Antagonism between retinoic acid receptors and AP-1: implications for tumor promotion and inflammation
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H F Yang-Yen1, X K Zhang, G Graupner
1Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla 92093.
Abstract:
Retinoids such as retinoic acid (RA) are potent anti-arthritic and anti-neoplastic agents. We investigated the mechanism by which RA inhibits induction of collagenase gene transcription by inflammatory mediators, tumor promoters, and proto-oncogenes. We found that the RA receptors (RARs) are potent inhibitors of AP-1 activity generated either by cJun homodimers or cJun/cFos heterodimers. In addition, both cJun and cFos can inhibit RAR activity. In vitro experiments suggested that this inhibition is due to an interaction between RAR and AP-1 proteins that results in mutual loss of DNA-binding activity. The RARs need not bind to the AP-1 site, neither does AP-1 bind to RA response elements. An understanding of this antagonism between the RAR and AP-1 might help to elucidate the anti-neoplastic and anti-arthritic effects of RA as well as its effects on cell differentiation and proliferation.
Insights
Retinoic acid (RA) and its receptors (RARs) inhibit collagenase gene transcription by interacting with and blocking the activity of AP-1 proteins. This molecular antagonism may explain RA's anti-arthritic and anti-neoplastic effects.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Retinoids, including retinoic acid (RA), exhibit significant anti-arthritic and anti-neoplastic properties.
- The precise molecular mechanisms underlying RA's therapeutic effects, particularly its influence on gene transcription, require further elucidation.
Purpose of the Study:
- To investigate how RA inhibits collagenase gene transcription induced by inflammatory mediators, tumor promoters, and proto-oncogenes.
- To elucidate the interaction between RA receptors (RARs) and Activator Protein-1 (AP-1) transcription factors.
Main Methods:
- In vitro experiments were conducted to assess the inhibitory effects of RARs on AP-1 activity.
- The study examined the impact of cJun homodimers and cJun/cFos heterodimers on RAR activity.
- Protein-protein interactions between RAR and AP-1 were analyzed to determine their effect on DNA-binding activity.
Main Results:
- RA receptors (RARs) were found to be potent inhibitors of AP-1 activity.
- Both cJun and cFos proteins were observed to inhibit RAR activity.
- In vitro studies indicated that RAR and AP-1 proteins interact, leading to a mutual loss of DNA-binding activity, independent of binding to specific DNA response elements.
Conclusions:
- A molecular antagonism exists between RARs and AP-1 transcription factors.
- This interaction, resulting in mutual inhibition of DNA-binding activity, provides a potential mechanism for the anti-neoplastic and anti-arthritic effects of RA.
- Understanding this cross-talk is crucial for comprehending RA's broader roles in cell differentiation and proliferation.