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The role of AP-1 in matrix metalloproteinase gene expression
C W Lin1, H I Georgescu, C H Evans
1Ferguson Laboratory for Orthopaedic Research, University of Pittsburgh School of Medicine, PA 15261.
Abstract:
In an effort to understand the mechanism of matrix metalloproteinase (MMP) induction, lapine synoviocytes were isolated and incubated with phorbol myristate acetate (PMA) and autocrine "cell-activating factors" (CAF), agents which significantly increase MMP mRNA abundance. AP-1 complexes, formed by c-fos and c-jun which bind to 5' residues of the MMP genes, seem causally related to MMP gene expression in response to PMA. However, although AP-1 DNA binding activity is strongly induced following exposure of synoviocytes to CAF, MMP gene expression in response to CAF does not correlate well with AP-1 activity and is not inhibited by antisense DNA to fos and jun. We hypothesize that there is a CAF-response factor involved in MMP gene expression and that this factor competes with the binding of the AP-1 complex to its target response element.
Insights
This study investigates matrix metalloproteinase (MMP) gene expression in lapine synoviocytes. A novel CAF-response factor, distinct from AP-1, appears to regulate MMP induction by cell-activating factors (CAF).
Area of Science:
- Molecular biology
- Cellular biology
- Biochemistry
Background:
- Matrix metalloproteinases (MMPs) play crucial roles in tissue remodeling and are implicated in various diseases.
- Understanding the regulation of MMP gene expression is vital for developing targeted therapies.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying MMP induction in lapine synoviocytes.
- To investigate the role of AP-1 transcription factor and identify novel regulatory factors in response to cell-activating factors (CAF).
Main Methods:
- Isolation and incubation of lapine synoviocytes with phorbol myristate acetate (PMA) and CAF.
- Analysis of MMP mRNA abundance.
- Assessment of AP-1 DNA binding activity.
- Use of antisense DNA to fos and jun to inhibit gene expression.
Main Results:
- PMA significantly increased MMP mRNA abundance and AP-1 DNA binding activity.
- CAF also increased MMP mRNA abundance, but this induction did not correlate with AP-1 activity.
- Antisense DNA targeting fos and jun failed to inhibit CAF-induced MMP gene expression.
Conclusions:
- While AP-1 is involved in PMA-induced MMP expression, it is not the primary mediator of CAF-induced MMP expression.
- A novel CAF-response factor, potentially competing with AP-1, is hypothesized to regulate MMP gene expression in response to CAF.