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

doi:10.1038/nsmb.1872

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

Institute of Chemistry

Research output: Contribution to journal › Article › peer-review

123 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 language	English
Pages (from-to)	982-989
Number of pages	8
Journal	Nature Structural and Molecular Biology
Volume	17
Issue number	8
DOIs	https://doi.org/10.1038/nsmb.1872
State	Published - 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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title = "The C terminus of p53 binds the N-terminal domain of MDM2",

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.",

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

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{\textquoteright}s Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement n°203413.",

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AU - Lokshin, Maria

AU - Ahn, Jinwoo

AU - Byeon, In Ja L.

AU - Gabizon, Ronen

AU - Mattia, Melissa

AU - Zupnick, Andrew

AU - Brown, Lewis M.

AU - Friedler, Assaf

AU - Prives, Carol

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

Abstract

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