THE A B DOMAIN OF TRUNCATED RETINOIC ACID RECEPTORS CAN BLOCK DIFFERENTIATION AND PROMOTE FEATURES OF MALIGNANCY/

Recently, we discovered that stable introduction of a carboxyl-termina lly truncated retinoic acid receptor gamma (tRAR gamma) into an epider mal keratinocyte line blocked the ability of these cells to differenti ate, as judged by their failure to express late markers of squamous di fferentiation, We now demonstrate a correlation between the level of r esidual endogenous RAR activity of tRAR gamma-expressing keratinocyte lines and degree of terminal differentiation. Mutagenesis studies loca lize the effects to the A/B subdomain of the truncated receptor. Despi te tRAR gamma's capacity to interfere with RAR-mediated transactivatio n of retinoic acid response elements (RAREs) in keratinocytes, the eff ects of the truncated receptor are independent of its ability to bind DNA and directly interact with endogenous RARs, tRAR alpha also inhibi ts RARE-mediated gene expression in keratinocytes, even though its ful l-length counterpart enhances RARE activity in these cells. Intriguing ly, both tRAR gamma and RAR gamma suppress keratin promoter activity i n epidermal cells, although for tRAR gamma, the effect is mediated thr ough the A/B domain whereas for RAR gamma, the effects require DNA bin ding. Taken together, these findings suggest that the truncation allow s for new and aberrant interactions with transcriptional proteins/co-f actors that participate in governing RARE activity. This discovery may have relevance in tumorigenesis, where genetic lesions can result in mutant RARs or in loss of receptor expression.