Disease relevance of Ahr

• We found that unliganded AhR shows a predominantly cytoplasmic diffuse distribution in mouse hepatoma cells [1].
• The dioxin-inducible mouse [Ah] battery contains at least six genes that "cross-talk" with one another and are believed to play important roles in reproduction and development, and in environmental toxicity, cancer, and oxidative stress [2].
• The AhR-ligand complex is known to mediate a range of biological responses, such as developmental toxicity, induction of cleft palate, and hydronephrosis [3].
• Concomitant treatment of cultures with hypoxia (1% O2) and 3-methylcholanthrene (an AhR ligand) did not significantly alter HIF target gene expression [4].
• We found that AhR(-/-) mice develop significant cardiac hypertrophy at 5 mo [5].

Psychiatry related information on Ahr

• AhR protein levels peaked between postnatal day (PND) 3-10, a critical period for granule neuroblast growth and maturation [6].
• We conclude that the alcohol drinking preference between the B6 and D2 inbred mouse strains is independent of the Ah receptor-but is genetically determined, in part, by the level of brain catalase activity which, in turn, regulates brain acetaldehyde concentrations [7].

High impact information on Ahr

• Thus, Ahr-driven Bax transcription is a novel and evolutionarily conserved cell-death signaling pathway responsible for environmental toxicant-induced ovarian failure [8].
• The Ahr is also activated by dioxin, one of the most intensively studied environmental contaminants [8].
• Mice lacking either Ahr or the pro-apoptotic protein Bax have an increased number of primordial follicles, and these mutant oocytes are resistant to PAH toxicity [9].
• Oocytes microinjected with a Bax promoter-reporter construct show Ahr-dependent transcriptional activation after PAH, but not dioxin, treatment, consistent with findings that dioxin is not cytotoxic to oocytes [8].
• This difference in the action of PAHs versus dioxin is conveyed by a single base pair flanking each Ahr response element in the Bax promoter [8].

Chemical compound and disease context of Ahr

• Aryl hydrocarbon receptor regulation of ceramide-induced apoptosis in murine hepatoma 1c1c7 cells. A function independent of aryl hydrocarbon receptor nuclear translocator [10].
• Down-regulation of aryl hydrocarbon receptor-regulated genes by tumor necrosis factor-alpha and lipopolysaccharide in murine hepatoma Hepa 1c1c7 cells [11].
• In the present study, the effect of tumor necrosis factor (TNF)-alpha and lipopolysaccharides (LPS) on the constitutive and inducible expression of the AHR-regulated genes cyp1a1, GST Ya, and QOR was determined in murine hepatoma Hepa 1c1c7 (WT), AHR-deficient (C12), and AHR nuclear translocator protein (ARNT)-deficient (C4) cells [11].
• 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other aryl hydrocarbon receptor (AhR) ligands suppress 17beta-estradiol (E)-induced responses in the rodent uterus and mammary tumors and in human breast cancer cells [12].
• ERalpha levels in the mouse uterus and breast cancer cells were significantly lower after cotreatment with E plus TCDD than after treatment with E or TCDD alone, and our results indicate that AhR-mediated inhibition of E-induced transactivation is mainly due to limiting levels of ERalpha in cells cotreated with E plus TCDD [12].

Biological context of Ahr

• Histomorphometric analysis of serial ovarian sections revealed a two-fold higher number of primordial follicles in Ahr-null versus wild-type females at day 4 postpartum [13].
• We present gene expression profiles of smooth muscle cells from wild type and Ahr(-/-) mice that show significant changes in the RNA levels of the transforming growth factor-beta3 (Tgfb3) gene and genes involved in the modulation and processing of TGF-beta [14].
• All AhR-positive male mice of both +/+ and +/- genotypes that received subcutaneous injection of B[a]P (2 mg) on the first and the eighth days had developed subcutaneous tumors at the site of injection at the end of the 18-week experiment [15].
• AHR content did not affect staurosporine- or doxorubicin-induced apoptosis [10].
• Such cross-talk between coexpressed bHLH/PAS factors can occur through competition for ARNT, which we find evident in SIM repression of DR-induced transcription from a xenobiotic response element reporter gene [16].

Anatomical context of Ahr

• Oestrogenic actions of AhR agonists were detected in wild-type ovariectomized mouse uteri, but were absent in AhR-/- or ER-alpha-/- ovariectomized mice [17].
• A variant cell line (Tao) having approximately 10% of the AHR content of 1c1c7 cells also arrested following exposure to C2-ceramide, but did not undergo apoptosis [10].
• The aryl hydrocarbon receptor predisposes hepatocytes to Fas-mediated apoptosis [18].
• Murine embryonic fibroblasts (NIH-3T3), rat aortic smooth muscle cells (A7), and murine skeletal muscle cells (C2C12) all exhibited >90% depletion of the AhR after 2-4 hr of TCDD treatment [19].
• Detailed evaluation by immunoelectron microscopy of the AhR and Arnt present in the nuclear compartment of WT cells shows that both proteins are uniformly distributed and do not appear to be associated with nuclear pores, membranes, or nucleoli [20].

Associations of Ahr with chemical compounds

• Gestational exposure of Ahr and Arnt hypomorphs to dioxin rescues vascular development [21].
• Dioxin treatment increased mitochondrial glutathione levels in the wt, Cyp1a1(-/-), and Cyp1a2(-/-) mice, but not in Ahr(-/-) mice [22].
• The level of mitochondrial H(2)O(2) production in vehicle-treated Ahr(-/-) mice was one fifth that found in vehicle-treated wt mice [22].
• Whereas dioxin caused a rise in succinate-stimulated mitochondrial H(2)O(2) production in the wt, Cyp1a1(-/-), and Cyp1a2(-/-) mice, this increase did not occur with the Ahr(-/-) knockout [22].
• A heterodimer of the dioxin receptor (AhR) and Arnt, which are basic helix-loop-helix/PAS-family transcription factors, mediates most of the toxic effects of dioxins [17].
• AhR KO mice challenged with inhaled endotoxin, which does not contain AhR ligands, also developed greater lung neutrophilia than controls, and bronchoalveolar lavage cells from AhR KO mice produced elevated levels of tumor necrosis factor-alpha and interleukin-6 when treated with endotoxin in vitro [23].
• Serum levels of IL-6, MCP-1, IFN-gamma, and TNF-alpha were comparable between L. monocytogenes-infected AhR(-/-) and AhR(+/-) mice [24].
• AHR activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) mediated the induction of cytochrome p450 1A1 and cycloxygenase-2 protein levels [25].
• In vivo treatment with an antisense oligonucleotide for AhR increased TGFbeta signaling and improved re-epithelialization in wounds of wild-type mice [26].

Physical interactions of Ahr

• Herein, we have investigated the subcellular distribution of the AhR/ARNT complex in response to ligand stimulation, by using live-cell confocal and high-resolution deconvolution microscopy [1].
• The reduction in Cyp1a gene transcription by TPA could be accounted for by reduced DNA binding of the dioxin receptor to the xenobiotic-responsive element (XRE) sequences, as measured by gel-retardation analysis [27].
• This study indicates that the effects of TCDD on EGF receptor ligand binding are mediated by the Ah receptor [28].
• At the two lowest doses used in the enzyme induction study, 5 and 10 ng/kg, the levels of specifically bound nuclear Ah receptor complex liganded with [3H]TCDD were 2.3 and 2.5 fmol/mg protein [29].
• We also provided evidence implicating the ubiquitin ligase protein C-terminal hsp70-interacting protein (CHIP) in the degradation of the DR, and we demonstrated that this degradation can be overcome by overexpression of XAP2 [30].

Enzymatic interactions of Ahr

• In order to minimize any artificial steric hindrances to dimerization and XRE binding, each Ahr mutant was also tested with an equivalently deleted Arnt mutant [31].

Co-localisations of Ahr

• To test whether TGF-beta and LTBP-1 overexpression colocalize within the fibrotic nodule of AhR(-/-) liver, we have characterized this hepatic portal fibrosis using collagen protein staining, immunohistochemistry and in situ hybridization [32].

Regulatory relationships of Ahr

• Other AHR ligands also induced AREG mRNA in Hepa-1 cells [33].
• The AhRR is thought to be involved in transcriptional control of AhR-regulated genes by sequestering ARNT [34].
• In this article, we present evidence demonstrating that AhR expression and function promote apoptosis in liver cells in response to Fas stimulation [18].
• The results thus suggest that Aldh-3 gene is regulated by a mechanism independent of the Ah receptor [35].
• Moreover, down-regulation of the aryl hydrocarbon receptor nuclear translocator protein in vivo by adenovirus-mediated RNA interference to suppress AhR activity provided wild-type mice partial protection from Jo2-induced lethality [18].

Other interactions of Ahr

• 5. These findings define the temporal regulation of receptor activation during normal ontogeny and provide evidence to support the idea that receptor activation and AHR-ARNT heterodimerization are essential for normal vascular development [21].
• In contrast, Cyp1a2 gene expression was positive in liver irrespective of the presence or absence of the AhR gene, or B[a]P treatment, although its inducibility was lost in the AhR(-/-) mouse [15].
• Taken together, these data suggest that the AHR cross talks with the EGFR signaling pathway by directly inducing the expression of growth factors that are important for EGFR signaling in the developing mouse ureter [33].
• Here, we report the tissue distribution of AhRR in AhR deficient and wild type C57BL/6 mice [34].
• These studies establish a critical role for ARNT in AHR and HIF-1alpha signal transduction in the intact mouse [36].

Analytical, diagnostic and therapeutic context of Ahr

• The lack of H(2)O(2) production in Ahr(-/-) mice was not due to low levels of Mn(2+)-superoxide dismutase (SOD2) as shown by Western immunoblot analysis, nor was it due to high levels of mitochondrial glutathione peroxidase (GPX1) activity [22].
• Moreover, by using gel mobility shift assays we were able to show that the AhR/Arnt heterodimer binds to the XREs with very low affinity, which is due to three varied nucleotides outside the XRE core sequence [37].
• Fluorescence in situ hybridization analysis has shown that the AhRR gene is located at mouse chromosome 13C2, at rat chromosome 1p11.2, and at human chromosome 5p15 [37].
• Determination of aryl hydrocarbon receptor nuclear translocator protein concentration and subcellular localization in hepatic and nonhepatic cell culture lines: development of quantitative Western blotting protocols for calculation of aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator protein in total cell lysates [38].
• The aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator protein show distinct subcellular localizations in Hepa 1c1c7 cells by immunofluorescence microscopy [20].

References