Genetic Variations of the AHR Gene Encoding Aryl Hydrocarbon Receptor in a Japanese Population

2004 ◽  
Vol 19 (4) ◽  
pp. 320-326 ◽  
Author(s):  
Hiromi Fukushima-Uesaka ◽  
Kimie Sai ◽  
Keiko Maekawa ◽  
Satoru Koyano ◽  
Nahoko Kaniwa ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Japanese Population ◽  
Genetic Variations ◽  
Gene Encoding ◽  
Aryl Hydrocarbon ◽  
Ahr Gene

scholarly journals A putative role for the aryl hydrocarbon receptor (AHR) gene in a patient with cyclical Cushing’s disease

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Sunita M. C. De Sousa ◽  
Jim Manavis ◽  
Jinghua Feng ◽  
Paul Wang ◽  
Andreas W. Schreiber ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Cushing’S Disease ◽  
Cushing's Disease ◽  
Aryl Hydrocarbon ◽  
Putative Role ◽  
Ahr Gene ◽  
Cyclical Cushing’S Disease

FUNCTIONAL ANALYSIS OF SIX HUMAN ARYL HYDROCARBON RECEPTOR VARIANTS IN A JAPANESE POPULATION

2005 ◽  
Vol 33 (8) ◽  
pp. 1254-1260 ◽  
Author(s):  
Satoru Koyano ◽  
Yoshiro Saito ◽  
Hiromi Fukushima-Uesaka ◽  
Seiichi Ishida ◽  
Shogo Ozawa ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Aryl Hydrocarbon Receptor ◽  
Japanese Population ◽  
Aryl Hydrocarbon

scholarly journals Staphylococcus aureus activates the Aryl Hydrocarbon Receptor in Human Keratinocytes

2022 ◽  
Author(s):  
Eva-Lena Stange ◽  
Franziska Rademacher ◽  
Katharina Antonia Drerup ◽  
Nina Heinemann ◽  
Lena Möbus ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Human Keratinocytes ◽  
Dependent Manner ◽  
Cutaneous Infections ◽  
Innate Defense ◽  
Aryl Hydrocarbon ◽  
Reporter Assays ◽  
Ahr Gene ◽  
Whole Transcriptome

Staphylococcus (S.) aureus is an important pathogen causing various infections including - as most frequently isolated bacterium - cutaneous infections. Keratinocytes as the first barrier cells of the skin respond to S. aureus by the release of defense molecules such as cytokines and antimicrobial peptides. Although several pattern recognition receptors expressed in keratinocytes such as Toll-like and NOD-like receptors have been reported to detect the presence of S. aureus, the mechanisms underlying the interplay between S. aureus and keratinocytes are still emerging. Here we report that S. aureus induced gene expression of CYP1A1 and CYP1B1, responsive genes of the aryl hydrocarbon receptor (AhR). AhR activation by S. aureus was further confirmed by AhR gene reporter assays. AhR activation was mediated by factor(s) < 2 kDa secreted by S. aureus. Whole transcriptome analyses and real-time PCR analyses identified IL-24, IL-6 and IL-1beta as cytokines induced in an AhR-dependent manner in S. aureus-treated keratinocytes. AhR inhibition in a 3D organotypic skin equivalent confirmed the crucial role of the AhR in mediating the induction of IL-24, IL-6 and IL-1beta upon stimulation with living S. aureus. Taken together, we further highlight the important role of the AhR in cutaneous innate defense and identified the AhR as a novel receptor mediating the sensing of the important skin pathogen S. aureus in keratinocytes.

Assessment of the Aryl Hydrocarbon Receptor Gene as a Therapeutic Target in Childhood T-Lineage Acute Lymphoblastic Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 536-536
Author(s):  
Marrit Meier ◽  
Monique L. den Boer ◽  
Mathilde J.C. Broekhuis ◽  
Ronald W. Stam ◽  
Elisabeth R. van Wering ◽  
...  
Keyword(s):  
Synergistic Effect ◽  
Aryl Hydrocarbon Receptor ◽  
Therapeutic Target ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Mrna Levels ◽  
Childhood All ◽  
Aryl Hydrocarbon ◽  
Fold Induction ◽  
Ahr Gene

Abstract T-lineage ALL is an unfavorable subtype of childhood ALL and is associated with in-vitro resistance to drugs. Therefore the identification of novel genes that may serve as targets to modulate drug resistance is desirable. We compared the gene expression profile of 28 pediatric T-ALL patients being either sensitive (DNRS) or resistant (DNRR) to daunorubicin. The aryl hydrocarbon receptor (AHR) gene appeared to be highly discriminating between DNRS and DNRR T-ALL patients. AHR is known to mediate signal transduction in response to xenobiotics by activating the transcription of xenobiotic-responsive genes such as CYP1A1 and CYP1A2. Expression analysis by real-time quantitative PCR confirmed that basal AHR mRNA levels in ALL cells derived from patients is correlated with DNR resistance (Rs=0.41, P=0.02). Exposure to DNR of the REH cell line expressing a low AHR level led to a 40-fold induction of AHR mRNA. In two other cell lines (i.e. HL60 and SEMK-2) expressing high levels of AHR the upregulation was only 1.4-fold. In REH, the 40-fold induction of AHR after DNR exposure was inhibited by 40% after pre-exposure to the AHR inhibitors salicylamide (SAL) and geldanamycin (GA). Pre-incubation of leukemic cells of T-ALL patients with SAL or GA prior to DNR exposure had a synergistic effect on DNR sensitivity. In addition, transfection of SEMK-2 cells with AHR-specific siRNA resulted in the reduction of AHR expression by 80% after 24 h and had also a synergistic effect on DNR induced cell kill up to 96 hours after siRNA treatment. We conclude that a high expression of the AHR gene is involved in DNR resistance in childhood T-ALL and that AHR may serve as a very attractive new therapeutic target.

scholarly journals Lack of association between multiple polymorphisms in aryl hydrocarbon receptor (AhR) gene and cancer susceptibility

2020 ◽  
Vol 25 (1) ◽  
Author(s):  
He Li ◽  
Li Luo ◽  
Dan Wang ◽  
Jun Duan ◽  
Rui Zhang
Keyword(s):  
Sensitivity Analysis ◽  
Cancer Risk ◽  
Aryl Hydrocarbon Receptor ◽  
Cancer Susceptibility ◽  
Meta Analysis ◽  
Cancer Type ◽  
China National Knowledge Infrastructure ◽  
Aryl Hydrocarbon ◽  
Negative Results ◽  
Ahr Gene

Abstract Background The aryl hydrocarbon receptor (AhR) is commonly known as an environmental sensor. Polymorphisms in AhR gene have been implicated in susceptibility to cancer. However, the results were controversial. This study was conducted to quantitatively summarize the association between AhR polymorphisms and cancer risk by meta-analysis. Methods Relevant reports were searched in four databases (Embase, PubMed, Wanfang, and China National Knowledge Infrastructure). We used pooled odds ratio (OR) and 95% confidence interval (95% CI) to evaluate the strength of the association in both standard and cumulative meta-analysis. Subgroup and sensitivity analysis was also performed, and between-study heterogeneity and publication bias were checked. Results A total of seventeen studies referring to three AhR polymorphisms (rs2066853, rs7796976, and rs2074113) were identified, and 9557 cases and 10038 controls were included. There was no statistically significant association of AhR rs2066853 polymorphism with cancer risk in the overall population, and the negative results were repeated in subgroup analysis by the ethnicity and cancer type. Concerning AhR rs7796976 or rs2074113 polymorphism, no significant correlation was detected. Moreover, these non-significant findings were stable in sensitivity analysis, and the cumulative meta-analysis indicated a trend of no significant link between this three AhR polymorphisms and cancer risk as more data accumulated over time. Conclusion This meta-analysis provides evidence that the rs2066853, rs7796976, or rs2074113 polymorphism in AhR gene is not a susceptible predictor of cancer. Further clinical and functional investigation between AhR polymorphisms and cancer susceptibility are needed.

scholarly journals Role of NF-kB RelB in Aryl Hydrocarbon Receptor-Mediated Ligand Specific Effects

2019 ◽  
Vol 20 (11) ◽  
pp. 2652 ◽  
Author(s):  
Yasuhiro Ishihara ◽  
Sarah Y. Kado ◽  
Christiane Hoeper ◽  
Shelly Harel ◽  
Christoph F. A. Vogel
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Functional Expression ◽  
Dependent Manner ◽  
Induced Expression ◽  
Aryl Hydrocarbon ◽  
Regulatory Enzymes ◽  
Basal Expression ◽  
Expression Of Genes ◽  
Ahr Gene

Here, we investigate the role of RelB in the regulation of genes which were identified to be induced in an aryl hydrocarbon receptor (AhR)-dependent manner and critically involved in regulation of immune responses. We analyzed the expression of genes of the AhR gene battery, cytokines, and immune regulatory enzymes in bone marrow-derived macrophages (BMM) and thymus of B6 wildtype (wt) mice and RelB knockout (RelB−/−) mice after treatment with various AhR ligands. The 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced expression of indoleamine 2,3-dioxygenase 1 (IDO1) and IDO2 was significantly repressed in thymus of RelB−/− mice but not in BMM derived from RelB−/− mice. Interestingly, the induced and basal expression of the cytokines interleukin (IL)-17A, IL-22, and CCL20 required the functional expression of RelB. The RelB-dependent expression of CCL20 was induced by the AhR ligands TCDD and 6-formylindolo[3,2-b]carbazole (FICZ), whereas indole-3-carbinol (I3C) suppressed CCL20 in lipopolysaccharide (LPS)-activated wt BMM. The LPS-induced expression of IL-6 and IL-10 was enhanced by TCDD and FICZ, whereas I3C significantly suppressed these cytokines in BMM. The exposure to FICZ led to higher increases of IL-17A and IL-22 mRNA compared to the effect of TCDD or I3C in thymus of wt mice. On the other hand, TCDD was the strongest inducer of CYP1A1, AhR Repressor (AhRR), and IDO2. In summary, these findings provide evidence for the important role of RelB in the transcriptional regulation of cytokines and enzymes induced by AhR ligands.

The contribution of genetic variations of aryl hydrocarbon receptor pathway genes to male factor infertility

2007 ◽  
Vol 88 (4) ◽  
pp. 854-859 ◽  
Author(s):  
Ave Merisalu ◽  
Margus Punab ◽  
Signe Altmäe ◽  
Kadri Haller ◽  
Tarmo Tiido ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Genetic Variations ◽  
Male Factor Infertility ◽  
Male Factor ◽  
Aryl Hydrocarbon

scholarly journals 93 Computational biology and tissue-based approaches to inform indication selection for a novel AHR inhibitor

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A102-A102
Author(s):  
Marta Sanchez-Martin ◽  
Lei Wang ◽  
Jeffrey Ecsedy ◽  
Karen Mcgovern ◽  
Michelle Zhang
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Aryl Hydrocarbon Receptor ◽  
Protein Detection ◽  
Transcriptional Analysis ◽  
Tumor Type ◽  
Aryl Hydrocarbon ◽  
Pathway Activation ◽  
Cancer Types ◽  
Ahr Gene

BackgroundAryl Hydrocarbon Receptor (AHR) is a ligand-activated transcription factor that regulates the activities of multiple innate and adaptive immune cell types. Multiple ligands such as kynurenine bind to AHR driving its nuclear translocation and transcriptional activation, leading to an immunosuppressive tumor microenvironment.1 2 AHR activation is implicated in tumor development in multiple cancer types. In addition, high levels of serum kynurenine are associated with resistance to checkpoint inhibitors.3 To overcome AHR-mediated immunosuppression in cancers, we developed a selective oral AHR inhibitor IK-175 and took a combined computational and tissue-based approach to select cancer indications for its clinical development.MethodsThe aim of this work is to identify tumor indications dependent on AHR signaling and design patient selection strategies based on a proprietary transcriptional signature, mRNA and protein detection assays to evaluate AHR pathway activation in tumors.ResultsGenomic profiling of solid and hematological cancers from TCGA and Project GENIE databases identified bladder and esophageal tumors among others, as frequently harboring AHR gene amplifications.A proprietary gene signature of AHR activation was developed integrating literature, pathway analysis, RNAseq and nanostring data from PBMC, T-cells and cell lines upon AHR inhibition. Transcriptional analysis of the TCGA data using this signature demonstrated bladder cancer has the highest expressions of AHR and AHR signature genes, suggesting increased pathway activity in bladder cancer relative to other cancer types. Increased AHR signature gene expression was associated with worse overall survival in the TCGA bladder cancer cohort. Furthermore, RNAscope analysis of a tissue microarray containing 10 different tumor types revealed bladder cancer had one of the highest AHR transcript expression in the tumor compartment.Finally, nuclear localization of AHR protein was assessed as an indicator of pathway activation through the development of a novel IHC method. Extensive TMA screening of AHR protein in 15 different indications demonstrated bladder cancer as the tumor type with the highest prevalence of AHR nuclear expression.ConclusionsIn summary, we demonstrated high prevalence of nuclear AHR protein expression, AHR gene amplification and target gene expression in bladder cancer, suggesting aberrant AHR activation may play an important role in the progression of this tumor type. This study provides rationale for therapeutic targeting of AHR in bladder cancer patients. Ikena is currently evaluating the anti-tumor activity of IK-175 as a single agent and in combination with nivolumab in bladder cancer in a Phase 1a/1b clinical study (NCT04200963).ReferencesQuintana FJ, Sherr DH. Aryl hydrocarbon receptor control of adaptive immunity. Pharmacol Rev 2013 Aug 1;65(4):1148–61.Murray IA, Patterson AD, Perdew GH. Aryl hydrocarbon receptor ligands in cancer: friend and foe. Nat Rev Cancer 2014 Dec;14(12):801–14.Li, Haoxin et al. ‘Metabolomic adaptations and correlates of survival to immune checkpoint blockade.’ Nature Communications 2019 Sep 25;10:1–4346.

Epigenetic modulation of transcription of human aryl-hydrocarboxylic receptor target genes in the Drosophila melanogaster transgenic line.

Biomics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 504-509
Author(s):  
A. A. Akishina ◽  
Yu. E. Vorontsova ◽  
R. O. Cherezov ◽  
E. E. Kuvaeva ◽  
O. B. Simonova ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Aryl Hydrocarbon Receptor ◽  
Target Genes ◽  
The Body ◽  
Epigenetic Mechanism ◽  
Aryl Hydrocarbon ◽  
Functional Features ◽  
Epigenetic Modulation ◽  
Ahr Gene

Aryl hydrocarbon receptor (AHR), is an important ligand-dependent transcription factor, which retained its structural and functional features during evolution. AHR target genes play a key role in detoxification, in the regulation of the development and maintenance of eukaryotic homeostasis. The high conservatism of human AHR allowed us to study its functions in vivo using transgenic Drosophila melanogaster lines with an inducible human AHR gene. It is believed that Drosophila AHR homolog isn't activated by exogenous ligands, so human AHR can be tissue-specific activated in the body of a transgenic fly. This allows us to analyze the transcription level of AHR target genes in various organs and tissues. Unexpectedly we found that exogenous AHR ligands can increase as well as decrease the transcription levels of the AHR target genes, including genes that control proliferation, motility, polarization, and programmed cell death. We hypothesized that the absence of the expected increase in the transcription of some AHR target genes was caused by its epigenetic silencing. This hypothesis was confirmed in the experiments using histone lysine-N-methyltransferase inhibitors and with Drosophila null mutation of the methyltransferase Pc gene. As a result a new epigenetic mechanism of modulation of human aryl hydrocarbon receptor target genes transcription was discovered. Since exogenous AHR ligands and small molecule inhibitors of epigenetic modifiers are often used as pharmaceutical anticancer drugs, our findings may have significant implications in designing new combinations of therapeutic treatments for oncological diseases.

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