Sl. Costa et Mw. Mcburney, DOMINANT-NEGATIVE MUTANT OF RETINOIC ACID RECEPTOR-ALPHA INHIBITS RETINOIC ACID-INDUCED P19 CELL-DIFFERENTIATION BY BINDING TO DNA, Experimental cell research, 225(1), 1996, pp. 35-43
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.