Showing papers on "Aryl hydrocarbon receptor nuclear translocator published in 2007"
TL;DR: The aryl hydrocarbon (dioxin) receptor (AhR) has been studied for several decades largely because of its critical role in xenobiotic‐induced toxicity and carcinogenesis and studies supporting the implication of the AhR in those endogenous cellular processes are summarized.
377 citations
TL;DR: A genetic association study designed to test the relevance of these findings in 1,304 individuals from 424 families primarily selected for type 2 diabetes showed that two BMAL1 haplotypes are associated with type 1 diabetes and hypertension.
Abstract: Many aspects of physiology and behavior follow a circadian rhythm. Brain and muscle Arnt-like protein-1 (BMAL1) is a key component of the mammalian molecular clock, which controls circadian oscillations. In the rat, the gene encoding Bmal1 is located within hypertension susceptibility loci. We analyzed the SNP distribution pattern in a congenic interval associated with hypertension in the spontaneously hypertensive rat (SHR), and we show that Bmal1 maps close to a region genetically divergent between SHR and its normotensive (Wistar-Kyoto) counterpart. Bmal1 sequencing in rat strains identified 19 polymorphisms, including an SHR promoter variant that significantly affects Gata-4 activation of transcription in transient transfection experiments. A genetic association study designed to test the relevance of these findings in 1,304 individuals from 424 families primarily selected for type 2 diabetes showed that two BMAL1 haplotypes are associated with type 2 diabetes and hypertension. This comparative genetics finding translated from mouse and rat models to human provides evidence of a causative role of Bmal1 variants in pathological components of the metabolic syndrome.
348 citations
TL;DR: The present state of knowledge about the molecular mechanisms of AhR-mediated CYP1 induction is summarized, and recent advances in the study of the physiological functions of Ahr are focused on.
198 citations
TL;DR: By blocking the modification of histone marks, HDAC1 plays a central role in Cyp1a1 expression and that its removal is a necessary but not sufficient condition for Cyp1o1 induction, underscoring the requirement for a concerted series of chromatin-remodeling events to complete the initial steps of gene trans-activation by the Ah receptor.
127 citations
TL;DR: The physicochemical characteristics of some residues and of their mutants, along with the effects of mutagenesis on TCDD and DNA binding, suggest some key features that are required for ligand binding and activation of mAhR at a molecular level, thus providing a framework for further studies.
Abstract: The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that is activated by a structurally diverse array of synthetic and natural chemicals, including toxic halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Analysis of the molecular events occurring in the AhR ligand binding and activation processes requires structural information on the AhR Per-Arnt-Sim (PAS) B-containing ligand binding domain, for which no experimentally determined structure has been reported. With the availability of extensive structural information on homologous PAS-containing proteins, a reliable model of the mouse AhR PAS B domain was developed by comparative modeling techniques. The PAS domain structures of the functionally related hypoxia-inducible factor 2α (HIF-2α) and AhR nuclear translocator (ARNT) proteins, which exhibit the highest degree of sequence identity and similarity with AhR, were chosen to develop a two-template model. To confirm the features of the modeled...
126 citations
TL;DR: Meta-analysis of published expression profiles of published microarray experiments is a powerful tool to gain novel insights into known and unknown systems.
117 citations
TL;DR: It is found that TCDD induces the expression of the B-cell activating factor of the tumor necrosis factor family (BAFF), B-lymphocyte chemoattractant (BLC), CC-chemokine ligand 1 (CCL1), and the transcription factor interferon gamma responsive factor (IFR3) in U937 macrophages in an aryl hydrocarbon receptor- (AhR) and RelB-dependent manner.
99 citations
TL;DR: This review examines the common theme of adaptive responses of bHLH/PAS proteins, using the dioxin receptor as a prototype to raise the issue of its toxic responses, in particular the idea that it is the dysregulation of its poorly characterised housekeeping functions that leads to these outcomes.
96 citations
TL;DR: The results suggest that an Arnt-dependent pathway in gut has an important role in regulation of the metabolism of dietary CYP 1A1 inducers and whole-body CYP1A1 expression in mice generated in which the Arnt gene is disrupted predominantly in the gut epithelium.
Abstract: Cytochrome P450 1A1 (CYP1A1) is one of the most important detoxification enzymes due to its broad substrate specificity and wide distribution throughout the body. On the other hand, CYP1A1 can also produce highly carcinogenic intermediate metabolites through oxidation of polycyclic aromatic hydrocarbons. We describe what we believe to be a novel regulatory system for whole-body CYP1A1 expression by a factor originating in the gut. A mutant mouse was generated in which the arylhydrocarbon receptor nuclear translocator (Arnt) gene is disrupted predominantly in the gut epithelium. Surprisingly, CYP1A1 mRNA expression and enzymatic activities were markedly elevated in almost all non-gut tissues in this mouse line. The induction was even observed in early-stage embryos in pregnant mutant females. Interestingly, the upregulation was CYP1A1 selective and lost upon administration of a synthetic purified diet. Moreover, the increase was recovered by addition of the natural phytochemical indole-3-carbinol to the purified diet. These results suggest that an Arnt-dependent pathway in gut has an important role in regulation of the metabolism of dietary CYP1A1 inducers and whole-body CYP1A1 expression. This machinery might be involved in naturally occurring carcinogenic processes and/or other numerous biological responses mediated by CYP1A1 activity.
93 citations
TL;DR: It is demonstrated that PAS domain function requires regions extending over the short PAS core repeats, and it is proposed that NPAS2 and BMAL2 also undergo similar posttranslational modifications, thereby establishing the mechanism proposed for CLOCK-BMAL1 as a common feature of transcriptional activators in the circadian clock.
Abstract: CLOCK and BMAL1 [brain and muscle ARNT (arylhydrocarbon receptor nuclear translocator)-like protein 1] are central components of the molecular clock in mammals and belong to the bHLH (basic helix–loop–helix)/PAS [PER (Period)/ARNT/SIM (single-minded)] family. Features of their dimerization have never been investigated. Here, we demonstrate that PAS domain function requires regions extending over the short PAS core repeats. Strikingly, while deleting PAS core repeats does not overtly affect dimerization, it abolishes the transcriptional activity of the heterodimer. Interestingly, these deletions also abolish co-dependent phosphorylation of CLOCK and BMAL1, suggesting a link between the phosphorylation status of the heterodimer and its transactivation potential. We demonstrate that NPAS2 (neuronal PAS domain protein 2) and BMAL2 also undergo similar posttranslational modifications, thereby establishing the mechanism proposed for CLOCK–BMAL1 as a common feature of transcriptional activators in the circadian clock. The discovery of two novel splice variants of BMAL2 confirms the crucial role of the PAS domain and further strengthens the view that co-dependent phosphorylation is of functional significance. In agreement with this, we demonstrate that CRY1–2 (cryptochromes 1–2) affect transactivation and phosphorylation of transcriptional activators of the clock. Furthermore, CRY proteins stabilize the unphosphorylated forms of BMAL1(BMAL2) thereby shifting the phosphorylated/unphosphorylated ratio towards a predominantly unphosphorylated (transcriptionally inactive) form. In contrast, PER proteins, which are weak repressors, are without effect. From these results, we propose a general mechanism for the inhibition of CLOCK(NPAS2)–BMAL1(BMAL2) circadian transcriptional activation by CRY1–2.
90 citations
TL;DR: These findings support previous reports on the endocrine effects of EE2, in addition to effects on hepatic biotransformation system, and suggest the use of DMSO as carrier vehicle in endocrine toxicological experimental studies should be re-evaluated.
29 Aug 2007
TL;DR: Cumulatively, the data suggest that the lung develops in a low-oxygen environment that allows for proper vascular development through HIF-regulated pathways.
Abstract: Lung development takes place in a relatively low-oxygen environment, which is beneficial for lung organogenesis, including vascular development. Hypoxia-inducible factor (HIF)-1 plays an important role in mediating oxygen-regulated events. HIF-1 is stable and initiates gene transcription under hypoxia, whereas in normoxia, interaction with the von Hippel-Lindau (VHL) tumor suppressor protein leads to rapid degradation of the HIF-1alpha subunit. Interaction with VHL requires hydroxylation of HIF-1alpha proline residues by prolyl hydroxylases (PHDs). We investigated the expression of the various components regulating HIF-1alpha stability in first trimester (8-14 weeks) human lungs. Spatial expression was assessed by immunohistochemistry and temporal expression by quantitative PCR. Immunoreactivity for PHD1, PHD3, and seven in absentia homolog (SIAH)1 was noted in the pulmonary epithelium. PHD2 was not expressed in the airway epithelium, but in the lung parenchyma. HIF-1alpha and vascular endothelial growth factor (VEGF) immunoreactivity were primarily detected in the branching epithelium. HIF-2alpha and ARNT proteins localized to the developing epithelium as well as mesenchymal, most likely vascular, structures in the parenchyma. VEGF receptor 2 (VEGFR2) was found in the subepithelium as well as in vascular structures of the mesenchyme. All components of the VEC complex (VHL, NEDD8, and Cullin2) were found in the epithelium. Quantitative PCR analysis demonstrated that VEGF, VEGFR1, HIF-1alpha, HIF-2alpha, ARNT, PHD1, PHD2, PHD3, and SIAH1 gene expression was constant during early pulmonary organogenesis. Cumulatively, the data suggest that the lung develops in a low-oxygen environment that allows for proper vascular development through HIF-regulated pathways.
TL;DR: A novel regulatory cassette is identified that mediates changes in Cyp2s1 expression and is dependent on hypoxiainducible factor-1 and is mediated in large part by three overlapping hypoxia response elements (HREs) embedded within the trimeric XRE segment.
TL;DR: Ablation of AHR resulted in enhancement of ischemia-induced angiogenesis, which in turn may be caused by an increased abundance and activity of the HIF-1&agr;–ARNT heterodimer.
Abstract: Objective— The aryl hydrocarbon receptor (AHR) is a transcription factor that binds to DNA as a heterodimer with the AHR nuclear translocator (ARNT) after interaction with ligands such as polycyclic and halogenated aromatic hydrocarbons found in tobacco smoke and the environment. We have investigated the interaction between AHR and hypoxia signaling pathways in regulation of angiogenesis with the use of a surgical model of ischemia. Methods and Results— Ischemia was induced by femoral artery occlusion in wild-type and AHR-null mice. Ischemia-induced angiogenesis was markedly enhanced in AHR-null mice compared with that in wild-type animals. Ischemia-induced upregulation of the expression of hypoxia-inducible factor–1α (HIF-1α) and ARNT as well as that of target genes for these transcription factors, such as that for vascular endothelial growth factor (VEGF), were also enhanced in AHR-null mice. Furthermore, the DNA binding activity of the HIF-1α–ARNT complex as well as the association of HIF-1α and ARNT w...
TL;DR: Results indicate that curcumin is able to bind to the AhR as a ligand, but suppresses its transformation by inhibiting the phosphorylation of AhR and Arnt, probably by PKC.
TL;DR: A complex mode of ER-AhR interaction is demonstrated, possibly involving competition for common cofactors, and it is found that exposure of salmon to NP singly or in combination with TCB produced differential gene expression patterns in salmon liver that were negatively influenced by individual receptor antagonists.
Abstract: In toxicogenomics, gene arrays are valuable tools in the identification of differentially expressed genes and potentially identify new gene biomarkers altered by exposure of organisms to xenobiotic compounds, either singly or as complex mixtures. In this study, we investigated the mechanisms of interaction between estrogen receptor (ER) and aryl hydrocarbon receptor (Ah receptor or AhR) signalling pathways using toxicogenomic approaches. First, we generated cDNA libraries using suppressive subtractive hybridization (SSH) of clones containing differentially expressed genes from Atlantic salmon (Salmo salar) separately exposed to ER and AhR agonists. Second, a targeted gene array (SalArray) was developed based on true-positive differentially expressed genes. In the experimental setup, primary cultures of salmon hepatocytes isolated by a two-step perfusion method were exposed for 48 h to nonylphenol (NP; 5 microM) and 3,3',4,4'-tetrachlorobiphenyl (TCB; 1 microM), singly and combined, in the absence or presence of antagonists. Using a targeted SalArray, we demonstrate that exposure of salmon to NP singly or in combination with TCB produced differential gene expression patterns in salmon liver. Array analysis showed that exposure of hepatocytes to NP mainly altered genes involved in the estrogenic pathway, including genes for steroid hormone synthesis and metabolism. The anti-estrogenic properties of TCB were demonstrated in the array analysis as genes induced by NP were decreased by TCB. To study the effects of TCB on ER-mediated transcription, hepatocytes were treated for 48 h with tamoxifen (Tam; 1 microM) and ICI182,780 (ICI; 1 microM). The effect of AhR on ER-mediated transcription was investigated by blocking AhR activity with alpha-naphthoflavone (ANF; 0.1 and 1 microM). Quantitative real-time polymerase chain reactions confirmed the changes in expression of ERalpha, ERbeta, vitellogenin (Vtg), zona radiata protein (Zr-protein), and vigilin for the ER pathway and AhRalpha, AhRbeta, AhRR, ARNT, CYP1A1, UDPGT, and a 20S proteasome beta-subunit for the AhR pathway. We found that exposure to NP and TCB both singly and in combination produced gene expression patterns that were negatively influenced by individual receptor antagonists. TCB caused decreased ER-mediated gene expression, and NP caused decreased AhR-mediated responses. Inhibition of AhR with ANF did not reverse the effect of TCB on ER-mediated transcription suggesting that AhRs do not have a direct role on TCB-mediated decreases of ER-mediated responses. In contrast, the inhibition of ER with Tam and ICI reversed the transcription of AhR-mediated responses (except AhRR). Taken together, the findings in the present study demonstrate a complex mode of ER-AhR interaction, possibly involving competition for common cofactors. This complex mode of interaction is further supported by the observation that the presence of ER antagonists potentiated the transcription of AhR isoforms and their mediated responses when TCB was given alone (more so for AhRbeta). Thus, the inhibitory ER-AhR interactions can be used to further investigate specific genes found to be affected in our targeted SalArray chip that are important for the reproductive effects of endocrine disruptors.
TL;DR: It is demonstrated that the AHRR Pro185Ala polymorphism contributed to a predisposition to male factor infertility in the Estonian population.
TL;DR: Considering HIF‐1α as a target that is controlled by the bioavailability of NO helps in the understanding of how signaling mechanisms are attributed to physiological and pathological transmission of NO actions with broad implications for medicine.
Abstract: Decreased oxygen availability evokes adaptive responses, which are primarily under the gene regulatory control of hypoxia-inducible factor 1 (HIF-1). HIF-1 is a heterodimer composed of the basic helix-loop-helix Per-ARNT-Sim (bHLH-PAS) protein HIF-1alpha (alpha) and the aryl hydrocarbon nuclear translocator (ARNT), also known as HIF-1beta (beta). The HIF-1 transcriptional system senses decreased oxygen availability and transmits this signal into pathophysiological responses, such as angiogenesis, erythropoiesis, vasomotor control, an altered energy metabolism, and/or cell survival decisions. It is now appreciated that nitric oxide (NO) and/or derived reactive nitrogen species (RNS) participate in stability control of HIF-1alpha. Although initial observations showed that NO inhibits hypoxia-induced HIF-1alpha stabilization and HIF-1 transcriptional activation, later studies revealed that the exposure of cells from different species to chemically diverse NO donors, or conditions of endogenous NO formation, induced HIF-1alpha accumulation, HIF-1-DNA binding, and activation of downstream target gene expression under normoxic conditions. The opposing effects of NO under hypoxia versus normoxia are discussed based on direct and indirect reaction properties of NO, taking metal interactions as well as secondary reaction products, generated in the presence of oxygen or superoxide, into account. Considering HIF-1alpha as a target that is controlled by the bioavailability of NO helps in the understanding of how signaling mechanisms are attributed to physiological and pathological transmission of NO actions with broad implications for medicine.
TL;DR: Results show that under normal conditions, CYP1A1 gene is kept silent in MEF cells by AhRR/Arnt heterodimer, which binds to the XRE sequence in its promoter and recruits ANKRA2, HDAC4, and HDAC5 as co-repressors.
TL;DR: It is suggested that the abundance of endogenous AhR level is an indispensable condition for an efficient cellular signaling of B[a]P and that control of AhR activity in Hepa1c1c7 cells might be important to cell fate resulting from CYP1A1 activation after B[ a]P.
TL;DR: Findings suggest that clock genes, especially Per1, may be involved in TCDD activation of AhR signaling pathways.
Abstract: The biological effects of many environmental toxins are mediated by genes containing Per-Arnt-Sim (PAS) domains, the aryl hydrocarbon receptor (AhR), and AhR nuclear translocator. Because these transcription factors interact with other PAS genes that form the circadian clockworks in mammals, we determined whether targeted disruption of the clock genes, Per1 and/or Per2, alters toxin-induced expression of known biological markers in the AhR signaling pathway. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a prototypical Ahr agonist, had an inductive effect on mammary gland expression of cytochrome P450, subfamily I, polypeptide 1 (Cyp1A1) mRNA regardless of genotype. However, TCDD-mediated Cyp1A1 induction in the mammary glands of Per1(ldc) and Per1(ldc)/Per2(ldc) mice was significantly (17.9- and 5.9-fold) greater than that in wild-type (WT) animals. In addition, TCDD-induced Cyp1B1 expression in Per1(ldc) and Per1(ldc)/Per2(ldc) mammary glands was significantly increased relative to that in WT mice. Similar to in vivo observations, experiments using primary cultures of mammary gland tissue demonstrated that TCDD-induced Cyp1A1 and Cyp1B1 expression in Per1(ldc) and Per1(ldc)/Per2(ldc) mutant cells was significantly greater than that in WT cultures. AhR mRNA levels were distinctively elevated in cells derived from all mutant genotypes, but they were commonly decreased in WT and mutant cultures after TCDD treatment. In WT mice, an interesting corollary is that the inductive effects of TCDD on mammary gland expression of Cyp1A1 and Cyp1B1 vary over time and are significantly greater during the night. These findings suggest that clock genes, especially Per1, may be involved in TCDD activation of AhR signaling pathways.
TL;DR: Findings suggest that the presence of XREs is not the sole determinant for regulation of aryl hydrocarbon receptor (AHR)-mediated gene and do not function in an additive manner.
TL;DR: It is concluded that partial agonists/antagonists of AhR can increase cell proliferation rate and AhR-dependent genes expression in both cell type- and gene-specific manner.
TL;DR: Transgenic misexpression of dysfusion revealed that Dysfusion has the ability to activate transcription in multiple cell types, although it does this most effectively in tracheal cells and can only function at mid-embryogenesis and later.
TL;DR: It is suggested that hypoxia rapidly induces protein(s) that inhibit Ah-responsiveness and these may be similar to constitutively expressed inhibitors of Ah- Responsiveness (under normoxia) that are also inhibited by cycloheximide.
TL;DR: Results indicate that ARNT controls Cyp2a5 transcription and thus, for the first time, suggest active involvement of the ARNT homodimer in mammalian gene regulation.
TL;DR: There was a significant positive correlation between ARNT1 and ARNT2 mRNA expression levels in the liver of wild cormorant population, indicating that their expressions may be enforced by similar transcriptional regulation mechanism.
Abstract: High levels of 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) and related planar halogenated aromatic hydrocarbons (PHAHs) are accumulated in fish-eating birds including common cormorant ( Phalacrocorax carbo ). Most of the biochemical and toxic effects of TCDD are mediated by a basic helix-loop-helix and a conserved region among Per, ARNT, and Sim (bHLH/PAS) proteins, aryl hydrocarbon receptor (AHR) and AHR nuclear translocator (ARNT). To study the molecular mechanism of TCDD toxicity in common cormorant as an avian model species, characterization of the AHR/ARNT signaling pathway in this species is necessary. The present study focuses on molecular characterization of ARNT from common cormorant ( cc ARNT). The cDNA of the cc ARNT isoform, cc ARNT1 obtained by the screening of hepatic cDNA library contains a 2424-bp open reading frame that encodes 807 amino acids, exhibiting high identities (92%) with chicken ARNT. This isoform contains a unique 22 amino acid residue in 3′ end of PAS A domain as is also recognized in chicken ARNT. The cc ARNT2 cDNA isolated from brain tissue has a 2151-bp open reading frame. The deduced amino acid sequence of cc ARNT2 protein (716 aa) shows a conservation of bHLH and PAS motif in its N-terminal region with high similarities (96% and 78%, respectively) to that of cc ARNT1. Using quantitative RT-PCR methods, the tissue distribution profiles of cc ARNT1 and cc ARNT2 were unveiled. Both cc ARNT1 and cc ARNT2 mRNAs were ubiquitously expressed in all examined tissues including liver. The expression profile of cc ARNT1 was comparable with that of rodent ARNT1, but cc ARNT2 was not with rodent ARNT2, implying different roles of ARNT2 between the two species. There was a significant positive correlation between ARNT1 and ARNT2 mRNA expression levels in the liver of wild cormorant population, indicating that their expressions may be enforced by similar transcriptional regulation mechanism. Novel variants of cc ARNT1 and cc ARNT2 isoforms that were supposed to arise from their splicing process were also identified and their hepatic expression profiles were determined. These results indicate that cc ARNT1, cc ARNT2 and their splice variants may more intricately regulate the AHR/ARNT signaling pathway and consequently may be responsible for the species diversity of toxic effects and susceptibility to PHAHs.
Patent•
16 Jan 2007TL;DR: In this article, the authors provide methods of screening for compounds that increase levels or activity of Aryl hydrocarbon Nuclear Receptor Translocator (ARNT) and/or Hypoxia Inducible Factor 1α (HIF1α), for the treatment and prevention of diabetes-related disorders, including type 1 and type 2 diabetes mellitus, impaired glucose tolerance, insulin resistance and beta cell dysfunction; compounds identified by said screening methods; and methods of using said compounds.
Abstract: The invention provides methods of screening for compounds that increase levels or activity of Aryl hydrocarbon Nuclear Receptor Translocator (ARNT) and/or Hypoxia Inducible Factor 1α (HIF1α), for the treatment and prevention of diabetes-related disorders, including type 1 and type 2 diabetes mellitus, impaired glucose tolerance, insulin resistance and beta cell dysfunction; compounds identified by said screening methods; and methods of using said compounds. Also included are methods for treating or preventing diabetes-related diseases using ARNT and/or HIF1α polypeptides and polynucleotides, and for using information regarding the expression, level or activity of ARNT and/or HIF1α in predictive medicine, e.g., diagnostic assays, prognostic assays, monitoring clinical trials, and pharmacogenetics.
TL;DR: The results suggest that the AhR-mediated reporter gene expression system has potential for the bioassay of dioxins in the environment and as a novel gene Expression system in plants.
Abstract: In mammals, the aryl hydrocarbon receptor (AhR) mediates expression of certain genes, including CYP1A1, in response to exposure to dioxins and related compounds. We have constructed a mouse AhR-mediated gene expression systems for a β-glucuronidase (GUS) reporter gene consisting of an AhR, an AhR nuclear translocator (Arnt), and a xenobiotic response element (XRE)-driven promoter in transgenic tobacco plants. On treatment with the AhR ligands 3-methylcholanthrene (MC), β-naphthoflavone (βNF), and indigo, the transgenic tobacco plants exhibited enhanced GUS activity, presumably by inducible expression of the reporter gene. The recombinant AhR (AhRV), with the activation domain replaced by that of the Herpes simplex virus protein VP16, induced GUS activity much more than the wild-type AhR in the transgenic tobacco plants. Plants carrying AhRV expressed the GUS reporter gene in a dose- and time-dependent manner when treated with MC; GUS activity was detected at 5 nM MC on solid medium and at 12 h after soaking in 25 μM MC. Histochemical GUS staining showed that this system was active mainly in leaf and stem. These results suggest that the AhR-mediated reporter gene expression system has potential for the bioassay of dioxins in the environment and as a novel gene expression system in plants.