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The C terminus of p53 binds the N-terminal domain of MDM2

Nature Structural & Molecular Biology volume 17, pages 982989 (2010) | Download Citation

  • A Corrigendum to this article was published on 06 April 2011

This article has been updated

Abstract

The p53 tumor suppressor interacts with its negative regulator Mdm2 via the former's N-terminal region and core domain, yet the extreme p53 C-terminal region contains lysine residues ubiquitinated by Mdm2 and can bear post-translational modifications that inhibit Mdm2-p53 association. We show that the Mdm2-p53 interaction is decreased upon deletion, mutation or acetylation of the p53 C terminus. Mdm2 decreases the association of full-length but not C-terminally deleted p53 with a DNA target sequence in vitro and in cells. Further, using multiple approaches, we show that a peptide from the p53 C terminus directly binds the Mdm2 N terminus in vitro. We also show that p300-acetylated p53 inefficiently binds Mdm2 in vitro, and Nutlin-3 treatment induces C-terminal modification(s) of p53 in cells, explaining the low efficiency of Nutlin-3 in dissociating p53-MDM2 in vitro.

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Change history

  • 25 July 2010

    In the version of this article initially published online, the Acknowledgments section was incomplete. The error has been corrected for the print, PDF and HTML versions of this article.

  • 21 September 2010

    In the version of this article initially published, the error bars in figures 1, 2, 4 and 5 were not defined, and a formatting mistake occurred in Supplementary Figure 1a. The errors have been corrected in the PDF and HTML versions of this article.

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Acknowledgements

We are exceedingly grateful to E. Freulich for her expert technical assistance and members of the Prives laboratory for their helpful suggestions. This work was supported by grant CA58316 from the US National Institutes of Health to C.P. A.F. is supported by a starting grant from the European Research Council under the European Community's Seventh Framework Programme (FP7/2007-2013) / ERC Grant agreement n° 203413.

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Affiliations

  1. Department of Biological Sciences, Columbia University, New York, New York, USA.

    • Masha V Poyurovsky
    • , Oleg Laptenko
    • , Rachel Beckerman
    • , Maria Lokshin
    • , Andrew Zupnick
    • , Lewis M Brown
    •  & Carol Prives
  2. Department of Structural Biology, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania, USA.

    • Jinwoo Ahn
    •  & In-Ja L Byeon
  3. Institute of Chemistry, Hebrew University of Jerusalem, Safra Campus, Givat Ram, Jerusalem, Israel.

    • Chen Katz
    • , Ronen Gabizon
    •  & Assaf Friedler
  4. Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York, USA.

    • Melissa Mattia

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Contributions

M.V.P., A.F. and C.P. designed research; M.V.P., C.K., O.L., M.L., J.A., I.-J.L.B., R.G., M.M., A.Z. and L.M.B. performed research and analyzed data; M.V.P. and C.P. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Carol Prives.

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DOI

https://doi.org/10.1038/nsmb.1872

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