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.
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York, USA.
authors.forename: Masha V
authors.initials: MV
authors.lastname: Poyurovsky
authors.forename: Chen
authors.initials: C
authors.lastname: Katz
authors.forename: Oleg
authors.initials: O
authors.lastname: Laptenko
authors.forename: Rachel
authors.initials: R
authors.lastname: Beckerman
authors.forename: Maria
authors.initials: M
authors.lastname: Lokshin
authors.forename: Jinwoo
authors.initials: J
authors.lastname: Ahn
authors.forename: In-Ja L
authors.initials: IJ
authors.lastname: Byeon
authors.forename: Ronen
authors.initials: R
authors.lastname: Gabizon
authors.forename: Melissa
authors.initials: M
authors.lastname: Mattia
authors.forename: Andrew
authors.initials: A
authors.lastname: Zupnick
authors.forename: Lewis M
authors.initials: LM
authors.lastname: Brown
authors.forename: Assaf
authors.initials: A
authors.lastname: Friedler
authors.forename: Carol
authors.initials: C
authors.lastname: Prives
mesh_terms: D000818:Animals; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D008954:Models, Biological; D010879:Piperazines / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics; D013329:Structure-Activity Relationship; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D003432:Cross-Linking Reagents; D007093:Imidazoles; D010879:Piperazines; D034741:RNA, Small Interfering; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D004247:DNA; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2