title: Tyrosine phosphorylation of RACK1 triggers cardiomyocyte hypertrophy by regulating the interaction between p300 and GATA4.
abstract: The zinc finger protein GATA4 is a transcription factor involved in cardiomyocyte hypertrophy. It forms a functional complex with the intrinsic histone acetyltransferase (HAT) p300. The HAT activity of p300 is required for the acetylation and transcriptional activity of GATA4, as well as for cardiomyocyte hypertrophy and the development of heart failure. In the present study, we have identified Receptor for Activated Protein Kinase C1 (RACK1) as a novel GATA4-binding protein using tandem affinity purification and mass spectrometry analyses. We found that exogenous RACK1 repressed phenylephrine (PE)-induced hypertrophic responses, such as myofibrillar organization, increased cell size, and hypertrophy-associated gene transcription, in cultured cardiomyocytes. RACK1 physically interacted with GATA4 and the overexpression of RACK1 reduced PE-induced formation of the p300/GATA4 complex and the acetylation and DNA binding activity of GATA4. In response to hypertrophic stimulation in cultured cardiomyocytes and in the hearts of hypertensive heart disease model rats, the tyrosine phosphorylation of RACK1 was increased, and the binding between GATA4 and RACK1 was reduced. In addition, the tyrosine phosphorylation of RACK1 was required for the disruption of the RACK1/GATA4 complex and for the formation of the p300/GATA4 complex. These findings demonstrate that RACK1 is involved in p300/GATA4-dependent hypertrophic responses in cardiomyocytes and is a promising therapeutic target for heart failure.
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan; Division of Translational Research, Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan; Shizuoka General Hospital, Shizuoka, Japan.
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Katanasaka
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan; Division of Translational Research, Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan; Shizuoka General Hospital, Shizuoka, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Sunagawa
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Miyazaki
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Funamoto
authors.affiliation: Division of Translational Research, Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Wada
authors.affiliation: Division of Translational Research, Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Hasegawa
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan; Division of Translational Research, Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan; Shizuoka General Hospital, Shizuoka, Japan. Electronic address: morimoto@u-shizuoka-ken.ac.jp.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Morimoto
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D006332:Cardiomegaly / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D049108:Cell Enlargement; D002478:Cells, Cultured; D004195:Disease Models, Animal; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D050991:GATA4 Transcription Factor / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D020303:Rats, Inbred Dahl; D000075370:Receptors for Activated C Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; C084365:Gata4 protein, rat; D009363:Neoplasm Proteins; C419368:RACK1 protein, human; C550931:RACK1 protein, rat; D000075370:Receptors for Activated C Kinase; D013777:Tetrazoles; D010656:Phenylephrine; D014443:Tyrosine; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; C494362:Ep300 protein, rat; C081643:candesartan
keywords: Acetyltransferase; Cardiac hypertrophy; GATA4; Phosphotyrosine; RACK1; p300