Identification of p300-targeted acetylated residues in GATA-4 during hypertrophic responses in cardiac myocytes

Identification of p300-targeted acetylated residues in GATA-4 during hypertrophic responses in cardiac myocytes

Tomohide Takaya, Teruhisa Kawamura, Tatsuya Morimoto, Koh Ono, Akira Shimatsu, Koji Hasegawa.

Division of Translational Research, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.

The 18th Great Wall International Congress of Cardiology (Beijing, China), 2007/10/11 (Poster).

Abstract

A zinc finger protein, GATA-4, is one of the hypertrophy-responsive transcription factors, and increases its DNA-binding and transcriptional activities in response to hypertrophic stimuli in cardiac myocytes. Activation of GATA-4 during this process is mediated, in part, through acetylation by an intrinsic histone acetyltransferase p300. Here, we have identified the most critical lysine residues acting as p300-mediated acetylation targets in GATA-4. By mutational analysis, we found that four lysine residues located at the C-terminal of the first zinc finger domain are required for p300-induced transcriptional activity of GATA-4. A tetra-mutant GATA-4, in which these four lysine residues were simultaneously substituted by alanines, not only showed lack of p300-induced acetylation, DNA-binding and transcriptional activities, but also inhibited transcriptional activation by wild-type GATA-4. Expression of this tetra-mutant GATA-4 in cardiac myocytes specifically inhibited the phenylephrine-induced increase in cell size and myofibrillar organization. Thus, GATA-4 with simultaneous mutation of p300-targeted lysine residues suppresses hypertrophic responses as a dominant-negative form, providing further evidence for the role of the p300/GATA-4 transcriptional pathway in myocardial cell hypertrophy.