WIDELY SPACED, DIRECTLY REPEATED PUGGTCA ELEMENTS ACT AS PROMISCUOUS ENHANCERS FOR DIFFERENT CLASSES OF NUCLEAR RECEPTORS

We describe here a novel class of cis-acting response elements for ret inoid, vitamin D, and estrogen receptors which are widely spaced (10 t o 200 pp) direct repeats (DRs) of the canonical 5'-AGGTCA half-site re cognition motif (DR10 to DR200). In contrast to the specificity previo usly observed with shortly spaced DRs (DR1 to DR5), the different rece ptors bind promiscuously to these novel elements to activate transcrip tion in the presence of retinoic acid (RA), vitamin D, or estrogen. Th e greatest RA-dependent transactivation, seen with DR15, was similar t o that observed with the canonical DR5. Both RA receptors and retinoid X receptors contribute to transactivation through widely spaced DR el ements. With the estrogen receptor, DR15 was one-third as efficient as the classical palindromic response element. A further increase of spa cer lengths progressively decreased the efficiency of transactivation. No transactivation was seen with widely spaced DRs when the thyroid a nd retinoid X receptors were coexpressed in the presence of their liga nds. The progesterone receptor was also unable to transactivate; throu gh a DR10 element composed of its cognate binding motifs. These result s considerably extend the response element repertoire of nuclear recep tors and suggest the existence of promiscuous transcriptional regulati on through common response elements, as well as the possibility of rec eptor ''cross-talk''.