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Conversion of HPV 18 positive non-tumorigenic HeLa-fibroblast hybrids to invasive growth involves loss of TNF-α mediated repression of viral transcription and modification of the AP-1 transcription complex

Oncogene volume 18, pages 3187–3198 (1999)Cite this article

Abstract

AP-1 represents a transcription factor, which plays a pivotal role in initiating and maintaining the expression of human papillomavirus (HPV) oncoproteins E6 and E7 during HPV-linked carcinogenesis of the uterine cervix. AP-1 stands as a synonym for different proteins such as c-Jun, JunB, JunD, c-Fos, FosB as well as the Fos-related antigens Fra-1 and Fra-2, which can either homo- or heterodimerize to build up a functional transcription complex. AP-1 is mainly considered as a positive regulator, which binds to cognate DNA sequences within the viral upstream regulatory region. By using non-tumorigenic HeLa-fibroblast hybrids (`444'), their tumorigenic segregants (`CGL3') as well as HPV 18 positive HeLa cells as a experimental model system, evidence is provided that AP-1 composition differs considerably between these cell lines. In nuclear extracts obtained from non-tumorigenic cells, Jun-family members (in the order c-Jun>JunD>JunB) were mainly heterodimerized with Fra-1, a protein, known to be involved in the abrogation of AP-1 activity under certain experimental conditions. In contrast, Fra-1 concentration is low in extracts from tumorigenic cells. Conversely, c-Fos, the canonical dimerization partner of Jun proteins is expressed in substantial quantity in HeLa- and `CGL3' cells, but it is completely absent in AP-1 complexes from non-tumorigenic `444' cells. Ectopical expression of c-fos under a heterologous promoter in `444'-cells induces tumorigenicity and a change of the Jun/Fra-1 ratio towards a constellation initially detected in `CGL3'-and HeLa cells. Furthermore, conversion to tumorigenicity is accompanied with a resistance against TNF-α, a cytokine, capable to selectively suppress HPV 18 transcription in formerly non-malignant cells. These data propose a novel role for AP-1 as an essential component of an inter- and intracellular surveillance mechanism negatively controlling HPV transcription in non-tumorigenic cells.

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References

  • Angel P and Karin M. . 1991 Biochem. Biophys. Acta 1072: 129–157.

  • Antinore MJ, Birrer MJ, Patel D, Nader L and McCance DJ. . 1996 EMBO J. 15: 1950–1960.

  • Arts J, Herr I, Lansink M, Angel P and Kooistra T. . 1997 Nucl. Acids Res. 25: 311–317.

  • Attia M and Weiss D. . 1966 Cancer Res. 26: 1787–1800.

  • Bartsch D, Boye B, Baust C, zur Hausen H and Schwarz E. . 1992 EMBO J. 11: 2283–2291.

  • Bergers G, Graninger P, Braselmann S, Wrighton C and Busslinger M. . 1995 Mol. Cell. Biol. 15: 3748–3758.

  • Bosch FX, Schwarz E, Boukamp P, Fusenig NE, Bartsch D and zur Hausen H. . 1990 J. Virol. 64: 4743–4754.

  • Boshart M, Gissmann L, Ikenberg H, Kleinheinz A, Scheurlen W and zur Hausen H. . 1984 EMBO J. 3: 1151–1157.

  • Butz K and Hoppe-Seyler F. . 1993 J. Virol. 67: 6476–6486.

  • Cavigelli M, Dolfi F, Claret F-X and Karin M. . 1995 EMBO J. 14: 5957–5964.

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

  • Cohen JJ. . 1993 Immunol. Today 14: 126–130.

  • Cripe TP, Alderborn A, Anderson RD, Parkinen S, Bergman P, Haugen TH, Petterson U and Turek LP. . 1990 New Biol. 2: 450–463.

  • Crum CP, Symbula M and Ward BE. . 1989 Am. J. Pathol. 134: 1183–1188.

  • Dani C, Blanchard JM, Piechaczyk M, El-Sabouty S, Marty L and Jeanteur P. . 1984 Proc. Natl. Acad. Sci. USA 81: 7046–7050.

  • de Villiers E-M. . 1989 J. Virol. 63: 4898–4903.

  • Dürst M, Bosch FX, Glitz D, Schneider A and zur Hausen H. . 1991 J. Virol. 65: 796–804.

  • Dürst M, Petrussevska RT, Boukamp P, Fusenig NE and Gissmann L. . 1987 Oncogene 1: 251–256.

  • Dürst M, Seagon S, Wanschura S, zur Hausen H and Bullerdiek J. . 1995 Cancer Genet. Cytogenet. 85: 105–112.

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

  • Feinberg A and Vogelstein BA. . 1984 Anal. Biochem. 137: 266–267.

  • Finzer P, Soto U, DeLius H, Patzelt A, zur Hausen H and Rösl F. . (1999) submitted.

  • Fuiji M, Niki T, Mori T, Matsuda T, Matsui M, Nomura N and Seiki M. . 1991 Oncogene 6: 1023–1029.

  • Garcia-Carranca A, Thierry F and Yaniv M. . 1988 J. Virol. 63: 4321–4330.

  • Gius D and Laimins L. . 1989 J. Virol. 63: 555–563.

  • Gunning P, Ponte P, Okayama H, Engel J, Blau H and Kedes L. . 1983 Mol. Cell. Biol. 3: 787–795.

  • Hoppe-Seyler F, Butz K and zur Hausen H. . 1991 J. Virol. 65: 5613–5618.

  • Hunter T and Karin M. . 1992 Cell 70: 375–387.

  • Jesudasan RA, Rahman RA, Chandrashekharappa S, Evans GA and Srivatsan E. . 1995 Am. J. Hum. Genet. 56: 705–715.

  • Johnston RF, Pickett SC and Barker DL. . 1990 Electrophoresis 11: 355–360.

  • Kaur P and McDougall JK. . 1989 Virology 173: 302–310.

  • Khan MA, Jenkins GR, Tolleson WH, Creek KE and Pirisi L. . 1993 Cancer Res. 53: 905–909.

  • Khandjian EW and Meric CA. . 1986 Anal. Biochem. 159: 227–232.

  • Kleine K, König G, Kreuzer J, Komitowski D, zur Hausen H and Rösl F. . 1995 Mol. Carcinog. 14: 179–189.

  • Koi M, Morita H, Yamada H, Satoh H, Barrett JK and Oshimura M. . 1989 Mol. Carcinog. 2: 12–21.

  • Lee W, Mitchell W and Tjian R. . 1987 Cell 49: 741–752.

  • Loetscher H, Steinmetz M and Lesslauer W. . 1991 Cancer Cells 3: 221–226.

  • Mils V, Piette J, Barette C, Veyrune JL, Tesniere A, Escot C, Guilhou JJ and Basset-Séguin N. . 1997 Oncogene 14: 1555–1561.

  • Morosov A, Phelps WC and Raychaudhuri P. . 1994 J. Biol. Chem. 269: 18434–18440.

  • O'Hara BM, Klinger HP, Curran T, Zhang Y-D and Blair DG. . 1987 Mol. Cell. Biol. 7: 2941–2946.

  • Offord EA and Beard P. . 1990 J. Virol. 64: 4792–4798.

  • Okazaki K and Sagata N. . 1995 EMBO J. 14: 5048–5059.

  • Papavassiliou AG, Treier M, Chavrier C and Bohmann D. . 1992 Science 258: 1941–1944.

  • Parker JN, Zhao W, Askins KJ, Broker TR and Chow LT. . 1997 Cell Growth Differ. 8: 751–762.

  • Pei XF, Meck JM, Greenhalgh D and Schlegel R. . 1993 Virology 196: 855–860.

  • Pognonec P, Boulukos KE, Aperlo C, Fujimoto M, Ariga H, Nomoto A and Kato H. . 1997 Oncogene 14: 2091–2098.

  • Polack A, Eick D, Koch E and Bornkamm GW. . 1987 EMBO J. 6: 2959–2964.

  • Rollins BJ, Stier P, Ernst T and Wong GG. . 1989 Mol. Cell. Biol. 9: 4687–4695.

  • Rollins BJ. . 1991 Cancer Cells 3: 517–524.

  • Rösl F, Achtstätter T, Bauknecht T, Futterman G, Hutter KJ and zur Hausen H. . 1991 EMBO J. 10: 1337–1345.

  • Rösl F, Das BC, Lengert M, Geletneky K and zur Hausen H. . 1997 J. Virol. 71: 362–370.

  • Rösl F, Dürst M and zur Hausen H. . 1988 EMBO J. 7: 1321–1328.

  • Rösl F, Kleine-Lowinski K and zur Hausen H. . 1999 In: Chemokines and Cancer. (ed.) B.J. Rollins Humana Press, NJ, USA in press.

    Google Scholar 

  • Rösl F, Lengert M, Albrecht J, Kleine K, Zawatzky R, Schraven B and zur Hausen H. . 1994 J. Virol. 68: 2142–2150.

  • Rösl F and Schwarz E . (1997). In: Papillomavirus in Human Cancer. (ed.) M. Tommasino. Molecular Intelligence Unit. Springer: Heidelberg, Germany pp. 25–70.

  • Rutberg SE, Saez E, Glick A, Dlugosz AA, Spiegelman BM andYuspa SH. . 1996 Oncogene 13: 167–176.

  • Rutberg SE, Saez E, Lo S, Jang S-I, Markova N, Spiegelman BM and Yuspa SH. . 1997 Oncogene 15: 1337–1346.

  • Ryseck R-P and Bravo R. . 1991 Oncogene 6: 533–542.

  • Sambrook J, Fritsch E and Maniatis T. . 1989 Cold Spring Harbor Laboratory Press Cold Spring Harbor, NY, 2nd edition.

    Google Scholar 

  • Saxon PJ, Srivatsan ES and Stanbridge EJ. . 1986 EMBO J. 5: 3461–3466.

  • Scheidereit C, Cromlish JA, Gerster T, Kawakami K, Balmaceda C, Currie RA and Roeder RD. . 1988 Nature 336: 551–557.

  • Schreiber E, Matthias P, Müller MM and Schaffner W. . 1989 Nucl. Acids Res. 17: 6419.

  • Shepard HM and Lewis GD. . 1988 J. Clin. Immunol. 8: 333–341.

  • Sinke RJ, Tanigami A, Nakamura Y and Geruts van Kessel A. . 1993 Genomics 18: 165.

  • Sluss HK, Barrett T, Dérijard B and Davis RJ. . 1994 Mol. Cell. Biol. 14: 8376–8384.

  • Smits PHM, Smits HL, Jebbink MF and ter Schegget J. . 1990 Virology 176: 158–165.

  • Smits PHM, Smits HL, Minnaar RP, Hemmings BA, Mayer-Jaekel RE, Schuurman R, van der Noordaa J and ter Schegget J. . 1992 EMBO J. 11: 4601–4608.

  • Srivatsan ES, Misra BC, Venugopalan M and Wilczynski SP. . 1991 Am. J. Hum. Genet. 49: 868–877.

  • Stanbridge E. . 1984 Cancer Surv. 3: 335–350.

  • Suzuki T, Okuno H, Yoshida T, Endo T, Nishina H and Iba H. . 1991 Nucl. Acids Res. 19: 5537–5542.

  • Thierry F, Spyrou G, Yaniv M and Howley PM. . 1992 J. Virol. 66: 3740–3748.

  • Traenckner EB, Wilk S and Baeuerle P. . 1994 EMBO J. 13: 5433–5441.

  • Tsuchiya H, Fujii M, Niki T, Tokuhara M, Matsui M and Seiki M. . 1993 J. Virol. 67: 7001–7007.

  • Tsurumi C, Ishida N, Tamura T, Kakizuka A, Nishida E, Okumura E, Kishimoto T, Inagaki M, Okazaki K, Sagata N, Ichihara A and Tanaka K. . 1995 Mol. Cell. Biol. 15: 5682–5687.

  • Wang H, Xie Z and Scott RE. . 1996 J. Cell. Biol. 135: 1151–1162.

  • Werness BA, Levine A and Howley PM. . 1990 Science 248: 76–79.

  • Yoshioka K, Deng T, Cavigelli M and Karin M. . 1995 Proc. Natl. Acad. Sci. USA 92: 4972–4976.

  • Zhao W, Chow LT and Broker TR. . 1997 J. Virol. 71: 8832–8840.

  • zur Hausen H. . 1986 Lancet 11: 489–491.

  • zur Hausen H. . 1994 Lancet 343: 955–957.

  • zur Hausen H. . 1996 Biochem. Biophys. Acta 1288: 55–78.

  • zur Hausen H and Rösl F. . 1994 Cold Spring Harbor Symposia on Quantitative Biology Vol. LIX, Cold Spring Harbor Laboratory Press. pp. 623–628.

    Google Scholar 

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Acknowledgements

We thank Dr Peter Angel for helpful discussion, Wolfgang Weinig for oligonucleotide synthesis and all our colleagues for kindly providing the various plasmid probes. Dr Ubaldo Soto (Catholic University of Chile) was supported by the Alexander von Humboldt Stiftung, Bonn, Germany.

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  1. Forschungsschwerpunkt Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum, 69120 Heidelberg, Im Neuenheimer Feld 242, 69120, Heidelberg, Germany

    Maike Lengert, Patrick Finzer, Harald zur Hausen & Frank Rösl

  2. Molecular Oncology Division, Institute of Cytology and Preventive Oncology, Maulana Azad Medical College, New Delhi, India

    Ubaldo Soto & Bhudev Chandra Das

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Soto, U., Das, B., Lengert, M. et al. Conversion of HPV 18 positive non-tumorigenic HeLa-fibroblast hybrids to invasive growth involves loss of TNF-α mediated repression of viral transcription and modification of the AP-1 transcription complex. Oncogene 18, 3187–3198 (1999). https://doi.org/10.1038/sj.onc.1202765

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