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The aryl hydrocarbon receptor constitutively represses c-myc transcription in human mammary tumor cells

Oncogene volume 24, pages 7869–7881 (2005)Cite this article

Abstract

The aryl hydrocarbon receptor (AhR) is an environmental carcinogen-activated transcription factor associated with tumorigenesis. High levels of apparently active AhR characterize a variety of tumors, even in the absence of environmental ligands. Despite this association between transformation and AhR upregulation, little is known of the transcriptional consequences of constitutive AhR activation. Here, the effects of constitutively active and environmental ligand-induced AhR on c-myc, an oncogene whose promoter contains six AhR-binding sites (AhREs (aryl hydrocarbon response elements)), were investigated. A reporter containing the human c-myc promoter, with its six AhREs and two NF-κB-binding sites, was constructed. This vector, and variants with deletions in the NF-κB and/or AhR-binding sites, was transfected into a human breast cancer cell line, Hs578T, which expresses high levels of apparently active, nuclear AhR. Results indicate that: (1) the AhR constitutively binds the c-myc promoter; (2) there is a low but significant baseline level of c-myc promoter activity, which is not regulated by NF-κB and is not affected by an environmental AhR ligand; (3) deletion of any one of the AhREs has no effect on constitutive reporter activity, while deletion of all six increases reporter activity approximately fivefold; (4) a similar increase in reporter activity occurs when constitutively active AhR is suppressed by transfection with an AhR repressor plasmid (AhRR); (5) AhRR transfection significantly increases background levels of endogenous c-myc mRNA and c-Myc protein. These results suggest that the AhR influences the expression of c-Myc, a protein critical to malignant transformation.

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Abbreviations

AhR:

aryl hydrocarbon receptor

AhRR:

aryl hydrocarbon receptor repressor

ChIP:

chromosome immunoprecipitation

DMBA:

7,12-dimethylbenzo[a]anthracene

DMSO:

dimethylsulfoxide

PAH:

polycyclic aromatic hydrocarbon

TCDD:

2,3,7,8 tetrachlrodibenzo-p-dioxin

References

  • Abdelrahim M, Smith III R and Safe S . (2003). Mol. Pharmacol., 63, 1373–1381.

  • Allan LL and Sherr DH . (2005). Mol. Pharmacol., 67, 1740–1750.

  • Baba T, Mimura J, Gradin K, Kuroiwa A, Watanabe T, Matsuda Y, Inazawa J, Sogawa K and Fujii-Kuriyama Y . (2001). J. Biol. Chem., 276, 33101–33110.

  • Beischlag TV and Perdew GH . (2005). J. Biol. Chem., 280, 21607–21611.

  • Beischlag TV, Wang S, Rose DW, Torchia J, Reisz-Porszasz S, Muhammad K, Nelson WE, Probst MR, Rosenfeld MG and Hankinson O . (2002). Mol. Cell. Biol., 22, 4319–4333.

  • Bellas RE and Sonenshein GE . (1999). Cell Growth Differ., 10, 287–294.

  • Blaustein JD . (2004). Endocrinology, 145, 1075–1081.

  • Borg A, Baldetorp B, Ferno M, Olsson H and Sigurdsson H . (1992). Int. J. Cancer, 51, 687–691.

  • Buters JT, Sakai S, Richter T, Pineau T, Alexander DL, Savas U, Doehmer J, Ward JM, Jefcoate CR and Gonzalez FJ . (1999). Proc. Natl. Acad. Sci. USA, 96, 1977–1982.

  • Calaf G and Russo J . (1993). Carcinogenesis, 14, 483–492.

  • Cao Y and Karin M . (2003). J. Mammary Gland Biol. Neoplasia, 8, 215–223.

  • Carrier F, Owens R, Nebert D and Puga A . (1992). Mol. Cell. Biol., 12, 1856–1863.

  • Caruso JA, Mathieu PA, Joiakim A, Leeson B, Kessel D, Sloane BF and Reiners Jr JJ . (2004). Mol. Pharmacol., 65, 1016–1028.

  • Carver LA, LaPres JJ, Jain S, Dunham EE and Bradfield CA . (1998). J. Biol. Chem., 273, 33580–33587.

  • Chan W, Yao G, Gu Y and Bradfield C . (1999). J. Biol. Chem., 274, 12115–12123.

  • Chang CY and Puga A . (1998). Mol. Cell. Biol., 18, 525–535.

  • Channavajhala P and Seldin DC . (2002). Oncogene, 21, 5280–5288.

  • Chen HS and Perdew GH . (1994). J. Biol. Chem., 269, 27554.

  • Chen ZP, Schell JB, Ho CT and Chen KY . (1998). Cancer Lett., 129, 173–179.

  • Chesire DR, Dunn TA, Ewing CM, Luo J and Isaacs WB . (2004). Cancer Res., 64, 2523–2533.

  • Christou M, Moore C, Gould M and Jefcoate C . (1987). Carcinogenesis, 8, 73–80.

  • Corton JC . (1996). Toxicol. Lett., 85, 67–75.

  • Daniel F and Joyce N . (1984). Carcinogenesis, 5, 1021–1026.

  • Das S, Delp C, Bandyopadhyay A, Mathiesen M, Baird W and Banerjee M . (1989). Cancer Res., 49, 920–924.

  • Davarinos NA and Pollenz RS . (1999). J. Biol. Chem., 274, 28708–28715.

  • Dean M, Cleveland J, Kim HY, Campisi J, Levine RA, Ihle JN and Rapp U . (1988). Curr. Top. Microbiol. Immunol., 141, 216–222.

  • Dertinger SD, Nazarenko DA, Silverstone AE and Gasiewicz TA . (2001). Carcinogenesis, 22, 171–177.

  • Dolwick KM, Swanson HI and Bradfield CA . (1993). Proc. Natl. Acad. Sci. USA, 90, 8566–8570.

  • Duyao M, Buckler A and Sonenshein G . (1990). Proc. Natl. Acad. Sci. USA, 87, 4727.

  • Escot C, Theillet C, Liderequ R, Spyratos F, Champeme M, Gest J and Callahan R . (1986). Proc. Natl. Acad. Sci. USA, 83, 4834–4838.

  • Fallone F, Villard PH, Seree E, Rimet O, Nguyen QB, Bourgarel-Rey V, Fouchier F, Barra Y, Durand A and Lacarelle B . (2004). Biochem. Biophys. Res. Commun., 322, 551–556.

  • Fowler AM, Solodin N, Preisler-Mashek MT, Zhang P, Lee AV and Alarid ET . (2004). FASEB J., 18, 81–93.

  • Garrison PM, Tullis K, Aarts JM, Brouwer A, Giesy JP and Denison MS . (1996). Fund. Appl. Toxicol., 30, 194–203.

  • Ge NL and Elferink CJ . (1998). J. Biol. Chem., 273, 22708–22713.

  • Gu YZ, Hogenesch JB and Bradfield CA . (2000). Annu. Rev. Pharmacol. Toxicol., 40, 519–561.

  • Hackett AJ, Smith HS, Springer EL, Owens RB, Nelson-Rees WA, Riggs JL and Gardner MB . (1977). J. Natl. Cancer Inst., 58, 1795–1806.

  • Han D, Nagy SR and Denison MS . (2004). Biofactors, 20, 11–22.

  • Hankinson O . (1995). Annu. Rev. Pharmacol. Toxicol., 35, 307.

  • Hayashibara T, Yamada Y, Mori N, Harasawa H, Sugahara K, Miyanishi T, Kamihira S and Tomonaga M . (2003). Biochem. Biophys. Res. Commun., 300, 128–134.

  • Helbig G, Christopherson II KW, Bhat-Nakshatri P, Kumar S, Kishimoto H, Miller KD, Broxmeyer HE and Nakshatri H . (2003). J. Biol. Chem., 278, 21631–21638.

  • Hestermann EV and Brown M . (2003). Mol. Cell. Biol., 23, 7920–7925.

  • Ishibe N, Hankinson SE, Colditz GA, Spiegelman D, Willett WC, Speizer FE, Kelsey KT and Hunter DJ . (1998). Cancer Res., 58, 667–671.

  • Jerry DJ, Butel JS, Donehower LA, Paulson EJ, Cochran C, Wiseman RW and Medina D . (1994). Mol. Carcinogen., 9, 175–183.

  • Karchner SI, Franks DG, Powell WH and Hahn ME . (2002). J. Biol. Chem., 277, 6949–6959.

  • Kessler D, Spicer D, Rosa FL and Sonenshein G . (1992). Oncogene, 7, 2447.

  • Kikuchi Y, Ohsawa S, Mimura J, Ema M, Takasaki C, Sogawa K and Fujii-Kuriyama Y . (2003). J. Biochem. (Tokyo), 134, 83–90.

  • Kim DW, Gazourian L, Quadri SA, Romieu-Mourez R, Sherr DH and Sonenshein GE . (2000a). Oncogene, 19, 5498–5506.

  • Kim DW, Sovak MA, Zanieski G, Nonet G, Romieu-Mourez R, Lau AW, Hafer LJ, Yaswen P, Stampfer M, Rogers AE, Russo J and Sonenshein GE . (2000b). Carcinogenesis, 21, 871–879.

  • Koliopanos A, Kleeff J, Xiao Y, Safe S, Zimmermann A, Buchler MW and Friess H . (2002). Oncogene, 21, 6059–6070.

  • Korkalainen M, Tuomisto J and Pohjanvirta R . (2004). Biochem. Biophys. Res. Commun., 315, 123–131.

  • Kumar MB and Perdew GH . (1999). Gene Expr., 8, 273–286.

  • Kumar MB, Tarpey RW and Perdew GH . (1999). J. Biol. Chem., 274, 22155–22164.

  • Lai Z-W, Pineau T and Esser C . (1996). Chemico-Biol. Interact., 100, 97–112.

  • LaPres JJ, Glover E, Dunham EE, Bunger MK and Bradfield CA . (2000). J. Biol. Chem. 275, 6153–6159.

  • Larsen M, Angus WGR, Brake P, Eltom S and Jefcoate CR . (1997). Fund. Appl. Toxicol., 36, 24.

  • Latil A, Vidaud D, Valeri A, Fournier G, Vidaud M, Lidereau R, Cussenot O and Biache I . (2000). Int. J. Cancer, 89, 172–176.

  • Leder A, Pattengale P, Kuo A, Stewart T and Leder P . (1986). Cell, 45, 485–495.

  • Lee SY, Walsh CT, Ng SF and Rogers AE . (1986). J. Nutr. Growth Cancer, 3, 167–176.

  • Levine-Fridman A, Chen L and Elferink CJ . (2004). Mol. Pharmacol., 65, 461–469.

  • Li Y, Welm B, Podsypanina K, Huang S, Chamorro M, Zhang X, Rowlands T, Egeblad M, Cowin P, Werb Z, Tan LK, Rosen JM and Varmus HE . (2003). Proc. Natl. Acad. Sci. USA, 100, 15853–15858.

  • Liao DJ and Dickson RB . (2003). Lab. Invest., 83, 1437–1449.

  • Liu C, Goshu E, Wells A and Fan CM . (2003). J. Biol. Chem., 278, 44857–44867.

  • Ma Q and Whitlock J . (1996). Mol. Cell. Biol., 16, 2144–2150.

  • Maecker B, Sherr DH, Vonderheide RH, von Bergwelt-Baildon MS, Hirano N, Anderson KS, Xia Z, Butler MO, Wucherpfennig KW, O'Hara C, Cole G, Kwak SS, Ramstedt U, Tomlinson AJ, Chicz RM, Nadler LM and Schultze JL . (2003). Blood, 102, 3287–3294.

  • Maltepe E, Schmidt JV, Baunoch D, Bradfield CA and Simon MC . (1997). Nature, 386, 403–407.

  • Marcus RS, Holsapple MP and Kaminski NE . (1998). J. Pharmacol. Exp. Ther., 287, 1113–1118.

  • Matikainen T, Perez GI, Jurisicova A, Mann KK, Schlezinger JJ, Ryu H-T, Sakai T, Korsmeyer SJ, Casper RF, Sherr DH and Tilly JT . (2001). Nat. Genet., 28, 1–6.

  • Matikainen TM, Moriyama T, Morita Y, Perez GI, Korsmeyer SJ, Sherr DH and Tilly JL . (2002). Endocrinology, 143, 615–620.

  • McDougal A, Wilson C and Safe S . (1997). Cancer Lett., 120, 53–63.

  • Meyer BK and Perdew GH . (1999). Biochemistry, 38, 8907–8917.

  • Meyer BK, Pray-Grant MG, Vanden Heuvel JP and Perdew GH . (1998). Mol. Cell. Biol., 18, 978–988.

  • Mimura J, Ema M, Sogawa K and Fujii-Kuriyama Y . (1999). Genes Dev., 13, 20–25.

  • Miyoshi K, Rosner A, Nozawa M, Byrd C, Morgan F, Landesman-Bollag E, Xu X, Seldin DC, Schmidt EV, Taketo MM, Robinson GW, Cardiff RD and Hennighausen L . (2002). Oncogene, 21, 5548–5556.

  • Nazarenko I, Lowe B, Darfler M, Ikonomi P, Schuster D and Rashtchian A . (2002). Nucleic Acids Res., 30, e37.

  • Nebert D, Petersen D and Puga A . (1991). Pharmacogenetics, 1, 68–78.

  • Negri E, Bosetti C, Fattore E and La Vecchia C . (2003). Eur. J. Cancer Prev., 12, 509–516.

  • Nguyen TA, Hoivik D, Lee JE and Safe S . (1999). Arch. Biochem. Biophys., 367, 250–257.

  • Ohtake F, Takeyama K, Matsumoto T, Kitagawa H, Yamamoto Y, Nohara K, Tohyama C, Krust A, Mimura J, Chambon P, Yanagisawa J, Fujii-Kuriyama Y and Kato S . (2003). Nature, 423, 545–550.

  • Okey A, Riddick D and Harper P . (1994). Toxicol. Lett., 70, 1–22.

  • Pelengaris S and Khan M . (2003). Arch. Biochem. Biophys., 416, 129–136.

  • Poland A, Glover E and Bradfield CA . (1990). Mol. Pharmacol., 39, 20–26.

  • Poland A, Glover E, Robinson J and Nebert D . (1974). J. Biol. Chem., 249, 5599–5606.

  • Porter W, Wang F, Duan R, Qin C, Castro-Rivera E, Kim K and Safe S . (2001). J. Mol. Endocrinol., 26, 31–42.

  • Puga A, Barnes SJ, Dalton TP, Chang C-y, Knudsen ES and Maier MA . (2000). J. Biol. Chem., 275, 2943–2950.

  • Puga A, Nebert D and Carrier F . (1992). DNA Cell Biol., 11, 269–281.

  • Puga A, Xia Y and Elferink C . (2002). Chem. Biol. Interact., 141, 117–130.

  • Ruggero D, Montanaro L, Ma L, Xu W, Londei P, Cordon-Cardo C and Pandolfi PP . (2004). Nat. Med., 10, 484–486.

  • Rushing SR and Denison MS . (2002). Arch. Biochem. Biophys., 403, 189–201.

  • Russo J and Russo I . (1987). Lab. Invest., 57, 112–137.

  • Ryu H-Y, Mann KK, Schlezinger JJ, Jensen B and Sherr DH . (2003). J. Immunol., 170, 4897–4904.

  • Sadek C and Allen-Hoffmann B . (1994). J. Biol. Chem., 269, 31505–31509.

  • Saez AI, Artiga MJ, Romero C, Rodriguez S, Cigudosa JC, Perez-Rosado A, Fernandez I, Sanchez-Beato M, Sanchez E, Mollejo M and Piris MA . (2003). Lab. Invest., 83, 143–152.

  • Safe S . (2001). Toxicol. Lett., 120, 1–7.

  • Safe S, Wang F, Porter W, Duan R and McDougal A . (1998). Toxicol. Lett., 102–103, 343–347.

  • Singh SS, Hord NG and Perdew GH . (1996). Arch. Biochem. Biophys., 329, 47–55.

  • Sulentic CE, Holsapple MP and Kaminski NE . (1998). Mol. Pharmacol., 53, 623–629.

  • Sulentic CE, Holsapple MP and Kaminski NE . (2000). J. Pharmacol. Exp. Ther., 295, 705–716.

  • Thompson EB . (1998). Annu. Rev. Physiol., 60, 575.

  • Thomsen JS, Kietz S, Strom A and Gustafsson JA . (2004). Mol. Pharmacol., 65, 165–171.

  • Thomsen JS, Wang X, Hines RN and Safe S . (1994). Carcinogenesis, 15, 933–937.

  • Tian Y, Ke S, Denison MS, Rabson AB and Gallo MA . (1999). J. Biol. Chem., 274, 510–515.

  • Tohkin M, Fukuhara M, Elizondo G, Tomita S and Gonzalez FJ . (2000). Mol. Pharmacol., 58, 845–851.

  • Trombino AF, Matulka RA, Yang S, Hafer LJ, Rogers AE, Tosselli P, Kim D, Sonenshein GE, Near RI and Sherr DH . (2000). Breast Cancer Res. Ther., 62, 117–131.

  • Vaziri C, Shneider A, Sherr DH and Faller DV . (1996). J. Biol. Chem., 271, 25921.

  • Wang F, Samudio I and Safe S . (2001). Mol. Cell. Endocrinol., 172, 91–103.

  • Wang F, Wang W and Safe S . (1999). Biochemistry, 38, 11490–11500.

  • Wang S, Ge K, Roeder RG and Hankinson O . (2004a). J. Biol. Chem., 279, 13593–13600.

  • Wang WL, Thomsen JS, Porter W, Moore M and Safe S . (1996). Br. J. Cancer, 73, 316–322.

  • Wang X, Thomsen JS, Santostefano M, Rosengren R, Safe S and Perdew GH . (1995). Eur. J. Pharmacol., 293, 191–205.

  • Wang Y, Engels IH, Knee DA, Nasoff M, Deveraux QL and Quon KC . (2004b). Cancer Cell, 5, 501–512.

  • Watanabe T, Imoto I, Kosugi Y, Fukuda Y, Mimura J, Fujii Y, Isaka K, Takayama M, Sato A and Inazawa J . (2001). J. Hum. Genet., 46, 342–346.

  • Weigel NL, Bai W, Zhang Y, Beck CA, Edwards DP and Poletti A . (1995). J. Steroid Biochem. Mol. Biol., 53, 509–514.

  • Weiss C, Kolluri SK, Kiefer F and Gottlicher M . (1996). Exp. Cell Res., 226, 154–163.

  • Whitlock JPJ . (1990). Annu. Rev. Pharmacol. Toxicol., 30, 251–277.

  • Wormke M, Stoner M, Saville B, Walker K, Abdelrahim M, Burghardt R and Safe S . (2003). Mol. Cell. Biol., 23, 1843–1855.

  • Wu M, Lee H, Bellas RE, Schauer SL, Arsura M, Katz D, FitzGerald MJ, Rothstein TL, Sherr DH and Sonenshein GE . (1996). Mol. Cell. Biol., 16, 5015–5021.

  • Yamaguchi K, Near RI, Matulka RA, Shneider A, Toselli P, Trombino AF and Sherr DH . (1997). J. Immunol., 158, 2165–2173.

  • Zhang S, Qin C and Safe SH . (2003). Environ. Health Perspect., 111, 1877–1882.

  • Ziccardi M, Gardner I and Denison M . (2000). Toxicol. Sci., 54, 183–193.

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Acknowledgements

This work was supported by DAMD17-03-1-0406, NIEHS Grants PO1-ES11624, RO1-ES06086, and P42-ES07381.

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  1. Department of Environmental Health, Boston University School of Public Health, Boston, MA, USA

    Xinhai Yang, Donghui Liu, Tessa J Murray & David H Sherr

  2. Biology Department, Furman University, Greenville, SC, USA

    Geoffrey C Mitchell & Eli V Hesterman

  3. Biology Department, Woods Hole Oceanographic Institute, Woods Hole, MA, USA

    Sibel I Karchner, Rebeka R Merson & Mark E Hahn

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Yang, X., Liu, D., Murray, T. et al. The aryl hydrocarbon receptor constitutively represses c-myc transcription in human mammary tumor cells. Oncogene 24, 7869–7881 (2005). https://doi.org/10.1038/sj.onc.1208938

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