Vitamin D³-thyroid hormone receptor heterodimer polarity directs ligand sensitivity of transactivation

Abstract

THE nuclear receptors for 1,25-dihydroxyvitamin D³ (YD) and 3,5,3′-triiodothyronine (T³), that is, VDRs and T³Rs 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 T³Rs bind to direct repeats spaced by four nucleotides⁹. VDRs and T₃Rs can function as homodimers^5,6,10but 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–T₃R heterodimers¹⁷. 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) calbindin¹⁸ gene promoter was 5′-T₃R–VDR-3′, whereas on the mouse 28K calbindin VD response element¹⁹ this polarity was reversed to 5′-VDR–T3R-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.