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Growth factors, growth factor response elements, and the cardiac phenotype
M D Schneider1, W R McLellan, F M Black
1Department of Medicine, Baylor College of Medicine, Houston, TX 77030.
Basic Research in Cardiology
|January 1, 1992
Summary
Fibroblast growth factors (FGF) regulate cardiac gene expression. Basic FGF stimulates skeletal alpha-actin (SkA) transcription, while acidic FGF represses it, mediated by specific promoter elements and proteins like SRF.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Gene Regulation
Background:
- Fibroblast growth factors (FGF) and TGF beta 1 are key regulatory peptides in cardiac development and response to stress.
- Mechanical load in the adult heart up-regulates these factors, suggesting autocrine/paracrine roles.
- Cardiac muscle cells respond to FGFs, mimicking fetal gene induction seen in pressure-overload hypertrophy.
Purpose of the Study:
- To investigate the differential effects of basic FGF (bFGF) and acidic FGF (aFGF) on cardiac gene transcription.
- To identify the promoter regions and trans-acting factors involved in FGF-mediated regulation of the skeletal alpha-actin (SkA) gene.
- To understand how cardiac myocytes distinguish between bFGF and aFGF signaling pathways.
Main Methods:
- Analysis of SkA promoter activity in neonatal cardiac muscle cells using reporter gene assays.
- Site-directed mutagenesis of CC[A/T]6GG motifs (SREs) within the SkA promoter.
- Electrophoretic mobility shift assays (EMSAs) to identify proteins binding to the SkA promoter, specifically SRE1.
Main Results:
- The proximal 200 nucleotides of the SkA promoter were sufficient for basal transcription, bFGF induction, and aFGF repression.
- bFGF induced SkA transcription via the proximal SRE (SRE1), while aFGF repressed the full promoter but not SRE1.
- Both FGFs activated the canonical c-fos serum response element (SRE), indicating SRE1's specific discrimination of FGF signals.
- Serum response factor (SRF) and F-ACT-1 were identified as key proteins binding to SRE1 in cardiac myocytes.
Conclusions:
- Both positive and negative regulation of SkA transcription by FGFs can be localized to the proximal SkA promoter.
- SRE1 is crucial for tissue-specific expression and bFGF-induced transcription of SkA in cardiac myocytes.
- SRF and F-ACT-1 are likely trans-acting factors mediating basal SkA transcription and bFGF induction in cardiac muscle cells.