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
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Polyak, K., Xia, Y., Zweier, J.L., Kinzler, K.W. & Vogelstein, B. A model for p53-induced apoptosis. Nature 389, 300–305 (1997).
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).
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).
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).
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).
Levine, A.J. p53, the cellular gatekeeper for growth and division. Cell 88, 323–331 (1997).
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).
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).
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).
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).
Zhu, K. et al. p53 induces TAP1 and enhances the transport of MHC class I peptides. Oncogene 18, 7740–7747 (1999).
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).
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).
Szak, S.T., Mays, D. & Pietenpol, J.A. Kinetics of p53 binding to promoter sites in vivo. Mol. Cell. Biol. 21, 3375–338 (2001).
Djian, P. Evolution of simple repeats in DNA and their relation to human disease. Cell 94, 155–160 (1998).
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).
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).
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).
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).
He, T.C. et al. A simplified system for generating recombinant adenoviruses. Proc. Natl Acad. Sci. USA 95, 2509–2514 (1998).
Koch, P. et al. Efficient replication of adenovirus despite the overexpression of active and non-degradable p53. Cancer Res. 61, 5941–5947 (2001).
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).
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
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights 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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng836
This article is cited by
-
HMOX1 STR polymorphism and malaria: an analysis of a large clinical dataset
Malaria Journal (2022)
-
Mapping short tandem repeats for liver gene expression traits helps prioritize potential causal variants for complex traits in pigs
Journal of Animal Science and Biotechnology (2022)
-
Characterization of microsatellites in the endangered snow leopard based on the chromosome-level genome
Mammal Research (2021)
-
STRs: Ancient Architectures of the Genome beyond the Sequence
Journal of Molecular Neuroscience (2021)
-
The impact of short tandem repeat variation on gene expression
Nature Genetics (2019)