Identification of p300-targeted acetylated residues in GATA-4 during myocardial cell hypertrophy

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.

  1. Division of Translational Research, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan.
  2. Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  3. 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.