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

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.
Mesh Terms:
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
Mol. Cell. Biol.
Date: Nov. 01, 2004
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