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.

  • Research Article
  • Published:

Adenoviruses with Tcf binding sites in multiple early promoters show enhanced selectivity for tumour cells with constitutive activation of the wnt signalling pathway

Gene Therapy volume 9, pages 270–281 (2002)Cite this article

Abstract

Mutation of the adenomatous polyposis coli and β-catenin genes in colon cancer leads to constitutive activation of transcription from promoters containing binding sites for Tcf/LEF transcription factors. We have constructed adenoviruses with Tcf binding sites in the early promoters, in order to target viral replication to colon tumours. Tcf regulation of the E1A promoter confers a 100-fold selectivity for cells with activated wnt signalling in viral burst and cytopathic effect assays. p300 is a coactivator for β-catenin, and E1A inhibits Tcf-dependent transcription through sequestration of p300, but mutation of the p300 binding site in E1A leads to a 10-fold reduction in cytopathic effect of all of the Tcf-regulated viruses. When Tcf sites are inserted in the E1A, E1B, E2 and E4 promoters the viruses show up to 100 000-fold selectivity for cells with activated wnt signalling.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • 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

Similar content being viewed by others

References

  1. Rodriguez R. et al. Prostate attenuated replication competent adenovirus (ARCA) CN706: a selective cytotoxic for prostate-specific antigen-positive prostate cancer cells Cancer Res 1997 57: 2559 2559

    CAS  PubMed  Google Scholar 

  2. Yu D.C., Sakamoto G.T., Henderson D.R. . Identification of the transcriptional regulatory sequences of human kallikrein 2 and their use in the construction of calydon virus 764, an attenuated replication competent adenovirus for prostate cancer therapy Cancer Res 1999 59: 1498 1498

    CAS  PubMed  Google Scholar 

  3. Hallenbeck P.L. et al. A novel tumor-specific replication-restricted adenoviral vector for gene therapy of hepatocellular carcinoma Hum Gene Ther 1999 10: 1721 1721

    Article  CAS  PubMed  Google Scholar 

  4. Hernandez-Alcoceba R., Pihalja M., Wicha M.S., Clarke M.F. . A novel, conditionally replicative adenovirus for the treatment of breast cancer that allows controlled replication of E1a-deleted adenoviral vectors Hum Gene Ther 2000 11: 2009 2009

    Article  CAS  PubMed  Google Scholar 

  5. Heise C. et al. An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy Nature Med 2000 6: 1134 1134

    Article  CAS  PubMed  Google Scholar 

  6. Khuri F. et al. A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer Nature Med 2000 6: 879 879

    Article  CAS  PubMed  Google Scholar 

  7. Heise C. et al. ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents Nature Med 1997 3: 639 639

    Article  CAS  PubMed  Google Scholar 

  8. Bischoff J.R. et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells Science 1996 274: 373 373

    Article  CAS  PubMed  Google Scholar 

  9. Chen Y., Yu D.C., Charlton D., Henderson D.R. . Pre-existent adenovirus antibody inhibits systemic toxicity and antitumor activity of CN706 in the nude mouse LNCaP xenograft model: implications and proposals for human therapy Hum Gene Ther 2000 11: 1553 1553

    Article  CAS  PubMed  Google Scholar 

  10. Teichler Z.D. . US gene therapy in crisis Trends Genet 2000 16: 272 272

    Article  Google Scholar 

  11. Brunori M., Malerba M., Kashiwazaki H., Iggo R. . Replicating adenoviruses that target tumors with constitutive activation of the wnt signaling pathway J Virol 2001 75: 2857 2857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Polakis P. . Wnt signaling and cancer Genes Dev 2000 14: 1837 1837

    CAS  PubMed  Google Scholar 

  13. Korinek V. et al. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma Science 1997 275: 1784 1784

    Article  CAS  PubMed  Google Scholar 

  14. He T.C. et al. Identification of c-MYC as a target of the APC pathway Science 1998 281: 1509 1509

    Article  CAS  PubMed  Google Scholar 

  15. Tetsu O., McCormick F. . Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells Nature 1999 398: 422 422

    Article  CAS  PubMed  Google Scholar 

  16. Roose J. et al. Synergy between tumor suppressor APC and the beta-catenin-Tcf4 target Tcf1 Science 1999 285: 1923 1923

    Article  CAS  PubMed  Google Scholar 

  17. Crawford H.C. et al. The metalloproteinase matrilysin is a target of beta-catenin transactivation in intestinal tumors Oncogene 1999 18: 2883 2883

    Article  CAS  PubMed  Google Scholar 

  18. Lipinski K.S. et al. High-level, beta-catenin/TCF-dependent transgene expression in secondary colorectal cancer tissue Molec Ther 2001 4: 365 365

    Article  CAS  Google Scholar 

  19. Chen R.H., McCormick F. . Selective targeting to the hyperactive beta-catenin/T-cell factor pathway in colon cancer cells Cancer Res 2001 61: 4445 4445

    CAS  PubMed  Google Scholar 

  20. Hearing P., Shenk T. . The adenovirus type 5 E1A enhancer contains two functionally distinct domains: one is specific for E1A and the other modulates all early units in cis Cell 1986 45: 229 229

    Article  CAS  PubMed  Google Scholar 

  21. Challberg M.D., Kelly T.J. . Animal virus DNA replication Annu Rev Biochem 1989 58: 671 671

    Article  CAS  PubMed  Google Scholar 

  22. Amalfitano A., Chamberlain J.S. . Isolation and characterization of packaging cell lines that coexpress the adenovirus E1, DNA polymerase, and preterminal proteins: implications for gene therapy Gene Therapy 1997 4: 258 258

    Article  CAS  PubMed  Google Scholar 

  23. Cottu P.H. et al. Inverse correlation between RER+ status and p53 mutation in colorectal cancer cell lines Oncogene 1996 13: 2727 2727

    CAS  PubMed  Google Scholar 

  24. Hecht A. . The p300/CBP acetyltransferases function as transcriptional coactivators of beta-catenin in vertebrates EMBO J 2000 19: 1839 1839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Takemaru K.I., Moon R.T. . The transcriptional coactivator CBP interacts with beta-catenin to activate gene expression J Cell Biol 2000 149: 249 249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Reid J.L. et al. E1A directly binds and regulates the P/CAF acetyltransferase EMBO J 1998 17: 4469 4469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Brannon M. et al. XCtBP is a XTcf-3 co-repressor with roles throughout Xenopus development Development 1999 126: 3159 3159

    CAS  PubMed  Google Scholar 

  28. Bauer A. et al. Pontin52 and Reptin52 function as antagonistic regulators of beta-catenin signalling activity EMBO J 2000 19: 6121 6121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Fajas L. et al. pRB binds to and modulates the transrepressing activity of the E1A-regulated transcription factor p120E4F Proc Natl Acad Sci USA 2000 97: 7738 7738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Roose J., Clevers H. . TCF transcription factors: molecular switches in carcinogenesis Biochim Biophys Acta 1999 1424: M23 M23

    CAS  PubMed  Google Scholar 

  31. Sun Y. et al. Regulation of beta-catenin transformation by the p300 transcriptional coactivator Proc Natl Acad Sci USA 2000 97: 12613 12613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lipinski K.S., Esche H., Brockmann D. . Amino acids 1-29 of the adenovirus serotypes 12 and 2 E1A proteins interact with rap30 (TF(II)F) and TBP in vitro Virus Res 1998 54: 99 99

    Article  CAS  PubMed  Google Scholar 

  33. Lewis B.A. et al. Adenovirus E1A proteins interact with the cellular YY1 transcription factor J Virol 1995 69: 1628 1628

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Lee J.S. et al. Relief of YY1 transcriptional repression by adenovirus E1A is mediated by E1A-associated protein p300 Genes Dev 1995 9: 1188 1188

    Article  CAS  PubMed  Google Scholar 

  35. Kraus V.B. et al. Interaction of the Dr1 inhibitory factor with the TATA binding protein is disrupted by adenovirus E1A Proc Natl Acad Sci USA 1994 91: 6279 6279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bonneaud N. et al. A family of low and high copy replicative integrative and single-stranded S. cerevisiae/E. coli shuttle vectors Yeast 1991 7: 609 609

    Article  CAS  PubMed  Google Scholar 

  37. Leza M.A., Hearing P. . Cellular transcription factor binds to adenovirus early region promoters and to a cyclic AMP response element J Virol 1988 62: 3003 3003

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Gagnebin J. et al. A photosensitising adenovirus for photodynamic therapy Gene Therapy 1999 6: 1742 1742

    Article  CAS  PubMed  Google Scholar 

  39. Alevizopoulos K., Catarin B., Vlach J., Amati B. . A novel function of adenovirus E1A is required to overcome growth arrest by the CDK2 inhibitor p27(Kip1) EMBO J 1998 17: 5987 5987

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Alevizopoulos K., Sanchez B., Amati B. . Conserved region 2 of adenovirus E1A has a function distinct from pRb binding required to prevent cell cycle arrest by p16INK4a or p27Kip1 Oncogene 2000 19: 2067 2067

    Article  CAS  PubMed  Google Scholar 

  41. van de Wetering M. et al. Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF Cell 1997 88: 789 789

    Article  CAS  PubMed  Google Scholar 

  42. Blanco J.C. et al. The histone acetylase PCAF is a nuclear receptor coactivator Genes Dev 1998 12: 1638 1638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wood M.A., McMahon S.B., Cole M.D. . An ATPase/helicase complex is an essential cofactor for oncogenic transformation by c-Myc Mol Cell 2000 5: 321 321

    Article  CAS  PubMed  Google Scholar 

  44. Cajot J.F., Sordat I., Silvestre T., Sordat B. . Differential display cloning identifies motility-related protein (MRP1/CD9) as highly expressed in primary compared to metastatic human colon carcinoma cells Cancer Res 1997 57: 2593 2593

    CAS  PubMed  Google Scholar 

  45. Chen X., Ko L.J., Jayaraman L., Prives C. . p53 levels, functional domains, and DNA damage determine the extent of the apoptotic response of tumor cells Genes Dev 1996 10: 2438 2438

    Article  CAS  PubMed  Google Scholar 

  46. Sarnow P., Sullivan C.A., Levine A.J. . A monoclonal antibody detecting the adenovirus type 5-E1b-58Kd tumor antigen: characterization of the E1b-58Kd tumor antigen in adenovirus-infected and -transformed cells Virology 1982 120: 510 510

    Article  CAS  PubMed  Google Scholar 

  47. Reich N.C., Sarnow P., Duprey E., Levine A.J. . Monoclonal antibodies which recognize native and denatured forms of the adenovirus DNA-binding protein Virology 1983 128: 480 480

    Article  CAS  PubMed  Google Scholar 

  48. Marton M.J., Baim S.B., Ornelles D.A., Shenk T. . The adenovirus E4 17-kilodalton protein complexes with the cellular transcription factor E2F, altering its DNA-binding properties and stimulating E1A-independent accumulation of E2 mRNA J Virol 1990 64: 2345 2345

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Evan G.I., Lewis G.K., Ramsay G., Bishop J.M. . Isolation of monoclonal antibodies specific for human c-myc proto-oncogene product Mol Cell Biol 1985 5: 3610 3610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank E Lurati and A Ducraux for expert technical assistance. We thank M Malerba for providing the cMM1 cell line. We thank K Alevizopoulos, J Chamberlain, H Clevers, MD Cole, T Dobner, AJ Levine, C Prives, B Sordat and D Trono for supplying reagents. We thank M Peter and P Beard for critical reading of the manuscript and M Brunori for helpful discussions. We thank the Swiss National Science Foundation, Swiss Cancer League, Roche Research Foundation and ISREC for financial support.

Author information

Authors and Affiliations

  1. Oncogene Group, Swiss Institute for Experimental Cancer Research (ISREC), Epalinges, Switzerland

    C Fuerer & R Iggo

Authors
  1. C Fuerer
    View author publications

    Search author on:PubMed Google Scholar

  2. R Iggo
    View author publications

    Search author on:PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fuerer, C., Iggo, R. Adenoviruses with Tcf binding sites in multiple early promoters show enhanced selectivity for tumour cells with constitutive activation of the wnt signalling pathway. Gene Ther 9, 270–281 (2002). https://doi.org/10.1038/sj.gt.3301651

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/sj.gt.3301651

Keywords

This article is cited by

Search

Advanced search

Quick links