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Separation of transactivation and AP1 antagonism functions of retinoic acid receptor alpha
S Nagpal1, J Athanikar, R A Chandraratna
1Department of Biology, Allergan Inc., Irvine, California 92713.
Abstract:
Retinoic acid receptors (RARs) regulate gene expression either by directly binding to the RAR-responsive elements or by antagonizing the action of c-Jun/c-Fos (AP1). AP1 is involved in the expression of metalloproteases, cytokines and other factors which play critical roles in the turnover of extracellular matrix, inflammation and hyperproliferation in diseases such as psoriasis, rheumatoid arthritis and in tumor metastases. We demonstrate here that synthetic retinoids inhibit 12-O-tetradecanoylphorbol-14-acetate-induced transcription from the stromelysin AP1 motif through RAR alpha, -beta, and -gamma. Interestingly, these diaryl acetylenic retinoids, which are potent agonists only for RAR beta and RAR gamma, but not for RAR alpha, in transactivation assays, are able to inhibit AP1-dependent gene expression through RAR alpha. Thus these analogs can differentially affect the transactivation and AP1 antagonistic functions of RAR alpha. These results demonstrate that the transactivation and AP1 antagonistic functions are separable, and it should be possible to develop retinoids that are completely specific for AP1 antagonism through all RARs. Furthermore, using an RAR-selective ligand, we also demonstrate the separation of ligand binding and AP1 antagonism functions of RARs.
Insights
Synthetic retinoids can inhibit AP1-dependent gene expression via retinoic acid receptors (RARs). This study shows that transactivation and AP1 antagonism functions of RARs are separable, enabling targeted retinoid development.
Area of Science:
- Molecular Biology
- Cell Biology
- Pharmacology
Background:
- Retinoic acid receptors (RARs) modulate gene expression through direct DNA binding or by antagonizing AP1 (activator protein 1).
- AP1 is crucial for extracellular matrix turnover, inflammation, and hyperproliferation in diseases like psoriasis, rheumatoid arthritis, and cancer metastasis.
Purpose of the Study:
- To investigate the differential effects of synthetic retinoids on RAR-mediated gene expression.
- To determine if the transactivation and AP1 antagonistic functions of RARs are separable.
- To explore the development of retinoids with specific AP1 antagonism across all RAR subtypes.
Main Methods:
- Utilized synthetic retinoids, including diaryl acetylenic analogs, to study their effects on AP1-dependent transcription.
- Employed transactivation assays to assess RAR agonism.
- Investigated AP1 motif inhibition through RAR alpha, -beta, and -gamma.
- Used RAR-selective ligands to differentiate ligand binding and AP1 antagonism.
Main Results:
- Synthetic retinoids inhibited AP1-dependent transcription through RAR alpha, -beta, and -gamma.
- Diaryl acetylenic retinoids, selective for RAR beta and RAR gamma, inhibited AP1-dependent gene expression via RAR alpha.
- Demonstrated that transactivation and AP1 antagonism functions of RAR alpha can be differentially affected by these analogs.
- Showed that ligand binding and AP1 antagonism functions of RARs are separable using a selective ligand.
Conclusions:
- Transactivation and AP1 antagonistic functions mediated by RARs are distinct and separable.
- It is feasible to design retinoids that specifically antagonize AP1 activity across all RAR subtypes.
- Ligand binding and AP1 antagonism are separable functions of RARs, offering opportunities for developing targeted therapeutics.