBP transcription was tested. Three different forms of human GHBP (recombinant non-glycosylated GHBP, recombinant glycosylated GHBP and GHBP purified and extracted from serum) were added in different concentrations determined by LIFA [0 pmol/l; 50 pmol/l (low level), 200 pmol/l (average level) and 500 pmol/l (high level in circulation)] to a human hepatoma cell line (HuH7 cells) cultured in a serum free hormonally-defined medium. Following the incubation with GHBP for 0, 1 and 2 h, GH-receptor expression was quantitatively assessed by using polymerase chain reaction amplification. Treatment with a GHBP concentration of 50 pmol/l resulted in a significant increase of GH-receptor mRNA molecules given as number of molecules x 10(6)/microg total RNA. In contrast, the concentration of 500 pmol/l presented a significant decrease of GH-receptor mRNA molecules, whereas 200 pmol/l GHBP produced a GH-receptor gene expression which was in between the values of the experiments with 50 and 500 pmol/l of GHBP added. Furthermore, the three different forms of human GHBP used provided similar data and, therefore, did not effect in any variation of GH-receptor expression. In addition, nuclear run-on experiments confirmed the changes in GH-receptor expression; and cycloheximide (10 microg/ml) did not alter the transcription indicating that the up and down regulating effects of GHBP on the GH-receptor/GHBP gene transcription was dependent, at least partly, on pre-existing factors and does not require protein synthesis. In conclusion, we present data showing that GHBP on its own has an effect on GH-receptor gene expression. PMID:9256367

Mullis, P E; Wagner, J K; Eblé, A; Nuoffer, J M; Postel-Vinay, M C

1997-07-01

376

Juvenile hormone and its receptor, methoprene-tolerant, control the dynamics of mosquito gene expression  

PubMed Central

Juvenile hormone III (JH) plays a key role in regulating the reproduction of female mosquitoes. Microarray time-course analysis revealed dynamic changes in gene expression during posteclosion (PE) development in the fat body of female Aedes aegypti. Hierarchical clustering identified three major gene clusters: 1,843 early-PE (EPE) genes maximally expressed at 6 h PE, 457 mid-PE (MPE) genes at 24 h PE, and 1,815 late-PE (LPE) genes at 66 h PE. The RNAi microarray screen for the JH receptor Methoprene-tolerant (Met) showed that 27% of EPE and 40% of MPE genes were up-regulated whereas 36% of LPE genes were down-regulated in the absence of this receptor. Met repression of EPE and MPE and activation of LPE genes were validated by an in vitro fat-body culture experiment using Met RNAi. Sequence motif analysis revealed the consensus for a 9-mer Met-binding motif, CACGC/TGA/GT/AG. Met-binding motif variants were overrepresented within the first 300 bases of the promoters of Met RNAi–down-regulated (LPE) genes but not in Met RNAi–up-regulated (EPE) genes. EMSAs using a combination of mutational and anti-Met antibody supershift analyses confirmed the binding properties of the Met consensus motif variants. There was a striking temporal separation of expression profiles among major functional gene groups, with carbohydrate, lipid, and xenobiotics metabolism belonging to the EPE and MPE clusters and transcription and translation to the LPE cluster. This study represents a significant advancement in the understanding of the regulation of gene expression by JH and its receptor Met during female mosquito reproduction.

Zou, Zhen; Saha, Tusar T.; Roy, Sourav; Shin, Sang Woon; Backman, Tyler W. H.; Girke, Thomas; White, Kevin P.; Raikhel, Alexander S.

2013-01-01

377

Evolutionary development and expression pattern of the myeloid lectin-like receptor gene family encoded within the NK gene complex.  

PubMed

The myeloid cluster within the natural killer (NK) gene complex comprises several C-type lectin-like receptor genes of diverse and highly important functions in the immune system such as LOX-1 and DECTIN-1. Based on sequences that have become available by whole genome sequencing, we conducted a comparison of the human, chimpanzee, mouse and rat NK gene complex to better characterize this gene family and additional genes of this region in regard of their phylogenetic relationship and evolution within the complex. We found that the arrangement of genes within the primate cluster differs from the order and orientation of the corresponding genes in the rodent complex which can be explained by evolutionary duplication and inversion events. Analysis of individual genes revealed a high sequence conservation supporting the prime importance of the encoded proteins. Expression analyses of the more recently described CLEC12B and CLEC9A genes displayed not only mRNA expression in monocytic and dendritic cells, but in contrast to other members of the family also in lymphocytes. Further, two additional genes were identified, which do not encode proteins with lectin-like domain structure and seem to be widely expressed. PMID:20883316

Sattler, S; Ghadially, H; Reiche, D; Karas, I; Hofer, E

2010-10-01

378

Oxytocin, vasopressin and estrogen receptor gene expression in relation to social recognition in female mice  

PubMed Central

Inter- and intra-species differences in social behavior and recognition-related hormones and receptors suggest that different distribution and/or expression patterns may relate to social recognition. We used qRT-PCR to investigate naturally occurring differences in expression of estrogen receptor-alpha (ER?), ER-beta (ER?), progesterone receptor (PR), oxytocin (OT) and receptor, and vasopressin (AVP) and receptors in proestrous female mice. Following four 5 min exposures to the same two conspecifics, one was replaced with a novel mouse in the final trial (T5). Gene expression was examined in mice showing high (85–100%) and low (40–60%) social recognition scores (i.e., preferential novel mouse investigation in T5) in eight socially-relevant brain regions. Results supported OT and AVP involvement in social recognition, and suggest that in the medial preoptic area, increased OT and AVP mRNA, together with ER? and ER? gene activation, relate to improved social recognition. Initial social investigation correlated with ERs, PR and OTR in the dorsolateral septum, suggesting that these receptors may modulate social interest without affecting social recognition. Finally, increased lateral amygdala gene activation in the LR mice may be associated with general learning impairments, while decreased lateral amygdala activity may indicate more efficient cognitive mechanisms in the HR mice.

Clipperton-Allen, Amy E.; Lee, Anna W.; Reyes, Anny; Devidze, Nino; Phan, Anna; Pfaff, Donald W.; Choleris, Elena

2012-01-01

379

Molecular cloning of a gene encoding the histamine H2 receptor  

SciTech Connect

The H2 subclass of histamine receptors mediates gastric acid secretion, and antagonists for this receptor have proven to be effective therapy for acid peptic disorders of the gastrointestinal tract. The physiological action of histamine has been shown to be mediated via a guanine nucleotide-binding protein linked to adenylate cyclase activation and cellular cAMP generation. The a