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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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.
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Poyurovsky, M., Katz, C., Laptenko, O. et al. The C terminus of p53 binds the N-terminal domain of MDM2. Nat Struct Mol Biol 17, 982–989 (2010). https://doi.org/10.1038/nsmb.1872
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DOI: https://doi.org/10.1038/nsmb.1872
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