Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Tumor-specific activation of hTERT-derived promoters by tumor suppressive E1A-mutants involves recruitment of p300/CBP/HAT and suppression of HDAC-1 and defines a combined tumor targeting and suppression system

Oncogene volume 21, pages 7991–8000 (2002)Cite this article

Abstract

Adenovirus (Ad) E1A proteins are transcriptional regulators with antioncogenic but also transforming properties. We have previously shown that transformation-defective Ad5 E1A-derivatives are excellent tumor suppressors. For tumor-specific expression of the E1A-derivatives we intend to use tumor specific human telomerase reverse transcriptase (hTERT) core promoters. Here, we show that Spm2 and other E1A proteins with an intact amino terminus activated all hTERT constructs 10–20-fold in malignant tumor cells but not in primary fibroblasts, without affecting the activity of endogenous telomerase. The transcription rate in tumor cells was in the range of transcription from the SV40 promoter, which qualifies an E1A-hTERT system as a putative tumor targeting/expression system. The activation of the hTERT promoter by E1A was enhanced upon deletion of the Wilms' tumor 1 negative regulatory element and maintained high after deletion of the adjacent c-Myc-responsive E-box, demonstrating an important role of the remaining sequences that contain several Sp1-motifs. E1A-mediated hTERT activation was independent from the presence of the conserved region 3 (CR3) of E1A but dependent on E1A's binding to p300/CBP and recruitment of its histone acetyltransferase activity. Moreover, E1A-Spm2 and histone deacetylase-1 behaved as antagonists with respect to the regulation of transcription from the hTERT promoter. Overall, hTERT promoter/E1A-Spm2 systems may turn out to be excellent tools for transcriptionally targeted anticancer gene therapy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figure 11
Figure 12

Similar content being viewed by others

Abbreviations

hTERT :

human telomerase reverse transcriptase

Ad:

adenovirus

HAT:

histone acetyltransferase

HDAC:

histone deacetylase

CR:

conserved region

References

  • Ait-Si-Ali S, Ramirez S, Barre FX, Dkhissi F, Magnaghi-Jaulin L, Girault JA, Robin P, Knibiehler M, Pritchard LL, Ducommun B, Trouche D, Harel-Bellan A . 1998 Nature 396: 184–186

  • Boyd JM, Subramanian T, Schaeper U, La Regina M, Bayley S, Chinnadurai G . 1993 EMBO J. 12: 469–478

  • Cong YS, Bacchetti S . 2000 J. Biol. Chem. 275: 35665–35668

  • Deng J, Kloosterbooer F, Xia W, Hung MC . 2002 Cancer Res. 62: 346–350

  • Dickopp A, Esche H, Swart G, Seeber S, Kirch HC, Opalka B . 2000 Cancer Gene Ther. 7: 1043–1050

  • Elliot G, O'Hare P . 1997 Cell 88: 223–233

  • Fax P, Lehmkühler O, Kühn C, Esche H, Brockmann D . 2000 J. Biol. Chem. 51: 40554–40560

  • Frisch SM, Mymryk JS . 2002 Nat. Rev. Mol. Cell Biol. 3: 441–452

  • Frisch SM, Dolter KE . 1995 Cancer Res. 55: 5551–5555

  • Frisch SM . 2001 Adv. Cancer Res. 80: 39–49

  • Frisch SM . 1991 Proc. Nat. Acad. Sci. USA 88: 9077–9081

  • Gallimore PH, Turnell AS . 2001 Oncogene 20: 7824–7835

  • Gu J, Kagawa S, Takakura M, Kyo S, Inoue M, Roth JA, Fang B . 2000 Cancer Res. 60: 5359–5364

  • Haley KP, Overhauser J, Babiss LE, Ginsberg HS, Jones NC . 1984 Proc. Nat. Acad. Sci. USA 81: 5734–5738

  • Hamamori Y, Sartorelli V, Ogryzko V, Puri PL, Wu HY, Wang JY, Nakatani Y, Kedes L . 1999 Cell 96: 405–413

  • Horikawa I, Cable LA, Afshari C, Barrett JC . 1999 Cancer Res. 59: 826–830

  • Hou M, Wang X, Popov N, Zhang A, Zhao X, Zetterberg A, Bjorkholm M, Henriksson M, Gruber A, Xu D . 2002 Exp. Cell. Res. 274: 25–34

  • Kilian A, Bowtell DD, Abud HE, Hime GR, Venter DJ, Keese PK, Duncan EL, Reddel RR, Jefferson RA . 1997 Hum. Mol. Genet. 6: 2011–2019

  • Kirch HC, Flaswinkel S, Rumpf H, Brockmann D, Esche H . 1999 Oncogene 29: 2728–2738

  • Komata T, Kondo Y, Kanzaba T, Hirohata S, Koga S, Sumiiyoshi H, Srinivazula SM, Barna BP, Germano IM, Takakura M, Inue M, Alnemri ES, Shay JW, Kyo S, Kondo S . 2001 Cancer Res. 61: 5796–5802

  • Komata T, Kanzaba T, Kondo Y, Kondo S . 2002 Oncogene 21: 656–663

  • Kyo S, Takakura M, Taira T, Kanaya T, Itoh H, Yutsudo M, Ariga H, Inoue M . 2000 Nucleic Acids Res. 28: 669–677

  • Mymryk JS . 1996 Oncogene 13: 1581–1589

  • Oh S, Song Y, Yim Y, Kim TK . 1999 J. Biol. Chem. 52: 37473–37487

  • Rumpf H, Esche H, Kirch HC . 1999 Virology 257: 45–53

  • Schuirer M, Hilger-Eversheim K, Dobner T, Bosserhoff AK, Moser M, Turner J, Crossley M, Büttner R . 2001 J. Biol. Chem. 276: 27944–27949

  • Shay JW, Zou Y, Hiyama E, Wright WE . 2001 Hum. Mol. Genet. 10: 677–685

  • Strom AC, Ohlsson P, Akusjarvi G . 1998 J. Virol. 72: 5978–5983

  • Sundqvist A, Bajak E, Kurup SD, Sollerbrant K, Svensson C . 2001 Exp. Cell. Res. 268: 284–293

  • Takakura M, Kyo S, Kanaya T, Hirano H, Takeda J, Yutsudo M, Inoue M . 1999 Cancer Res. 59: 551–557

  • Takakura M, Kyo S, Sowa Y, Wang Z, Yatabe N, Maida Y, Tabaka M, Inoue M . 2001 Nucleic Acids Res. 29: 3006–3011

  • Turner J, Crossley M . 2001 Bioessays 23: 683–690

  • Van Groningen JJM, Cornelissen IMAH, van Muijen GNP, Bloemerts HPJ, Swart GWM . 1996 Biochem. Biophys. Res. Comm. 225: 808–816

  • Van Muijen GN, Cornelissen LM, Jansen CF, Figdor CG, Johnson JP, Brocker EB, Ruiter DJ . 1991 Clin. Exp. Metastasis 9: 259–272

  • White E . 2001 Oncogene 20: 7836–7846

  • Wu KJ, Grandori C, Amacker M, Simon-Vermot N, Polack A, Lingner J, Dalla-Favera R . 1999 Nat. Genet. 21: 220–224

  • Yoshida M, Furumai R, Nishiyama M, Komatsu Y, Nishino N, Horinouchi S . 2001 Cancer Chemother. Pharmacol. 48: S20–S26

  • Yu D, Suen TC, Yan DH, Chang LS, Hung MC . 1990 Proc. Natl. Acad. Sci. USA 87: 4499–4503

  • Zhang Q, Yao H, Fo N, Goodman RH . 2000 Proc. Natl. Acad. Sci. USA 97: 14323–14328

Download references

Acknowledgements

We like to thank A Harel-Bellan (Laboratoire Oncogenese, Differentiation et Transduction du Signal, Villejuif, France) for the pCMV-HA-HDAC-1 expression plasmid, Katrin Thiel, and Achim Sternberg for excellent technical assistance, Nicole C Bartosch for editorial support and Jan Maschke for helpful critical discussions. This work was partly supported by the IFORES program, Medical Faculty of the University of Essen, and the Joachim Kuhlmann AIDS-Foundation, Essen, Germany.

Author information

Authors and Affiliations

  1. Department of Internal Medicine (Cancer Research), University of Essen, Essen, Germany

    Hans-Christoph Kirch, Sabine Ruschen & Bertram Opalka

  2. Institute of Molecular Biology (Cancer Research), University of Essen, Essen, Germany

    Dieter Brockmann & Helmut Esche

  3. Laboratory of Biosystems and Cancer Research, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA

    Izumi Horikawa & J Carl Barrett

  4. Department of Dermatology, University of Essen, Essen, Germany

    Hans-Christoph Kirch & Ulrich R Hengge

Authors
  1. Hans-Christoph Kirch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sabine Ruschen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dieter Brockmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Helmut Esche
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Izumi Horikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Carl Barrett
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bertram Opalka
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ulrich R Hengge
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hans-Christoph Kirch.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kirch, HC., Ruschen, S., Brockmann, D. et al. Tumor-specific activation of hTERT-derived promoters by tumor suppressive E1A-mutants involves recruitment of p300/CBP/HAT and suppression of HDAC-1 and defines a combined tumor targeting and suppression system. Oncogene 21, 7991–8000 (2002). https://doi.org/10.1038/sj.onc.1205965

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205965

Keywords

This article is cited by

Search

Advanced search

Quick links