The aryl hydrocarbon receptor at the crossroads of multiple signaling pathways

  • Ci Ma
  • Jennifer L. Marlowe
  • Alvaro Puga
Part of the Experientia Supplementum book series (EXS, volume 99)


The aryl hydrocarbon receptor (AHR) has long been recognized as a ligand-activated transcription factor responsible for the induction of drug-metabolizing enzymes. Its role in the combinatorial matrix of cell functions was established long before the first report of an AHR cDNA sequence was published. It is only recently that other functions of this protein have begun to be recognized, and it is now clear that the AHR also functions in pathways outside of its well-characterized role in xenobiotic enzyme induction. Perturbation of these pathways by xenobiotic ligands may ultimately explain much of the toxicity of these compounds. This chapter focuses on the interactions of the AHR in pathways critical to cell cycle regulation, mitogen-activated protein kinase cascades, differentiation and apoptosis. Ultimately, the effect of a particular AHR ligand on the biology of the organism will depend on the milieu of critical pathways and proteins expressed in specific cells and tissues with which the AHR itself interacts.


Aryl Hydrocarbon Receptor Multiple Signaling Pathway Aryl Hydrocarbon Receptor Ligand Adipose Differentiation Mouse Embryo Fibroblast Cell 
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  1. 1.
    Safe S (2001) Molecular biology of the Ah receptor and its role in carcinogenesis. Toxicol Lett 120: 1–7PubMedCrossRefGoogle Scholar
  2. 2.
    Okey AB (2007) An aryl hydrocarbon receptor odyssey to the shores of toxicology: The Deichmann Lecture, International Congress of Toxicology-XI. Toxicol Sci 98: 5–38PubMedCrossRefGoogle Scholar
  3. 3.
    Hogenesch JB, Chan WK, Jackiw V, Brown RC, Gu Y-Z, Pray-Grant M, Perdew GH, Bradfield CA (1997) Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway. J Biol Chem 272: 8581–8593PubMedCrossRefGoogle Scholar
  4. 4.
    Crews ST, Fan CM (1999) Remembrance of things PAS: Regulation of development by bHLHPAS proteins. Curr Opin Genet Dev 9: 580–587PubMedCrossRefGoogle Scholar
  5. 5.
    Barouki R, Coumoul X, Fernandez-Salguero PM (2007) The aryl hydrocarbon receptor, more than a xenobiotic-interacting protein. FEBS Lett 581: 3608–3615PubMedCrossRefGoogle Scholar
  6. 6.
    Abbott BD, Birnbaum LS, Perdew GH (1995) Developmental expression of two members of a new class of transcription factors: I. Expression of aryl hydrocarbon receptor in the C57BL/6N mouse embryo. Dev Dyn 204: 133–143PubMedGoogle Scholar
  7. 7.
    Ma Q, Whitlock JP Jr, (1997) A novel cytoplasmic protein that interacts with the Ah receptor, contains tetratricopeptide repeat motifs, and augments the transcriptional response to 2,3,7,8-tetrachlorodibenzo-p-dioxin. J Biol Chem 272: 8878–8884PubMedCrossRefGoogle Scholar
  8. 8.
    Carver LA, Bradfield CA (1997) Ligand-dependent interaction of the aryl hydrocarbon receptor with a novel immunophilin homolog in vivo. J Biol Chem 272: 11452–11456PubMedCrossRefGoogle Scholar
  9. 9.
    Petrulis JR, Kusnadi A, Ramadoss P, Hollingshead B, Perdew GH (2003) The hsp90 co-chaperone XAP2 alters importin b recognition of the bipartite nuclear localization signal of the Ah receptor and represses transcriptional activity. J Biol Chem 278: 2677–2685PubMedCrossRefGoogle Scholar
  10. 10.
    Beischlag TV, Wang S, Rose DW, Torchia J, Reisz-Porszasz S, Muhammad K, Nelson WE, Probst MR, Rosenfeld MG, Hankinson O (2002) Recruitment of the NCoA/SRC-1/p160 family of transcriptional coactivators by the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator complex. Mol Cell Biol 22: 4319–4333PubMedCrossRefGoogle Scholar
  11. 11.
    Wang S, Hankinson O (2002) Functional involvement of the Brahma/SWI2-related gene 1 protein in cytochrome P4501A1 transcription mediated by the aryl hydrocarbon receptor complex. J Biol Chem 277: 11821–11827PubMedCrossRefGoogle Scholar
  12. 12.
    Hestermann EV, Brown M (2003) Agonist and chemopreventative ligands induce differential transcriptional cofactor recruitment by aryl hydrocarbon receptor. Mol Cell Biol 23: 7920–7925PubMedCrossRefGoogle Scholar
  13. 13.
    Wang S, Ge K, Roeder RG, Hankinson O (2004) Role of mediator in transcriptional activation by the aryl hydrocarbon receptor. J Biol Chem 279: 13593–13600PubMedCrossRefGoogle Scholar
  14. 14.
    Schnekenburger M, Peng L, Puga A (2007) HDAC1 bound to the Cyp1a1 promoter blocks histone acetylation associated with Ah receptor-mediated trans-activation. Biochim Biophys Acta 1769: 569–578PubMedGoogle Scholar
  15. 15.
    Pollenz RS (2002) The mechanism of Ah receptor protein down-regulation (degradation) and its impact on Ah receptor-mediated gene regulation. Chem Biol Interact 141: 41–61PubMedCrossRefGoogle Scholar
  16. 16.
    Puga A, Xia Y, Elferink C (2002) Role of the aryl hydrocarbon receptor in cell cycle regulation. Chem Biol Interact 141: 117–130PubMedCrossRefGoogle Scholar
  17. 17.
    Henklova P, Vrzal R, Ulrichova J, Dvorak Z (2008) Role of mitogen-activated protein kinases in aryl hydrocarbon receptor signaling. Chem Biol Interact 172: 93–104PubMedCrossRefGoogle Scholar
  18. 18.
    Carrier F, Owens RA, Nebert DW, Puga A (1992) Dioxin-dependent activation of murine Cyp1a-1 gene transcription requires protein kinase C-dependent phosphorylation. Mol Cell Biol 12: 1856–1863PubMedGoogle Scholar
  19. 19.
    Chen YH, Tukey RH (1996) Protein kinase C modulates regulation of the CYP1A1 gene by the The aryl hydrocarbon receptor at the crossroads of multiple signaling pathways 253 aryl hydrocarbon receptor. J Biol Chem 271: 26261–26266PubMedCrossRefGoogle Scholar
  20. 20.
    Long WP, Pray-Grant M, Tsai JC, Perdew GH (1998) Protein kinase C activity is required for aryl hydrocarbon receptor pathway-mediated signal transduction. Mol Pharmacol 53: 691–700PubMedGoogle Scholar
  21. 21.
    Okino ST, Pendurthi UR, Tukey RH (1992) Phorbol esters inhibit the dioxin receptor-mediated transcriptional activation of the mouse Cyp1a-1 and Cyp1a-2 genes by 2,3,7,8-tetrachlorodibenzo-p-dioxin. J Biol Chem 267: 6991–6998PubMedGoogle Scholar
  22. 22.
    Ikegwuonu FI, Christou M, Jefcoate CR (1999) Regulation of cytochrome P4501B1 (CYP1B1) in mouse embryo fibroblast (C3H10T1/2) cells by protein kinase C (PKC). Biochem Pharmacol 57: 619–630PubMedCrossRefGoogle Scholar
  23. 23.
    Li SY, Dougherty JJ (1997) Inhibitors of serine/threonine-specific protein phosphatases stimulate transcription by the Ah receptor/Arnt dimer by affecting a step subsequent to XRE binding. Arch Biochem Biophys 340: 73–82PubMedCrossRefGoogle Scholar
  24. 24.
    Pongratz I, Strömstedt PE, Mason GG, Poellinger L (1991) Inhibition of the specific DNA binding activity of the dioxin receptor by phosphatase treatment. J Biol Chem 266: 16813–16817PubMedGoogle Scholar
  25. 25.
    Mahon MJ, Gasiewicz TA (1995) Ah receptor phosphorylation: Localization of phosphorylation sites to the C-terminal half of the protein. Arch Biochem Biophys 318: 166–174PubMedCrossRefGoogle Scholar
  26. 26.
    Park S, Henry EC, Gasiewicz TA (2000) Regulation of DNA binding activity of the ligand-activated aryl hydrocarbon receptor by tyrosine phosphorylation. Arch Biochem Biophys 381: 302–312PubMedCrossRefGoogle Scholar
  27. 27.
    Dieter MZ, Freshwater SL, Solis WA, Nebert DW, Dalton TP (2001) Tryphostin AG879, a tyrosine kinase inhibitor: Prevention of transcriptional activation of the electrophile and the aromatic hydrocarbon response elements. Biochem Pharmacol 61: 215–225PubMedCrossRefGoogle Scholar
  28. 28.
    Ikuta T, Kobayashi Y, Kawajiri K (2004) Phosphorylation of nuclear localization signal inhibits the ligand-dependent nuclear import of aryl hydrocarbon receptor. Biochem Biophys Res Commun 317: 545–550PubMedCrossRefGoogle Scholar
  29. 29.
    Minsavage GD, Park SK, Gasiewicz TA (2004) The aryl hydrocarbon receptor (AhR) tyrosine 9, a residue that is essential for AhR DNA binding activity, is not a phosphoresidue but augments AhR phosphorylation. J Biol Chem 279: 20582–20593PubMedCrossRefGoogle Scholar
  30. 30.
    Pratt WB (1997) The role of the hsp90-based chaperone system in signal transduction by nuclear receptors and receptors signaling via MAP kinase. Annu Rev Pharmacol Toxicol 37: 297–326PubMedCrossRefGoogle Scholar
  31. 31.
    Ogiso H, Kagi N, Matsumoto E, Nishimoto M, Arai R, Shirouzu M, Mimura J, Fujii-Kuriyama Y, Yokoyama S (2004) Phosphorylation analysis of 90 kDa heat shock protein within the cytosolic arylhydrocarbon receptor complex. Biochemistry 43: 15510–15519PubMedCrossRefGoogle Scholar
  32. 32.
    Cobb MH, Goldsmith EJ (2000) Dimerization in MAP-kinase signaling. Trends Biochem Sci 25: 7–9PubMedCrossRefGoogle Scholar
  33. 33.
    Weston CR, Davis RJ (2007) The JNK signal transduction pathway. Curr Opin Cell Biol 19: 142–149PubMedCrossRefGoogle Scholar
  34. 34.
    Tan Z, Chang X, Puga A, Xia Y (2002) Activation of mitogen-activated protein kinases (MAPKs) by aromatic hydrocarbons: Role in the regulation of aryl hydrocarbon receptor (AHR) function. Biochem Pharmacol 64: 771–780PubMedCrossRefGoogle Scholar
  35. 35.
    Tan Z, Huang M, Puga A, Xia Y (2004) A critical role for MAP kinases in the control of Ah receptor complex activity. Toxicol Sci 82: 80–87PubMedCrossRefGoogle Scholar
  36. 36.
    Diry M, Tomkiewicz C, Koehle C, Coumoul X, Bock KW, Barouki R, Transy C (2006) Activation of the dioxin/aryl hydrocarbon receptor (AhR) modulates cell plasticity through a JNK-dependent mechanism. Oncogene 25: 5570–5574PubMedCrossRefGoogle Scholar
  37. 37.
    Puga A, Nebert DW, Carrier F (1992) Dioxin induces expression of c-fos and c-jun proto-oncogenes and a large increase in transcription factor AP-1. DNA Cell Biol 11: 269–281PubMedCrossRefGoogle Scholar
  38. 38.
    Hoffer A, Chang CY, Puga A (1996) Dioxin induces fos and jun gene expression by Ah receptordependent and-independent pathways. Toxicol Appl Pharmacol 141: 238–247PubMedGoogle Scholar
  39. 39.
    Weiss C, Faust D, Durk H, Kolluri SK, Pelzer A, Schneider S, Dietrich C, Oesch F, Göttlicher M (2005) TCDD induces c-jun expression via a novel Ah (dioxin) receptor-mediated p38-MAPKdependent pathway. Oncogene 24: 4975–4983PubMedCrossRefGoogle Scholar
  40. 40.
    Weiss C, Faust D, Schreck I, Ruff A, Farwerck T, Melenberg A, Schneider S, Oesch-Bartlomowicz B, Zatloukalova J, Vondracek J, Oesch F, Dietrich C (2008) TCDD deregulates contact inhibition in rat liver oval cells via Ah receptor, JunD and cyclin A. Oncogene 27: 2198–2207PubMedCrossRefGoogle Scholar
  41. 41.
    Ikuta T, Kobayashi Y, Kawajiri K (2004) Cell density regulates intracellular localization of aryl hydrocarbon receptor. J Biol Chem 279: 19209–19216PubMedCrossRefGoogle Scholar
  42. 42.
    Park SJ, Yoon WK, Kim HJ, Son HY, Cho SW, Jeong KS, Kim TH, Kim SH, Kim SR, Ryu SY (2005) 2,3,7,8-Tetrachlorodibenzo-p-dioxin activates ERK and p38 mitogen-activated protein kinases in RAW 264.7 cells. Anticancer Res 25: 2831–2836PubMedGoogle Scholar
  43. 43.
    Reiners JJ Jr, Lee JY, Clift RE, Dudley DT, Myrand SP (1998) PD98059 is an equipotent antagonist of the aryl hydrocarbon receptor and inhibitor of mitogen-activated protein kinase kinase. Mol Pharmacol 53: 438–445PubMedGoogle Scholar
  44. 44.
    Joiakim A, Mathieu PA, Palermo C, Gasiewicz TA, Reiners JJ Jr, (2003) The Jun N-terminal kinase inhibitor SP600125 is a ligand and antagonist of the aryl hydrocarbon receptor. Drug Metab Dispos 31: 1279–1282PubMedCrossRefGoogle Scholar
  45. 45.
    Andrieux L, Langouet S, Fautrel A, Ezan F, Krauser JA, Savouret JF, Guengerich FP, Baffet G, Guillouzo A (2004) Aryl hydrocarbon receptor activation and cytochrome P450 1A induction by the mitogen-activated protein kinase inhibitor U0126 in hepatocytes. Mol Pharmacol 65: 934–943PubMedCrossRefGoogle Scholar
  46. 46.
    Caruso JA, Mathieu PA, Joiakim A, Zhang H, Reiners JJ Jr, (2006) Aryl hydrocarbon receptor modulation of tumor necrosis factor-a-induced apoptosis and lysosomal disruption in a hepatoma model that is caspase-8-independent. J Biol Chem 281: 10954–10967PubMedCrossRefGoogle Scholar
  47. 47.
    Dvorak Z, Vrzal R, Henklova P, Jancova P, Anzenbacherova E, Maurel P, Svecova L, Pavek P, Ehrmann J, Havlik R, Bednar P, Lemr K, Ulrichova J (2008) JNK inhibitor SP600125 is a partial agonist of human aryl hydrocarbon receptor and induces CYP1A1 and CYP1A2 genes in primary human hepatocytes. Biochem Pharmacol 75: 580–588PubMedCrossRefGoogle Scholar
  48. 48.
    Shibazaki M, Takeuchi T, Ahmed S, Kikuchi H (2004) Suppression by p38 MAP kinase inhibitors (pyridinyl imidazole compounds) of Ah receptor target gene activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin and the possible mechanism. J Biol Chem 279: 3869–3876PubMedCrossRefGoogle Scholar
  49. 49.
    Shibazaki M, Takeuchi T, Ahmed S, Kikuchi H (2004) Blockade by SB203580 of Cyp1a1 induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin, and the possible mechanism: Possible involvement of the p38 mitogen-activated protein kinase pathway in shuttling of Ah receptor overexpressed in COS-7 cells. Ann NY Acad Sci 1030: 275–281PubMedCrossRefGoogle Scholar
  50. 50.
    Ramakrishna G, Perella C, Birely L, Diwan BA, Fornwald LW, Anderson LM (2002) Decrease in K-ras p21 and increase in Raf1 and activated Erk 1 and 2 in murine lung tumors initiated by N-nitrosodimethylamine and promoted by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol 179: 21–34PubMedCrossRefGoogle Scholar
  51. 51.
    Lecureur V, Ferrec EL, N’diaye M, Vee ML, Gardyn C, Gilot D, Fardel O (2005) ERK-dependent induction of TNFa expression by the environmental contaminant benzo[a]pyrene in primary human macrophages. FEBS Lett 579: 1904–1910PubMedCrossRefGoogle Scholar
  52. 52.
    Chen S, Operana T, Bonzo J, Nguyen N, Tukey RH (2005) ERK kinase inhibition stabilizes the aryl hydrocarbon receptor: Implications for transcriptional activation and protein degradation. J Biol Chem 280: 4350–4359PubMedCrossRefGoogle Scholar
  53. 53.
    Yim S, Oh M, Choi SM, Park H (2004) Inhibition of the MEK-1/p42 MAP kinase reduces aryl hydrocarbon receptor-DNA interactions. Biochem Biophys Res Commun 322: 9–16PubMedCrossRefGoogle Scholar
  54. 54.
    Cheng M, Olivier P, Diehl JA, Fero M, Roussel MF, Roberts JM, Sherr CJ (1999) The p21(Cip1) and p27(Kip1) CDK ‘inhibitors’ are essential activators of cyclin D-dependent kinases in murine fibroblasts. EMBO J 18: 1571–1583PubMedCrossRefGoogle Scholar
  55. 55.
    Sherr CJ, Roberts JM (1999) CDK inhibitors: Positive and negative regulators of G1-phase progression. Genes Dev 13: 1501–1512PubMedCrossRefGoogle Scholar
  56. 56.
    Smits VA, Medema RH (2001) Checking out the G(2)/M transition. Biochim Biophys Acta 1519: 1–12PubMedGoogle Scholar
  57. 57.
    Weiss C, Kolluri SK, Kiefer F, Göttlicher M (1996) Complementation of Ah receptor deficiency in hepatoma cells: Negative feedback regulation and cell cycle control by the Ah receptor. Exp Cell Res 226: 154–163PubMedCrossRefGoogle Scholar
  58. 58.
    Ma Q, Whitlock JPJ (1996) The aromatic hydrocarbon receptor modulates the Hepa 1c1c7 cell cycle and differentiated state independently of dioxin. Mol Cell Biol 16: 2144–2150PubMedGoogle Scholar
  59. 59.
    Kolluri SK,Weiss C, Koff A, Göttlicher M (1999) P27Kip1 induction and inhibition of proliferation by the intracellular Ah receptor in developing thymus and hepatoma cells. Genes Dev 13: 1742–1753PubMedCrossRefGoogle Scholar
  60. 60.
    Puga A, Barnes SJ, Dalton TP, Chang C, Knudsen ES, Maier MA (2000) Aromatic hydrocarbon receptor interaction with the retinoblastoma protein potentiates repression of E2F-dependent transcription and cell cycle arrest. J Biol Chem 275: 2943–2950PubMedCrossRefGoogle Scholar
  61. 61.
    Ge NL, Elferink CJ (1998) A direct interaction between the aryl hydrocarbon receptor and retinoblastoma protein. J Biol Chem 273: 22708–22713PubMedCrossRefGoogle Scholar
  62. 62.
    Elferink CJ, Ge NL, Levine A (2001) Maximal aryl hydrocarbon receptor activity depends on an The aryl hydrocarbon receptor at the crossroads of multiple signaling pathways 255 interaction with the retinoblastoma protein. Mol Pharmacol 59: 664–673PubMedGoogle Scholar
  63. 63.
    Elizondo G, Fernandez-Salguero P, Sheikh MS, Kim GY, Fornace AJ, Lee KS, Gonzalez FJ (2000) Altered cell cycle control at the G(2)/M phases in aryl hydrocarbon receptor-null embryo fibroblast. Mol Pharmacol 57: 1056–1063PubMedGoogle Scholar
  64. 64.
    Tohkin M, Fukuhara M, Elizondo G, Tomita S, Gonzalez FJ (2000) Aryl hydrocarbon receptor is required for p300-mediated induction of DNA synthesis by adenovirus E1A. Mol Pharmacol 58: 845–851PubMedGoogle Scholar
  65. 65.
    Gierthy JF, Crane D (1984) Reversible inhibition of in vitro epithelial cell proliferation by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol 74: 91–98PubMedCrossRefGoogle Scholar
  66. 66.
    Hushka DR, Greenlee WF (1995) 2,3,7,8-Tetrachlorodibenzo-p-dioxin inhibits DNA synthesis in rat primary hepatocytes. Mutat Res 333: 89–99PubMedGoogle Scholar
  67. 67.
    Bauman JW, Goldsworthy TL, Dunn CS, Fox TR (1995) Inhibitory effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on rat hepatocyte proliferation induced by 2/3 partial hepatectomy. Cell Prolif 28: 437–451PubMedCrossRefGoogle Scholar
  68. 68.
    Marlowe JL, Puga A (2005) Aryl hydrocarbon receptor, cell cycle regulation, toxicity, and tumorigenesis. J Cell Biochem 96: 1174–1184PubMedCrossRefGoogle Scholar
  69. 69.
    Marlowe JL, Knudsen ES, Schwemberger S, Puga A (2004) The aryl hydrocarbon receptor displaces p300 from E2F-dependent promoters and represses S-phase specific gene expression. J Biol Chem 279: 29013–29022PubMedCrossRefGoogle Scholar
  70. 70.
    Barnes-Ellerbe S, Knudsen KE, Puga A (2004) 2,3,7,8-Tetrachlorodibenzo-p-dioxin blocks androgen-dependent cell proliferation of LNCaP cells through modulation of pRB phosphorylation. Mol Pharmacol 66: 502–511PubMedCrossRefGoogle Scholar
  71. 71.
    Huang G, Elferink CJ (2005) Multiple mechanisms are involved in Ah receptor-mediated cell cycle arrest. Mol Pharmacol 67: 88–96PubMedCrossRefGoogle Scholar
  72. 72.
    Chang X, Fan Y, Karyala S, Schwemberger S, Tomlinson CR, Sartor MA, Puga A (2007) Ligandindependent regulation of transforming growth factor b1 expression and cell cycle progression by the aryl hydrocarbon receptor. Mol Cell Biol 27: 6127–6139PubMedCrossRefGoogle Scholar
  73. 73.
    Andrysik Z, Vondracek J, Machala M, Krcmar P, Svihalkova-Sindlerova L, Kranz A, Weiss C, Faust D, Kozubik A, Dietrich C (2007) The aryl hydrocarbon receptor-dependent deregulation of cell cycle control induced by polycyclic aromatic hydrocarbons in rat liver epithelial cells. Mutat Res 615: 87–97PubMedGoogle Scholar
  74. 74.
    Bock KW, Kohle C (2005) Ah receptor-and TCDD-mediated liver tumor promotion: Clonal selection and expansion of cells evading growth arrest and apoptosis. Biochem Pharmacol 69: 1403–1408PubMedCrossRefGoogle Scholar
  75. 75.
    McConkey DJ, Hartzell P, Duddy SK, Hakansson H, Orrenius S (1988) 2,3,7,8-Tetrachlorodibenzo-p-dioxin kills immature thymocytes by Ca2+-mediated endonuclease activation. Science 242: 256–259PubMedCrossRefGoogle Scholar
  76. 76.
    Kurl RN, Abraham M, Olnes MJ (1993) Early effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on rat thymocytes in vitro. Toxicology 77: 103–114PubMedCrossRefGoogle Scholar
  77. 77.
    Silverstone AE, Frazier DE Jr, Gasiewicz TA (1994) Alternate immune system targets for TCDD: Lymphocyte stem cells and extrathymic T-cell development. Exp Clin Immunogenet 11: 94–101PubMedGoogle Scholar
  78. 78.
    Nebert DW, Roe AL, Dieter MZ, Solis WA,Yang Y, Dalton TP (2000) Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis. Biochem Pharmacol 59: 65–85PubMedCrossRefGoogle Scholar
  79. 79.
    Chen S, Nguyen N, Tamura K, Karin M, Tukey RH (2003) The role of the Ah receptor and p38 in benzo[a]pyrene-7,8-dihydrodiol and benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide-induced apoptosis. J Biol Chem 278: 19526–19533PubMedCrossRefGoogle Scholar
  80. 80.
    Schlezinger JJ, Liu D, Farago M, Seldin DC, Belguise K, Sonenshein GE, Sherr DH (2006) A role for the aryl hydrocarbon receptor in mammary gland tumorigenesis. Biol Chem 387: 1175–1187PubMedCrossRefGoogle Scholar
  81. 81.
    Gonzalez FJ, Fernandez-Salguero P (1998) The aryl hydrocarbon receptor: Studies using the AHR-null mice. Drug Metab Dispos 26: 1194–1198PubMedGoogle Scholar
  82. 82.
    Viluksela M, Bager Y, Tuomisto JT, Scheu G, Unkila M, Pohjanvirta R, Flodstrom S, Kosma VM, Maki-Paakkanen J, Vartiainen T et al (2000) Liver tumor-promoting activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in TCDD-sensitive and TCDD-resistant rat strains. Cancer Res 60: 6911–6920PubMedGoogle Scholar
  83. 83.
    Pääjärvi G, Viluksela M, Pohjanvirta R, Stenius U, Högberg J (2005) TCDD activates Mdm2 and attenuates the p53 response to DNA damaging agents. Carcinogenesis 26: 201–208PubMedCrossRefGoogle Scholar
  84. 84.
    Vogel CF, Li W, Sciullo E, Newman J, Hammock B, Reader JR, Tuscano J, Matsumura F (2007) Pathogenesis of aryl hydrocarbon receptor-mediated development of lymphoma is associated with increased cyclooxygenase-2 expression. Am J Pathol 171: 1538–1548PubMedCrossRefGoogle Scholar
  85. 85.
    Wu R, Zhang L, Hoagland MS, Swanson HI (2007) Lack of the aryl hydrocarbon receptor leads to impaired activation of AKT/protein kinase B and enhanced sensitivity to apoptosis induced via the intrinsic pathway. J Pharmacol Exp Ther 320: 448–457PubMedCrossRefGoogle Scholar
  86. 86.
    Sarioglu H, Brandner S, Haberger M, Jacobsen C, Lichtmannegger J, Wormke M, Andrae U (2008) Analysis of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced proteome changes in 5L rat hepatoma cells reveals novel targets of dioxin action including the mitochondrial apoptosis regulator VDAC2. Mol Cell Proteomics 7: 394–410PubMedGoogle Scholar
  87. 87.
    Coutts SM, Fulton N, Anderson RA (2007) Environmental toxicant-induced germ cell apoptosis in the human fetal testis. Hum Reprod 22: 2912–2918PubMedCrossRefGoogle Scholar
  88. 88.
    Shimba S, Todoroki K, Aoyagi T, Tezuka M (1998) Depletion of arylhydrocarbon receptor during adipose differentiation in 3T3-L1 cells. Biochem Biophys Res Commun 249: 131–137PubMedCrossRefGoogle Scholar
  89. 89.
    Shimba S, Hayashi M, Ohno T, Tezuka M (2003) Transcriptional regulation of the AhR gene during adipose differentiation. Biol Pharm Bull 26: 1266–1271PubMedCrossRefGoogle Scholar
  90. 90.
    Alexander DL, Ganem LG, Fernandez-Salguero P, Gonzalez F, Jefcoate CR (1998) Aryl-hydrocarbon receptor is an inhibitory regulator of lipid synthesis and of commitment to adipogenesis. J Cell Sci 111: 3311–3322PubMedGoogle Scholar
  91. 91.
    Shimba S, Wada T, Tezuka M (2001) Arylhydrocarbon receptor (AhR) is involved in negative regulation of adipose differentiation in 3T3-L1 cells: AhR inhibits adipose differentiation independently of dioxin. J Cell Sci 114: 2809–2817PubMedGoogle Scholar
  92. 92.
    Hanlon PR, Ganem LG, Cho YC, Yamamoto M, Jefcoate CR (2003) AhR-and ERK-dependent pathways function synergistically to mediate 2,3,7,8-tetrachlorodibenzo-p-dioxin suppression of peroxisome proliferator-activated receptor-g1 expression and subsequent adipocyte differentiation. Toxicol Appl Pharmacol 189: 11–27PubMedCrossRefGoogle Scholar
  93. 93.
    Cimafranca MA, Hanlon PR, Jefcoate CR (2004) TCDD administration after the pro-adipogenic differentiation stimulus inhibits PPARg through a MEK-dependent process but less effectively suppresses adipogenesis. Toxicol Appl Pharmacol 196: 156–168PubMedCrossRefGoogle Scholar
  94. 94.
    Hanlon PR, Cimafranca MA, Liu X, Cho YC, Jefcoate CR (2005) Microarray analysis of early adipogenesis in C3H10T1/2 cells: Cooperative inhibitory effects of growth factors and 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol 207: 39–58PubMedCrossRefGoogle Scholar
  95. 95.
    Cho YC, Zheng W, Yamamoto M, Liu X, Hanlon PR, Jefcoate CR (2005) Differentiation of pluripotent C3H10T1/2 cells rapidly elevates CYP1B1 through a novel process that overcomes a loss of Ah receptor. Arch Biochem Biophys 439: 139–153PubMedCrossRefGoogle Scholar
  96. 96.
    Vogel CF, Matsumura F (2003) Interaction of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with induced adipocyte differentiation in mouse embryonic fibroblasts (MEFs) involves tyrosine kinase c-Src. Biochem Pharmacol 66: 1231–1244PubMedCrossRefGoogle Scholar
  97. 97.
    Park S, Dong B, Matsumura F (2007) Rapid activation of c-Src kinase by dioxin is mediated by the Cdc37-HSP90 complex as part of Ah receptor signaling in MCF10A cells. Biochemistry 46: 899–908PubMedCrossRefGoogle Scholar
  98. 98.
    Shin S, Wakabayashi N, Misra V, Biswal S, Lee GH, Agoston ES, Yamamoto M, Kensler TW (2007) NRF2 modulates aryl hydrocarbon receptor signaling: Influence on adipogenesis. Mol Cell Biol 27: 7188–7197PubMedCrossRefGoogle Scholar
  99. 99.
    Puga A, Tomlinson CR, Xia Y (2005) Ah receptor signals cross-talk with multiple developmental pathways. Biochem Pharmacol 69: 199–207PubMedCrossRefGoogle Scholar
  100. 100.
    Gaido KW, Maness SC, Leonard LS, Greenlee WF (1992) 2,3,7,8-Tetrachlorodibenzo-p-dioxindependent regulation of transforming growth factors-a and-b2 expression in a human keratinocyte cell line involves both transcriptional and post-transcriptional control. J Biol Chem 267: 24591–24595PubMedGoogle Scholar
  101. 101.
    Döhr O, Abel J (1997) Transforming growth factor-b1 coregulates mRNA expression of aryl hydrocarbon receptor and cell-cycle-regulating genes in human cancer cell lines. Biochem Biophys Res Commun 241: 86–91PubMedCrossRefGoogle Scholar
  102. 102.
    Döhr O, Sinning R, Vogel C, Münzel P, Abel J (1997) Effect of transforming growth factor-b1 on expression of aryl hydrocarbon receptor and genes of Ah gene battery: Clues for independent down-regulation in A549 cells. Mol Pharmacol 51: 703–710PubMedGoogle Scholar
  103. 103.
    Wolff S, Harper PA, Wong JM, Mostert V, Wang Y, Abel J (2001) Cell-specific regulation of human aryl hydrocarbon receptor expression by transforming growth factor-b(1). Mol Pharmacol 59: 716–724PubMedGoogle Scholar
  104. 104.
    Zaher H, Fernandez-Salguero PM, Letterio J, Sheikh MS, Fornace AJ Jr, Roberts AB, Gonzalez FJ (1998) The involvement of aryl hydrocarbon receptor in the activation of transforming growth factor-b and apoptosis. Mol Pharmacol 54: 313–321PubMedGoogle Scholar
  105. 105.
    Guo J, Sartor M, Karyala S, Medvedovic M, Kann S, Puga A, Ryan P, Tomlinson CR (2004) Expression of genes in the TGF-b signaling pathway is significantly deregulated in smooth muscle cells from aorta of aryl hydrocarbon receptor knockout mice. Toxicol Appl Pharmacol 194: 79–89PubMedCrossRefGoogle Scholar
  106. 106.
    Thomae TL, Stevens EA, Bradfield CA (2005) Transforming growth factor-b3 restores fusion in palatal shelves exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. J Biol Chem 280: 12742–12746PubMedCrossRefGoogle Scholar
  107. 107.
    Santiago-Josefat B, Mulero-Navarro S, Dallas SL, Fernandez-Salguero PM (2004) Overexpression of latent transforming growth factor-b binding protein 1 (LTBP-1) in dioxin receptor-null mouse embryo fibroblasts. J Cell Sci 117: 849–859PubMedCrossRefGoogle Scholar
  108. 108.
    Gomez-Duran A, Mulero-Navarro S, Chang X, Fernandez-Salguero PM (2006) LTBP-1 blockade in dioxin receptor-null mouse embryo fibroblasts decreases TGF-b activity: Role of extracellular proteases plasmin and elastase. J Cell Biochem 97: 380–392PubMedCrossRefGoogle Scholar
  109. 109.
    Corchero J, Martin-Partido G, Dallas SL, Fernandez-Salguero PM (2004) Liver portal fibrosis in dioxin receptor-null mice that overexpress the latent transforming growth factor-b-binding protein-1. Int J Exp Pathol 85: 295–302PubMedCrossRefGoogle Scholar
  110. 110.
    Liou HC (2002) Regulation of the immune system by NF-kB and IkB. J Biochem Mol Biol 35: 537–546PubMedGoogle Scholar
  111. 111.
    Tian Y, Rabson AB, Gallo MA (2002) Ah receptor and NF-kB interactions: Mechanisms and physiological implications. Chem Biol Interact 141: 97–115PubMedCrossRefGoogle Scholar
  112. 112.
    Tian Y, Ke S, Denison MS, Rabson AB, Gallo MA (1999) Ah receptor and NF-kB interactions, a potential mechanism for dioxin toxicity. J Biol Chem 274: 510–515PubMedCrossRefGoogle Scholar
  113. 113.
    Kim DW, Gazourian L, Quadri SA, Romieu-Mourez R, Sherr DH, Sonenshein GE (2000) The RelA NF-kB subunit and the aryl hydrocarbon receptor (AhR) cooperate to transactivate the c-myc promoter in mammary cells. Oncogene 19: 5498–5506PubMedCrossRefGoogle Scholar
  114. 114.
    Sarkar P, Shiizaki K, Yonemoto J, Sone H (2006) Activation of telomerase in BeWo cells by estrogen and 2,3,7,8-tetrachlorodibenzo-p-dioxin in co-operation with c-Myc. Int J Oncol 28: 43–51PubMedGoogle Scholar
  115. 115.
    Yang X, Liu D, Murray TJ, Mitchell GC, Hesterman EV, Karchner SI, Merson RR, Hahn ME, Sherr DH (2005) The aryl hydrocarbon receptor constitutively represses c-myc transcription in human mammary tumor cells. Oncogene 24: 7869–7881PubMedCrossRefGoogle Scholar
  116. 116.
    Camacho IA, Nagarkatti M, Nagarkatti PS (2004) Evidence for induction of apoptosis in T cells from murine fetal thymus following perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Toxicol Sci 78: 96–106PubMedCrossRefGoogle Scholar
  117. 117.
    Camacho IA, Singh N, Hegde VL, Nagarkatti M, Nagarkatti PS (2005) Treatment of mice with 2,3,7,8-tetrachlorodibenzo-p-dioxin leads to aryl hydrocarbon receptor-dependent nuclear translocation of NF-kB and expression of Fas ligand in thymic stromal cells and consequent apoptosis in T cells. J Immunol 175: 90–103PubMedGoogle Scholar
  118. 118.
    Thatcher TH, Maggirwar SB, Baglole CJ, Lakatos HF, Gasiewicz TA, Phipps RP, Sime PJ (2007) Aryl hydrocarbon receptor-deficient mice develop heightened inflammatory responses to cigarette smoke and endotoxin associated with rapid loss of the nuclear factor-kB component RelB. Am J Pathol 170: 855–864PubMedCrossRefGoogle Scholar
  119. 119.
    Hwang JA, Lee JA, Cheong SW, Youn HJ, Park JH (2007) Benzo[a]pyrene inhibits growth and functional differentiation of mouse bone marrow-derived dendritic cells. Downregulation of RelB and eIF3 p170 by benzo[a]pyrene. Toxicol Lett 169: 82–90PubMedCrossRefGoogle Scholar
  120. 120.
    Lee JA, Hwang JA, Sung HN, Jeon CH, Gill BC, Youn HJ, Park JH (2007) 2,3,7,8-Tetrachlorodibenzo-p-dioxin modulates functional differentiation of mouse bone marrow-derived dendritic cells: Downregulation of RelB by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Lett 173: 31–40PubMedCrossRefGoogle Scholar
  121. 121.
    Vogel CF, Sciullo E, Li W, Wong P, Lazennec G, Matsumura F (2007) RelB, a new partner of aryl hydrocarbon receptor-mediated transcription. Mol Endocrinol 21: 2941–2955PubMedCrossRefGoogle Scholar
  122. 122.
    Vogel CF, Sciullo E, Matsumura F (2007) Involvement of RelB in aryl hydrocarbon receptormediated induction of chemokines. Biochem Biophys Res Commun 363: 722–726PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag/Switzerland 2009

Authors and Affiliations

  • Ci Ma
    • 1
  • Jennifer L. Marlowe
    • 2
  • Alvaro Puga
    • 1
  1. 1.Department of Environmental Health and Center for Environmental GeneticsUniversity of Cincinnati College of MedicineCincinnatiUSA
  2. 2.Novartis Pharma AGMuttenzSwitzerland

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