Skip to main content

Advertisement

SpringerLink
Log in

Effect of an hdm-2 antagonist peptide inhibitor on cell cycle progression in p53-deficient H1299 human lung carcinoma cells

  • Short Communication
  • Published:
Oncogene Submit manuscript

Abstract

The hdm-2 oncogene is overexpressed in several types of malignancies including osteosarcomas, soft tissue sarcomas and gliomas and hdm-2 has been associated with accelerated tumor formation in both hereditary and sporadic cancers. Among the other key binding partners, hdm-2 forms a complex with the tumor suppressor p53, resulting in a rapid proteasome-mediated degradation of the p53 protein. This positions the hdm-2–p53 complex as an attractive target for the development of anticancer therapy and recently the first small molecule hdm-2 antagonist has been reported. Development of hdm-2 antagonists is currently focused on malignancies containing a wild-type p53 genotype, which is the case in approximately half of human cancer indications. However, hdm-2 has also been implicated in oncogenesis in the absence of p53. We therefore studied the effect of hdm-2 antagonists in p53-deficient human H1299 lung carcinoma cells. The hdm-2 antagonistic peptide caused G1 cell cycle arrest, inhibited colony growth and induced expression of G1 checkpoint regulatory proteins, such as p21waf1,cip1. These data demonstrate that hdm-2 regulates the G1 cell cycle checkpoint in a p53-independent manner, suggesting that hdm-2 antagonists represent a novel class of anticancer therapeutics with broad applicability towards tumors with different p53 genetic backgrounds.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  • Blattner C, Sparks A, Lane D . (1999). Mol Cell Biol 19: 3704–3713.

  • Blaydes JP, Gire V, Rowson JM, Wynford-Thomas D . (1997). Oncogene 14: 1859–1868.

  • Bond GL, Hu WW, Bond EE, Robins H, Lutzker SG, Arva NC et al. (2004). Cell 119: 591–602.

  • Bottger A, Bottger V, Garcia-Echeverria C, Chene P, Hochkeppel HK, Sampson W et al. (1997a). J Mol Biol 269: 744–756.

  • Bottger A, Bottger V, Sparks A, Liu WL, Howard SF, Lane DP . (1997b). Curr Biol 7: 860–869.

  • Cordon-Cardo C, Latres E, Drobnjak M, Oliva MR, Pollack D, Woodruff JM et al. (1994). Cancer Res 54: 794–799.

  • Dobbelstein M, Wienzek S, Konig C, Roth J . (1999). Oncogene 18: 2101–2106.

  • Fakharzadeh SS, Rosenblumvos L, Murphy M, Hoffman EK, George DL . (1993). Genomics 15: 283–290.

  • Fischer PM, Lane DP . (2004). Trends Pharmacol Sci 25: 343–346.

  • Hollstein M, Sidransky D, Vogelstein B, Harris CC . (1991). Science 253: 49–53.

  • Jones SN, Hancock AR, Vogel H, Donehouwer LA, Bradley A . (1998). Proc Natl Acad Sci USA 95: 15608–15612.

  • Jost CA, Marin MC, Kaelin WG . (1997). Nature 389: 191–194.

  • Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ et al. (1996). Science 274: 948–953.

  • Lane DP . (1992). Nature 358: 15–16.

  • Lorens JB, Bennet MK, Pearsall DM, Throndset WR, Rossi AB, Armstrong R et al. (2000). Mol Ther 1: 438–447.

  • Martin K, Trouche D, Hagemeier C, Sorensen TS, Lathangue NB, Kouzarides T . (1995). Nature 375: 691–694.

  • Momand J, Zambetti GP . (1997). J Cell Biochem 64: 343–352.

  • Sdek P, Ying H, Chang DL, Qiu W, Zheng H, Touitou R et al. (2005). Mol Cell 20: 699–708.

  • Swift SE, Lorens JB, Achacoso P, Nolan GP . (1999) In Coligan RCJE, K. A. M. D. S. E. S. W. e. N. Y. W. (ed). Current Protocols in Immunology. Unit 10.28 Suppl 31.

  • Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z et al. (2004). Science 303: 844–848.

  • Vindelov LL, Christensen IJ, Jensen G, Nissen N . (1983). Cytometry 3: 332–339.

  • Zhang Z, Wang H, Li M, Agrawal S, Chen XB, Zhang RW . (2004). J Biol Chem 279: 16000–16006.

Download references

Acknowledgements

We thank Lut Janssen and Kristin Mertens for technical assistance and support. Special acknowledgements to Najoua Dendouga for helpful discussions about this manuscript and associated work.

Author information

Authors and Affiliations

  1. Oncology Discovery Research and Early Development, Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium

    A VanderBorght, A Valckx, J Van Dun, T Grand-Perret, S De Schepper, J Vialard, M Janicot & J Arts

Authors
  1. A VanderBorght
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Valckx
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Van Dun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T Grand-Perret
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S De Schepper
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Vialard
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Janicot
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J Arts
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Arts.

Rights and permissions

Reprints and permissions

About this article

Cite this article

VanderBorght, A., Valckx, A., Van Dun, J. et al. Effect of an hdm-2 antagonist peptide inhibitor on cell cycle progression in p53-deficient H1299 human lung carcinoma cells. Oncogene 25, 6672–6677 (2006). https://doi.org/10.1038/sj.onc.1209667

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209667

  • Springer Nature Limited

Keywords

This article is cited by

Search

Navigation