Cyclin-dependent kinase-9 is a component of the p300/GATA4 complex required for phenylephrine-induced hypertrophy in cardiomyocytes.
A zinc finger protein GATA4 is one of the hypertrophy-responsive transcription factors and forms a complex with an intrinsic histone acetyltransferase, p300. Disruption of this complex results in the inhibition of cardiomyocyte hypertrophy and heart failure in vivo. By tandem affinity purification and mass spectrometric analyses, we identified cyclin-dependent kinase-9 (Cdk9) as a novel GATA4-binding partner. Cdk9 also formed a complex with p300 as well as GATA4 and cyclin T1. We showed that p300 was required for the interaction of GATA4 with Cdk9 and for the kinase activity of Cdk9. Conversely, Cdk9 kinase activity was required for the p300-induced transcriptional activities, DNA binding, and acetylation of GATA4. Furthermore, the kinase activity of Cdk9 was required for the phosphorylation of p300 as well as for cardiomyocyte hypertrophy. These findings demonstrate that Cdk9 forms a functional complex with the p300/GATA4 and is required for p300/GATA4- transcriptional pathway during cardiomyocyte hypertrophy.
Sunagawa
Yoichi
Y
Division of Translational Research, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555.
Morimoto
Tatsuya
T
Division of Translational Research, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555. Electronic address: mori@kuhp.kyoto-u.ac.jp.
Takaya
Tomohide
T
Division of Translational Research, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555; Department of Cardiovascular Medicine, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Kaichi
Shinji
S
Division of Translational Research, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555; Department of Pediatrics, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Wada
Hiromichi
H
Division of Translational Research, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555.
Kawamura
Teruhisa
T
Division of Translational Research, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555.
Fujita
Masatoshi
M
Human Health Sciences, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Shimatsu
Akira
A
Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555.
Kita
Toru
T
Department of Cardiovascular Medicine, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Hasegawa
Koji
K
Division of Translational Research, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555.
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism*; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D050991:GATA4 Transcription Factor / Q000378:metabolism*; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D006984:Hypertrophy; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010656:Phenylephrine / Q000378:metabolism*; D051381:Rats; D014158:Transcription, Genetic
D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; C084365:Gata4 protein, rat; D006657:Histones; D010656:Phenylephrine; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; C494362:Ep300 protein, rat; D042863:Cyclin-Dependent Kinase 9