Bioflavonoids are plant compounds touted for their potential to treat or prevent several diseases including cancers induced by common environmental chemicals. Much of the biologic activity of one such class of pollutants, polycyclic aromatic hydrocarbons (PAH), is mediated by the aryl hydrocarbon receptor/transcription factor (AhR). For example, the AhR regulates PAH immunotoxicity that manifests as pre-B cell apoptosis in models of B cell development. Because bioflavonoids block PAH-induced cell transformation and are structurally similar to AhR ligands, it was postulated that some of them would suppress PAH-induced, AhR-dependent immunotoxicity, possibly through a direct AhR blockade. This hypothesis was tested using a model of B cell development in which pre-B cells are cultured with and are dependent on bone marrow stromal or hepatic parenchymal cell monolayers. Of seven bioflavonoids screened, galangin (3,5,7-trihydroxyflavone) blocked PAH-induced but not C(2)-ceramide- or H(2)O(2)-induced ...
The aryl hydrocarbon receptor (AhR) is a transcription factor belonging to the Per-ARNT-Sim family of proteins. These proteins sense molecules and stimuli from the cellular/tissue environment, and initiate signaling cascades to elicit appropriate cellular responses. Recent literature suggests an important function of AhR in hematopoietic stem cell (HSC) biology. However, the molecular mechanisms by which AhR signaling regulates HSC functions are unknown. In previous studies, we and others reported that treatment of mice with the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) compromises the competitive reconstitution of bone marrow (BM) cells into irradiated host animals. Additional studies indicated a requirement for AhR in hematopoietic cells and not marrow microenvironment cells. In this study, we tested the hypothesis that TCDD-mediated phenotypic and functional changes of HSCs are a result of changes in gene expression that disrupt stem cell numbers and/or their migration. TCDD ...
The ligand-dependent transcription factor aryl hydrocarbon receptor (AhR) has been implicated in various immune functions. Our previous studies have shown that AhR activation by exposure of ovalbumin (OVA)-immunized mice to the potent ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases immunization-induced IFN- production in the spleen and suppresses the production of Th2 cytokines and OVA-specific antibodies. In the present study, we used transgenic (Tg) mice that express a constitutively active mutant of aryl hydrocarbon receptor (CA-AhR) specifically in T-lineage cells to clarify the role of AhR activation in T cells in these reactions. The results of this study clearly demonstrated that AhR activation only in the T cells augments IFN- production upon OVA immunization. By contrast, production of Th2 cytokines and antibodies were not significantly suppressed by CA-AhR in the T cells. These results suggest that suppression of Th2 cytokines and antibodies production require AhR ...
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the prototypic ligand for the aryl hydrocarbon receptor (AhR), promotes tumor formation in some model systems. However, with regard to breast cancer, epidemiological and animal studies are inconclusive as to whether exposure increases tumor incidence or may instead be protective. We have previously reported that mice exposed to TCDD during pregnancy have impaired differentiation of mammary tissue, including decreased branching and poor development of lobuloalveolar structures. Because normal pregnancy-induced mammary differentiation may protect against subsequent neoplastic transformation, we hypothesized that TCDD-treated mice would be more susceptible to chemical carcinogenesis after parturition. To test this, mice were treated with TCDD or vehicle during pregnancy. Four weeks later, 7,12-dimethylbenz[a]anthracene (DMBA) was administered to induce mammary tumor formation. Contrary to our hypothesis, TCDD-exposed parous mice showed a 4-week delay in ...
Patients with ER-negative breast tumors are among the most difficult to treat and exhibit low survival rates due, in part, to metastasis from the breast to various distal sites. Aryl hydrocarbon receptor (AHR) ligands show promise as antimetastatic drugs for estrogen receptor (ER)-negative breast cancer. Triple negative MDA-MB-231 breast cancer cells were treated with eight AHR-active pharmaceuticals including 4-hydroxtamoxifen, flutamide leflunomide, mexiletine, nimodipine, omeprazole, sulindac and tranilast, and the effects of these compounds on cell proliferation (MTT assay) and cell migration (Boyden chamber assay) were examined. The role of the AHR in mediating inhibition of MDA-MB-231 cell invasion was investigated by RNA interference (RNAi) and knockdown of AHR or cotreatment with AHR agonists. Lung metastasis of MDA-MB-231 cells was evaluated in mice administered cells by tail vein injection and prometastatic gene expression was examined by immunohistochemistry. We showed that only the proton
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that upon activation by the toxicant 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) stimulates gene expression and toxicity. AHR is also important for normal mouse physiology and may play a role in cancer progression in the absence of environmental toxicants. The objective of this report was to identify AHR-dependent genes (ADGs) whose expression is regulated by AHR in the absence of toxicants. RNA-Seq analysis revealed that AHR regulated the expression of over 600 genes at an FDR | 10% in MCF-7 breast cancer cells upon knockdown with short interfering RNA. Pathway analysis revealed that a significant number of ADGs were components of TCDD and tumor necrosis factor (TNF) pathways. We also demonstrated that siRNA knockdown of AHR modulated TNF induction of MNSOD and cytotoxicity in MCF-7 cells. Collectively, the major new findings of this report are: (1) endogenous AHR promotes the expression of xenobiotic metabolizing enzymes
Cigarette smoke exposure is associated with chronic and enhanced pulmonary inflammation characterized by increased cytokine production and leukocyte recruitment to the lung. Although the aryl hydrocarbon receptor (AhR) is well-known to mediate toxic effects of environmental contaminants, the AhR has emerged as a suppressor of acute cigarette smoke-induced neutrophilia. As there is currently no information on the AhR prevention of lung inflammation due to varied and prolonged exposure regimes, we exposed control and AhR-/- mice to cigarette smoke for 2 weeks (sub-chronic exposure) utilizing low and high exposure protocols and evaluated pulmonary inflammation. Sub-chronic cigarette smoke exposure increased pulmonary neutrophilia dose-dependently in AhR-/- mice. There was no difference between smoke-exposed AhR+/- and AhR-/- mice in the expression of cytokines associated with neutrophil recruitment. However, expression of pulmonary intercellular adhesion molecule-1 (ICAM-1), an adhesion molecule ...
Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and its expression is influenced by environmental compounds, such as 3-methylcholanthrene (3-MC) and β-naphthoflavone (β-NF). AhR and its downstream genes, such as CYP1A1, are considered to play a pivotal role in xenobiotic responses. AhR signaling has also been proposed to mediate osteogenesis in experimental animals, but its details have remained unclear. Therefore, in this study, we examined the possible roles of AhR in human bone. Immunohistochemical analysis revealed that AhR was detected in both osteoblasts and osteoclasts. We then screened AhR-target genes using a microarray analysis in human osteoblastic hFOB cells. Results of microarray and subsequent PCR analysis did reveal that estrogen metabolizing and synthesizing enzymes, such as CYP1B1 and aromatase, were increased by 3-MC in hFOB and osteosarcoma cell line, MG-63. The subsequent antibody cytokine analysis also demonstrated that interleukin-1β and -6 expression
TY - JOUR. T1 - Ligand-independent activation of the arylhydrocarbon receptor by ETK (Bmx) tyrosine kinase helps MCF10AT1 breast cancer cells to survive in an apoptosis-inducing environment. AU - Fujisawa, Yasuko. AU - Li, Wen. AU - Wu, Dalei. AU - Wong, Patrick. AU - Vogel, Christoph. AU - Dong, Bin. AU - Kung, Hsing Jien. AU - Matsumura, Fumio. PY - 2011/10/1. Y1 - 2011/10/1. N2 - It has been reported that the arylhydrocarbon receptor (AHR) is overexpressed in certain types of breast tumors. However, so far no concrete evidence has been provided yet as to why and how the overexpressed AHR in those cancer cells is functionally activated without exogenous ligands. Here we show that the AHR was functionally activated when estrogen receptor-negative, AHR overexpressing MCF10AT1 human breast cancer cells (designated P20E) were subjected to serum starvation. Transfection of cells with ETK-KQ, a plasmid for kinase-dead epithelial and endothelial tyrosine kinase (ETK), attenuated this AHR activation. ...
GNF351 is a full aryl hydrocarbon receptor (AHR) antagonist. GNF351 competes with a photoaffinity AHR ligand for binding to the AHR with an IC50 of 62 nM. GNF351 is minimal toxicity in mouse or human keratinocytes. - Mechanism of Action & Protocol.
The vT{2} cell line was derived by co-transfection of a 6 thioguanine-resistant derivative of c4 (B13NBii1) [ATCC CRL-2717] cell line using the plasmid pSV2gpt and pBM5/NEO-M1-1. M1-1 is a cDNA clone containing the entire human ARNT cDNA sequence. The cells were expanded in G418 to obtain vT{2} (ATCC CRL-2712). The vT{2} cell line expresses the human aryl hydrocarbon receptor nuclear translocator (ARNT) gene The vectors contain cytomegalovirus (CMV) and SV40 viral DNA sequences and the neomycin resistance gene. ARNT is directly involved in the regulation of xenobiotic metabolism (including chemical carcinogenesis), hypoxia and differentiation during embryogeneses. The parental cell line c4 (B13NBii1) (ATCC CRL-2717) lacks functional ARNT while its derivative vT{2} (ATCC CRL-2712) possesses a complete transfected ARNT cDNA. Together, they can be used to study ARNT processes and the role of ARNT in vivo.
Mouse anti Human ARNT antibody, clone 3D10 recognizes human Aryl hydrocarbon receptor nuclear translocator, also known as ARNT, Class E ba
The aryl hydrocarbon receptor (AhR) is a cytosolic ligand-activated transcription factor that mediates most of the toxic and carcinogenic effects of drugs and environmental toxins collectively known as xenobiotics. Ligand activation of the AhR stimulates the transcription of genes that encode several xenobiotic-metabolizing enzymes. The molecular mechanisms and signaling pathways evoked by the activation of the AhR are becoming increasingly understood and underscore the participation of the AhR in crucial processes, including cellular stress response, proliferation, differentiation, inflammation, and carcinogenesis. Studies now implicate the AhR as an integral part of the multifaceted signal transduction pathway initiated by the exposure of keratinocytes to ultraviolet B radiation (UVB), which is the most ubiquitous hazard to human skin and the principal risk factor for skin cancer. Ligand-dependent activation of the AhR in the cytosol provides a molecular bridge that links cytoplasmic events to ...
Pollutant particles containing environmentally persistent free radicals (EPFRs) are formed during many combustion processes (e.g. thermal remediation of hazardous wastes, diesel/gasoline combustion, wood smoke, cigarette smoke, etc.). Our previous studies demonstrated that acute exposure to EPFRs results in dendritic cell maturation and Th17-biased pulmonary immune responses. Further, in a mouse model of asthma, these responses were enhanced suggesting exposure to EPFRs as a risk factor for the development and/or exacerbation of asthma. The aryl hydrocarbon receptor (AHR) has been shown to play a role in the differentiation of Th17 cells. In the current study, we determined whether exposure to EPFRs results in Th17 polarization in an AHR dependent manner. Exposure to EPFRs resulted in Th17 and IL17A dependent pulmonary immune responses including airway neutrophilia. EPFR exposure caused a significant increase in pulmonary Th17 cytokines such as IL6, IL17A, IL22, IL1β, KC, MCP-1, IL31 and IL33. To
Page contains details about example of polymer-coated aryl hydrocarbon receptor transcription factor-binding ligand loaded magnetic nanoparticles . It has composition images, properties, Characterization methods, synthesis, applications and reference articles : nano.nature.com
... , Authors: Sayka Barry, Márta Korbonits. Published in: Atlas Genet Cytogenet Oncol Haematol.
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p>The checksum is a form of redundancy check that is calculated from the sequence. It is useful for tracking sequence updates.,/p> ,p>It should be noted that while, in theory, two different sequences could have the same checksum value, the likelihood that this would happen is extremely low.,/p> ,p>However UniProtKB may contain entries with identical sequences in case of multiple genes (paralogs).,/p> ,p>The checksum is computed as the sequence 64-bit Cyclic Redundancy Check value (CRC64) using the generator polynomial: x,sup>64,/sup> + x,sup>4,/sup> + x,sup>3,/sup> + x + 1. The algorithm is described in the ISO 3309 standard. ,/p> ,p class="publication">Press W.H., Flannery B.P., Teukolsky S.A. and Vetterling W.T.,br /> ,strong>Cyclic redundancy and other checksums,/strong>,br /> ,a href="http://www.nrbook.com/b/bookcpdf.php">Numerical recipes in C 2nd ed., pp896-902, Cambridge University Press (1993),/a>),/p> Checksum:i ...
We have analyzed the possible role of the aryl-hydrocarbon receptor (AHR) in the aging process of mice using a homozygous null mouse (Ahr-/-) line as a model. We studied 52 male and female Ahr-/- mice aged from 6-13 months. Forty-six percent died or were ill by 13 months of age. Ahr-/- mice developed age-related lesions in several organs, some of which were apparent after only 9 months of age. Cardiovascular alterations included cardiomyopathy (100%) with hypertrophy and focal fibrosis. Vascular hypertrophy and mild fibrosis were found in the portal areas of the liver (81%), and vascular hypertrophy and mineralization were common in the uterus (70%). Gastric hyperplasia that progressed with age into polyps was evident in the pylorus of 71% of the mice over 9 months of age. Ahr-/- mice had T-cell deficiency in their spleens but not in other lymphoid organs. The immune system deficiency described previously could be the origin for the rectal prolapse found in 48% of the null mice, associated
ARNTL - ARNTL (untagged)-Human aryl hydrocarbon receptor nuclear translocator-like (ARNTL), transcript variant 1 available for purchase from OriGene - Your Gene Company.
Conclusions and implications.Currently, there are several signaling cascades that define a novel biological theme in which the interplay between nuclear export and protein degradation plays a major role in determining the magnitude and duration of gene regulation. For example, the level of p53 protein is controlled in part by nuclear export and subsequent degradation by cytoplasmic proteases (8, 14,44, 45). If nuclear export of p53 is inhibited, there is a general upregulation of p53-dependent genes (8, 37). Another pathway involves p27Kip1, p27Kip1 is a cyclin-dependent kinase that arrests cells in G1(40) and appears to be reduced in certain types of cancer (43). Importantly, the level of p27Kip1 is controlled in part through nuclear export following association with p38 (JAB1), a protein that contains an NES and allows export of p27Kip1 to the cytoplasm for degradation (27,46). The common theme in both pathways is that the export of the effector protein from the nucleus results in reduced ...
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Analysis of compounds present in complex matrices is always a challenge, which can be partly overcome by applying various sample preparation techniques prior to detection. Ideally, the extraction techniques should be as selective as possible, to minimize the concentration of interfering substances. In addition, results can be improved by efficient chromatographic separation of the sample components. The elimination of interfering substances is especially important when utilizing mass spectrometry (MS) as a detection technique since they influence the ionization yields. It is also important to optimize ionization methods in order to minimize detection limits.. In the work this thesis is based upon, selective solid phase extraction (SPE) materials, a restricted access material (RAM) and graphitized carbon black (GCB) were employed for clean up and/or pre-concentration of analytes in plasma, urine and agricultural drainage water prior to liquid chromatography/mass spectrometry (LC/MS). Two SPE ...
Genetic heterogeneity is widespread in tumors, but poorly documented in cell lines. According to immunoglobulin hypermutation analysis, the diffuse large B-cell lymphoma cell line U-2932 comprises two subpopulations faithfully representing original tumor subclones. We set out to identify molecular causes underlying subclone-specific expression affecting 221 genes including surface markers and the germinal center oncogenes BCL6 and MYC. Genomic copy number variations explained 58/221 genes differentially expressed in the two U-2932 clones. Subclone-specific expression of the aryl-hydrocarbon receptor (AhR) and the resulting activity of the AhR/ARNT complex underlaid differential regulation of 11 genes including MEF2B. Knock-down and inhibitor experiments confirmed that AhR/ARNT regulates MEF2B, a key transcription factor for BCL6. AhR, MEF2B and BCL6 levels correlated not only in the U-2932 subclones but in the majority of 23 cell lines tested, indicting overexpression of AhR as a novel mechanism ...
Genetic heterogeneity is widespread in tumors, but poorly documented in cell lines. According to immunoglobulin hypermutation analysis, the diffuse large B-cell lymphoma cell line U-2932 comprises two subpopulations faithfully representing original tumor subclones. We set out to identify molecular causes underlying subclone-specific expression affecting 221 genes including surface markers and the germinal center oncogenes BCL6 and MYC. Genomic copy number variations explained 58/221 genes differentially expressed in the two U-2932 clones. Subclone-specific expression of the aryl-hydrocarbon receptor and the resulting activity of the AhR/ARNT complex underlay differential regulation of 11 genes including MEF2B. Knock-down and inhibitor experiments confirmed that AhR/ARNT regulates MEF2B, key transcription factor for BCL6. AhR, MEF2B and BCL6 levels correlated not only in the U-2932 subclones but in the majority of 23 cell lines tested, indicting overexpression of AhR as novel mechanism behind ...
Complete information for AHR gene (Protein Coding), Aryl Hydrocarbon Receptor, including: function, proteins, disorders, pathways, orthologs, and expression. GeneCards - The Human Gene Compendium
Fig. 6. Functional investigation of the AHRR 3-MC-dependent PGx-eQTL. (A) The 3-MC-dependent PGx-eQTL for AHRR included 10 SNPs across peaks 13161, 13163, and 13164 in intron 4 of the AHRR gene. (B) The variant SNP genotypes for the 10 linked SNPs that were across three AHR-binding peaks in intron 4 of the AHRR gene were associated with an increase after 3-MC treatment, and the wild-type was associated with a decrease after 3-MC treatment. (C) The luciferase plasmid that contained the variant SNP genotypes for the SNPs surrounding peak 13161 (as indicated by the dashed lines) demonstrated no difference in LCLs or HepG2 cells and a smaller increase than the wild-type SNP genotype in HMC3 cells, which was suggestive. (D) The luciferase plasmid that contained the variant genotypes for the five SNPs near peak 13163 in intron 4 of the AHRR gene (as indicated by the dashed lines) demonstrated a larger increase in luciferase activity after 3-MC treatment than the wild-type in LCLs, HepG2, and HMC3-the ...
Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a "candidate interactome" (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon ...
Preface. A. Historical background.. 1. History of Research on the AHR (Thomas A. Gasiewocz and Ellen C. Henry).. B. AHR as a ligand-activated transcription factor.. 2. Overview of AHR functional domains and the classical signaling pathway: induction of drug-metabolizing enzymes (Qiang Ma).. 3. Role of chaperone proteins in AHR function (Iain A. Murray and Gary H. Perdew).. 4. AHR Ligands: Promiscuity in Binding and Diversity in Response (Danica DeGroot, Guochun He, Domenico Fraccalvieri, Laura Bonati, Allesandro Pandin and Michael S. Denison).. 5. Dioxin response elements and regulation of gene transcription (Hollie Swanson).. 6. The AHR/ARNT dimer and transcriptional coactivators (Oliver Hankinson).. 7. Regulation of AHR by the AHR repressor (AHRR) (Yoshiaki Fujii-Kuriyama and Kaname Kawajiri).. 8. Influence of HIF-1α and Nrf2 signaling on AHR-mediated gene expression, toxicity and biological functions (Thomas Haarmann-Stemmann and Josef Abel).. 9. Functional interactions of AHR with other ...
Rabbit polyclonal Aryl hydrocarbon Receptor antibody validated for WB and tested in Human and Mouse. With 2 independent reviews. Immunogen corresponding to…
This study shows that expression of CA-AhR in transgenic mice induces lethality beginning at 6 months of age. This effect correlated with the development of severe tumors in the stomach, demonstrating an oncogenic potential of the AhR. It has been difficult to interpret the histopathology of the stomach tumors in the CA-AhR mice unambiguously. The well organized glandular structures and low levels of cellular atypia argue for a benign phenotype. On the other hand, the reduced life span, the aggressive, expanding invasion of all stomach layers, and the adherence to surrounding organs point toward a more malignant phenotype. Intestinal metaplasia, which is regarded as a precancerous lesion (18), was widespread in the CA-AhR tumors. Furthermore, a subgroup of human intestinal-type gastric carcinoma contains highly differentiated cells (19). Given the striking gastric oncogenic phenotype of the CA-AhR mice it is interesting to note that several physiological candidates of receptor ligands are indole ...
Maternal smoking during pregnancy is associated with a variety of adverse neonatal outcomes including altered reproductive performance. Herein we provide molecular evidence for a pathway involved in the elimination of the female germline due to prepregnancy and/or lactational exposure to polycyclic aromatic hydrocarbons (PAHs), environmental toxicants found in cigarette smoke. We show that ovaries of offspring born to mice exposed to PAHs contained only a third of the ovarian follicle pool compared with offspring of unexposed female mice. Activation of the cell death pathway in immature follicles of exposed females was mediated by the aryl hydrocarbon receptor (Ahr), as ovarian reserve was fully rescued by maternal cotreatment with the Ahr antagonist, resveratrol, or by inactivation of the Ahr gene. Furthermore, in response to PAHs, Ahr-mediated activation of the harakiri, BCL2 interacting protein (contains only BH3 domain), was necessary for execution of cell death. This pathway appeared to be ...
Multidrug resistance protein 4 (MRP4; ABCC4) is an ATP binding cassette transporter that facilitates the excretion of bile salt conjugates and other conjugated steroids in hepatocytes and renal proximal tubule epithelium. MRP4/Mrp4 undergoes adaptive upregulation in response to oxidative and cholest …
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Principal Investigator:ICHIHARA Sahoko, Project Period (FY):2006 - 2008, Research Category:Grant-in-Aid for Scientific Research (C), Section:一般, Research Field:Hygiene
4940 The arylhydrocarbon receptor (AhR) is a ligand-activated transcription factor regulating transcription of genes encoding primarily drug metabolizing enzymes. Use of its persistent agonists such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds demonstrated that the AhR mediates species- and tissue-dependent toxicities, including wasting syndrome, immunotoxicty, and carcinogenesis. It has been reported that expression of a constitutively active mutant AhR in transgenic mice resulted in development of stomach tumors, demonstrating the oncogenic potentials of the AhR in gastric cancer. On the other hand, recent reports showed that AhR agonists inhibited pancreatic cancer cell growth and that AhR pathway mediated the effect of antitumor agent in breast tumor cells. To elucidate the functional significance of the AhR pathway in gastric cancer, we examined the expression of AhR in gastric cancer tissues and cell lines and the effect of AhR agonists in gastric cancer cell lines. ...
Advertisement In utero Exposure of Mice to Dibenzo[a,l]Pyrene Produces Lymphoma in the Offspring: Role of the Aryl Hydrocarbon Receptor
Hypoxia-inducible factor 1 alpha (HIF-1 alpha) and the intracellular dioxin receptor mediate hypoxia and dioxin signalling, respectively. Both proteins are conditionally regulated basic helix-loop-helix (bHLH) transcription factors that, in addition to the bHLH motif, share a Per-Arnt-Sim (PAS) region of homology and form heterodimeric complexes with the common bHLH/PAS partner factor Arnt. Here we demonstrate that HIF-1 alpha required Arnt for DNA binding in vitro and functional activity in vivo. Both the bHLH and PAS motifs of Arnt were critical for dimerization with HIF-1 alpha. Strikingly, HIF-1 alpha exhibited very high affinity for Arnt in coimmunoprecipitation assays in vitro, resulting in competition with the ligand-activated dioxin receptor for recruitment of Arnt. Consistent with these observations, activation of HIF-1 alpha function in vivo or overexpression of HIF-1 alpha inhibited ligand-dependent induction of DNA binding activity by the dioxin receptor and dioxin receptor function ...
Postdoctoral Training, Harvard Medical School. BUMC Research Profile. Recent studies have demonstrated that a number of common environmental pollutants (i.e. aromatic hydrocarbons, dioxins, PCBs) compromise the immune system as well as induce cancer. Like immunosuppressive therapeutics (e.g. steroids), these compounds induce thymic atrophy, decrease resistance to infectious agents and transplantable tumors, reduce bone marrow cellularity, alter lymphocyte homing, impair B cell antibody responses, decrease cytotoxic T cell activity, inhibit natural killer activity and decrease cytokine production. Immunotoxicity mediated by extremely low concentrations of environmental pollutants is regulated by an intracellular aromatic hydrocarbon receptor (AhR) which, when bound by hydrocarbons, dioxins, or PCBs, translocates to the nucleus, activates gene promoters, and induces transcription of a number of genes including proto-oncogenes and cytokine genes. Although the endogenous AhR ligand is unknown, work ...
Due to large knowledge gaps in chemical composition and toxicological data for substances involved, paper and board food-contact materials (P&B FCM) have been emerging as a FCM type of particular concern for consumer safety. This study describes the development of a step-by-step strategy, including extraction, high-performance liquid chromatography (HPLC) fractionation, tentative identification of relevant substances and in vitro testing of selected tentatively identified substances. As a case study, we used two fractions from a recycled pizza box sample which exhibited aryl hydrocarbon receptor (AhR) activity. These fractions were analysed by gas chromatography (GC) and ultra-HPLC (UHPLC) coupled to quadrupole time-of-flight mass spectrometers (QTOF MS) in order tentatively to identify substances. The elemental composition was determined for peaks above a threshold, and compared with entries in a commercial mass spectral library for GC-MS (GC-EI-QTOF MS) analysis and an in-house built library ...
The compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, also referred to as dioxin) is a highly toxic environmental pollutant that acts by regulating a ligand-activated transcription factor known as the aryl hydrocarbon receptor (AHR), for which the endogenous regulatory ligand or ligands remain uncertain. Two papers report that the AHR has an important role in controlling T cell differentiation that could help explain increased prevalence of autoimmune diseases in industrialized countries in which exposure to environmental toxins may be a factor. T cells can differentiate into Treg cells, which help keep inflammation in check by inhibiting proliferation of effector cells and secretion of inflammatory cytokines, or TH17 cells, which generally promote inflammation. Dioxin exposure suppresses immune responses, but the mechanism has been unclear. Quintana et al. made the connection of the AHR to T cell differentiation because the regulatory region near a gene that is highly expressed in Treg cells ...
Although the perception of dioxins is predominantly negative, they have also been shown to exert beneficial effects in animal models, such as immunostimulation, reduced cancer rates and prolongation of life at sufficiently low (hormetic) doses. Furthermore, some effects at supra-hormetic doses can be considered desirable under certain conditions. Lowering of body weight or increased insulin sensitivity could contribute to the quest for treating obesity or diabetes mellitus type II. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) binds readily to the aryl hydrocarbon receptor (AhR), and, thereby exerts many of its effects. The binding of potential drug candidates to the AhR, however, is often considered detrimental. The expected subsequent induction of CYP1A1 activity is still associated with the metabolic activation of potential carcinogens despite naturally occurring AhR agonists in food. Therefore, a separation of AhR interaction and downstream effects could lead to the exploitation of the ...
Abstract Background Environmental toxicants, whose actions are often mediated through the aryl hydrocarbon receptor (AhR) pathway, pose risks to the health and well-being of exposed species, including humans. Of particular ...
The environmental contaminant 2 3 7 8 ligand model of human being Go 6976 B cell differentiation have shown that TCDD impairs both B cell activation and differentiation. high BCL-6 levels showed decreased CD80 and CD69 manifestation indicative of impaired cellular activation. The elevated BCL-6 levels resulted in a concomitant increase in BCL-6 DNA binding activity at its cognate binding site within an enhancer region for CD80. Furthermore a small molecule inhibitor of BCL-6 activity reversed TCDD-mediated suppression of CD80 manifestation in human being B cells. In the presence of Go 6976 a low-affinity ligand of the aryl hydrocarbon receptor (AHR) suppression of B cell activation and modified BCL-6 regulation were not observed. These results provide fresh mechanistic insights into the part of BCL-6 in the suppression of human being B cell activation by TCDD. tradition of main lymphocytes (Solid wood (Roche Applied Sciences) with a final salt concentration of 180?mM NaCl. Double-stranded DNA ...
Introduction: Markers for treatment resistance in breast cancer are needed. The Aryl hydrocarbon receptor (AhR) is involved in the regulation of estrogen metabolism. Previous studies have observed a crosstalk between AhR and the estrogen receptor (ER), indicating that the AhR may be of importance in the response of endocrine treatment.. Materials and methods: A functional polymorphism in the AhR Arg554Lys (G,A) was analyzed in a cohort of 634 breast cancer patients included at their preoperative visits in Lund, Sweden between 2002 and 2008. AhR genotypes were studied in relation to ER status and risk for breast cancer events.. Results: The frequencies of the AhR GG/ GA/ AA genotypes were 82.0%, 16.7%, and 1.3%, respectively. There was a trend towards increasing frequency of ER+ tumors with increasing number of A-alleles (P-trend = 0.03). Since few patients had the A/A genotype, patients with the G/A and A/A genotypes were combined in the survival analyses of the 576 patients with invasive ...
Humans are exposed daily to low concentrations of many different chemical substances, natural and some man-made. Although many of these substances can be toxic at high levels, typical exposures are far below the effect levels. The responses produced by man-made aromatic hydrocarbon receptor agonists, such as dioxins, polychlorinated...
Chrysin greatly increased UGT1A1 expression in immortalized cell lines, such as Caco-2 and HepG2 cells, in previous reports (Galijatovic et al., 2000, 2001; Walle et al., 2000). Our studies confirmed the large induction observed in HepG2 cells. However, only a few reports have focused on the mechanism by which chrysin induces drug-metabolizing enzymes. Zhang et al. (2003) found that the induction of CYP1A1 reporter activity by chrysin was mediated through AhR activation and subsequent binding to dioxin-responsive elements present in the gene in HepG2 cells. In a separate study, Sugatani et al. (2004) found that the UGT1A1 response to chrysin was alleviated the most when the AhRE within the gtPBREM was mutated in transactivation experiments conducted in HepG2 cells. UGT1A1 and CYP2B6 gene reporter activation by chrysin and 3-MC was compared in HepG2 cells in the present study. CYP2B6 was not responsive to chrysin, but it was responsive to PB, a PXR and CAR activator, when the PBREM was ...
Hyperplasia of Intermediate Lobe may be related to mutation in the Aryl Hydrocarbon Protein Gene in a Context of Familial Isolated Pituitary Adenoma (FIPA ...
Lavine, J.A.*, A.J. Rowatt,*T. Klimova,* A.J. Whitington,* E. Dengler,* C. Beck,* and W.H. Powell (2005) Aryl Hydrocarbon Receptors in the frog Xenopus laevis: Two AHR1 paralogs exhibit low affinity for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) Toxicol. Sci., in press ...
Beta-naphthoflavone (BNF, DB06732) is an agonist of aryl hydrocarbon receptor (AhR) and a putative chemotherapeutic agent that offers antitumor activity against mammary carcinomas (4C6); nevertheless, its system of actions continues to be uncertain. of advancement, defenses, circadian tempo and tumor biology (7,9,10). The part of AhR in breasts tumor biology offers been thoroughly looked into, and remarkably raising proof shows that the best response of breasts tumor to AhR is definitely reliant upon estrogen receptor (Emergency room) position, ligand existence and cell type (11C13). Deregulation of Emergency room expression is buy TAPI-0 definitely important in the development of breasts tumor, and estrogen-mediated ER alpha dog (ER) activation promotes breasts tumor growth (14). Under particular conditions, agonist-activated AhR requests Emergency room protein ubiquitination and degradation, and upregulation of enzymes that metabolize estrogen, which inhibits estrogen-induced ER-positive ...