Related Experiment Videos
Differential induction of the c-fos promoter through distinct PDGF receptor-mediated signaling pathways
K E Salhany1, C Robinson-Benion, A F Candia
1Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
Abstract:
The multiple isoforms of PDGF induce fibroblastic mitogenesis through two distinct PDGF receptors, alpha and beta. The molecular mechanisms by which these alpha and beta PDGF receptors regulate gene expression are poorly understood. We present data which indicates that differential induction of c-fos gene expression by PDGF isoforms occurs through distinct PDGF alpha and beta receptor-mediated signaling pathways. Comparison of PDGF-AA with PDGF-BB stimulation showed that PDGF-BB induced prolonged expression of the c-fos gene in BALB/c-3T3 cells, but that PDGF-AA induced more potent activation of the serum response element (SRE) in transient transfection assays. PDGF-AA, which binds alpha but not beta PDGF receptors, could only induce the SRE through a protein kinase C (PKC)-dependent pathway, whereas PDGF-BB, which binds both alpha and beta PDGF receptors, could also induce the SRE through a PKC-independent pathway. These results suggest that PDGF alpha receptors activate the PKC-dependent signaling pathway while PDGF beta receptors also activate a PKC-independent pathway. In addition, we found that PDGF-BB could induce another c-fos promoter element within the -90 to +10 region, suggesting that the more potent mitogenic effect and prolonged c-fos gene expression induced by PDGF-BB may result from cooperativity between more than one c-fos promoter elements.
Insights
Platelet-derived growth factor (PDGF) isoforms differentially regulate c-fos gene expression via distinct PDGF receptor pathways. PDGF alpha receptors activate protein kinase C (PKC)-dependent signaling, while PDGF beta receptors utilize PKC-independent pathways.
Area of Science:
- Molecular Biology
- Cell Signaling
- Gene Regulation
Background:
- Platelet-derived growth factor (PDGF) isoforms mediate cell growth through alpha and beta PDGF receptors.
- The precise molecular mechanisms of PDGF receptor-mediated gene expression remain unclear.
Purpose of the Study:
- To investigate the distinct signaling pathways employed by PDGF alpha and beta receptors in regulating c-fos gene expression.
- To elucidate how different PDGF isoforms induce c-fos expression and cellular responses.
Main Methods:
- Comparing the effects of PDGF-AA and PDGF-BB on c-fos gene expression in BALB/c-3T3 cells.
- Utilizing transient transfection assays to assess serum response element (SRE) activation.
- Investigating the role of protein kinase C (PKC) in PDGF-mediated signaling.
Main Results:
- PDGF-BB induced prolonged c-fos expression, while PDGF-AA more potently activated the SRE.
- PDGF-AA (alpha receptor-specific) activated the SRE via a PKC-dependent pathway.
- PDGF-BB (binding both receptors) activated the SRE via both PKC-dependent and independent pathways.
- PDGF-BB also induced another c-fos promoter element, suggesting cooperative effects.
Conclusions:
- PDGF alpha receptors activate a PKC-dependent signaling pathway.
- PDGF beta receptors activate a PKC-independent pathway, contributing to enhanced c-fos expression and mitogenesis.
- Cooperative interactions between c-fos promoter elements may underlie the potent effects of PDGF-BB.