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  • Original Paper
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Inhibition of Rel/Nuclear Factor-κB signaling in skin results in defective DNA damage-induced cell cycle arrest and Ha-ras- and p53-independent tumor development

Oncogene volume 21, pages 4969–4977 (2002)Cite this article

Abstract

In recent years a growth inhibitory role in skin for the Rel/NF-κB transcription factors has been established, and the block of Rel/NF-κB signaling results in rapid development of spontaneous skin cancer. The molecular mechanism underlying tumor development is however unknown. In the present study, we show that inhibition of NF-κB signaling in mouse skin by targeted expression of degradation resistant IκB-α generates transgenic keratinocytes unable to arrest the cell cycle in response to DNA damage induced by γ-radiation. The results indicate that transgenic keratinocytes have a defect at the G1-S checkpoint whereas the G2-M checkpoint response was found to be intact. However, transgenic keratinocytes still respond by induction of the cyclin dependent kinase inhibitor p21Cip1/Waf after exposure to γ-radiation. In the spontaneous skin tumors that develop in transgenic mice no mutations were found in the Ha-ras or p53 gene, suggesting that inhibition of NF-κB signaling in skin can induce cancer development independently of initiating mutations in the Ha-ras gene or additional mutations in the p53 gene. These findings demonstrate an involvement of NF-κB signaling in the DNA damage response and cell cycle checkpoint control in the skin.

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References

  • Ahmed NU, Ueda M, Ichihashi M . 1997 J. Cutan. Pathol. 24: 223–227

  • Amundson SA, Myers TG, Fornace Jr AJ . 1998 Oncogene 17: 3287–3299

  • Auer GU, Heselmeyer KM, Steinbeck RG, Munck-Wikland E, Zetterberg AD . 1994 Virchows Arch. 424: 343–347

  • Bartek J, Lukas J . 2001 FEBS Letts. 490: 117–122

  • Bash J, Zong WX, Gelinas C . 1997 Mol. Cell. Biol. 17: 6526–6536

  • Brash DE, Rudolph JA, Simon JA, Lin A, McKenna GJ, Baden HP, Halperin AJ, Ponten J . 1991 Proc. Natl. Acad. Sci. USA 88: 10124–10128

  • Campbell C, Quinn AG, Rees JL . 1993 Br. J. Dermatol. 128: 111–114

  • Chen E, Li CC . 1998 Biochem. Biophys. Res. Commun. 249: 728–734

  • Coleman WB, Tsongalis GJ . 1995 Clin. Chem. 41: 644–657

  • Devereux TR, Foley JF, Maronpot RR, Kari F, Anderson MW . 1993 Carcinogenesis 14: 795–801

  • Doffinger R, Smahi A, Bessia C, Geissmann F, Feinberg J, Durandy A, Bodemer C, Kenwrick S, Dupuis-Girod S, Blanche S, Wood P, Rabia SH, Headon DJ, Overbeek PA, Le Deist F, Holland SM, Belani K, Kumararatne DS, Fischer A, Shapiro R, Conley ME, Reimund E, Kalhoff H, Abinun M, Munnich A, Israel A, Courtois G, Casanova JL . 2001 Nat. Genet. 27: 277–285

  • Hanahan D, Weinberg RA . 2000 Cell 100: 57–70

  • Hegi ME, Soderkvist P, Foley JF, Schoonhoven R, Swenberg JA, Kari F, Maronpot R, Anderson MW, Wiseman RW . 1993 Carcinogenesis 14: 803–810

  • Hendzel MJ, Wei Y, Mancini MA, Van Hooser A, Ranalli T, Brinkley BR, Bazett-Jones DP, Allis CD . 1997 Chromosoma 106: 348–360

  • Hinz M, Krappmann D, Eichten A, Heder A, Scheidereit C, Strauss M . 1999 Mol. Cell. Biol. 19: 2690–2698

  • Hu Y, Baud V, Delhase M, Zhang P, Deerinck T, Ellisman M, Johnson R, Karin M . 1999 Science 284: 316–320

  • Hu Y, Baud V, Oga T, Kim KI, Yoshida K, Karin M . 2001 Nature 410: 710–714

  • Inohara S, Kitagawa K, Kitano Y . 1996 Dermatology 192: 94–98

  • Karin M, Ben-Neriah Y . 2000 Annu. Rev. Immunol. 18: 621–663

  • Korstanje MJ, Bessems PJ . 1991 Dermatologica 183: 234–236

  • Landy SJ, Donnai D . 1993 J. Med. Genet. 30: 53–59

  • Larner JM, Lee H, Hamlin JL . 1994 Mol. Cell. Biol. 14: 1901–1908

  • Li Q, Lu Q, Hwang JY, Buscher D, Lee KF, Izpisua-Belmonte JC, Verma IM . 1999 Genes Dev. 13: 1322–1328

  • Makris C, Godfrey VL, Krahn-Senftleben G, Takahashi T, Roberts JL, Schwarz T, Feng L, Johnson RS, Karin M . 2000 Mol. Cell 5: 969–979

  • Matsuta M, Kon S, Sasaki K . 1997 J. Dermatol. Sci. 14: 233–239

  • McGregor JM, Yu CC, Dublin EA, Levison DA, MacDonald DM . 1992 Br. J. Dermatol. 127: 463–469

  • Mitsunaga SI, Zhang SY, Ruggeri BA, Gimenez-Conti I, Robles AI, Conti CJ, Klein-Szanto AJ . 1995 Carcinogenesis 16: 1629–1635

  • Pahl HL . 1999 Oncogene 18: 6853–6866

  • Perkins ND, Felzien LK, Betts JC, Leung K, Beach DH, Nabel GJ . 1997 Science 275: 523–527

  • Pierceall WE, Goldberg LH, Tainsky MA, Mukhopadhyay T, Ananthaswamy HN . 1991 Mol. Carcinog. 4: 196–202

  • Poon RY, Hunter T . 1998 Oncogene 16: 1333–1343

  • Quintanilla M, Brown K, Ramsden M, Balmain A . 1986 Nature 322: 78–80

  • Ren ZP, Hedrum A, Ponten F, Nister M, Ahmadian A, Lundeberg J, Uhlen M, Ponten J . 1996a Oncogene 12: 765–773

  • Ren ZP, Ponten F, Nister M, Ponten J . 1996b Int. J. Cancer 69: 174–179

  • Ro YS, Cooper PN, Lee JA, Quinn AG, Harrison D, Lane D, Horne CH, Rees JL, Angus B . 1993 Br. J. Dermatol. 128: 237–241

  • Robles AI, Conti CJ . 1995 Carcinogenesis 16: 781–786

  • Robles AI, Larcher F, Whalin RB, Murillas R, Richie E, Gimenez-Conti IB, Jorcano JL, Conti CJ . 1996 Proc. Natl. Acad. Sci. USA 93: 7634–7638

  • Robles AI, Rodriguez-Puebla ML, Glick AB, Trempus C, Hansen L, Sicinski P, Tennant RW, Weinberg RA, Yuspa SH, Conti CJ . 1998 Genes Dev. 12: 2469–2474

  • Rumsby G, Carter RL, Gusterson BA . 1990 Br. J. Cancer 61: 365–368

  • Sakai H, Minami M, Satoh E, Matsuo S, Iizuka H . 2000 Dermatology 200: 258–261

  • Schluter C, Duchrow M, Wohlenberg C, Becker MH, Key G, Flad HD, Gerdes J . 1993 J. Cell Biol. 123: 513–522

  • Schmidt-Supprian M, Bloch W, Courtois G, Addicks K, Israel A, Rajewsky K, Pasparakis M . 2000 Mol. Cell 5: 981–992

  • Seitz CS, Deng H, Hinata K, Lin Q, Khavari PA . 2000 Cancer Res. 60: 4085–4092

  • Seitz CS, Lin Q, Deng H, Khavari PA . 1998 Proc. Natl. Acad. Sci. USA 95: 2307–2312

  • Sherr CJ, Roberts JM . 1999 Genes Dev. 13: 1501–1512

  • Smahi A, Courtois G, Vabres P, Yamaoka S, Heuertz S, Munnich A, Israel A, Heiss NS, Klauck SM, Kioschis P, Wiemann S, Poustka A, Esposito T, Barado T, Gianfrancesco F, Ciccodicola A, D'Urso M, Woffendin H, Jakins T, Donnai D, Stewart H, Kenwrick SJ, Aradhya S, Yamagata T, Levy M, Lewis RA, Nelson DL . 2000 Nature 405: 466–472

  • Song S, Lambert PF . 1999 Am. J. Pathol. 155: 1121–1127

  • Sutter C, Strickland PT, Mukhtar H, Agarwal R, Winter H, Schweizer J . 1993 Mol. Carcinog. 8: 13–19

  • Takeda K, Takeuchi O, Tsujimura T, Itami S, Adachi O, Kawai T, Sanjo H, Yoshikawa K, Terada N, Akira S . 1999 Science 284: 313–316

  • Tong Y, Smith MA, Tucker SB . 1997 J. Toxicol. Env. Health. 51: 219–234

  • Topley GI, Okuyama R, Gonzales JG, Conti C, Dotto GP . 1999 Proc. Natl. Acad. Sci. USA 96: 9089–9094

  • Tron VA, Tang L, Yong WP, Trotter MJ . 1996 Am. J. Pathol. 149: 1139–1146

  • van der Schroeff JG, Evers LM, Boot AJ, Bos JL . 1990 J. Invest. Dermatol. 94: 423–425

  • van Hogerlinden M, Rozell BL, Ahrlund-Richter L, Toftgard R . 1999 Cancer Res. 59: 3299–3303

  • Webster GA, Perkins ND . 1999 Mol. Cell. Biol. 19: 3485–3495

  • Weinberg WC, Fernandez-Salas E, Morgan DL, Shalizi A, Mirosh E, Stanulis E, Deng C, Hennings H, Yuspa SH . 1999 Cancer Res. 59: 2050–2054

  • Xie G, Habbersett RC, Jia Y, Peterson SR, Lehnert BE, Bradbury EM, D'Anna JA . 1998 Oncogene 16: 721–736

  • Zhou BP, Liao Y, Xia W, Spohn B, Lee MH, Hung MC . 2001 Nat. Cell. Biol. 3: 245–252

  • Zonana J, Elder ME, Schneider LC, Orlow SJ, Moss C, Golabi M, Shapira SK, Farndon PA, Wara DW, Emmal SA, Ferguson BM . 2000 Am. J. Hum. Genet. 67: 1555–1562

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Acknowledgements

We thank the Unit for Embryology and Genetics for generation and maintenance of transgenic mice, B Sundelin for technical assistance, T Skarin for tumor samples and P Söderkvist for primers used in mutation analysis. This work was supported by grants from the Swedish Cancer Fund, the Swedish Radiation Protection Institute, the Swedish Society for Medical Research and Robert Lundbergs Minnesfond.

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  1. Department of Bioscience at Novum, Karolinska Institutet, NOVUM, Huddinge, SE-141 57, Sweden

    Max van Hogerlinden & Rune Toftgård

  2. Department of Oncology-Pathology, Division of Cellular and Molecular Tumor Pathology, Cancer Center Karolinska, Stockholm, SE-171 76, Sweden

    Gert Auer

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  1. Max van Hogerlinden
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Correspondence to Gert Auer.

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van Hogerlinden, M., Auer, G. & Toftgård, R. Inhibition of Rel/Nuclear Factor-κB signaling in skin results in defective DNA damage-induced cell cycle arrest and Ha-ras- and p53-independent tumor development. Oncogene 21, 4969–4977 (2002). https://doi.org/10.1038/sj.onc.1205620

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