The transcription factor MEF2C mediates cardiomyocyte hypertrophy induced by IGF-1 signaling.
Myocyte enhancer factor 2C (MEF2C) plays an important role in cardiovascular development and is a key transcription factor for cardiac hypertrophy. Here, we describe MEF2C regulation by insulin-like growth factor-1 (IGF-1) and its role in IGF-1-induced cardiac hypertrophy. We found that IGF-1 addition to cultured rat cardiomyocytes activated MEF2C, as evidenced by its increased nuclear localization and DNA binding activity. IGF-1 stimulated MEF2 dependent-gene transcription in a time-dependent manner, as indicated by increased MEF2 promoter-driven reporter gene activity; IGF-1 also induced p38-MAPK phosphorylation, while an inhibitor of p38-MAPK decreased both effects. Additionally, inhibitors of phosphatidylinositol 3-kinase and calcineurin prevented IGF-1-induced MEF2 transcriptional activity. Via MEF2C-dependent signaling, IGF-1 also stimulated transcription of atrial natriuretic factor and skeletal alpha-actin but not of fos-lux reporter genes. These novel data suggest that MEF2C activation by IGF-1 mediates the pro-hypertrophic effects of IGF-1 on cardiac gene expression.
Muñoz
Juan Pablo
JP
Centro FONDAP Estudios Moleculares de la Célula, Universidad de Chile, Santiago, Chile.
Collao
Andres
A
Chiong
Mario
M
Maldonado
Carola
C
Adasme
Tatiana
T
Carrasco
Loreto
L
Ocaranza
Paula
P
Bravo
Roberto
R
Gonzalez
Leticia
L
Díaz-Araya
Guillermo
G
Hidalgo
Cecilia
C
Lavandero
Sergio
S
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018006:Myogenic Regulatory Factors / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011401:Promoter Regions, Genetic; D051381:Rats; D015398:Signal Transduction; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D019703:Calcineurin; D065095:Calcineurin Inhibitors; D007334:Insulin-Like Growth Factor I; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases; C578042:MEF2C protein, rat