title: Transcription coactivator Eya2 is a critical regulator of physiological hypertrophy.
abstract: Despite its significant clinical implications, physiological hypertrophy remains poorly understood. In this study, the transcription coactivator Eya2 was shown to be up-regulated during physiological hypertrophy. Transgene- or adenovirus-mediated overexpression of Eya2 led to up-regulation of mTOR, a critical mediator of physiological hypertrophy. Luciferase reporter and chromatin immunoprecipitation assays revealed that Eya2 directly binds to and activates mTOR expression. The phosphorylation of mTOR downstream molecules was significantly enhanced in Eya2 transgenic (TG) hearts, implying that the Eya2-mediated induction of mTOR expression leads to an elevated mTOR activity. The transcription factor Six1 was also up-regulated during physiological hypertrophy and formed a complex with Eya2. Luciferase reporter and electrophoretic mobility shift assays revealed that the Eya2-Six1 complex binds to and enhances the expression of mTOR in a synergistic manner. Under pressure overload, Eya2 transgenic hearts developed hypertrophy which exhibited important molecular signatures of physiological hypertrophy, as assessed by gene expression profiling and measurements of expression levels of physiological hypertrophy-related genes by quantitative (q) RT-PCR. Examination of heart sections under electron microscopy revealed that the mitochondrial integrity remained largely intact in Eya2 transgenic mice, but not in wild-type littermates, under pressure overload. This finding was confirmed by measurements of mitochondrial DNA contents and the expression levels of mitochondrial function-related genes by qRT-PCR. These data suggest that Eya2 in a physical complex with Six1 plays a critical role in physiological hypertrophy. The cardioprotective effect of Eya2 appears to be due, at least in part, to its preservation of mitochondrial integrity upon pressure overload.
authors.affiliation: College of Life Sciences, Global Research Lab, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
authors.forename: Seung Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Jooyeon
authors.initials: J
authors.lastname: Kim
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Ryu
authors.forename: Suho
authors.initials: S
authors.lastname: Lee
authors.forename: Dong Kwon
authors.initials: DK
authors.lastname: Yang
authors.forename: Dongtak
authors.initials: D
authors.lastname: Jeong
authors.forename: Jaetaek
authors.initials: J
authors.lastname: Kim
authors.forename: Sang-Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Jin Man
authors.initials: JM
authors.lastname: Kim
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Park
mesh_terms: D000818:Animals; D049108:Cell Enlargement; D002460:Cell Line; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D017027:Protein Tyrosine Phosphatases / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C490947:Six1 protein, mouse; D058570:TOR Serine-Threonine Kinases; C501159:Eya2 protein, mouse; D017027:Protein Tyrosine Phosphatases