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Thymic hyperplasia and lung carcinomas in a line of mice transgenic for keratin 5-driven HPV16 E6/E7 oncogenes

Abstract

Human Papillomavirus type 16 (HPV-16) is the cause of both benign lesions and ano-genital cancers. In HPV-associated cancers the transforming properties of the expressed viral E6 and E7 proteins have been revealed by a number of different assays. We have generated transgenic mice expressing HPV-16 E6/E7 genes under the control of the murine keratin 5 gene promoter, which should confer cell-type specific expression in the basal cells of squamous stratified epithelia. Transgenic mice developed thymic hyperplasia and lung neoplasia with 100% frequency, the thymus showing a size increase at 2 months and reaching the maximum dimension at 6 months, when lung carcinomas appeared. After this time the size of hyperplastic thymi decreased, while malignant formations invaded the mediastinal area. Hepatic metastasis could be also observed in some of the animals at the autopsy and death invariably occurred around 10–11 months of age.

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References

  • Arbeit JM, Munger K, Howley PM, Hanahan D . 1993 Am. J. Pathol. 142: 1187–1197

  • Arbeit JM, Munger K, Howley PM, Hanahan D . 1994 J. Virol. 68: 4358–4368

  • Auewarakul P, Gissmann L, Cid-Arregui A . 1994 Mol. Cell. Biol. 14: 8250–8258

  • Bedell MA, Jones KH, Grossman SR, Laimins LA . 1989 J. Virol. 63: 1247–1255

  • Bol D, Kiguchi K, Beltran L, Rupp T, Moats S, Gimenez-Conti I, Jorcano J, DiGiovanni J . 1998 Mol. Carcinog. 21: 2–12

  • Boyer SN, Wazer DE, Band V . 1996 Cancer Res. 56: 4620–4624

  • Byrne C, Fuchs E . 1993 Mol. Cell. Biol. 13: 3176–3190

  • Butel JS . 2000 Carcinogenesis 21: 405–426

  • Chellappan S, Kraus VB, Kroger B, Munger K, Howley PM, Nevins JR . 1992 Proc. Natl. Acad. Sci. USA 89: 4549–4553

  • Chen JJ, Reid CE, Band V, Androphy EJ . 1995 Science 269: 529–531

  • Chomczynski P, Sacchi N . 1987 Anal. Biochem. 162: 156–159

  • Clavel CE, Nawrocki B, Bosseaux B, Poitevin G, Putaud IC, Mangeonjean CC, Monteau M, Birembaut PL . 2000 Cancer 88: 1347–1352

  • Comerford SA, Maika SD, Laimins LA, Messing A, Elsasser H-P, Hammer RE . 1995 Oncogene 10: 587–597

  • Coussens LM, Hanahan D, Arbeit JM . 1996 Am. J. Pathol. 149: 1899–1917

  • Damak S, Harnboonsong Y, George PM, Bullock . 1996 Mol. Carcinog. 17: 84–91

  • Dyson N, Howley PM, Munger K, Harlow E . 1989 Science 243: 934–937

  • Dyson N . 1998 Genes Dev. 12: 2245–2262

  • Eckert RL, Crish JF, Balasubramanian S, Rorke EA . 2000 Int. J. Oncol. 16: 853–870

  • el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B . 1993 Cell 75: 817–825

  • Fero ML, Rivkin M, Tasch M, Porter P, Carow CE, Firpo E, Polyak K, Tsai LH, Broudy V, Perlmutter RM, Kaushansky K, Roberts JM . 1996 Cell 85: 733–744

  • Funk JO, Waga S, Harry JB, Espling E, Stillman B, Galloway DA . 1997 Genes Dev. 11: 2090–2100

  • Gao Q, Srinivasan S, Boyer SN, Wazer DE, Band V . 1999 Mol. Cell. Biol. 19: 733–744

  • Gouyer V, Gazzeri S, Bolon I, Drevet C, Brambilla C, Brambilla E . 1998 Am. J. Respir. Cell. Mol. Biol. 18: 188–196

  • Grana X, Reddy EP . 1995 Oncogene 11: 573–582

  • Griep AE, Herber R, Jeon S, Lohse JK, Dubielzig RR, Lambert PF . 1993 J. Virol. 67: 1373–1384

  • Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ . 1993 Cell 75: 805–816

  • Heck DV, Yee CL, Howley PM, Munger K . 1992 Proc. Natl. Acad. Sci. USA 89: 4442–4446

  • Hennig EM, Suo Z, Karlsen F, Holm R, Thoresen S, Nesland JM . 1999 Acta. Oncol. 38: 639–647

  • Herber R, Liem A, Pitot H, Lambert PF . 1996 J. Virol. 70: 1873–1881

  • Hirayasu T, Iwamasa T, Kamada Y, Koyanagi Y, Usuda H, Genka K . 1996 J. Clin. Pathol. 49: 810–817

  • Hogan B, Costantini F, Lacy E . 1986 Manipulating the Mouse Embryo Cold Spring Harbor, NY, Cold Spring Harbor Laboratory Press

  • Howes KA, Ransom N, Papermaster DS, Lasudry JG, Albet DM, Windle JJ . 1994 Genes Dev. 8: 1300–1310

  • Huang MT, Gorman CM . 1990 Nucleic Acids Res. 18: 937–947

  • Hunter T, Pines J . 1994 Cell 79: 573–582

  • Jones DL, Alani RM, Munger K . 1997 Genes Dev. 11: 2101–2111

  • Kiyono T, Hiraiwa A, Fujita M, Hayashi Y, Akiyama T, Ishibashi M . 1997 Proc. Natl. Acad. Sci. USA 94: 11612–11616

  • Klug DB, Carter C, Crouch E, Roop D, Conti CJ, Richie ER . 1998 Proc. Natl. Acad. Sci. USA 95: 11822–11827

  • Kondoh G, Murata Y, Aozasa K, Yutsudo M, Hakura A . 1991 J. Virol. 65: 3335–3339

  • Lambert PF, Pan H, Pitot HC, Liem A, Jackson M, Griep AE . 1993 Proc. Natl. Sci. USA 90: 5583–5587

  • Lechner MS, Laimins LA . 1994 J. Virol. 68: 4262–4273

  • Ledent C, Marcotte A, Dumont JE, Vassart G, Parmentier M . 1995 Oncogene 10: 1789–1797

  • Leder A, Pattengale PK, Kuo A, Stewart TA, Leder P . 1986 Cell 45: 485–495

  • Lee SS, Weiss RS, Javier RT . 1997 Proc. Natl. Acad. Sci. USA 94: 6670–6675

  • Mansur CP, Androphy EJ . 1993 Biochim. Biophys. Acta 1155: 323–345

  • McIntyre MC, Ruesch MN, Laimins LA . 1996 Virology 215: 73–82

  • Missero C, Serra C, Stenn K, Dotto GP . 1993 J. Cell. Biol. 121: 1109–1120

  • Moll R, Dhouailly D, Sun T-T . 1989 Virchows Archiv. B Cell. Pathol. 58: 129–145

  • Morozov A, Shiyanov P, Barr E, Leiden JM, Raychaudhuri P . 1997 J. Virol. 71: 3451–3457

  • Morris GF, Hoyle GW, Athas GB, Lei WH, Xu J, Morris CB, Friedman M . 1998 J. La State Med. Soc. 150: 179–185

  • Munger K, Werness BA, Dyson N, Phelps WC, Harlow E, Howley PM . 1989a EMBO J. 8: 4099–4105

  • Munger K, Phelps WC, Bubb V, Howley PM, Schlegel R . 1989b J. Virol. 63: 4417–4421

  • Murillas R, Larcher F, Conti CJ, Santos M, Ulrich A, Jorcano JL . 1995 EMBO J. 14: 5216–5223

  • Nakagawa S, Watanabe S, Yoshikawa H, Taketani Y, Yoshiike K, Kanda T . 1995 Virology 212: 535–542

  • Nakayama K, Ishida N, Shirane M, Inomata A, Inoue T, Shishido N, Horii I, Loh DY . 1996 Cell 85: 707–720

  • Nelson WG, Sun TT . 1983 J. Cell. Biol. 97: 244–251

  • Nikitin AY, Juarez-Perez MI, Li S, Huang L, Lee WH . 1999 Proc. Natl. Acad. Sci. USA 96: 3916–3921

  • Ogawa K, Imaida K, Masui T, Kawabe M, Hasegawa R, Kato K, Ito N, Shirai T . 1996 Carcinogenesis 17: 341–345

  • Pan H, Griep AE . 1994 Genes Dev. 8: 1285–1299

  • Phelps WC, Yee CL, Munger K, Howley PM . 1988 Cell 53: 539–547

  • Pim D, Thomas M, Javier R, Gardiol D, Banks L . 2000 Oncogene 19: 719–725

  • Ramirez A, Bravo A, Jorcano JL, Vidal M . 1994 Differentiation 58: 53–64

  • 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

  • Rodriguez-Puebla ML, LaCava M, Miliani de Marval PL, Jorcano JL, Richie ER, Conti CJ . 2000 Am. J. Pathol. 157: 1039–1050

  • Ronco LV, Karpova AY, Vidal M, Howley PM . 1998 Genes Dev. 12: 2061–2072

  • Ruesch MN, Laimins LA . 1997 J. Virol. 71: 5570–5578

  • Sampietro G, Tomasi G, Collini P, Biganzoli E, Boracchi P, Bidoli P, Pilotti S . 2000 Appl. Immunohistochem. Molecul. Morphol. 8: 49–56

  • Sandmoller A, Halter R, Suske G, Paul D, Beato M . 1995 Cell Growth Differ. 6: 97–103

  • Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM . 1990 Cell 63: 1129–1136

  • Scheffner M, Huibregtse JM, Vierstra RD, Howley PM . 1993 Cell 75: 495–505

  • Seavey SE, Holubar M, Saucedo LJ, Perry ME . 1999 J. Virol. 73: 7590–7598

  • Sedman SA, Hubbert NL, Vass WC, Lowy DR, Schiller JT . 1992 J. Virol. 66: 4201–4208

  • Seedorf K, Krammer G, Durst M, Suhai S, Rowekamp WG . 1985 Virology 145: 181–185

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

  • Smotkin D, Prokoph H, Wettstein FO . 1989 J. Virol. 63: 1441–1447

  • Song S, Pitot HC, Lambert PF . 1999 J. Virol. 73: 5887–5893

  • Storey A, Pim D, Murray A, Osborn K, Banks L, Crawford L . 1988 EMBO J. 7: 1815–1820

  • Storey A, Banks L . 1993 Oncogene 8: 914–924

  • Sunday ME, Haley KJ, Sikorski K, Graham SA, Emanuel RL, Zhang F, Mu Q, Shahsafaei A, Hatzis D . 1999 Oncogene 18: 4336–4347

  • Tong X, Howley PM . 1997 Proc. Natl. Acad. Sci. USA 94: 4412–4417

  • Zerfass-Thome K, Zwerschke W, Mannhardt B, Tindle R, Botz JW, Jansen-Durr P . 1996 Oncogene 13: 2323–2330

  • zur Hausen H, de Villiers EM . 1994 Annu. Rev. Microbiol. 48: 427–447

  • zur Hausen H . 1996 Biochim. Biophys. Acta. 1288: F55–F78

  • zur Hausen H . 2000 J. Natl. Cancer Inst. 92: 690–698

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Acknowledgements

We thank Dr GP Dotto for providing the K5Ti plasmid, Drs Cesira Galeotti and Barry Howes for careful reading of the manuscript. Alessio Benanchi for technical assistance and Giorgio Corsi for artwork.

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Correspondence to Mara Rossini.

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Carraresi, L., Tripodi, S., Mulder, L. et al. Thymic hyperplasia and lung carcinomas in a line of mice transgenic for keratin 5-driven HPV16 E6/E7 oncogenes. Oncogene 20, 8148–8153 (2001). https://doi.org/10.1038/sj.onc.1205007

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