SEPARATION OF TRANSACTIVATION AND AP1 ANTAGONISM FUNCTIONS OF RETINOIC ACID RECEPTOR-ALPHA

Retinoic acid receptors (RARs) regulate gene expression either by dire ctly binding to the RAR-responsive elements or by antagonizing the act ion of c-Jun/c-Fos (AP1). AP1 is involved in the expression of metallo proteases, cytokines and other factors which play critical roles in th e turnover of extracellular matrix, inflammation and hyperproliferatio n in diseases such as psoriasis, rheumatoid arthritis and in tumor met astases. We demonstrate here that synthetic retinoids inhibit 12-O-tet radecanoylphorbol-14-acetate-induced transcription from the stromelysi n AP1 motif through RAR alpha, -beta, and -gamma. Interestingly, these diaryl acetylenic retinoids, which are potent agonists only for RAR b eta and -beta, but not for RAR alpha, in transactivation assays, are a ble to in hibit AP1-dependent gene expression through RAR alpha. Thus these analogs can differentially affect the transactivation and AP1 an tagonistic functions of RAR alpha. These results demonstrate that the transactivation and AP1 antagonistic functions are separable, and it s hould be possible to develop retinoids that are completely specific fo r AP1 antagonism through all RARs. Furthermore, using an RAR-selective ligand, we also demonstrate the separation of ligand binding and API antagonism functions of RARs.