FOG-2 competes with GATA-4 for transcriptional coactivator p300 and represses hypertrophic responses in cardiac myocytes.
A multizinc finger protein, FOG-2, associates with a cardiac transcription factor, GATA-4, and represses GATA-4-dependent transcription. GATA-4 is required not only for normal heart development but is also involved in hypertrophic responses in cardiac myocytes; however, the effects of FOG-2 on these responses are unknown. The interaction of GATA-4 with a transcriptional coactivator p300 is required for its full transcriptional activity and the activation of the embryonic program during myocardial cell hypertrophy. We show here that exogenous FOG-2 represses phenylephrine-induced hypertrophic responses such as myofibrillar organization, increases in cell size, and hypertrophy-associated gene transcription. Using immunoprecipitation Western blotting, we demonstrate that FOG-2 physically interacted with p300 and reduced the binding of GATA-4 to p300. In addition, in COS7 cells, in which the function of endogenous p300 is disrupted, FOG-2 is unable to repress the GATA-4-dependent transcriptional activities; however, FOG-2 markedly repressed the p300-mediated increase in the DNA-binding and transcriptional activities of GATA-4 in these cells. Similarly, FOG-2 inhibited a phenylephrine-induced increase in the p300/GATA-4 interaction, the GATA-4/DNA-binding, and transcriptional activities of GATA-4-dependent promoters in cardiac myocytes as well. These findings demonstrate that FOG-2 represses hypertrophic responses in cardiac myocytes and that p300 is involved in these repressive effects.
Hirai
Maretoshi
M
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
Ono
Koh
K
Morimoto
Tatsuya
T
Kawamura
Teruhisa
T
Wada
Hiromichi
H
Kita
Toru
T
Hasegawa
Koji
K
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D050881:E1A-Associated p300 Protein; D024202:Electrophoretic Mobility Shift Assay; D050991:GATA4 Transcription Factor; D006321:Heart / Q000503:physiopathology*; D009687:Nuclear Proteins / Q000378:metabolism*; D051381:Rats; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology
D017931:DNA Primers; D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C117427:ZFPM2 protein, human; D050881:E1A-Associated p300 Protein; C494362:Ep300 protein, rat