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'-triiodothyronine (T-3), that is, VDRs and T(3)Rs respectively, control aspects of homeostasis, cell growth and differentiation(1-4). They activate 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(5,6,10) but heterodimerization with retinoid X(11-14) Or retinoic acid receptors(15,16) increases their affinity for DNA in vitro and resulting transcriptional activity in vivo. We recently observed the formation of VDR-T(3)R heterodimers(17). Here we show that the polarity of the binding of such heterodimers to the VD response element of the rat 9K (relative molecular mass 9,000) calbindin's gene promoter was 5'-T(3)R-VDR-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 regulatory property of heterodimeric nuclear receptor complexes.