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

Masha V. Poyurovsky, Chen Katz, Oleg Laptenko, Rachel Beckerman, Maria Lokshin, Jinwoo Ahn, In Ja L. Byeon, Ronen Gabizon, Melissa Mattia, Andrew Zupnick, Lewis M. Brown, Assaf Friedler, Carol Prives*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

121 Scopus citations

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.

Original languageAmerican English
Pages (from-to)982-989
Number of pages8
JournalNature Structural and Molecular Biology
Volume17
Issue number8
DOIs
StatePublished - Aug 2010

Bibliographical note

Funding Information:
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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