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Growth factors regulate transin gene expression by c-fos-dependent and c-fos-independent pathways
L D Kerr1, J T Holt, L M Matrisian
1Department of Cell Biology, Vanderbilt University, Nashville, TN 37232.
Abstract:
The rapid induction of the proto-oncogene c-fos by growth factors and other bioactive agents, and the recent evidence that the c-fos protein (Fos) is associated with transcriptional complexes, suggests that Fos may represent an integral part of an intracellular messenger pathway that triggers changes in gene expression and ultimately phenotypic alterations. This report examines the role of c-fos in growth factor stimulation of transin, a matrix-degrading secreted metalloproteinase. Platelet-derived growth factor (PDGF) stimulation of transin RNA was blocked by a selective reduction in Fos synthesis with antisense c-fos mRNA, whereas epidermal growth factor (EGF) stimulation of transin occurred despite an equivalent inhibition of Fos levels. The stimulatory effect of both PDGF and EGF on transin transcription involved factors recognizing the sequence TGAGTCA, which is found in the transin promoter and is reported to be a binding site for the transcriptional factor Jun/AP-1 and for associated Fos and Fos-related complexes. Thus both Fos-dependent and Fos-independent pathways exist for growth factor regulation of gene expression, and both effects may be mediated through the same cis-acting transcription element.
Insights
Growth factors regulate gene expression via c-fos protein (Fos) pathways. Platelet-derived growth factor (PDGF) stimulation of transin requires Fos, but epidermal growth factor (EGF) stimulation does not, indicating dual regulatory mechanisms.
Area of Science:
- Molecular Biology
- Cell Signaling
- Gene Regulation
Background:
- Proto-oncogene c-fos rapidly induces upon growth factor stimulation.
- The c-fos protein (Fos) is implicated in transcriptional regulation and phenotypic changes.
- Transin, a matrix-degrading metalloproteinase, is regulated by growth factors.
Purpose of the Study:
- To investigate the role of c-fos in growth factor-mediated transin gene expression.
- To differentiate between Fos-dependent and Fos-independent signaling pathways.
Main Methods:
- Utilized antisense c-fos mRNA to selectively inhibit Fos synthesis.
- Assessed transin RNA levels following stimulation with Platelet-Derived Growth Factor (PDGF) and Epidermal Growth Factor (EGF).
- Analyzed promoter regions for cis-acting elements involved in transcriptional regulation.
Main Results:
- Antisense inhibition of Fos blocked PDGF-induced transin RNA.
- EGF-induced transin expression proceeded despite Fos inhibition.
- Both PDGF and EGF effects involved factors binding to the TGAGTCA sequence in the transin promoter, a site for Jun/AP-1 and Fos complexes.
Conclusions:
- Demonstrated the existence of both Fos-dependent and Fos-independent pathways for growth factor regulation of gene expression.
- Identified a common cis-acting transcription element (TGAGTCA) mediating these distinct regulatory effects.
- Highlighted the complex interplay of transcription factors in controlling target gene expression.