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Molecular and Cellular Biology, November 2004, p. 10083-10098, Vol. 24, No. 22
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.22.10083-10098.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Interferon Regulatory Factor 1 Binding to p300 Stimulates DNA-Dependent Acetylation of p53

David Dornan,^1, Mirjam Eckert,² Maura Wallace,² Harumi Shimizu,^1, Eleanor Ramsay,² Ted R. Hupp,¹ and Kathryn L. Ball^2*

CRUK p53 Signal Transduction Group,¹ CRUK Interferon and Cell Signalling Group, Cell Signalling Unit, Cancer Research Centre, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom²

Received 19 November 2003/ Returned for modification 2 March 2004/ Accepted 13 August 2004

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.

Present address: Genentech Inc., South San Francisco, CA 94080.

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