Separation of Transactivation and AP1 Antagonism Functions of Retinoic Acid Receptor α(∗)

• Published in: The Journal of biological chemistry 1995-01, Vol.270 (2), p.923-927
• Main Authors: Nagpal, Sunil, Athanikar, Jyoti, Chandraratna, Roshantha A.S.
• Format: Article
• Language: English
• Subjects: Base Sequence; DNA Primers; HeLa Cells; Humans; Ligands; Molecular Sequence Data; Receptors, Retinoic Acid - physiology; Retinoic Acid Receptor alpha; Transcription Factor AP-1 - antagonists & inhibitors; Transcriptional Activation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.270.2.923

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 RARα, -β, and -γ. Interestingly, these diaryl acetylenic retinoids, which are potent agonists only for RARβ and RARγ, but not for RARα, in transactivation assays, are able to inhibit AP1-dependent gene expression through RARα. Thus these analogs can differentially affect the transactivation and AP1 antagonistic functions of RARα. 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.