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

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

Yoichi Sunagawa, Tatsuya Morimoto, Tomohide Takaya, Masatoshi Fujita, Toru Kita, 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 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 activity 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.