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J. Biol. Chem., Vol. 283, Issue 29, 20077-20086, July 18, 2008

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TIP60 Represses Transcriptional Activity of p73β via an MDM2-bridged Ternary Complex^*

Jung-Woong Kim¹, Peter I. Song¹, Mi-Hee Jeong, Joo-Hee An, So-Youn Lee, Sang-Min Jang, Ki-Hyun Song, Cheryl A. Armstrong, and Kyung-Hee Choi²

From the Department of Life Science, Chung-Ang University, 221 Heuksuk-Dong, Dongjak-Ku, Seoul 156-756, South Korea and Department of Dermatology, University Colorado Health Sciences Center, Denver, Colorado 80045

TIP60, a histone acetyl transferase, acts as a p53 coactivator by interfering with MDM2-mediated degradation of p53. However, little is known about its functional regulation of p73, which has structural features similar to p53. In this study we found that TIP60 represses apoptosis, which is induced by exogenous and endogenous p73β. TIP60 also negatively regulated the expression of p73β downstream target genes such as p21 and Bax. Moreover, the specific repression of p73β-mediated transactivation by TIP60 was independent of p53 expression and not due to histone deacetylase recruiting transcriptional machinery. Transcriptional activities of both p73 splicing variants, p73 and p73β, were also repressed by TIP60. Furthermore, TIP60 markedly enhanced p73β binding affinity to MDM2 and physically associated with MDM2 through its zinc finger domain, which is specifically localized in the nucleus. Therefore, we demonstrate that TIP60 forms a ternary complex with p73β, which is directly bridged by MDM2. It is important to note that our findings contribute to a functional linkage between TIP60 and p73β through MDM2 in the transcriptional regulation of cellular apoptosis.

Received for publication, January 8, 2008 , and in revised form, May 2, 2008.

^* This work was supported by Korea Research Foundation Grant KRF-2006-531-C00041 funded by the Korean Government (MOEHRD), and this research was partially supported by the Chung-Ang University Excellent Researcher grant in 2007. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 82-2-820-5209; Fax: 82-2-824-7302; E-mail: khchoi{at}cau.ac.kr.

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