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Molecular and Cellular Biology, August 2002, p. 5650-5661, Vol. 22, No. 16
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.16.5650-5661.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Transcriptional Regulation of the mdm2 Oncogene by p53 Requires TRRAP Acetyltransferase Complexes

Penny G. Ard, Chandrima Chatterjee, Sudeesha Kunjibettu, Leon R. Adside, Lisa E. Gralinski, and Steven B. McMahon*

The Wistar Institute, Philadelphia, Pennsylvania 19104

Received 26 November 2001/ Returned for modification 23 January 2002/ Accepted 9 May 2002

The p53 tumor suppressor regulates the cellular response to genetic damage through its function as a sequence-specific transcription factor. Among the most well-characterized transcriptional targets of p53 is the mdm2 oncogene. Activation of mdm2 is critical in the p53 pathway because the mdm2 protein marks p53 for proteosome-mediated degradation, thereby providing a negative-feedback loop. Here we show that the ATM-related TRRAP protein functionally cooperates with p53 to activate mdm2 transcription. TRRAP is a component of several multiprotein acetyltransferase complexes implicated in both transcriptional regulation and DNA repair. In support of a role for these complexes in mdm2 expression, we show that transactivation of the mdm2 gene is augmented by pharmacological inhibition of cellular deacetylases. In vitro analysis demonstrates that p53 directly binds to a TRRAP domain previously shown to be an activator docking site. Furthermore, transfection of cells with antisense TRRAP blocks p53-dependent transcription of mdm2. Finally, using chromatin immunoprecipitation, we demonstrate direct p53-dependent recruitment of TRRAP to the mdm2 promoter, followed by increased histone acetylation. These findings suggest a model in which p53 directly recruits a TRRAP/acetyltransferase complex to the mdm2 gene to activate transcription. In addition, this study defines a novel biochemical mechanism utilized by the p53 tumor suppressor to regulate gene expression.

* Corresponding author. Mailing address: Molecular Genetics Program, The Wistar Institute, 3601 Spruce St., Philadelphia, PA 19104. Phone: (215) 898-3736. Fax: (215) 898-3933. E-mail: smcmahon{at}wistar.upenn.edu.

Molecular and Cellular Biology, August 2002, p. 5650-5661, Vol. 22, No. 16
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.16.5650-5661.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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