Identification of p300-targeted acetylated residues in GATA-4 during myocardial cell hypertrophy
Tomohide Takaya1,2, Teruhisa Kawamura1, Tatsuya Morimoto1, Koh Ono2, Toru Kita2, Akira Shimatsu3, Koji Hasegawa1.
- Division of Translational Research, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan.
- Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
- Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan.
第30回心筋代謝研究会 (京都), 2007/07/14 (口演).
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 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, 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 mutant GATA-4 in cardiac myocytes specifically inhibited the phenylephrine-induced in cell size and myofibrillar organization. Thus, this mutant GATA-4 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.