VITAMIN-D-3 THYROID-HORMONE RECEPTOR HETERODIMER POLARITY DIRECTS LIGAND SENSITIVITY OF TRANSACTIVATION

The nuclear receptors for 1,25-dihydroxyvitamin D-3 (VD) and 3,5,3'-tr iiodothyronine (T-3), that is, VDRs and T(3)Rs respectively, control a spects of homeostasis, cell growth and differentiation(1-4). They acti vate transcription from response elements consisting of direct repeats , palindromes and inverted palindromes(5-8) of a variety of hexameric core-binding motifs. VDRs bind preferentially to direct repeats spaced by three nucleotides, whereas T(3)Rs bind to direct repeats spaced by four nucleotides(9). VDRs and T(3)Rs can function as homodimers(5,6,1 0) but heterodimerization with retinoid X(11-14) Or retinoic acid rece ptors(15,16) increases their affinity for DNA in vitro and resulting t ranscriptional activity in vivo. We recently observed the formation of VDR-T(3)R heterodimers(17). Here we show that the polarity of the bin ding of such heterodimers to the VD response element of the rat 9K (re lative molecular mass 9,000) calbindin's gene promoter was 5'-T(3)R-VD R-3', whereas on the mouse 28K calbindin VD response element(19) this polarity was reversed to 5'-VDR-T(3)R-3'. We also show that the ligand for the downstream receptor controls the transcriptional activity of the heterodimeric complex. Thus, polarity seems to be an important reg ulatory property of heterodimeric nuclear receptor complexes.