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A polymorphic microsatellite that mediates induction of PIG3 by p53

Nature Genetics volume 30, pages 315320 (2002) | Download Citation

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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.

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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.

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Affiliations

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

    • Ana Contente
    • , Alexandra Dittmer
    •  & Matthias Dobbelstein
  2. Institut für Humangenetik, Abteilung Gastroenterologie und Stoffwechsel, Klinikum der Philipps-Universität Marburg, Germany.

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

    • Judith Roth

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The authors declare no competing financial interests.

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Correspondence to Matthias Dobbelstein.

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DOI

https://doi.org/10.1038/ng836

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