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.

  • Letter
  • Published:

iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human

Nature Genetics volume 33, pages 162–167 (2003)Cite this article

Abstract

We have previously shown that ASPP1 and ASPP2 are specific activators of p53; one mechanism by which wild-type p53 is tolerated in human breast carcinomas is through loss of ASPP activity. We have further shown that 53BP2, which corresponds to a C-terminal fragment of ASPP2, acts as a dominant negative inhibitor of p53 (ref. 1). Hence, an inhibitory form of ASPP resembling 53BP2 could allow cells to bypass the tumor-suppressor functions of p53 and the ASPP proteins. Here, we characterize such a protein, iASPP (inhibitory member of the ASPP family), encoded by PPP1R13L in humans and ape-1 in Caenorhabditis elegans. iASPP is an evolutionarily conserved inhibitor of p53; inhibition of iASPP by RNA-mediated interference or antisense RNA in C. elegans or human cells, respectively, induces p53-dependent apoptosis. Moreover, iASPP is an oncoprotein that cooperates with Ras, E1A and E7, but not mutant p53, to transform cells in vitro. Increased expression of iASPP also confers resistance to ultraviolet radiation and to cisplatin-induced apoptosis. iASPP expression is upregulated in human breast carcinomas expressing wild-type p53 and normal levels of ASPP. Inhibition of iASPP could provide an important new strategy for treating tumors expressing wild-type p53.

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: iASPP and Ce-iASPP specifically inhibited p53-mediated apoptosis in vivo and in vitro.
Figure 2: Regulation of p53 by the ASPP family members was conserved, and binding was required for iASPP to inhibit the apoptotic function of p53.
Figure 3: iASPP competes with ASPP to inhibit p53.
Figure 4: iASPP cooperated with Ras, E7 and E1A but not mutant p53 to transform REFs in vitro.
Figure 5: iASPP inhibits p53-induced apoptosis, confers drug resistance and is overexpressed in some tumors.

Similar content being viewed by others

References

  1. Samuels-Lev, Y. et al. ASPP proteins specifically stimulate the apoptotic function of p53. Mol. Cell 8, 781–794 (2001).

    Article  CAS  Google Scholar 

  2. Metzstein, M.M., Stanfield, G.M. & Horvitz, H.R. Genetics of programmed cell death in C. elegans: past, present and future. Trends Genet. 14, 410–416 (1998).

    Article  CAS  Google Scholar 

  3. Derry, W.B., Putzke, A.P. & Rothman, J.H. Caenorhabditis elegans p53: role in apoptosis, meiosis and stress resistance. Science 294, 591–595 (2001).

    Article  CAS  Google Scholar 

  4. Schumacher, B., Hofmann, K., Boulton, S. & Gartner, A. The C. elegans homolog of the p53 tumor suppressor is required for DNA damage–induced apoptosis. Curr. Biol. 11, 1722–1727 (2001).

    Article  CAS  Google Scholar 

  5. Yang, J.-P., Hori, M., Sanda, T. & Okamoto, T. Identification of a novel inhibitor of nuclear factor-kB, RelA-associated inhibitor. J. Biol. Chem. 274, 15662–15670 (1999).

    Article  CAS  Google Scholar 

  6. Gorina, S. & Pavletich, N.P. Structure of the p53 tumor suppressor bound to the ankyrin and SH3 domains of 53BP2. Science 274, 1001–1005 (1996).

    Article  CAS  Google Scholar 

  7. Brodsky, M.H. et al. Drosophila p53 binds a damage-response element at the reaper locus. Cell 101, 103–113 (2000).

    Article  CAS  Google Scholar 

  8. Ollmann, M. et al. Drosophila p53 is a structural and functional homolog of the tumor suppressor p53. Cell 101, 91–101 (2000).

    Article  CAS  Google Scholar 

  9. Harlow, E.E. & Lane, D.P. Antibodies: A Laboratory Manual (Cold Spring Harbor Laboratory Press, New York, 1988).

    Google Scholar 

  10. Crook, T., Marston, N.J., Sara, E.A. & Vousden, K.H. Transcription activation by p53 correlates with suppression of growth but not transformation. Cell 79, 817–827 (1994).

    Article  CAS  Google Scholar 

  11. Hsieh, J.-K., Fredersdorf, S., Kouzarides, T., Martin, K. & Lu, X. E2F1-induced apoptosis requires DNA binding but not transcriptional activity and is inhibited by the retinoblastoma protein through direct interaction. Genes Dev. 11, 1840–1852 (1997).

    Article  CAS  Google Scholar 

  12. Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank E. Slee and C. Stephens for reading the manuscript, S. Ali for technical help, the Human Genome Mapping Project Resource Centre for providing the EST clone of iASPP and The Caenorhabditis Genetics Center and the international C. elegans gene knockout consortium for providing the ced-3 and cep-1 mutants. This work was primarily funded by the Ludwig Institute for Cancer Research. D.B. is funded by Association of International Cancer Research, and P.E.K. is supported by a Medical Research Council Senior Fellowship and grants from the Biotechnology and Biological Science Research Council and Janssen Pharmaceutica N.V.

Author information

Author notes

  1. Daniele Bergamaschi, Yardena Samuels and Nigel J. O'Neil: These authors contributed equally to this work.

Authors and Affiliations

  1. Ludwig Institute for Cancer Research, Imperial College School of Medicine, St. Mary's Campus, Norfolk Place, London, W2 1PG, UK

    Daniele Bergamaschi, Yardena Samuels, Giuseppe Trigiante, Tim Crook, Jung-Kuang Hsieh, Daniel J. O'Connor, Shan Zhong, Isabelle Campargue & Xin Lu

  2. The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK

    Nigel J. O'Neil, Matthew L. Tomlinson & Patricia E. Kuwabara

Authors
  1. Daniele Bergamaschi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yardena Samuels
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nigel J. O'Neil
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Giuseppe Trigiante
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tim Crook
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jung-Kuang Hsieh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Daniel J. O'Connor
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shan Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Isabelle Campargue
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Matthew L. Tomlinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Patricia E. Kuwabara
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Xin Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xin Lu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bergamaschi, D., Samuels, Y., O'Neil, N. et al. iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human. Nat Genet 33, 162–167 (2003). https://doi.org/10.1038/ng1070

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1070

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing