Interferon regulatory factor 1 binding to p300 stimulates DNA-dependent acetylation of p53

David Dornan, Mirjam Eckert, Maura Wallace, Harumi Shimizu, Eleanor Ramsay, Ted R Hupp, Kathryn L Ball

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Interferon regulatory factor 1 (IRF-1) and p53 control distinct sets of downstream genes; however, these two antioncogenic transcription factors converge to regulate p21 gene expression and to inhibit tumor formation. Here we investigate the mechanism by which IRF-1 and p53 synergize at the p21 promoter and show that stimulation of p21 transcription by IRF-1 does not require its DNA-binding activity but relies on the ability of IRF-1 to bind the coactivator p300 and to stimulate p53-dependent transcription by an allosteric mechanism. Deletion of the p300-binding sites in IRF-1 eliminates the ability of IRF-1 to stimulate p53 acetylation and associated p53 activity. Complementing this, small peptides derived from the IRF-1-p300 interface can bind to p300, stabilize the binding of p300 to DNA-bound p53, stimulate p53 acetylation in trans, and up-regulate p53-dependent activity from the p21 promoter. The nonacetylatable p53 mutant (p53-6KR) cannot be stimulated by IRF-1, further suggesting that p53 acetylation is the mechanism whereby IRF-1 modifies p53 activity. These data expand the core p300-p53 protein LXXLL and PXXP interface by including an IRF-1-p300 interface as an allosteric modifier of DNA-dependent acetylation of p53 at the p21 promoter.
Original languageEnglish
Pages (from-to)10083-98
Number of pages16
JournalMolecular and Cellular Biology
Issue number22
Publication statusPublished - Nov 2004

Keywords / Materials (for Non-textual outputs)

  • Acetylation
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cell Line
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • DNA
  • DNA-Binding Proteins
  • E1A-Associated p300 Protein
  • Humans
  • Interferon Regulatory Factor-1
  • Mice
  • Models, Biological
  • Molecular Sequence Data
  • Nuclear Proteins
  • Phosphoproteins
  • Promoter Regions, Genetic
  • Protein Binding
  • Recombinant Proteins
  • Trans-Activators
  • Tumor Suppressor Protein p53


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