DOMINANT-NEGATIVE MUTANT OF RETINOIC ACID RECEPTOR-ALPHA INHIBITS RETINOIC ACID-INDUCED P19 CELL-DIFFERENTIATION BY BINDING TO DNA

Retinoic acid (RA) is a potent inducer of P19 cell differentiation. RA activity is thought to be mediated by nuclear RA receptors (RARs), tr anscription factors whose activity is dependent on RA. There are three RARs called alpha, beta, and gamma. We created truncated versions of the three RARs and compared their activities as inhibitors of RA-media ted gene transcription and of P19 cell differentiation. Only mutants o f the RAR alpha were inhibitory in these assays. A mutant of RAR alpha carrying a 10-amino-acid insert was able to heterodimerize with RXR b eta or with the normal RAR alpha and the inhibitory activity of this m utant was dependent on an intact DNA binding domain. We conclude that dominant negative mutants of RAR alpha act by heterodimerizing with RX Rs or RARs and binding to RA response elements on DNA, thereby prevent ing binding of the normal receptors to those sites. (C) 1996 Academic Press, Inc.