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Negative regulation of gene expression by TGF-beta
L M Matrisian1, G L Ganser, L D Kerr
1Department of Cell Biology, Vanderbilt University, Nashville, Tennessee.
Molecular Reproduction and Development
|June 1, 1992
Summary
Transforming growth factor-beta (TGF-β) regulates stromelysin gene expression via a TGF-β inhibitory element (TIE) and c-fos induction. This mechanism influences gene expression patterns, impacting embryonic development and lung morphogenesis.
Area of Science:
- Molecular biology
- Developmental biology
- Gene regulation
Background:
- Stromelysin gene expression is activated by growth factors, tumor promoters, and oncogenes via AP-1.
- Transforming growth factor-beta (TGF-β) represses stromelysin induction through a TGF-β inhibitory element (TIE) at position -709.
- A TIE-binding protein complex, including c-fos, is induced by TGF-β, mediating repression of stromelysin.
Purpose of the Study:
- To investigate the molecular mechanisms underlying TGF-β's regulation of stromelysin gene expression.
- To explore the role of c-fos and jun family genes in mediating TGF-β's effects.
- To examine the role of growth factor regulation of matrix metalloproteinases in embryonic lung development.
Main Methods:
- Analysis of rat stromelysin promoter activity.
- Induction of TIE-binding protein complexes in rat fibroblasts.
- Organ culture of murine embryonic lungs treated with growth factors and matrix metalloproteinases.
Main Results:
- TGF-β induces a TIE-binding complex containing c-fos, which is required for stromelysin repression.
- c-fos induction is also necessary for epidermal growth factor (EGF)-stimulated stromelysin expression.
- Differential regulation of jun family genes may determine whether growth factors induce or repress stromelysin.
- EGF and TGF-alpha stimulate murine lung growth but inhibit branching morphogenesis, an effect reversed by TIMP.
- TGF-β inhibits murine lung rudiment growth.
Conclusions:
- TGF-β initiates a gene expression cascade involving early-response genes like c-fos, leading to specific induction or repression patterns.
- Growth factor regulation of matrix metalloproteinases plays a significant role in complex developmental processes, exemplified by murine lung morphogenesis.