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Dual Regulation of c-Myc by p300 via Acetylation-Dependent Control of Myc Protein Turnover and Coactivation of Myc-Induced Transcription

Francesco Faiola,^1, Xiaohui Liu,^1, Szuying Lo,¹ Songqin Pan,² Kangling Zhang,³ Elena Lymar,⁴ Anthony Farina,¹ and Ernest Martinez^1*

Department of Biochemistry,¹ Department of Chemistry,³ W. M. Keck Proteomics Laboratory, Department of Botany and Plant Science, University of California, Riverside, California,² Biology Department, Brookhaven National Laboratory, Upton, New York⁴

Received 22 August 2005/ Accepted 24 August 2005

The c-Myc oncoprotein (Myc) controls cell fate by regulating gene transcription in association with a DNA-binding partner, Max. While Max lacks a transcription regulatory domain, the N terminus of Myc contains a transcription activation domain (TAD) that recruits cofactor complexes containing the histone acetyltransferases (HATs) GCN5 and Tip60. Here, we report a novel functional interaction between Myc TAD and the p300 coactivator-acetyltransferase. We show that p300 associates with Myc in mammalian cells and in vitro through direct interactions with Myc TAD residues 1 to 110 and acetylates Myc in a TAD-dependent manner in vivo at several lysine residues located between the TAD and DNA-binding domain. Moreover, the Myc:Max complex is differentially acetylated by p300 and GCN5 and is not acetylated by Tip60 in vitro, suggesting distinct functions for these acetyltransferases. Whereas p300 and CBP can stabilize Myc independently of acetylation, p300-mediated acetylation results in increased Myc turnover. In addition, p300 functions as a coactivator that is recruited by Myc to the promoter of the human telomerase reverse transcriptase gene, and p300/CBP stimulates Myc TAD-dependent transcription in a HAT domain-dependent manner. Our results suggest dual roles for p300/CBP in Myc regulation: as a Myc coactivator that stabilizes Myc and as an inducer of Myc instability via direct Myc acetylation.

Supplemental material for this article may be found at http://mcb.asm.org/.

F.F. and X.L. contributed equally to this study.

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