The C terminus of p53 binds the N-terminal domain of MDM2.
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.
Poyurovsky
Masha V
MV
Department of Biological Sciences, Columbia University, New York, New York, USA.
Katz
Chen
C
Laptenko
Oleg
O
Beckerman
Rachel
R
Lokshin
Maria
M
Ahn
Jinwoo
J
Byeon
In-Ja L
IJ
Gabizon
Ronen
R
Mattia
Melissa
M
Zupnick
Andrew
A
Brown
Lewis M
LM
Friedler
Assaf
A
Prives
Carol
C
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*
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