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:

Cell cycle arrest is sufficient for p53-mediated tumor regression

Gene Therapy volume 8, pages 1705–1712 (2001)Cite this article

Abstract

p53 gene therapy can induce tumor regression, but the low efficacy of in vivo gene transfer has greatly hampered the mechanistic analysis of this antitumoral activity. We therefore used a p53-null human NSCLC cell line in which we reintroduced the wild-type p53 gene under control of a tetracycline-dependent promoter. P53 induction provokes cell cycle arrest in G0/G1 and G2/M phase, an up-regulation of p21, a down-regulation of cyclin B1 and appearance of senescence features without down-regulation of human telomerase reverse transcriptase. No detectable morphological changes of apoptosis nor procaspase-3 activation are observed. In subcutaneous tumors grafted in nude mice, the induction of p53 expression leads to a complete and long-lasting tumor regression in 28 days which is associated with cell cycle arrest, but not detectable apoptosis nor inhibition of angiogenesis. These results show that irreversible cell cycle arrest is sufficient to elicit tumor regression after p53 gene transfer in p53-deficient tumor cells.

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

Similar content being viewed by others

References

  1. Klein G . The approaching era of the tumor suppressor genes Science 1987 238: 1539–1545

    Article  CAS  Google Scholar 

  2. Takahashi T et al. Wild-type but not mutant p53 suppresses the growth of human lung cancer cells bearing multiple genetic lesions Cancer Res 1992 52: 230–2343

    Google Scholar 

  3. Cai DW et al. Stable expression of the wild-type p53 gene in human lung cancer cells after retrovirus-mediated gene transfer Hum Gene Ther 1993 4: 617–624

    Article  CAS  Google Scholar 

  4. Baker SJ et al. Suppression of human colorectal carcinoma cell growth by wild-type p53 Science 1990 249: 912–915

    Article  CAS  Google Scholar 

  5. Takahashi T et al. p53: a frequent target for genetic abnormalities in lung cancer Science 1989 246: 491–494

    Article  CAS  Google Scholar 

  6. Favrot M, Coll JL, Louis N, Negoescu A . Cell death and cancer: replacement of apoptotic genes and inactivation of death suppressor genes in therapy Gene Therapy 1998 5: 728–739

    Article  CAS  Google Scholar 

  7. Fujiwara T et al. Therapeutic effect of a retroviral wild-type p53 expression vector in an orthotopic lung cancer model J Natl Cancer Inst 1994 86: 1458–1462

    Article  CAS  Google Scholar 

  8. Wills KN et al. Development and characterization of recombinant adenoviruses encoding human p53 for gene therapy of cancer Hum Gene Ther 1994 5: 1079–1088

    Article  CAS  Google Scholar 

  9. Coll JL et al. Antitumoral activity of bax and p53 gene transfer in lung cancer: in vitro and in vivo analysis Hum Gene Ther 1998 9: 2063–2074

    Article  CAS  Google Scholar 

  10. Hamada K et al. Adenovirus-mediated transfer of a wild-type p53 gene and induction of apoptosis in cervical cancer Cancer Res 1996 56: 3047–3054

    CAS  PubMed  Google Scholar 

  11. Symonds H . P53-dependent apoptosis suppresses tumor growth and progression in vivo Cell 1994 78: 703–711

    Article  CAS  Google Scholar 

  12. Dameron KM et al. Control of angiogenesis in fibroblast by p53 regulation of thrombospondin-1 Science 1994 265: 1582–1584

    Article  CAS  Google Scholar 

  13. Kistner A et al. Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice Proc Natl Acad Sci USA 1996 93: 10933–10938

    Article  CAS  Google Scholar 

  14. Kistner A et al. Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice

  15. Yang ZY et al. The p21 cyclin-dependent kinase inhibitor suppresses tumorigenicity in vivo Nat Med 1995 1: 1052–1056

    Article  CAS  Google Scholar 

  16. Michalovitz D, Halevy O, Oren M . Conditional inhibition of transformation and of cell proliferation by a temperature-sensitive mutant of p53 Cell 1990 62: 671–680

    Article  CAS  Google Scholar 

  17. Chen X, Ko LJ, 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: 2438–2451

    Article  CAS  Google Scholar 

  18. Chen QM, Liu J, Merrett JB . Apoptosis or senescence-like growth arrest: influence of cell-cycle position, p53, p21 and BAX in H2O2 response of normal human fibroblasts Biochem J 2000 347: 543–551

    Article  CAS  Google Scholar 

  19. Mukhopadhyay T, Roth JA . Superinduction of wild-type p53 protein after 2-methoxyestradiol treatment of Ad5p53-transduced cells induces tumor cell apoptosis Oncogene 1998 17: 241–246

    Article  CAS  Google Scholar 

  20. Craig et al. Effects of adenovirus-mediated p16INK4A expression on cell cycle arrest are determined by endogenous p16 and Rb status in human cancer cells Oncogene 1998 16: 265–272

    Article  CAS  Google Scholar 

  21. Alemany R et al. Growth inhibitory effect of anti-K-ras adenovirus on lung cancer cells Cancer Gene Ther 1996 3: 296–301

    CAS  PubMed  Google Scholar 

  22. Lundberg AS, Hahn WC, Gupta P, Weinberg RA . Genes involved in senescence and immortalization Curr Opin Cell Biol 2000 12: 705–709

    Article  CAS  Google Scholar 

  23. Sugrue MM et al. Wild-type p53 triggers a rapid senescence program in human tumor cells lacking functional p53 Proc Natl Acad Sci USA 1997 94: 9468–9653

    Article  Google Scholar 

  24. Xu D et al. Down-regulation of telomerase reverse transcriptase mRNA expression by wild type p53 in human tumor cells Oncogene 2000 19: 5123–5133

    Article  CAS  Google Scholar 

  25. Kanaya T et al. Adenoviral expression of p53 represses telomerase activity through down-regulation of human telomerase reverse transcriptase transcription Clin Cancer Res 2000 6: 1239–1247

    CAS  Google Scholar 

  26. Jones CJ et al. Evidence for a telomere-independent ‘clock’ limiting RAS oncogene-driven proliferation of human thyroid epithelial cells Mol Cell Biol 2000 20: 5690–5699

    Article  CAS  Google Scholar 

  27. Wei S, Sedivy JM . Expression of catalytically active telomerase does not prevent premature senescence caused by overexpression of oncogenic Ha-Ras in normal human fibroblasts Cancer Res 1999 59: 1539–1543

    CAS  PubMed  Google Scholar 

  28. Holmgren L, Jackson G, Arbiser J . p53 induces angiogenesis-restricted dormancy in a mouse fibrosarcoma Oncogene 1998 17: 819–824

    Article  CAS  Google Scholar 

  29. Riccioni T et al. Adenovirus-mediated wild-type p53 overexpression inhibits endothelial cell differentiation in vitro and angiogenesis in vivo Gene Therapy 1998 5: 747–754

    Article  CAS  Google Scholar 

  30. Smith et al. Replicative senescence: implications for in vivo aging and tumor suppression Science 1996 273: 63–67

    Article  CAS  Google Scholar 

  31. Negoescu A et al. In situ apoptotic cell labeling by the TUNEL method improvement and evolution on cell preparations J Histochem Cytochem 1996 44: 959–968

    Article  CAS  Google Scholar 

  32. Dimri GP et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo Proc Natl Acad Sci USA 1995 92: 9363–9367

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank Dominique Desplanques et Corine Tenaud for technical assistance. This work was supported by ARC (Association de Recherche Contre le Cancer), the Ligue Nationale de Lutte Contre le Cancer (Unité de l'Isère) and FEGEFUC, as well as by grants from the region Rhône-Alpes (programme emergence) and from the Health Ministry (CRTG). Laurence Dubrez acknowledges ARC and region Rhône-Alpes for research fellowships.

Author information

Authors and Affiliations

  1. Groupe de Recherche sur le Cancer du Poumon, Equipe INSERM 9924, Institut Albert Bonniot Cedex, Tronche, 38706 La, France

    L Dubrez, J-L Coll, A Hurbin, S Lantejoul & M-C Favrot

  2. Département de Biologie Intégrée, Hôpital de La Tronche, Pavillon B, CHU de Grenoble, Grenoble, France

    F de Fraipont & M-C Favrot

Authors
  1. L Dubrez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J-L Coll
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Hurbin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F de Fraipont
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Lantejoul
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M-C Favrot
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dubrez, L., Coll, JL., Hurbin, A. et al. Cell cycle arrest is sufficient for p53-mediated tumor regression. Gene Ther 8, 1705–1712 (2001). https://doi.org/10.1038/sj.gt.3301592

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3301592

Keywords

This article is cited by

Search

Advanced search

Quick links