The Aryl Hydrocarbon Receptor Complex and the Control of Gene Expression

Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA.
Critical Reviews in Eukaryotic Gene Expression (Impact Factor: 1.57). 02/2008; 18(3):207-50. DOI: 10.1615/CritRevEukarGeneExpr.v18.i3.20
Source: PubMed


The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that controls the expression of a diverse set of genes. The toxicity of the potent AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin is almost exclusively mediated through this receptor. However, the key alterations in gene expression that mediate toxicity are poorly understood. It has been established through characterization of AhR-null mice that the AhR has a required physiological function, yet how endogenous mediators regulate this orphan receptor remains to be established. A picture as to how the AhR/ARNT heterodimer actually mediates gene transcription is starting to emerge. The AhR/ARNT complex can alter transcription both by binding to its cognate response element and through tethering to other transcription factors. In addition, many of the coregulatory proteins necessary for AhR-mediated transcription have been identified. Cross talk between the estrogen receptor and the AhR at the promoter of target genes appears to be an important mode of regulation. Inflammatory signaling pathways and the AhR also appear to be another important site of cross talk at the level of transcription. A major focus of this review is to highlight experimental efforts to characterize nonclassical mechanisms of AhR-mediated modulation of gene transcription.

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    • "To prove the role of nuclear AhR as a transcription factor in the context of DNA repair, we knocked down the expression of ARNT via specific siRNA (Fig. 3C). ARNT is reported as a nuclear interacting protein of AhR and is relevant for its transcriptional activity (Beischlag et al., 2008). ARNT siRNA treatment reduced ARNT protein levels in nuclear protein fraction significantly (Fig. 3C). "
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    ABSTRACT: In the present study, we explored the role of the aryl hydrocarbon receptor (AhR) for - H2AX associated DNA repair in response to treatment with ionizing radiation. Ionizing radiation was able to stabilize AhR protein and to induce a nuclear translocation in a similar way as described for exposure to aromatic hydrocarbons. A comparable AhR protein stabilization was obtained by treatment with hydroxyl-nonenal - generated by radiation-induced lipid peroxidation. AhR knockdown resulted in significant radio-sensitization of both A549- and HaCaT cells. Under these conditions an increased amount of residual - H2AX foci and a delayed decline of - H2AX foci was observed. Knockdown of the co-activator ARNT, which is essential for transcriptional activation of AhR target genes, reduced AhR-dependent CYP1A expression in response to irradiation, but was without effect on the amount of residual - H2AX foci. Nuclear AhR was found in complex with - H2AX, DNA-PK, ATM and Lamin A. AhR and - H2AX form together nuclear foci, which disappear during DNA repair. Presence of nuclear AhR protein is associated with ATM activation and chromatin relaxation indicated by acetylation of histone H3. Taken together, we could show, that beyond the function as a transcription factor the nuclear AhR is involved in the regulation of DNA repair. Reduction of nuclear AhR inhibits DNA-double stand repair and radiosensitizes cells. First hints for its molecular mechanism suggest a role during ATM activation and chromatin relaxation, both essential for DNA repair.
    No preview · Article · Nov 2015 · Toxicology Letters
    • "NF-jB/Rel proteins play a significant physiological and pathophysiological role in many cellular processes and are prominent regulatory proteins of immune cell function (Vallabhapurapu and Karin, 2009). Interestingly, associations between the AhR and NF-jB/ Rel have been shown to mediate TCDD-induced biological effects , such as cytokine expression (Beischlag et al., 2008; Kim et al., 2000; Tian, 2009; Tian et al., 1999; Vogel et al., 2007). As NFjB/Rel is an essential regulator of B-lymphocyte activation and differentiation (Gerondakis and Siebenlist, 2009), interactions between the AhR and NF-jB/Rel may also mediate the inhibitory effects of TCDD on immunoglobulin (Ig) expression and therefore antibody levels. "
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    ABSTRACT: Transcriptional regulation of the murine immunoglobulin heavy chain gene (Igh) involves several regulatory elements including the 3′Igh regulatory region (3′IghRR), which is composed of at least four enhancers (hs3A; hs1.2; hs3B; hs4). The hs1.2 and hs4 enhancers exhibit the greatest transcriptional activity and contain binding sites for several transcription factors including NF-κB/Rel proteins and the aryl hydrocarbon receptor (AhR). Interestingly, the environmental immunosuppressant 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (TCDD), which potently inhibits antibody secretion, also profoundly inhibits 3′IghRR and hs1.2 enhancer activation induced by the B-lymphocyte activator lipopolysaccharide (LPS), but enhances LPS-induced activation of the hs4 enhancer. Within the hs1.2 and hs4 enhancers, the AhR binding site is in close proximity or overlaps an NF-κB/Rel binding site suggesting a potential reciprocal modulation of the 3′IghRR by AhR and NF-κB/Rel. The objective of the current study was to evaluate the role of NF-κB/Rel and the AhR on the 3′IghRR and its enhancers using the AhR ligand TCDD, the AhR antagonist CH223191, and toll-like receptor agonists LPS, Resiquimod (R848), or cytosine-phosphate-guanine (CpG)-oligodeoxynucleotides. Utilizing the CH12.LX B-lymphocyte cell line and variants expressing either a 3′IghRR-regulated transgene reporter or an inducible IκBα super repressor (IκBαAA), we demonstrate an AhR- and NF-κB/Rel-dependent modulation of 3′IghRR and hs4 activity. Additionally, in mouse splenocytes or CH12.LX cells, binding within the hs1.2 and hs4 enhancer of the AhR and the NF-κB/Rel proteins RelA and RelB were differentially altered by the co-treatment of LPS and TCDD. These results suggest the AhR and NF-κB/Rel protein binding profile within the 3′IghRR mediates the inhibitory effects of TCDD on Ig expression and therefore antibody levels.
    No preview · Article · Sep 2015 · Toxicological Sciences
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    • "ERα, ERβ and androgen receptor (AR) as has been reported in cell lines and the mouse uterus (Beischlag and Perdew 2005; Matthews et al. 2005; Ohtake et al. 2003; Ohtake et al. 2007; Ohtake et al. 2008). How ligand-activated AHR influences ER signaling on a molecular level remains unclear. "
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    ABSTRACT: Background: Cross-talk between Aryl hydrocarbon receptor (AHR) and Estrogen receptor (ER) plays a major role in female reproductive organs. Objectives: This study investigated the influence of the AHR-ligand 3-methylcholanthrene (3-MC) on ER-mediated signaling in mammary gland tissue of ovariectomized (ovx) female rats. Methods: After 14 days of hormonal decline, ovx rats were treated for 3 days with 4 µg/kg 17β-estradiol (E2), 15 mg/kg 8-Prenylnaringenin (8-PN), 15 mg/kg 3-MC or a combination (E2+3-MC, 8-PN+3-MC). Whole mount preparations of the mammary gland were used to count terminal end buds (TEBs). Protein expression studies (Immunohistochemistry, Immunofluorescence), a cDNA microarray, pathway analyses and qPCRs were performed to evaluate the interaction between AHR- and ER-mediated signaling pathways. Results: E2 treatment increased the number of TEBs, protein levels of Ki-67 and progesterone receptor (PR) and changed the expression level of 325 genes more than 1.5 fold. 3-MC treatment alone had marginal impact on gene or protein expression. However, in the situation of a co-treatment of the rats, 3-MC strongly inhibited E2 induced TEB development, protein expression and the expression of nearly half of E2 induced genes. This inhibitory effect of 3-MC was partially mirrored as 8-PN was used as an ER-ligand. The anti-estrogenicity of ligand-activated AHR was at least partly due to decreased protein levels of ERα in ductal epithelial cells. Conclusion: Our data show transcriptome wide anti-estrogenic properties of ligand-activated AHR on ER-mediated processes in the mammary gland, thereby contributing to evaluate the chemopreventive and endocrine disrupting potential of AHR-ligands.
    Full-text · Article · Sep 2015 · Environmental Health Perspectives
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