Cyclin-dependent kinase-9 is recruited on cardiac hypertrophic response gene promoters through GATA4 in cardiomyocytes

Cyclin-dependent kinase-9 is recruited on cardiac hypertrophic response gene promoters through GATA4 in cardiomyocytes

Yoichi Sunagawa1, Tatsuya Morimoto1, Tomohide Takaya1, Hiromichi Wada1, Akira Shimatsu1, Masatoshi Fujita3, Toru Kita2, 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. Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

第73回日本循環器学会学術集会 (大阪), 2009/03/22 (ポスター).

Abstract

Introduction: A zinc finger protein GATA4 is one of the factors involved in transcriptional regulation during myocardial cell hypertrophy. In response to hypertrophic stimuli, GATA4 forms a complex with an intrinsic histone acetyltransferase (HAT), p300, and increases its transcriptional activity by acetylation. We have shown that cyclin-dependent kinase (Cdk9), a component of positive transcription elongation factor b, is a novel GATA4-binding partner. Cdk9 forms a complex with p300 as well as GATA4. However, precise functional relationships among p300/GATA4 and Cdk9 are unknown.

Methods and Results: By chromatin immunoprecipitation (ChIP) and re-ChIP, we showed that GATA4 recruited Cdk9 and p300 onto GATA elements within the endothelin-1 and ANF promoters in cardiomyocytes. Phenylephrine (PE) enhanced these recruitments. PE induced not only the acetylation of GATA4, but also the interaction of GATA4 with Cdk9 and the phosphorylation of p300. A Cdk9 inhibitor, DRB inhibited all of these effects by PE, suggesting that the kinase activity of Cdk9 is required for the HAT activity of p300. Furthermore, a dominant-negative form of Cdk9 as well as DRB inhibited PE-induced hypertrophic responses in cardiomyocytes.

Conclusion: These findings demonstrate that the kinase activity of Cdk9 is required for the phosphorylation of p300 and its HAT activity, and that Cdk9 forms a functional complex with p300/GATA4 on hypertrophic response gene promoters in cardiomyocytes.