Abstract
NF-κB/Rel transcription factors regulate many genes involved in control of cellular proliferation, neoplastic transformation, and apoptosis, including the c-myc oncogene. Recently, we have observed that levels of NF-κB and aryl hydrocarbon receptor (AhR), which mediates malignant transformation by environmental carcinogens, are highly elevated and appear constitutively active in breast cancer cells. Rel factors have been found to functionally interact with other transcription factors. Here we demonstrate a physical and functional association between the RelA subunit of NF-κB and AhR resulting in the activation of c-myc gene transcription in breast cancer cells. RelA and AhR proteins were co-immunoprecipitated from cytoplasmic and nuclear extracts of non-malignant MCF-10F breast epithelial and malignant Hs578T breast cancer cells. In transient co-transfection, RelA and AhR gene products demonstrated cooperation in transactivation of the c-myc promoter, which was dependent on the NF-κB elements, and in induction of endogenous c-Myc protein levels. A novel AhR/RelA-containing NF-κB element binding complex was identified by electrophoretic mobility shift analysis of nuclear extracts from RelA and AhR co-transfected Hs578T cells. Thus, the RelA and AhR proteins functionally cooperate to bind to NF-κB elements and induce c-myc gene expression. These findings suggest a novel signaling mechanism whereby the Ah receptor can stimulate proliferation and tumorigenesis of mammary cells.
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References
Abbott BD, Schmid JE, Pitt JA, Buckalew AR, Wood CR, Held GA and Diliberto JJ. . 1999 Toxicol. Appl. Pharmacol. 155: 62–70.
Ballard DW, Dixon EP, Peffer NJ, Bogerd H, Doerre S, Stein B and Greene WC. . 1992 Proc. Natl. Acad. Sci. USA 89: 1875–1879.
Bassuk AG, Anandappa RT and Leiden JM. . 1997 J. Virol. 71: 3563–3573.
Berns EM, Klijn JG, van Putten WL, van Staveren IL, Portengen H and Foekens JA. . 1992 Cancer Res. 52: 1107–1113.
Bellas RE and Sonenshein GE. . 1999 Cell. Growth Differ. 10: 287–294.
Borg A, Baldetorp B, Ferno M, Olsson H and Sigurdsson H. . 1992 Int. J. Cancer 51: 687–691.
Calaf G and Russo J. . 1993 Carcinogenesis 14: 483–492.
Carver LA and Bradfield CA. . 1997 J. Biol. Chem. 272: 11452–11456.
Carver LA, LaPres JJ, Jain S, Dunham EE and Bradfield CA. . 1998 J. Biol. Chem. 273: 33580–33587.
Chang CY and Puga A. . 1998 Mol. Cell. Biol. 18: 525–535.
Dickinson LA, Trauger JW, Baird EE, Dervan PB, Graves BJ and Gottesfeld JM. . 1999 J. Biol. Chem. 274: 12765–12773.
Dignam JD, Lebovitz RM and Roeder RG. . 1983 Nucleic Acids Res. 11: 1475–1489.
Dolwick KM, Swanson HI and Bradfield CA. . 1993 Proc. Natl. Acad. Sci. USA 90: 8566–8570.
Duyao MP, Buckler AJ and Sonenshein GE. . 1990 Proc. Natl. Acad. Sci. USA 87: 4727–4731.
Duyao MP, Kessler DJ, Spicer DB, Bartholomew C, Cleveland J, Siekevitz M and Sonenshein GE. . 1992 J. Biol. Chem. 267: 16288–16291.
Enan E and Matsumura F. . 1996 Biochem. Pharmacol. 52: 1599–1612.
Fernandez-Salguero P, Pineau T, Hilber DM, McPhail T, Lee SS, Kimura S, Nebert DW, Rudikoff S, Ward JM and Gonzalez FJ. . 1995 Science 268: 722–726.
Ferrier R, Nougarede R, Doucet S, Kahn-Perles B, Imbert J and Mathieu-Mahul D. . 1999 Oncogene 18: 995–1005.
Ge NL and Elferink CJ. . 1998 J. Biol. Chem. 273: 22708–22713.
Grilli M, Chiu J and Lenardo M. . 1991 Intl. Rev. Cytol. 143: 1–62.
Grimm S and Baeuerle PA. . 1993 Biochem. J. 290: 297–308.
Hackett AJ, Smith HS, Springer EL, Owens RB, Nelson-Rees WA, Riggs JL and Gardner MB. . 1977 J. Natl. Cancer. Inst. 58: 1795–1806.
Hushka LJ, Williams JS and Greenlee WF. . 1998 Toxicol. Appl. Pharmacol. 152: 200–210.
Jain S, Dolwick KM, Schmidt JV and Bradfield CA. . 1994 J. Biol. Chem. 269: 31518–31524.
Kalkhoven E, Wissink S, van der Saag PT and van der Burg B. . 1996 J. Biol. Chem. 271: 6217–6224.
Kessler DJ, Duyao MP, Spicer DB and Sonenshein GE. . 1992a J. Exp. Med. 176: 787–792.
Kessler DJ, Spicer DB, La Rosa FA and Sonenshein GE. . 1992b Oncogene 7: 2447–2453.
Lahvis GP and Bradfield CA. . 1998 Biochem. Pharmacol. 56: 781–787.
La Rosa FA, Pierce JW and Sonenshein GE. . 1994 Mol. Cell. Biol. 4: 1039–1044.
Ma Q and Whitlock Jr. JP. . 1996 Mol. Cell. Biol. 16: 2144–2150.
Meyer BK, Pray-Grant MG, Vanden Heuvel JP and Perdew GH. . 1998 Mol. Cell. Biol. 18: 978–988.
Na SY, Choi JE, Kim HJ, Jhun BH, Lee YC and Lee JW. . 1999 J. Biol. Chem. 274: 28491–28496.
Nebert DW, Petersen DD and Fornace Jr. AJ. . 1990 Environ. Health Perspect. 88: 13–25.
Nebert DW, Petersen DD and Puga A. . 1991 Pharmacogenetics 1: 68–78.
Okey AB, Riddick DS and Harper PA. . 1994 Toxicol. Lett. 70: 1–22.
Pavelic ZP, Steele P and Presler HD. . 1991 Anticancer Res. 11: 1421–1427.
Perdew GH and Bradfield CA. . 1996 Biochem. Mol. Biol. Int. 39: 589–593.
Pollenz RS, Sattler CA and Poland A. . 1994 Mol. Pharmacol. 45: 428–438.
Raj GV, Safak M, MacDonald GH and Khalili K. . 1996 J. Virol. 70: 5944–5953.
Robles R, Morita Y, Mann KK, Perez GI, Yang S, Matikainen T, Sherr DH and Tilly JL. . 2000 Endocrinology 141: 450–453.
Shen CH and Stavnezer J. . 1998 Mol. Cell. Biol. 18: 3395–3404.
Singh SS, Hord NG and Perdew GH. . 1996 Arch. Biochem. Biophys. 329: 47–55.
Sovak MA, Bellas RE, Kim DW, Zanieski GJ, Rogers AE, Traish AM and Sonenshein GE. . 1997 J. Clin. Invest. 100: 2952–2960.
Stein B, Cogswell PC and Baldwin Jr. AS. . 1993 Mol. Cell. Biol. 13: 3964–3974.
Tian Y, Ke S, Denison MS, Rabson AB and Gallo MA. . 1999 J. Biol. Chem. 274: 510–515.
Trombino AF, Near RI, Matulka RA, Yang S, Hafer LJ, Toselli PA, Kim DW, Rogers AE, Sonenshein GE and Sherr DH. . 2000 Breast Cancer Research and Treatment 63: 117–131.
Verma IM, Stevenson JK, Schwartz EM, Van Antwerp D and Miyamoto S. . 1995 Genes Develop. 9: 2723–2735.
Wissink S, van Heerde ED, Schmitz ML, Kalkhoven E, van der Burg B, Baeuerle PA and van der Saag PT. . 1997 J. Biol. Chem. 272: 22278–22284.
Yamaguchi K, Matulka RA, Shneider AM, Toselli P, Trombino AF, Yang S, Hafer LJ, Mann KK, Tao XJ, Tilly JL, Near RI and Sherr DH. . 1997a Toxicol. Appl. Pharmacol. 147: 190–203.
Yamaguchi K, Near RI, Matulka RA, Shneider A, Toselli P, Trombino AF and Sherr DH. . 1997b J. Immunol. 158: 2165–2173.
Acknowledgements
We thank Nancy Rice, S Hann, R Sen and C Bradfield for generously providing antibody, and cloned DNAs, respectively. Darin Sloneker is acknowledged for assistance in preparation of the manuscript. This work was supported by grants from the Department of Army DAMD 17-98-1-8034 (DW Kim), and DAMD 17-98-1 (GE Sonenshein), the Association pour la Recherche sur le Cancer (R Romieu-Mourez), the Fondation Bettencourt-Schueller (R Romieu-Mourez), and the NIH RO1 ES06086 (DH Sherr) and RO1 CA 82742 (GE Sonenshein) and a Superfund Basic Research Grant #1P42ES 07381 (DH Sherr).
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Kim, D., Gazourian, L., Quadri, S. et al. The RelA NF-κB subunit and the aryl hydrocarbon receptor (AhR) cooperate to transactivate the c-myc promoter in mammary cells. Oncogene 19, 5498–5506 (2000). https://doi.org/10.1038/sj.onc.1203945
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DOI: https://doi.org/10.1038/sj.onc.1203945
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