Genomes and Genes
aryl hydrocarbon receptors
Summary: Cytoplasmic proteins that bind certain aryl hydrocarbons, translocate to the nucleus, and activate transcription of particular DNA segments. AH receptors are identified by their high-affinity binding to several carcinogenic or teratogenic environmental chemicals including polycyclic aromatic hydrocarbons found in cigarette smoke and smog, heterocyclic amines found in cooked foods, and halogenated hydrocarbons including dioxins and polychlorinated biphenyls. No endogenous ligand has been identified, but an unknown natural messenger with a role in cell differentiation and development is suspected.
- Peng T, Chen J, Mao W, Liu X, Tao Y, Chen L, et al. Potential therapeutic significance of increased expression of aryl hydrocarbon receptor in human gastric cancer. World J Gastroenterol. 2009;15:1719-29 pubmed..TCDD inhibited proliferation of AGS cells via induction of growth arrest at the G1-S phase. AhR plays an important role in gastric carcinogenesis. AhR may be a potential therapeutic target for GC treatment. ..
- Esser C, Rannug A, Stockinger B. The aryl hydrocarbon receptor in immunity. Trends Immunol. 2009;30:447-54 pubmed publisher..In particular, Th17 cells and dendritic cells express high levels of AhR. We review here current evidence for the physiological role of AhR in the immune system, focussing in particular on T-cell biology. ..
- Kobayashi S, Okamoto H, Iwamoto T, Toyama Y, Tomatsu T, Yamanaka H, et al. A role for the aryl hydrocarbon receptor and the dioxin TCDD in rheumatoid arthritis. Rheumatology (Oxford). 2008;47:1317-22 pubmed publisher..TCDD induces inflammatory cytokines via its association with AhR, resulting in stimulation of the NF-kappaB and ERK signalling cascades. Thus TCDD exposure, such as smoking exacerbates RA pathophysiology. ..
- Lin B, Nguyen L, Walisser J, Bradfield C. A hypomorphic allele of aryl hydrocarbon receptor-associated protein-9 produces a phenocopy of the AHR-null mouse. Mol Pharmacol. 2008;74:1367-71 pubmed publisher..That expression level of ARA9 correlates with the frequency of a phenocopy of the Ahr-null allele supports the conclusion that the ARA9 protein is essential for AHR signaling during development. ..
- Kawajiri K, Kobayashi Y, Ohtake F, Ikuta T, Matsushima Y, Mimura J, et al. Aryl hydrocarbon receptor suppresses intestinal carcinogenesis in ApcMin/+ mice with natural ligands. Proc Natl Acad Sci U S A. 2009;106:13481-6 pubmed publisher..These findings suggest that chemoprevention with naturally-occurring and chemically-designed AhR ligands can be used to successfully prevent intestinal cancers. ..
- Chiaro C, Morales J, Prabhu K, Perdew G. Leukotriene A4 metabolites are endogenous ligands for the Ah receptor. Biochemistry. 2008;47:8445-55 pubmed publisher..This work suggests a connection between AHR activation and inflammatory signaling molecules produced by the 5-lipoxygenase pathway. ..
- Marshall N, Vorachek W, Steppan L, Mourich D, Kerkvliet N. Functional characterization and gene expression analysis of CD4+ CD25+ regulatory T cells generated in mice treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin. J Immunol. 2008;181:2382-91 pubmed..The generation of CD4(+) cells with regulatory function mediated through activation of the AhR by TCDD may represent a novel pathway for the induction of T-regs. ..
- Bunger M, Glover E, Moran S, Walisser J, Lahvis G, Hsu E, et al. Abnormal liver development and resistance to 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity in mice carrying a mutation in the DNA-binding domain of the aryl hydrocarbon receptor. Toxicol Sci. 2008;106:83-92 pubmed publisher..Furthermore, Ahr(dbd/dbd) mice are resistant to TCDD-induced toxicity for all endpoints tested. These data suggest that DNA binding is necessary for AHR-mediated developmental and toxic signaling. ..
- Puga A, Ma C, Marlowe J. The aryl hydrocarbon receptor cross-talks with multiple signal transduction pathways. Biochem Pharmacol. 2009;77:713-22 pubmed publisher..Ultimately, the effect of a particular AHR ligand may depend as much on the adaptive interactions that it established with pathways and proteins expressed in a specific cell or tissue as on the toxic responses that it raises. ..
- Soshilov A, Denison M. Role of the Per/Arnt/Sim domains in ligand-dependent transformation of the aryl hydrocarbon receptor. J Biol Chem. 2008;283:32995-3005 pubmed publisher..This study provides insights into mechanisms of AhR transformation, dimerization of PAS domain proteins, and Hsp90 dissociation in activation of its client proteins. ..
- Kimura A, Naka T, Nakahama T, Chinen I, Masuda K, Nohara K, et al. Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses. J Exp Med. 2009;206:2027-35 pubmed publisher..Ahr thus plays an essential role in the negative regulation of the LPS signaling pathway through interaction with Stat1. ..
- Kanno Y, Takane Y, Takizawa Y, Inouye Y. Suppressive effect of aryl hydrocarbon receptor repressor on transcriptional activity of estrogen receptor alpha by protein-protein interaction in stably and transiently expressing cell lines. Mol Cell Endocrinol. 2008;291:87-94 pubmed publisher..AhRR might play a role of co-repressor on the transcriptional activity of the ERalpha homodimer. ..
- Hauben E, Gregori S, Draghici E, Migliavacca B, Olivieri S, Woisetschläger M, et al. Activation of the aryl hydrocarbon receptor promotes allograft-specific tolerance through direct and dendritic cell-mediated effects on regulatory T cells. Blood. 2008;112:1214-22 pubmed publisher..Collectively, our data indicate that AhR activation induces islet allograft-specific tolerance through direct as well as DC-mediated effects on Tr-cell survival and function. ..
- Mathew L, Sengupta S, Ladu J, Andreasen E, Tanguay R. Crosstalk between AHR and Wnt signaling through R-Spondin1 impairs tissue regeneration in zebrafish. FASEB J. 2008;22:3087-96 pubmed publisher..Collectively, these results indicate that inappropriate regulation of R-Spondin/LRP6 is absolutely required for TCDD to inhibit fin regeneration. ..
- Detmar J, Rennie M, Whiteley K, Qu D, Taniuchi Y, Shang X, et al. Fetal growth restriction triggered by polycyclic aromatic hydrocarbons is associated with altered placental vasculature and AhR-dependent changes in cell death. Am J Physiol Endocrinol Metab. 2008;295:E519-30 pubmed publisher..The results of this investigation suggest that chronic exposure to PAHs is a contributing factor to the development of IUGR in human smokers and that the AhR pathway is involved. ..
- Ashida H, Nishiumi S, Fukuda I. An update on the dietary ligands of the AhR. Expert Opin Drug Metab Toxicol. 2008;4:1429-47 pubmed..As to the food factors, they act as antagonists because they basically suppress the AhR transformation by different mechanisms. Moreover, the fate and metabolism of food factors are important to understand their mechanisms. ..
- Villalobos Molina R, Vázquez Cuevas F, Lopez Guerrero J, Figueroa García M, Gallardo Ortiz I, Ibarra M, et al. Vascular alpha-1D-adrenoceptors are overexpressed in aorta of the aryl hydrocarbon receptor null mouse: role of increased angiotensin II. Auton Autacoid Pharmacol. 2008;28:61-7 pubmed publisher
- Ohtake F, Fujii Kuriyama Y, Kato S. AhR acts as an E3 ubiquitin ligase to modulate steroid receptor functions. Biochem Pharmacol. 2009;77:474-84 pubmed publisher..We propose that target-specific regulation of protein destruction, as well as gene expression, is modulated by environmental toxins through the E3 ubiquitin ligase activity of AhR. ..
- Marlowe J, Fan Y, Chang X, Peng L, Knudsen E, Xia Y, et al. The aryl hydrocarbon receptor binds to E2F1 and inhibits E2F1-induced apoptosis. Mol Biol Cell. 2008;19:3263-71 pubmed publisher..These results point to a proproliferative, antiapoptotic function of the Ah receptor that likely plays a role in tumor progression. ..
- Hahn M, Allan L, Sherr D. Regulation of constitutive and inducible AHR signaling: complex interactions involving the AHR repressor. Biochem Pharmacol. 2009;77:485-97 pubmed publisher..Collectively, this discussion emphasizes the importance of this understudied bHLH-PAS protein in tissue development, normal cell biology, xenobiotic responsiveness, and AHR-regulated malignancy. ..
- Kopf P, Huwe J, Walker M. Hypertension, cardiac hypertrophy, and impaired vascular relaxation induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin are associated with increased superoxide. Cardiovasc Toxicol. 2008;8:181-93 pubmed publisher..Our model is the first to definitely demonstrate that sustained AhR activation by TCDD increases blood pressure and induces cardiac hypertrophy, which may be mediated, in part, by increased superoxide. ..
- Vogel C, Matsumura F. A new cross-talk between the aryl hydrocarbon receptor and RelB, a member of the NF-kappaB family. Biochem Pharmacol. 2009;77:734-45 pubmed publisher..Based on such information, a hypothesis has been proposed in this review that AhR together with RelB functions as a coordinator of inflammatory responses. ..
- Kerkvliet N. AHR-mediated immunomodulation: the role of altered gene transcription. Biochem Pharmacol. 2009;77:746-60 pubmed publisher..Based on studies using AHR(-/-) mice, evidence for a role of endogenous AHR ligands in regulation of the immune response is growing, with bilirubin and lipoxinA4 representing two promising candidates. ..
- Gluschnaider U, Hidas G, Cojocaru G, Yutkin V, Ben Neriah Y, Pikarsky E. beta-TrCP inhibition reduces prostate cancer cell growth via upregulation of the aryl hydrocarbon receptor. PLoS ONE. 2010;5:e9060 pubmed publisher..Together these observations suggest that AhR activation may be a cancer counteracting mechanism in the prostate. We maintain that combining beta-TrCP inhibition with androgen ablation could benefit advanced prostate cancer patients. ..
- Schneider D, Manzan M, Yoo B, Crawford R, Kaminski N. Involvement of Blimp-1 and AP-1 dysregulation in the 2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated suppression of the IgM response by B cells. Toxicol Sci. 2009;108:377-88 pubmed publisher..In summary, our findings link the TCDD-mediated suppression of Blimp-1 through AP-1 to the dysregulation of Pax5, which ultimately leads to the suppression of B cell differentiation and humoral immune responses. ..
- Oshima M, Mimura J, Sekine H, Okawa H, Fujii Kuriyama Y. SUMO modification regulates the transcriptional repressor function of aryl hydrocarbon receptor repressor. J Biol Chem. 2009;284:11017-26 pubmed publisher..AhRR, but not AhR, also significantly enhanced the SUMOylation of Arnt. The SUMOylation of both AhRR and Arnt is important for the efficient transcriptional repression activity of the AhRR/Arnt heterodimer. ..
- Zhang S, Lei P, Liu X, Li X, Walker K, Kotha L, et al. The aryl hydrocarbon receptor as a target for estrogen receptor-negative breast cancer chemotherapy. Endocr Relat Cancer. 2009;16:835-44 pubmed publisher..MCDF also inhibited tumor growth in athymic nude mice in which MDA-MB-468 cells were injected directly into the mammary fat pad. These results suggest that the AhR is a potential drug target for treatment of ER-negative breast cancer. ..
- Beischlag T, Luis Morales J, Hollingshead B, Perdew G. The aryl hydrocarbon receptor complex and the control of gene expression. Crit Rev Eukaryot Gene Expr. 2008;18:207-50 pubmed..A major focus of this review is to highlight experimental efforts to characterize nonclassical mechanisms of AhR-mediated modulation of gene transcription. ..
- Aragon A, Kopf P, Campen M, Huwe J, Walker M. In utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure: effects on fetal and adult cardiac gene expression and adult cardiac and renal morphology. Toxicol Sci. 2008;101:321-30 pubmed..These results demonstrate that in utero and lactational TCDD exposures alter cardiac gene expression and cardiac and renal morphology in adulthood, which may increase the susceptibility to cardiovascular dysfunction. ..
- Barnett K, Tomic D, Gupta R, Babus J, Roby K, Terranova P, et al. The aryl hydrocarbon receptor is required for normal gonadotropin responsiveness in the mouse ovary. Toxicol Appl Pharmacol. 2007;223:66-72 pubmed..Thus, in addition to mediating toxicity of environmental chemicals, the Ahr is required for normal ovulation. ..
- Sonneveld E, Jonas A, Meijer O, Brouwer A, van der Burg B. Glucocorticoid-enhanced expression of dioxin target genes through regulation of the rat aryl hydrocarbon receptor. Toxicol Sci. 2007;99:455-69 pubmed
- Coutts S, Fulton N, Anderson R. Environmental toxicant-induced germ cell apoptosis in the human fetal testis. Hum Reprod. 2007;22:2912-8 pubmed
- Morales J, Krzeminski J, Amin S, Perdew G. Characterization of the antiallergic drugs 3-[2-(2-phenylethyl) benzoimidazole-4-yl]-3-hydroxypropanoic acid and ethyl 3-hydroxy-3-[2-(2-phenylethyl)benzoimidazol-4-yl]propanoate as full aryl hydrocarbon receptor agonists. Chem Res Toxicol. 2008;21:472-82 pubmed publisher..This is consistent with M50354 being the active metabolite of M50367. In conclusion, two selective inhibitors of TH2 differentiation are full AhR agonists. ..
- Zudaire E, Cuesta N, Murty V, Woodson K, Adams L, Gonzalez N, et al. The aryl hydrocarbon receptor repressor is a putative tumor suppressor gene in multiple human cancers. J Clin Invest. 2008;118:640-50 pubmed publisher..These results therefore demonstrate that AHRR is a putative new tumor suppressor gene in multiple types of human cancers. ..
- Yang X, Solomon S, Fraser L, Trombino A, Liu D, Sonenshein G, et al. Constitutive regulation of CYP1B1 by the aryl hydrocarbon receptor (AhR) in pre-malignant and malignant mammary tissue. J Cell Biochem. 2008;104:402-17 pubmed..These studies suggest that constitutively active AhR mediates different molecular outcomes than environmental chemical-activated AhR, and further implicate the AhR in mammary tumorigenesis. ..
- Jurisicova A, Taniuchi A, Li H, Shang Y, Antenos M, Detmar J, et al. Maternal exposure to polycyclic aromatic hydrocarbons diminishes murine ovarian reserve via induction of Harakiri. J Clin Invest. 2007;117:3971-8 pubmed
- Connor K, Harris M, Edwards M, Budinsky R, Clark G, Chu A, et al. AH receptor agonist activity in human blood measured with a cell-based bioassay: evidence for naturally occurring AH receptor ligands in vivo. J Expo Sci Environ Epidemiol. 2008;18:369-80 pubmed..and herbs. Our findings also suggest that dietary NAHRAs constitute a substantial daily dietary intake of AHR-active compounds, and these NAHRAs could influence AHR status in humans and play a role in a basal level of AHR activation. ..
- Vogel C, Sciullo E, Matsumura F. Involvement of RelB in aryl hydrocarbon receptor-mediated induction of chemokines. Biochem Biophys Res Commun. 2007;363:722-6 pubmed..The interaction of AhR with RelB binding on a novel type of NF-kappaB binding site represents a new regulatory function of the AhR. ..
- Quintana F, Basso A, Iglesias A, Korn T, Farez M, Bettelli E, et al. Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature. 2008;453:65-71 pubmed publisher..Thus, AHR regulates both T(reg) and T(H)17 cell differentiation in a ligand-specific fashion, constituting a unique target for therapeutic immunomodulation. ..
- Vogel C, Sciullo E, Li W, Wong P, Lazennec G, Matsumura F. RelB, a new partner of aryl hydrocarbon receptor-mediated transcription. Mol Endocrinol. 2007;21:2941-55 pubmed..The interaction of RelB with AhR signaling, and AhR with NF-kappaB RelB signaling pathways represent a new mechanism of cross talk between the two transcription factors. ..
- Moffat I, Boutros P, Celius T, Lindén J, Pohjanvirta R, Okey A. microRNAs in adult rodent liver are refractory to dioxin treatment. Toxicol Sci. 2007;99:470-87 pubmed..It is unlikely that mRNA downregulation by dioxins is mediated by miRNAs, nor are miRNAs likely to play a significant role in dioxin toxicity in adult rodent liver. ..
- Veldhoen M, Hirota K, Westendorf A, Buer J, Dumoutier L, Renauld J, et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature. 2008;453:106-9 pubmed publisher..AHR ligands may therefore represent co-factors in the development of autoimmune diseases. ..
- Franc M, Moffat I, Boutros P, Tuomisto J, Tuomisto J, Pohjanvirta R, et al. Patterns of dioxin-altered mRNA expression in livers of dioxin-sensitive versus dioxin-resistant rats. Arch Toxicol. 2008;82:809-30 pubmed publisher..Type-II genes may lie in pathways that are central to the difference in susceptibility to TCDD lethality in this animal model. ..
- Chang X, Fan Y, Karyala S, Schwemberger S, Tomlinson C, Sartor M, et al. Ligand-independent regulation of transforming growth factor beta1 expression and cell cycle progression by the aryl hydrocarbon receptor. Mol Cell Biol. 2007;27:6127-39 pubmed
- Moffat I, Roblin S, Harper P, Okey A, Pohjanvirta R. Aryl hydrocarbon receptor splice variants in the dioxin-resistant rat: tissue expression and transactivational activity. Mol Pharmacol. 2007;72:956-66 pubmed
- Schnekenburger M, Peng L, Puga A. HDAC1 bound to the Cyp1a1 promoter blocks histone acetylation associated with Ah receptor-mediated trans-activation. Biochim Biophys Acta. 2007;1769:569-78 pubmed
- Sato S, Shirakawa H, Tomita S, Ohsaki Y, Haketa K, Tooi O, et al. Low-dose dioxins alter gene expression related to cholesterol biosynthesis, lipogenesis, and glucose metabolism through the aryl hydrocarbon receptor-mediated pathway in mouse liver. Toxicol Appl Pharmacol. 2008;229:10-9 pubmed publisher..These results indicate that changes in gene expression by TCDD are mediated by AHR and that exposure to low-dose TCDD could affect energy metabolism via alterations of gene expression. ..
- Nguyen L, Bradfield C. The search for endogenous activators of the aryl hydrocarbon receptor. Chem Res Toxicol. 2008;21:102-16 pubmed..In light of the essential function of the AHR in embryonic development, we discuss the candidacy of each of these compounds as physiologically important activators. ..
- Lund A, Agbor L, Zhang N, Baker A, Zhao H, Fink G, et al. Loss of the aryl hydrocarbon receptor induces hypoxemia, endothelin-1, and systemic hypertension at modest altitude. Hypertension. 2008;51:803-9 pubmed publisher..Our studies establish the AHR KO mouse as a model in which modest decreases in PIO(2) lead to hypoxemia, increased plasma ET-1, and systemic hypertension without increased pulmonary prepro-ET-1 mRNA expression. ..
- Nannelli A, Rossignolo F, Tolando R, Rossato P, Longo V, Gervasi P. Effect of beta-naphthoflavone on AhR-regulated genes (CYP1A1, 1A2, 1B1, 2S1, Nrf2, and GST) and antioxidant enzymes in various brain regions of pig. Toxicology. 2009;265:69-79 pubmed publisher..The high expression of metabolic enzymes found in blood-brain interfaces could represent a very important defence toward toxins of CNS. ..