CDK9 is a novel component of p300/GATA-4 complex required for hypertrophic responses in cardiac myocytes

CDK9 is a novel component of p300/GATA-4 complex required for hypertrophic responses in cardiac myocytes

Tatsuya Morimoto1, Yoichi Sunagawa1, Teruhisa Kawamura1, Tomohide Takaya1, Hiromichi Wada1, Akira Shimatsu1, Masatoshi Fujita2, Toru Kita3, Koji Hasegawa1.

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

第11回日本心不全学会学術集会 (千葉), 2007/09/10 (ポスター).

Abstract

A zinc finger protein GATA-4 is one of hypertrophy-responsive transcription factors, and increases its DNA-binding and transcriptional activities in response to hypertrophic stimuli in cardiac myocytes. Here, we show that cyclin-dependent kinase-9 (Cdk9), a component of positive transcription elongation factor b (P-TEFb) which increases activitiy of RNA Pol II by hyperphosphorylation, is a novel component of p300/GATA-4 complex. Immunoblotting analyses demonstrated that GATA-4 formed a complex with p300, Cdk9 and cyclin T1, another component of P-TEFb. A dominant-negative form of p300 disrupted the interaction of GATA-4 with Cdk9 or cyclin T1. Conversely, a dominant-negative form of Cdk9 and a Cdk9 kinase inhibitor, DRB inhibited p300-induced activation of GATA-4-dependent transcription as well as acetylation of GATA-4. Stimulation of cardiac myocytes with phenylephrine (PE) increased the binding of GATA-4/p300 with Cdk9 or cyclin T1. DRB and a dominant-negative Cdk9 not only disrupted a complex of GATA-4/p300 with Cdk9 or cyclin T1, but also repressed PE-induced hypertrophic responses in cardiac myocytes. These findings demonstrate that Cdk9 and cyclin T1 form a functional protein complex with GATA-4/p300 and that this large complex is required for hypertrophic responses in cardiac myocytes.