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:

A polymorphic microsatellite that mediates induction of PIG3 by p53

Nature Genetics volume 30, pages 315–320 (2002)Cite this article

Abstract

The gene PIG3 is induced by the tumor suppressor p53 but not by p53 mutants unable to induce apoptosis, suggesting its involvement in p53-mediated cell death1,2,3. Here we show that p53 directly binds and activates the PIG3 promoter, but not through the previously described DNA element1. Instead, p53 interacts with a pentanucleotide microsatellite sequence within the PIG3 promoter (TGYCC)n where Y=C or T. Despite its limited similarity to the p53-binding consensus4,5, this sequence is necessary and sufficient for transcriptional activation of the PIG3 promoter by p53 and binds specifically to p53 in vitro and in vivo. In a population of 117 healthy donors from Germany, the microsatellite was found to be polymorphic, the number of pentanucleotide repeats being 10, 15, 16 or 17, and the frequency of alleles 5.1%, 62.0%, 21.4% and 11.5%, respectively. The number of repeats directly correlated with the extent of transcriptional activation by p53. This is the first time that a microsatellite has been shown to mediate the induction of a promoter through direct interaction with a transcription factor. Moreover, this sequence of PIG3 is the first p53-responsive element found to be polymorphic. Inheritance of this microsatellite may affect an individual's susceptibility to cancer.

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: Mapping of the PIG3 promoter.
Figure 2: A microsatellite DNA that functions as a p53-responsive element.
Figure 3: A microsatellite DNA binds p53 in vitro and in vivo.
Figure 4: Mutational analysis of the (TGYCC)15 motif as a p53-responsive element.
Figure 5: A polymorphism associated with the (TGYCC)n motif.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Polyak, K., Xia, Y., Zweier, J.L., Kinzler, K.W. & Vogelstein, B. A model for p53-induced apoptosis. Nature 389, 300–305 (1997).

    Article  CAS  Google Scholar 

  2. Roth, J., Koch, P., Contente, A. & Dobbelstein, M. Tumor-derived mutations within the DNA-binding domain of p53 that phenotypically resemble the deletion of the proline-rich domain. Oncogene 19, 1834–1842 (2000).

    Article  CAS  Google Scholar 

  3. Venot, C. et al. The requirement for the p53 proline-rich functional domain for mediation of apoptosis is correlated with specific PIG3 gene transactivation and with transcriptional repression. EMBO J. 17, 4668–4679 (1998).

    Article  CAS  Google Scholar 

  4. Zauberman, A., Barak, Y., Ragimov, N., Levy, N. & Oren, M. Sequence-specific DNA binding by p53: identification of target sites and lack of binding to p53 - MDM2 complexes. EMBO J. 12, 2799–2808 (1993).

    Article  CAS  Google Scholar 

  5. Funk, W.D., Pak, D.T., Karas, R.H., Wright, W.E. & Shay, J.W. A transcriptionally active DNA-binding site for human p53 protein complexes. Mol. Cell. Biol. 12, 2866–2871 (1992).

    Article  CAS  Google Scholar 

  6. Levine, A.J. p53, the cellular gatekeeper for growth and division. Cell 88, 323–331 (1997).

    Article  CAS  Google Scholar 

  7. Zhu, J., Jiang, J., Zhou, W., Zhu, K. & Chen, X. Differential regulation of cellular target genes by p53 devoid of the PXXP motifs with impaired apoptotic activity. Oncogene 18, 2149–2155 (1999).

    Article  CAS  Google Scholar 

  8. Brachmann, R.K., Yu, K., Eby, Y., Pavletich, N.P. & Boeke, J.D. Genetic selection of intragenic suppressor mutations that reverse the effect of common p53 cancer mutations. EMBO J. 17, 1847–1859 (1998).

    Article  CAS  Google Scholar 

  9. Sakamuro, D., Sabbatini, P., White, E. & Prendergast, G.C. The polyproline region of p53 is required to activate apoptosis but not growth arrest. Oncogene 15, 887–898 (1997).

    Article  CAS  Google Scholar 

  10. Ryan, K.M. & Vousden, K.H. Characterization of structural p53 mutants which show selective defects in apoptosis but not cell cycle arrest. Mol. Cell. Biol. 18, 3692–3698 (1998).

    Article  CAS  Google Scholar 

  11. Zhu, K. et al. p53 induces TAP1 and enhances the transport of MHC class I peptides. Oncogene 18, 7740–7747 (1999).

    Article  CAS  Google Scholar 

  12. Muller, M. et al. p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. J. Exp. Med. 188, 2033–2045 (1998).

    Article  CAS  Google Scholar 

  13. Shi, Y., Seto, E., Chang, L.S. & Shenk, T. Transcriptional repression by YY1, a human GLI-Kruppel-related protein, and relief of repression by adenovirus E1A protein. Cell 67, 377–388 (1991).

    Article  CAS  Google Scholar 

  14. Szak, S.T., Mays, D. & Pietenpol, J.A. Kinetics of p53 binding to promoter sites in vivo. Mol. Cell. Biol. 21, 3375–338 (2001).

    Article  CAS  Google Scholar 

  15. Djian, P. Evolution of simple repeats in DNA and their relation to human disease. Cell 94, 155–160 (1998).

    Article  CAS  Google Scholar 

  16. Lin, J., Chen, J., Elenbaas, B. & Levine, A.J. Several hydrophobic amino acids in the p53 amino-terminal domain are required for transcriptional activation, binding to mdm-2 and the adenovirus 5 E1B 55-kD protein. Genes Dev. 8, 1235–1246 (1994).

    Article  CAS  Google Scholar 

  17. Roth, J. et al. Inactivation of p53 but not p73 by adenovirus type 5 E1B 55-kilodalton and E4 34-kilodalton oncoproteins. J. Virol. 72, 8510–8516 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Wienzek, S., Roth, J. & Dobbelstein, M. E1B 55-kilodalton oncoproteins of adenovirus types 5 and 12 inactivate and relocalize p53, but not p51 or p73, and cooperate with E4orf6 proteins to destabilize p53. J. Virol. 74, 193–202 (2000).

    Article  CAS  Google Scholar 

  19. Roth, J., Dobbelstein, M., Freedman, D.A., Shenk, T. & Levine, A.J. Nucleo-cytoplasmic shuttling of the hdm2 oncoprotein regulates the levels of the p53 protein via a pathway used by the human immunodeficiency virus rev protein. EMBO J. 17, 554–564 (1998).

    Article  CAS  Google Scholar 

  20. He, T.C. et al. A simplified system for generating recombinant adenoviruses. Proc. Natl Acad. Sci. USA 95, 2509–2514 (1998).

    Article  CAS  Google Scholar 

  21. Koch, P. et al. Efficient replication of adenovirus despite the overexpression of active and non-degradable p53. Cancer Res. 61, 5941–5947 (2001).

    CAS  PubMed  Google Scholar 

  22. Hupp, T.R., Meek, D.W., Midgley, C.A. & Lane, D.P. Regulation of the specific DNA binding function of p53. Cell 71, 875–886 (1992).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank H.-D. Klenk and R. Arnold for their continuous support and C. Lenz-Stöppler for excellent technical assistance. We are indebted to B. Vogelstein for helpful suggestions. We thank A. Levine, N. Horikoshi and T. Shenk for plasmids; P. Koch for recombinant adenoviruses; W. Deppert and S. Dehde for early passage H1299 cells; and A. Baniahmad, M. Beato, C. Bouchard, H. Christiansen, M. Eilers, W. Lutz, A. Neubauer, M. Ritter, C. Polyak, K.-H. Seifart and G. Suske for helpful discussions. This work was supported by the W. Sander foundation and the P.E. Kempkes foundation. A.C. received a fellowship from PRAXIS XXI, FCT, Portugal, and M.D. was a recipient of the Stipendium für Infektionsbiologie of the German Cancer Research Center during this work.

Author information

Authors and Affiliations

  1. Abteilung Gastroenterologie und Stoffwechsel, Institut für Virologie, Klinikum der Philipps-Universität Marburg, Germany

    Ana Contente, Alexandra Dittmer & Matthias Dobbelstein

  2. Abteilung Gastroenterologie und Stoffwechsel, Institut für Humangenetik, Klinikum der Philipps-Universität Marburg, Germany

    Manuela C. Koch

  3. Abteilung Gastroenterologie und Stoffwechsel, Innere Medizin, Klinikum der Philipps-Universität Marburg, Germany

    Judith Roth

Authors
  1. Ana Contente
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexandra Dittmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Manuela C. Koch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Judith Roth
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Matthias Dobbelstein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Matthias Dobbelstein.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Contente, A., Dittmer, A., Koch, M. et al. A polymorphic microsatellite that mediates induction of PIG3 by p53. Nat Genet 30, 315–320 (2002). https://doi.org/10.1038/ng836

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng836

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