Scripps VIVO scripps research logo

  • Index
  • Log in
  • Home
  • People
  • Organizations
  • Research
  • Events
Search form

Cooperative regulation of p53 by modulation of ternary complex formation with cbp/p300 and hdm2

Academic Article
uri icon
  • Overview
  • Research
  • Identity
  • Additional Document Info
  • View All
scroll to property group menus

Overview

authors

  • Ferreon, J. C.
  • Lee, C. W.
  • Arai, M.
  • Martinez-Yamout, M. A.
  • Dyson, Jane
  • Wright, Peter

publication date

  • April 2009

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • The tumor suppressor activity of p53 is regulated by interactions with the ubiquitin ligase HDM2 and the general transcriptional coactivators CBP and p300. Using NMR spectroscopy and isothermal titration calorimetry, we have dissected the binding interactions between the N-terminal transactivation domain (TAD) of p53, the TAZ1, TAZ2, KIX, and nuclear receptor coactivator binding domains of CBP, and the p53-binding domain of HDM2. The p53 TAD contains amphipathic binding motifs within the AD1 and AD2 regions that mediate interactions with CBP and HDM2. Binding of the p53 TAD to CBP domains is dominated by interactions with AD2, although the affinity is enhanced by additional interactions with AD1. In contrast, binding of p53 TAD to HDM2 is mediated primarily by AD1. The p53 TAD can bind simultaneously to HDM2 (through AD1) and to any one of the CBP domains (through AD2) to form a ternary complex. Phosphorylation of p53 at T18 impairs binding to HDM2 and enhances affinity for the CBP KIX domain. Multisite phosphorylation of the p53 TAD at S15, T18, and S20 leads to increased affinity for the TAZ1 and KIX domains of CBP. These observations suggest a mechanism whereby HDM2 and CBP/p300 function synergistically to regulate the p53 response. In unstressed cells, CBP/p300, HDM2 and p53 form a ternary complex that promotes polyubiquitination and degradation of p53. After cellular stress and DNA damage, p53 becomes phosphorylated at T18 and other residues in the AD1 region, releases HDM2 and binds preferentially to CBP/p300, leading to stabilization and activation of p53.

subject areas

  • Amino Acid Sequence
  • Animals
  • CREB-Binding Protein
  • Kinetics
  • Magnetic Resonance Spectroscopy
  • Mice
  • Models, Biological
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Binding
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-mdm2
  • Tumor Suppressor Protein p53
scroll to property group menus

Research

keywords

  • p53 transactivation domain
  • phosphorylation
  • protein-protein interaction
  • transcriptional coactivator
  • tumor suppressor
scroll to property group menus

Identity

PubMed Central ID

  • PMC2672497

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0811023106

PubMed ID

  • 19357310
scroll to property group menus

Additional Document Info

start page

  • 6591

end page

  • 6596

volume

  • 106

issue

  • 16

©2021 The Scripps Research Institute | Terms of Use | Powered by VIVO

  • About
  • Contact Us
  • Support