The mammalian aryl hydrocarbon (Ah) receptor: from mediator of dioxin toxicity toward physiological functions in skin and liver

2009 ◽  
Vol 390 (12) ◽  
Author(s):  
Karl Walter Bock ◽  
Christoph Köhle
Keyword(s):  
Target Genes ◽  
Feedback Loops ◽  
Ah Receptor ◽  
Metabolizing Enzymes ◽  
Physiological Functions ◽  
Aryl Hydrocarbon ◽  
Associated Functions ◽  
Dioxin Toxicity ◽  
Multiple Signaling ◽  
Sustained Activation

AbstractThe mammalian Ah receptor (AhR) is a ligand-activated transcription factor with multiple functions in adaptive metabolism, development and dioxin toxicity in a variety of organs and cell systems. Phenotypes observed following sustained activation by dioxin or in AhR-null mice suggest organ-dependent physiological functions. These functions are probably deregulated following exposure to dioxin. We focus on skin and liver to facilitate discussion of mechanisms linking phenotypes and AhR-modulated genotypes. After a brief summary of currently discussed AhR ligand candidates, two groups of direct AhR target genes/proteins and associated functions are highlighted: (i) xenobiotic-metabolizing enzymes which are also involved in homeostasis of endogenous ligands and (ii) proteins controlling cell proliferation/apoptosis, differentiation and inflammation. Homeostatic feedback loops might not only include CYP1A1 but also Phase II enzymes such as UGT1A1 which controls the antioxidant AhR ligand bilirubin. The AhR is involved in extensive crosstalk with other transcription factors and multiple signaling pathways. Efforts elucidating the pathway toward identification of physiological functions of the AhR remain challenging and promising.

The human Ah receptor: hints from dioxin toxicities to deregulated target genes and physiological functions

2013 ◽  
Vol 394 (6) ◽  
pp. 729-739 ◽  
Author(s):  
Karl Walter Bock
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Target Genes ◽  
Intestinal Inflammation ◽  
Ah Receptor ◽  
Physiological Functions ◽  
Interleukin 22 ◽  
Transient Activation ◽  
Dioxin Toxicity

Abstract Marked species differences of dioxin toxicity prompted the review of three well-studied human dioxin toxicities (chloracne, inflammation and cancer) and deregulated Ah receptor (AhR) target genes to obtain hints as to the physiological functions of this receptor. Dioxin here stands for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Microarray analysis of dermal cysts from a dioxin-poisoned patient revealed, in addition to induced CYP1A1, increased expression of gremlin, an antagonist of bone morphogenetic proteins. Dioxin-mediated skin and intestinal inflammation is associated with deregulated T cell differentiation. In the supernatant of CD4+ T cells obtained from the dioxin-poisoned patient, increased interleukin-22 was detected, a cytokine that may be controlled in part by AhR-regulated Notch. Cancer is one of the long-term consequences of chronic inflammation. In line with dioxin-sensitive lymphoid tissue, enhanced death of lymphoid cancer was observed in the dioxin-exposed Seveso population 25 years after poisoning. Accumulating evidence suggests that endogenous AhR ligands, notably the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole, in contrast to TCDD, is rapidly metabolized by AhR-induced CYP1A1. The feedback loop between 6-formylindolo[3,2-b]carbazole, AhR and CYP1A1 guarantees transient activation that, in contrast to sustained activation by TCDD, may be essential for a putative role of the AhR in stem/progenitor cell homeostasis.

scholarly journals The Aryl Hydrocarbon Receptor Binds to E2F1 and Inhibits E2F1-induced Apoptosis

2008 ◽  
Vol 19 (8) ◽  
pp. 3263-3271 ◽  
Author(s):  
Jennifer L. Marlowe ◽  
Yunxia Fan ◽  
Xiaoqing Chang ◽  
Li Peng ◽  
Erik S. Knudsen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Chromatin Immunoprecipitation ◽  
Expression Vector ◽  
Target Genes ◽  
Ah Receptor ◽  
Aryl Hydrocarbon ◽  
Mrna Induction ◽  
Induced Apoptosis ◽  
Interfering Rna ◽  
Transcriptional Induction

Cellular stress by DNA damage induces checkpoint kinase-2 (CHK2)-mediated phosphorylation and stabilization of the E2F1 transcription factor, leading to induction of apoptosis by activation of a subset of proapoptotic E2F1 target genes, including Apaf1 and p73. This report characterizes an interaction between the aryl hydrocarbon (Ah) receptor (AHR), a ligand-activated transcription factor, and E2F1 that results in the attenuation of E2F1-mediated apoptosis. In Ahr−/− fibroblasts stably transfected with a doxycycline-regulated AHR expression vector, inhibition of AHR expression causes a significant elevation of oxidative stress, γH2A.X histone phosphorylation, and E2F1-dependent apoptosis, which can be blocked by small interfering RNA-mediated knockdown of E2F1 expression. In contrast, ligand-dependent AHR activation protects these cells from etoposide-induced cell death. In cells expressing both proteins, AHR and E2F1 interact independently of the retinoblastoma protein (RB), because AHR and E2F1 coimmunoprecipitate from extracts of RB-negative cells. Additionally, chromatin immunoprecipitation assays indicate that AHR and E2F1 bind to the Apaf1 promoter at a region containing a consensus E2F1 binding site but no AHR binding sites. AHR activation represses Apaf1 and TAp73 mRNA induction by a constitutively active CHK2 expression vector. Furthermore, AHR overexpression blocks the transcriptional induction of Apaf1 and p73 and the accumulation of sub-G0/G1 cells resulting from ectopic overexpression of E2F1. These results point to a proproliferative, antiapoptotic function of the Ah receptor that likely plays a role in tumor progression.

scholarly journals Synthesizing artificial devices that redirect cellular information at will

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Yuchen Liu ◽  
Jianfa Li ◽  
Zhicong Chen ◽  
Weiren Huang ◽  
Zhiming Cai
Keyword(s):  
Cancer Cells ◽  
Signaling Pathway ◽  
Gene Networks ◽  
Target Genes ◽  
Logic Gates ◽  
Feedback Loops ◽  
Oncogenic Signaling ◽  
Multiple Signals ◽  
Translational Level ◽  
At Will

Natural signaling circuits could be rewired to reprogram cells with pre-determined procedures. However, it is difficult to link cellular signals at will. Here, we describe signal-connectors—a series of RNA devices—that connect one signal to another signal at the translational level. We use them to either repress or enhance the translation of target genes in response to signals. Application of these devices allows us to construct various logic gates and to incorporate feedback loops into gene networks. They have also been used to rewire a native signaling pathway and even to create novel pathways. Furthermore, logical AND gates based on these devices and integration of multiple signals have been used successfully for identification and redirection of the state of cancer cells. Eventually, the malignant phenotypes of cancers have been reversed by rewiring the oncogenic signaling from promoting to suppressing tumorigenesis. We provide a novel platform for redirecting cellular information.

The search of CAR, AhR, ESRs binding sites in promoters of intronic and intergenic microRNAs

2018 ◽  
Vol 16 (01) ◽  
pp. 1750029 ◽  
Author(s):  
Vladimir Y. Ovchinnikov ◽  
Denis V. Antonets ◽  
Lyudmila F. Gulyaeva
Keyword(s):  
Transcriptional Activation ◽  
Binding Sites ◽  
In Silico ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Regulation Of Gene Expression ◽  
Experimental Studies ◽  
Transcriptional Level ◽  
Aryl Hydrocarbon ◽  
Exogenous Compounds

MicroRNAs (miRNAs) play important roles in the regulation of gene expression at the post-transcriptional level. Many exogenous compounds or xenobiotics may affect microRNA expression. It is a well-established fact that xenobiotics with planar structure like TCDD, benzo(a)pyrene (BP) can bind aryl hydrocarbon receptor (AhR) followed by its nuclear translocation and transcriptional activation of target genes. Another chemically diverse group of xenobiotics including phenobarbital, DDT, can activate the nuclear receptor CAR and in some cases estrogen receptors ESR1 and ESR2. We hypothesized that such chemicals can affect miRNA expression through the activation of AHR, CAR, and ESRs. To prove this statement, we used in silico methods to find DRE, PBEM, ERE potential binding sites for these receptors, respectively. We have predicted AhR, CAR, and ESRs binding sites in 224 rat, 201 mouse, and 232 human promoters of miRNA-coding genes. In addition, we have identified a number of miRNAs with predicted AhR, CAR, and ESRs binding sites that are known as oncogenes and as tumor suppressors. Our results, obtained in silico, open a new strategy for ongoing experimental studies and will contribute to further investigation of epigenetic mechanisms of carcinogenesis.

scholarly journals Expression, Localization, and Activity of the Aryl Hydrocarbon Receptor in the Human Placenta

2018 ◽  
Vol 19 (12) ◽  
pp. 3762 ◽  
Author(s):  
Anaïs Wakx ◽  
Margaux Nedder ◽  
Céline Tomkiewicz-Raulet ◽  
Jessica Dalmasso ◽  
Audrey Chissey ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Human Placenta ◽  
Target Genes ◽  
Environmental Pollutants ◽  
Cell Fractionation ◽  
Protein Levels ◽  
Aryl Hydrocarbon ◽  
Epithelial Barriers ◽  
Expression And Activity

The human placenta is an organ between the blood of the mother and the fetus, which is essential for fetal development. It also plays a role as a selective barrier against environmental pollutants that may bypass epithelial barriers and reach the placenta, with implications for the outcome of pregnancy. The aryl hydrocarbon receptor (AhR) is one of the most important environmental-sensor transcription factors and mediates the metabolism of a wide variety of xenobiotics. Nevertheless, the identification of dietary and endogenous ligands of AhR suggest that it may also fulfil physiological functions with which pollutants may interfere. Placental AhR expression and activity is largely unknown. We established the cartography of AhR expression at transcript and protein levels, its cellular distribution, and its transcriptional activity toward the expression of its main target genes. We studied the profile of AhR expression and activity during different pregnancy periods, during trophoblasts differentiation in vitro, and in a trophoblast cell line. Using diverse methods, such as cell fractionation and immunofluorescence microscopy, we found a constitutive nuclear localization of AhR in every placental model, in the absence of any voluntarily-added exogenous activator. Our data suggest an intrinsic activation of AhR due to the presence of endogenous placental ligands.

scholarly journals How Ah Receptor Ligand Specificity Became Important in Understanding Its Physiological Function

2020 ◽  
Vol 21 (24) ◽  
pp. 9614
Author(s):  
Iain A. Murray ◽  
Gary H. Perdew
Keyword(s):  
Physiological Function ◽  
Innate Immune ◽  
Ah Receptor ◽  
Ligand Specificity ◽  
Aryl Hydrocarbon ◽  
Innate Immune Signaling ◽  
Tryptophan Metabolites ◽  
Barrier Tissues ◽  
Endogenous Metabolites

Increasingly, the aryl hydrocarbon receptor (AHR) is being recognized as a sensor for endogenous and pseudo-endogenous metabolites, and in particular microbiota and host generated tryptophan metabolites. One proposed explanation for this is the role of the AHR in innate immune signaling within barrier tissues in response to the presence of microorganisms. A number of cytokine/chemokine genes exhibit a combinatorial increase in transcription upon toll-like receptors and AHR activation, supporting this concept. The AHR also plays a role in the enhanced differentiation of intestinal and dermal epithelium leading to improved barrier function. Importantly, from an evolutionary perspective many of these tryptophan metabolites exhibit greater activation potential for the human AHR when compared to the rodent AHR. These observations underscore the importance of the AHR in barrier tissues and may lead to pharmacologic therapeutic intervention.

scholarly journals Comparative In Vitro and In Silico Analysis of the Selectivity of Indirubin as a Human Ah Receptor Agonist

2018 ◽  
Vol 19 (9) ◽  
pp. 2692 ◽  
Author(s):  
Samantha Faber ◽  
Anatoly Soshilov ◽  
Sara Giani Tagliabue ◽  
Laura Bonati ◽  
Michael Denison
Keyword(s):  
Gene Expression ◽  
Dna Binding ◽  
Ligand Binding ◽  
Species Differences ◽  
In Silico Analysis ◽  
Site Directed Mutagenesis ◽  
Ah Receptor ◽  
Aryl Hydrocarbon ◽  
Silico Analysis

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that modulates gene expression following its binding and activation by structurally diverse chemicals. Species differences in AhR functionality have been observed, with the mouse AhR (mAhR) and human AhR (hAhR) exhibiting significant differences in ligand binding, coactivator recruitment, gene expression and response. While the AhR agonist indirubin (IR) is a more potent activator of hAhR-dependent gene expression than the prototypical ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), it is a significantly less potent activator of the mAhR. DNA binding analysis confirmed the greater potency/efficacy of IR in stimulating transformation/DNA binding of the hAhR in vitro and domain-swapping experiments demonstrated that the enhanced response to IR was primarily due to the hAhR ligand binding domain (LBD). Site-directed mutagenesis and functional analysis studies revealed that mutation of H326 and A349 in the mAhR LBD to the corresponding residues in the hAhR LBD significantly increased the potency of IR. Since these mutations had no significant effect on ligand binding, these residues likely contribute to an enhanced efficiency of transformation/DNA binding by IR-bound hAhR. Molecular docking to mAhR LBD homology models further elucidated the different roles of the A375V mutation in TCDD and IR binding, as revealed by [3H]TCDD competitive binding results. These results demonstrate the differential binding of structurally diverse ligands within the LBD of a given AhR and confirm that amino acid differences within the LBD of AhRs contribute to significant species differences in ligand response.

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