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

被引:156
作者
NAGPAL, S [1 ]
ATHANIKAR, J [1 ]
CHANDRARATNA, RAS [1 ]
机构
[1] ALLERGAN PHARMACEUT INC,DEPT CHEM,RETINOID RES,IRVINE,CA 92713
关键词
D O I
10.1074/jbc.270.2.923
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 -beta, but not for RAR alpha, in transactivation assays, are able to in hibit 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 API antagonism functions of RARs.
引用
收藏
页码:923 / 927
页数:5
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