Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis

Mol Cell. 2006 Dec 28;24(6):827-39. doi: 10.1016/j.molcel.2006.11.021.

Abstract

Upon DNA damage and other types of stress, p53 induces either cell-cycle arrest or apoptosis depending on the cellular context. However, the molecular mechanisms that govern the choice between cell-cycle arrest and apoptosis are not well understood. Here, we show that Tip60 is required for both cell growth arrest and apoptosis mediated by p53 and also induces its acetylation specifically at lysine 120 (K120) within the DNA-binding domain. Interestingly, this modification is crucial for p53-dependent apoptosis but is dispensable for its mediated growth arrest. K120 is a recurrent site for p53 mutation in human cancer, and the corresponding acetylation-defective tumor mutant (K120R) abrogates p53-mediated apoptosis, but not growth arrest. Thus, our study demonstrates that Tip60-dependent acetylation of p53 at K120 modulates the decision between cell-cycle arrest and apoptosis, and it reveals that the DNA-binding core domain is an important target for p53 regulation by posttranslational modifications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Amino Acid Sequence
  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Apoptosis*
  • Binding Sites
  • Catalysis
  • Cell Cycle Proteins / physiology
  • Cell Cycle*
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Histone Acetyltransferases / metabolism
  • Histone Acetyltransferases / physiology*
  • Humans
  • Lysine Acetyltransferase 5
  • Mice
  • Models, Biological
  • Molecular Sequence Data
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Sequence Homology, Amino Acid
  • Transcription Factors / physiology
  • Transcriptional Activation*
  • Transfection
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • p300-CBP Transcription Factors / physiology

Substances

  • Apoptosis Regulatory Proteins
  • BBC3 protein, human
  • CDKN1A protein, human
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Proto-Oncogene Proteins
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Histone Acetyltransferases
  • KAT5 protein, human
  • Lysine Acetyltransferase 5
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2