title: Translation of Myocyte Enhancer Factor-2 is induced by hypertrophic stimuli in cardiomyocytes through a Calcineurin-dependent pathway.
abstract: The Myocyte Enhancer Factor-2 (MEF2) family of transcription factors regulates gene expression during cardiomyocyte differentiation and adaptation of the myocardium to stress. MEF2 activity is enhanced by increasing its transcription and by MAPK-dependent phosphorylation, and is reduced by binding to class-II Histone Deacetylases and by miR-1-mediated degradation of its transcript. Here we show that MEF2 protein abundance is regulated at the translational level, determining myocyte size, during hypertrophy. In order to reduce MEF2 protein expression, its silencing through RNA interference required serum deprivation and, even in this condition, MEF2 protein abundance recovered to basal levels in presence of phenylephrine. Hypertrophic agonist stimulation of neonatal ventricular cardiomyocytes increased Mef2 expression by enhancing its translation, without changing its transcription or blocking degradation of the protein. MEF2 abundance was increased by Calcineurin overexpression in vivo and was reduced by Calcineurin inhibition in vitro, without affecting Mef2 mRNA levels. Calcineurin activity influenced expression of Polypyrimidine Tract Protein (PTB), contributing to MEF2 translation. Thus, our results show a previously unrecognized but relevant level of MEF2 activity regulation through the control of its translation that involves Calcineurin and PTB.
authors: Institut de Recerca Biomèdica de Lleida, Universitat de Lleida, Edifici Biomedicina-I Av Rovira Roure, 80. 25198 Lleida, Spain.
authors: Junmei
authors: J
authors: Ye
authors: Maria
authors: M
authors: Cardona
authors: Marta
authors: M
authors: Llovera
authors: Joan X
authors: JX
authors: Comella
authors: Daniel
authors: D
authors: Sanchis
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D026161:MADS Domain Proteins / Q000096:biosynthesis* / Q000235:genetics*; D064326:MEF2 Transcription Factors; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000096:biosynthesis* / Q000235:genetics*; D038941:Polypyrimidine Tract-Binding Protein / Q000096:biosynthesis*; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: C546889:6-(3,4-dichlorophenyl)-4-(N,N-dimethylaminoethylthio)-2-phenylpyrimidine; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; D018006:Myogenic Regulatory Factors; D011743:Pyrimidines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D038941:Polypyrimidine Tract-Binding Protein; D019703:Calcineurin