RETINOIC ACID RECEPTOR ISOFORM RAR-GAMMA-1 - AN ANTAGONIST OF THE TRANSACTIVATION OF THE RAR-BETA RARE IN EPITHELIAL-CELL LINES AND NORMAL HUMAN KERATINOCYTES

The diversity of isoforms of retinoic acid (RA) receptors (RARs) and of DNA sequences of retinoic acid-responsive elements (RAREs) suggests the existence of selectivities in the RAR/RARE recognition or in the subsequent gene modulation. Such selectivities might be particularly important for RAREs involved in positive feedback, eg. the RARbeta RARE. In the present work we found that in several epithelial cell lines, reporter constructs containing the RARbeta RARE linked to the HSV-tk promoter were transactivated in the presence of RA by endogenous RARs and co-transfected RARalpha1 and RARbeta2 isoforms, but not by RARgamma1. On the contrary, this latter isoform behaved towards the RARbeta RARE as an inhibitor of the transactivation produced by endogenous RARs and by cotransfected RARalpha1 and RARbeta2. RARgamma1 also behaved as an antagonist of the transactivation produced by cotransfected RXRalpha. The natural RARbeta gene promoter or RARbeta RARE tk constructs were not activated by the endogenous receptors of normal human keratinocytes (NHK), which are known to contain predominantly RARgamma1. It was, however, possible to activate to a certain extent RARbeta RARE-reporter constructs in NHK by co-transfecting RARalpha1, RARbeta2 or RXRalpha. The antagonist behavior of RARgamma1 towards the RARbeta RARE may explain why in certain cell types such as keratinocytes, RARbeta is neither expressed nor induced by RA.