MOZ increases p53 acetylation and premature senescence through its complex formation with PML

Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):3895-900. doi: 10.1073/pnas.1300490110. Epub 2013 Feb 19.

Abstract

Monocytic leukemia zinc finger (MOZ)/KAT6A is a MOZ, Ybf2/Sas3, Sas2, Tip60 (MYST)-type histone acetyltransferase that functions as a coactivator for acute myeloid leukemia 1 protein (AML1)- and Ets family transcription factor PU.1-dependent transcription. We previously reported that MOZ directly interacts with p53 and is essential for p53-dependent selective regulation of p21 expression. We show here that MOZ is an acetyltransferase of p53 at K120 and K382 and colocalizes with p53 in promyelocytic leukemia (PML) nuclear bodies following cellular stress. The MOZ-PML-p53 interaction enhances MOZ-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression. Moreover, we identified an Akt/protein kinase B recognition sequence in the PML-binding domain of MOZ protein. Akt-mediated phosphorylation of MOZ at T369 has a negative effect on complex formation between PML and MOZ. As a result of PML-mediated suppression of Akt, the increased PML-MOZ interaction enhances p21 expression and induces p53-dependent premature senescence upon forced PML expression. Our research demonstrates that MOZ controls p53 acetylation and transcriptional activity via association with PML.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Base Sequence
  • Cells, Cultured
  • Cellular Senescence
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Gene Knockout Techniques
  • Histone Acetyltransferases / antagonists & inhibitors
  • Histone Acetyltransferases / chemistry
  • Histone Acetyltransferases / deficiency
  • Histone Acetyltransferases / genetics
  • Histone Acetyltransferases / metabolism*
  • Humans
  • Intranuclear Inclusion Bodies / metabolism
  • Leukemia, Promyelocytic, Acute / genetics
  • Leukemia, Promyelocytic, Acute / metabolism*
  • Mice
  • Models, Biological
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Small Interfering / genetics
  • Rats
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / metabolism*
  • p300-CBP Transcription Factors / metabolism

Substances

  • Cyclin-Dependent Kinase Inhibitor p21
  • Multiprotein Complexes
  • RNA, Small Interfering
  • Recombinant Proteins
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Histone Acetyltransferases
  • KAT6A protein, human
  • MOZ protein, mouse
  • p300-CBP Transcription Factors
  • Proto-Oncogene Proteins c-akt