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J. Biol. Chem., Vol. 279, Issue 36, 37640-37650, September 3, 2004

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FOG-2 Competes with GATA-4 for Transcriptional Coactivator p300 and Represses Hypertrophic Responses in Cardiac Myocytes^*

Maretoshi Hirai, Koh Ono, Tatsuya Morimoto, Teruhisa Kawamura, Hiromichi Wada, Toru Kita, and Koji Hasegawa¶

From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan and Division of Translational Research, Kyoto Medical Center, National Hospital Organization, Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555, Japan

A multizinc finger protein, FOG-2, associates with a cardiac transcription factor, GATA-4, and represses GATA-4-dependent transcription. GATA-4 is required not only for normal heart development but is also involved in hypertrophic responses in cardiac myocytes; however, the effects of FOG-2 on these responses are unknown. The interaction of GATA-4 with a transcriptional coactivator p300 is required for its full transcriptional activity and the activation of the embryonic program during myocardial cell hypertrophy. We show here that exogenous FOG-2 represses phenylephrine-induced hypertrophic responses such as myofibrillar organization, increases in cell size, and hypertrophy-associated gene transcription. Using immunoprecipitation Western blotting, we demonstrate that FOG-2 physically interacted with p300 and reduced the binding of GATA-4 to p300. In addition, in COS7 cells, in which the function of endogenous p300 is disrupted, FOG-2 is unable to repress the GATA-4-dependent transcriptional activities; however, FOG-2 markedly repressed the p300-mediated increase in the DNA-binding and transcriptional activities of GATA-4 in these cells. Similarly, FOG-2 inhibited a phenylephrine-induced increase in the p300/GATA-4 interaction, the GATA-4/DNA-binding, and transcriptional activities of GATA-4-dependent promoters in cardiac myocytes as well. These findings demonstrate that FOG-2 represses hypertrophic responses in cardiac myocytes and that p300 is involved in these repressive effects.

Received for publication, February 17, 2004 , and in revised form, June 3, 2004.

^* This work was supported in part by the Advanced and Innovational Research Program in Life Science and by grants from the Ministry of Education, Science, and Culture of Japan (to T. K. and K. H.). 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.

^¶ To whom correspondence should be addressed. Tel.: 81-75-641-9161; Fax: 81-75-641-9252. E-mail: koj{at}kuhp.kyoto-u.ac.jp.

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