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Multiprotein bridging factor 1 cooperates with c-Jun and is necessary for cardiac hypertrophy in vitro
Peter K Busk1, Linda Wulf-Andersen, Claes C Strøm
1Laboratory of Molecular Cardiology, Medical Department B, H:S Rigshospitalet, University of Copenhagen, Juliane Mariesvej 20, DK-2100 Copenhagen Ø, Denmark.
Insights
MBF1, a transcriptional coactivator, is upregulated in cardiac hypertrophy. It plays a key role in hypertrophic growth by coactivating the transcription factor c-Jun and regulating gene expression.
Area of Science:
- Cardiology
- Molecular Biology
- Gene Regulation
Background:
- Cardiac hypertrophy, a precursor to heart failure, involves increased cardiomyocyte size and altered gene expression.
- Understanding the molecular mechanisms driving hypertrophy is crucial for developing therapeutic strategies.
Purpose of the Study:
- To investigate the role of the transcriptional coactivator MBF1 in cardiac hypertrophy.
- To elucidate the molecular interactions of MBF1 in regulating hypertrophic gene expression.
Main Methods:
- Differential-display polymerase chain reaction and Western blotting to assess MBF1 levels in cardiomyocyte cultures and animal models.
- MBF1 antisense oligodeoxynucleotides to inhibit hypertrophy.
- Transient transfection assays to study MBF1's interaction with transcription factors like c-Jun and GATA4.
- In vitro binding assays to confirm MBF1-c-Jun interaction.
Main Results:
- MBF1 was upregulated in cardiomyocyte hypertrophy models (in vitro and in vivo).
- MBF1 inhibition blocked phenylephrine-induced hypertrophy, while its overexpression potentiated promoter activity.
- MBF1 coactivated transcription with c-Jun, but not GATA4, and bound to c-Jun in vitro.
- MBF1 activated the atrial natriuretic peptide promoter independently of calcineurin and CaMK pathways.
Conclusions:
- MBF1 acts as a transcriptional coactivator for c-Jun in regulating hypertrophic gene expression.
- MBF1 is a key participant in hormone-induced cardiomyocyte hypertrophy.
Abstract:
Cardiac hypertrophy is induced by a number of stimuli and can lead to cardiomyopathy and heart failure. Cardiomyocyte hypertrophy is characterized by increased cell size and altered gene expression. By differential-display polymerase chain reaction and Western blotting we found that the transcriptional coactivator MBF1 was upregulated during hypertrophy in cardiomyocyte cultures. Furthermore, MBF1 protein level increased in two animal models of hypertrophy, angiotensin II treatment and aortic banding. MBF1 antisense oligodeoxynuclotides blocked phenylephrine-induced hypertrophy, suggesting MBF1 plays a key role in hypertrophic growth. In contrast, overexpression of MBF1 potentiated the hormone-induced response of the atrial natriuretic peptide promoter. MBF1 overexpressed by transient transfection cooperated with the transcription factor c-Jun in activation of transcription but not with GATA4. MBF1 and c-Jun induced the activity of a transiently transfected atrial natriuretic peptide promoter, whereas neither MBF1 nor c-Jun could induce the promoter alone. Moreover, MBF1 bound to c-Jun in vitro. These data suggest that MBF1 is a transcriptional coactivator of c-Jun regulating hypertrophic gene expression. Inhibitor studies suggested that MBF1 activates the atrial natriuretic peptide promoter independently of the calcineurin and CaMK signaling pathways. Our results indicate that MBF1 participates in hormone-induced cardiomyocyte hypertrophy and activates hypertrophic gene expression as a coactivator of c-Jun.