Tyrosine phosphorylation of RACK1 triggers cardiomyocyte hypertrophy by regulating the interaction between p300 and GATA4
| Autor: | Tatsuya Morimoto, Hidetoshi Suzuki, Yoichi Sunagawa, Koji Hasegawa, Masafumi Funamoto, Yasufumi Katanasaka, Yusuke Miyazaki, Hiromichi Wada |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Male Transcription Genetic Tetrazoles chemistry.chemical_compound Phenylephrine Myocytes Cardiac Phosphorylation reproductive and urinary physiology Cells Cultured Zinc finger biology GATA4 respiratory system Cell biology Neoplasm Proteins Gene Knockdown Techniques embryonic structures cardiovascular system Molecular Medicine Protein Binding Mef2 endocrine system medicine.medical_specialty Cardiomegaly Cell Enlargement Receptors for Activated C Kinase 03 medical and health sciences Internal medicine medicine Animals Humans Protein kinase A Molecular Biology Transcription factor Rats Inbred Dahl Biphenyl Compounds Tyrosine phosphorylation Histone acetyltransferase GATA4 Transcription Factor Rats Disease Models Animal 030104 developmental biology Endocrinology T-box HEK293 Cells chemistry biology.protein Tyrosine Benzimidazoles Angiotensin II Type 1 Receptor Blockers E1A-Associated p300 Protein |
| Zdroj: | Biochimica et biophysica acta. 1862(9) |
| ISSN: | 0006-3002 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|